Child Neurology Continuum

REVIEW ARTICLE

Pediatric Traumatic Brain
C O N T I NU U M A UD I O
I NT E R V I E W A V AI L A B L E Injury and Concussion
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ONLINE
By Meeryo Choe, MD; Karen M. Barlow, MD
Downloaded from http://journals.lww.com/continuum by Ow/0SBWVU9WJmc0CG7aUTurZYduR8lLD72scP58L5s0zQxb
ABSTRACT
PURPOSE OF REVIEW: This article summarizes the impact and complications
of mild traumatic brain injury and concussion in children and outlines the
recent evidence for its assessment and early management. Useful
evidence-based management strategies are provided for children who
have a typical recovery following concussion as well as for those who
have persistent postconcussion syndrome. Cases are used to demonstrate
the commonly encountered pathologies of headache, cognitive issues,
and mood disturbances following injury.
09/2022
A clinical risk score using risk factors for poor recovery

RECENT FINDINGS:
(eg, female sex, adolescence, previous migraine, and a high degree of
CITE AS: acute symptoms) can be used to help the clinician plan follow-up in the
CONTINUUM (MINNEAP MINN) community. Prolonged periods of physical and cognitive rest should be
2018;24(1, CHILD NEUROLOGY):300–311.
avoided. Multidisciplinary treatment plans are often required in the
Address correspondence to
management of persistent postconcussion syndrome.
Dr Meeryo Choe, UCLA Mattel
Children’s Hospital, Department SUMMARY: A paucity of research exists for the treatment of postconcussion
of Pediatrics, Division of Pediatric
Neurology, 22–474 MDCC, 10833
syndrome. Current treatments target individual symptoms.
LeConte Ave, Los Angeles, CA
90095–1752, mchoe@mednet.
ucla.edu.
RELATIONSHIP DISCLOSURE: INTRODUCTION
T
Dr Choe receives research/grant raumatic brain injury is a major public health issue causing significant
support from the National
Institutes of Health/Small
morbidity and mortality in the pediatric population and with increasing
Business Innovation Research for awareness among the lay population and considerable attention in
Neural Analytics (R44NS09209) the media. This article focuses on mild traumatic brain injury (TBI),
and the University of California,
Los Angeles Steve Tisch or concussion, which makes up the majority of injuries. While most
BrainSPORT Program and has mild TBIs improve quickly, some result in more long-lasting sequelae. This
provided expert legal testimony article provides recommendations for evidence-based management strategies for
regarding concussion. Dr Barlow
receives research/grant support treatment in the acute period. Risk factors that may predispose certain children
from the Alberta Children’s to persistent postconcussion symptoms and approaches for management of these
Hospital Research Institute and
the Canadian Institutes of Health
symptoms are also presented.
Research (293375).
DEFINITIONS
UNLABELED USE OF Efforts to define TBI have been widespread over the past several years. The
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
International and Interagency Initiative Toward Common Data Elements for
Drs Choe and Barlow report Research on Traumatic Brain Injury and Psychological Health defines TBI as “an
no disclosure. alteration in brain function, or other evidence of brain pathology, caused by an
© 2018 American Academy external force.”1 Alteration in brain function is defined as one of the following
of Neurology. clinical signs:
300 FEBRUARY 2018

u Any period of loss of consciousness or decreased level of consciousness KEY POINTS
u Any loss of memory for events immediately before or after the injury ● Alteration in brain
(posttraumatic amnesia) function due to an external
force is the hallmark of
u Any neurologic deficits
traumatic brain injury.

u Any alteration in mental state at the time of the injury (eg, confusion,
● The symptoms and signs
disorientation, slowed thinking)
of traumatic brain injury and
concussion should not be
To qualify as a TBI, alteration in brain function should not be more reasonably better explained by another
explained by other pathologic processes (eg, shock, substance use, metabolic medical or psychological
condition.
derangement), although these can co-occur with TBI. External forces may
include rotational acceleration-deceleration forces transmitted to the brain
without a direct blow to the head and forces due to blasts or explosions.
The definition of mild TBI poses particular problems, partly because of the
timing of the initial assessment and partly because of the overlap of neurologic
symptoms and signs from mild TBI with other medical and psychological
conditions (eg, posttraumatic stress disorder, depression, alcohol intoxication).2
The Glasgow Coma Scale score after TBI should be assessed at least 30 minutes
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postinjury to allow for a brief period of loss of consciousness with rapid neurologic
improvement, which occurs in around 10% to 20% of cases of mild TBI. This,
however, is not always practical, leading to some patients with mild TBI being
incorrectly classified as having a moderate TBI when they are evaluated during
the initial period of loss of consciousness. Symptoms due to an emotional or
psychological response to the traumatic event may be incorrectly attributed to
confusion due to a brain injury. As many people with mild TBI present to medical
attention several days or weeks later, it is apparent that determining whether
their symptoms were due to a brain injury or other factors can be complicated.
Concussion is often viewed as being on the milder end of the spectrum of TBI,
and the term is often used interchangeably with mild TBI. The Zurich Consensus
(2012) states that a concussion is a brain injury that “is defined as a complex
pathophysiological process affecting the brain, induced by biomechanical
forces.” The injury can be sustained “either by a direct blow to the head…or
elsewhere on the body with an ‘impulsive’ force transmitted to the head.”3
Various physical symptoms can be caused by a concussion. The Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR)4
lists these as physical fatigue, disordered sleep, headaches, and/or vertigo/
dizziness, and the International Classification of Diseases, Tenth Revision (ICD-10)5
expands these to include tinnitus/hyperacusis, photosensitivity, and reduced
tolerance to alcohol or medications. These symptoms should be present in the
first few days following the injury, but they should not be the sole basis
of the diagnosis. A plausible mechanism of injury or another brain injury
indicator should also exist, such as loss of consciousness, amnesia, or other
evidence of neurologic dysfunction.
The diagnosis of TBI and concussion relies on multimodal clinical assessments,
including a thorough history (eg, the mechanism of insult, presence of loss of
consciousness and amnesia, any acute symptoms) and examination (eg, presence
of coma, Glasgow Coma Scale score, focal neurologic signs), and may include
neuroimaging. The severity of TBI is determined following resuscitation (or
30 minutes postinjury) using clinical parameters. A Glasgow Coma Scale score of
CONTINUUMJOURNAL.COM 301
TRAUMATIC BRAIN INJURY AND CONCUSSION
8 or less is classified as a severe TBI, a score of 9 to 12 is classified as a moderate

TBI, and a score of 13 to 15 is classified as a mild TBI. The length of posttraumatic
amnesia is related to injury severity and predictive of outcome. Neuroimaging
(MRI or CT) is used acutely in moderate and severe injuries to determine the
severity and extent of the brain injury and to determine the need for neurosurgical
intervention. Little role exists for neuroimaging in mild TBI outside of research
unless the clinician suspects an intracranial hemorrhage. Several clinical decision

rules and guidelines exist to help the emergency physician determine the need for
neuroimaging.6,7 A 2015 review explored the use of ICD-10 codes across the
spectrum of TBI in children. Despite the wide range of codes used, many TBIs
may go uncoded, particularly when a patient has coincident injuries.8 It is clear
that better diagnostic methods to determine and categorize pediatric TBI are
needed to help with future research and outreach and prevention efforts. It is
important to note that while much research is being done to determine an objective
diagnostic tool for mild TBI and concussion (eg, blood or imaging biomarkers,
cognitive or reaction time testing, balance tests), no single measure can take the
place of a multimodal clinical assessment that includes a thorough history, physical
examination, and other validated diagnostic tools or adjunctive tests. Unfortunately,
few diagnostic tools have been validated in the pediatric population.
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EPIDEMIOLOGY
TBI is the leading cause of death and disability among children and young adults
in the United States. These injuries may have persistent effects on a child’s
functioning throughout his/her development and into adulthood, even when
the initial insult is mild. As childhood is a critical stage of neurodevelopment,
a TBI during this period has the potential for causing serious long-term
consequences. Data from the Centers for Disease Control and Prevention (CDC)
show that the incidence of TBI in the United States is highest in children under
4 years of age and in those between 15 and 19 years of age.9
In Canada, the largest number of concussions is seen in the adolescent
population, which also saw the greatest increase in incidence between 2003 and
2013.10 The majority of TBIs at all ages are mild, and most heal after a short
recovery period, typically less than 4 weeks. The term concussion is frequently
used in place of mild TBI, particularly in the emergency department setting; this
is likely to play a role in clinical outcome, as parents may infer that there will be
no long-term consequences from a concussion versus a brain injury.11 However,
some children do go on to develop chronic issues and require carefully monitored
care. These complications may persist for months to years and include somatic,
cognitive, psychological, and sleep disturbances. Certain risk factors for these
complications can help to identify these children earlier in their recovery. It is
critical to identify these patients in the acute period so that early interventions
that may benefit them can be initiated, perhaps shortening recovery and
improving outcome.
Although falls are a common cause of mild TBI or concussion in children
presenting to the emergency department, mild TBI and concussion are often
sustained during sports participation. With more than 44 million youth participating
in sports each year, this is particularly important.12 A 2016 epidemiologic study
estimated that 1.1 to 1.9 million sports concussions occur each year among children
18 years of age or younger in the United States.13 However, only a fraction of these
patients seek medical care, with 630,000 estimated as presenting to emergency
302 FEBRUARY 2018

departments annually.9 Although an additional portion may also be seen in the KEY POINTS
outpatient clinic setting or by other nonphysician health care providers, the
● Traumatic brain injury is
number seeking some form of medical attention still falls short of the estimated the leading cause of death
total number of concussions. This suggests the need for further community and neurologic morbidity in
outreach to encourage presentation to health care providers to help guide the children.
recovery processes of injured youth.

● Mild traumatic brain
injury and concussion are

MANAGEMENT often sustained during
Despite guidelines endorsed by multiple provider associations, including the sports participation.
American Academy of Neurology, discharge management differs among health
● Removal from
care providers caring for children with TBI.14–16 Patients may not receive
sport-related activities
appropriate discharge instructions from the emergency department,17 which decreases early repeat
may delay the recovery process. As the majority of concussions in childhood injury and speeds recovery.
occur during sport or athletic activities, most of the guidelines have focused on
athletic-related concussions, although most of these can be reasonably ● After a short period of
rest following a concussion,
extrapolated to other etiologies. a graduated reentry into
While no specific treatment for TBI is known, many studies have shown that, normal activities is
for student athletes, removal from play after a concussion significantly improves encouraged.
the time course of recovery.18 Beginning with the state of Washington in 2009,
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● Early involvement with a

states began passing concussion legislation for youth athletes. As of 2014, every
specialized concussion
state in the United States has enacted legislation regarding a mandated approach clinic should be considered
to concussion.19 Although the specific language sometimes differs, state in those children at risk of
legislation typically includes three components: education for the athletes and delayed recovery.
parents, removal from play, and return only after evaluation by a licensed health
● Management of
care provider trained in the evaluation and management of concussion. concussion is targeted to
Education for children and families should be emphasized, both for the problematic symptoms
prevention and during the postinjury period. Education of adolescents, while gradually increasing
families, and coaches should be emphasized and can take place even before participation in activities of
daily life.
injury to help prevent concussion and aid in early recognition of injury.
Unfortunately, current education tactics may not be sufficient for improving
self-report of injury by youth athletes despite increased knowledge,20–23 with
only half of respondents saying they would always or sometimes report a
concussion and 26% to 53% saying they may continue to play with an injury.
Clearly, education should focus on changing the attitudes of athletes and
coaches away from perceived negative consequences of reporting.
Return to Learn and Return to Play

Avoidance of a repeat injury within the hypothetical time period of increased
vulnerability (7 to 10 days postinjury) is the mainstay of acute management.24
Following an injury, a brief period of physical and cognitive rest should be
prescribed, usually 2 to 3 days or less. Current evidence suggests that children
can be encouraged to slowly return to their typical activities even while still
symptomatic. A prolonged period of rest has been associated with increased
recovery time, and so strict rest protocols are being revised, especially as
symptom exacerbations in the acute phase due to activity do not affect overall
recovery.25 Instead, earlier mobilization and a gradual return to modest levels of
physical activity within the first week after injury are encouraged as this may
decrease the risk of prolonged symptoms.26 Return to activities may be facilitated
by a provider trained in concussion management who can help devise an
individualized treatment plan for the eventual return to sport.27
The first priority after recovery should be returning to school (TABLE 15-128).
School not only provides an educational environment but is also crucial in social
development and mental well-being. DeMatteo and colleagues29 proposed a
protocol focusing on four main areas: timetable/attendance, curriculum,
environmental modifications, and activity modifications through a graduated
return, similar to return-to-play. To implement any protocol, it is critical to

create an interdisciplinary team and foster relationships with staff within the
school to facilitate an effective and successful return to the academic
environment. Multiple individuals within the school will be involved in the
return-to-learn plan, including a health care provider (nurse, athletic trainer),
teachers, and administration (counselors, dean, principal/assistant principal).
Forty-one percent of student athletes in the United States return to school
with academic accommodations, which necessitates good communication
between the health care provider, school, and the student and his/her family.30
However, ensuring good communication is a challenge. Schools often feel that
communication with the provider is inadequate, and education and training for
the school staff may be insufficient, including at the administrative level.31,32
In some secondary schools, the athletic trainer may be the contact point for
the student, family, school staff, and the health care provider who has made
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the recommendations. Athletic trainers, however, may not be familiar with

the various academic accommodations that may be suggested (such as 504 plans
and individualized education programs [IEPs]) and so will need to be supported
by school staff and health care providers.30
After the child has returned to school without restrictions, the return-to-play
protocol can be implemented (TABLE 15-2). The Acute Concussion Evaluation
(ACE), endorsed by the CDC, proposes a return-to-play protocol that slowly
returns the student athlete to his or her sport in a stepwise progressive process.3,33,34
Although originally designed for contact sports, modifications can be made to
TABLE 15-1 Graduated Return-to-School Strategya
Stage Aim Activity Goal of Each Step
1 Daily activities at home that do Typical activities of the child during Gradual return to typical activities
not give the child symptoms the day as long as they do not increase
symptoms (eg, reading, texting, screen
time); start with 5–15 minutes at a time
and gradually build up
2 School activities Homework, reading, or other cognitive Increase tolerance to cognitive work
activities outside of the classroom
3 Return to school part-time Gradual introduction of schoolwork; Increase academic activities

may need to start with a partial school
day or with increased breaks during
the day
4 Return to school full-time Gradually progress school activities Return to full academic activities and
until a full day can be tolerated catch up on missed work
a 28
Reprinted with permission from McCrory P, et al, Br J Sports Med. © 2017 BMJ Publishing Group Ltd and British Association of Sport and Exercise
Medicine.
304 FEBRUARY 2018

individualize the protocol for each athlete’s specific needs. Appropriate
individualization can help the athlete to return to physical activity sooner.35
POSTCONCUSSION SYNDROME
The ICD-10 coding system deems that organic disturbances (eg, headache,
dizziness, sleep problems) and psychogenic disturbances (eg, irritability,

emotional issues, affect changes) after closed head injuries that are chronic,
permanent, or late emerging may be termed postconcussion syndrome. Although
most children with mild TBIs recover within the first few weeks after injury,
one-third of children may go on to have prolonged postconcussion symptoms.
Demographic/premorbid factors, injury characteristics, and initial
symptomatology all may contribute to delayed resolution after injury.36 The
Predicting and Preventing Postconcussive Problems in Pediatrics study (5P
Study) developed a clinical risk score to identify those children who may go on to
have persistent postconcussion symptoms after presentation to an emergency
department within the first 48 hours after injury. Within this population,
presenting with early signs of headache, answering questions slowly, poor
balance, and phonophobia were associated with persistent postconcussion
symptoms. Additionally, female sex, age older than 13 years, a history of
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migraine, and previous concussion with prolonged recovery also correlated with
prolonged recovery.37 Other studies have shown that vestibuloocular (visual
symptoms plus evidence of a visuomotor or vestibuloocular reflex abnormality)
and cognitive deficits acutely may also predict longer symptom duration.38,39
Role of Exercise in Recovery From Persistent Postconcussion Symptoms

Based on recent evidence that too much rest may in fact be detrimental to
recovery, a trend toward recommending stepwise return to physical aerobic
Graduated Return-to-Sport Strategya,b TABLE 15-2
Stage Aim Activity Goal of Each Step
1 Symptom-limited activity Daily activities that do not provoke symptoms Gradual reintroduction of work/school
activities
2 Light aerobic exercise Walking or stationary cycling at slow to medium Increase heart rate
pace; no resistance training
3 Sport-specific exercise Running or skating drills; no head impact Add movement

activities
4 Noncontact training drills Harder training drills, eg, passing drills; may Exercise, coordination, and increased
start progressive resistance training thinking
5 Full contact practice Following medical clearance, participate in Restore confidence and assess functional
normal training activities skills by coaching staff
6 Return to sport Normal game play
a 28
Reprinted with permission from McCrory P, et al, Br J Sports Med. © 2017 BMJ Publishing Group Ltd and British Association of Sport and Exercise Medicine.
b
An initial period of 24 to 48 hours of both relative physical rest and cognitive rest is recommended before beginning the return-to-play progression.
There should be at least 24 hours (or longer) for each step of the progression. If any symptoms worsen during exercise, the athlete should go back
to the previous step. Resistance training should be added only in the later stages (stage 3 or 4 at the earliest). If symptoms are persistent (eg, more
than 10 to 14 days in adults or more than 1 month in children), the athlete should be referred to a health care professional who is an expert in the
management of concussion.
activity even while some symptoms remain is growing.40 Individualized

subthreshold exercise may be prescribed during the recovery to help those who
experience persistent postconcussion symptoms. Studies have shown that
exertion testing in youth does not prolong symptom recovery and may in
fact help to direct activity in children with postconcussion symptoms.29 In a
retrospective review of children who had experienced sport-related concussion,

106 patients underwent graded aerobic treadmill testing to assess recovery and
tolerance of activity, helping to individualize the plan for the specific needs of
the patient.41 Recent studies have shown that this type of rehabilitation program
can lead to symptom resolution and improve mood.42
THE INFLUENCE OF PREINJURY LEARNING DIFFICULTIES ON RECOVERY

Cognitive factors antecedent to the injury may also play a role in a recovery.
Children who sustain a mild TBI and have a premorbid history of attention deficit
hyperactivity disorder (ADHD) tend to have more severe concussion symptoms
than those without ADHD (CASE 15-1).45 The theory of brain reserve suggests that
children with preexisting difficulties with learning may have less capacity to
compensate for a brain injury.46,47 Many parents may consider difficulties that were
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CASE 15-1 A 9-year-old boy with a history of untreated attention deficit

hyperactivity disorder (ADHD) fell in class. He was initially dazed and
slightly confused. He was picked up from school by his mother, who took
him to the emergency department.
On arrival to the emergency department 2 hours after the fall, he
looked well but had a mild headache. His neurologic examination,
including his balance, was normal, and his family was reassured about
the likelihood of a good outcome. He was discharged home, told to
rest for the next 1 to 2 days, given some information by the emergency
department physician about returning to school and play, and advised to
follow up with his family doctor in the next few days. He did very well
initially and was back to normal activities by 2 weeks.
Several weeks later, his teacher raised some concerns about his school
performance, particularly his attention and concentration. He was
assessed by his school psychologist, who found no evidence
of change. After behavioral management strategies for ADHD were
incorporated for several weeks, medication for ADHD was initiated
3 months postinjury.
COMMENT This case is an example of a child with ADHD and concussion. Children
sustaining any kind of traumatic injury are more likely to have a premorbid
history of ADHD, perhaps because of increased risk-taking behaviors and
impulsivity.43 Unlike more severe forms of traumatic brain injury, concussion
itself is unlikely to cause secondary ADHD.44 Children with ADHD, however,
often have more short-term symptoms following a concussion.45
Appropriate treatments for primary ADHD should be administered even, or
especially in, the setting of a concussion.
306 FEBRUARY 2018

present in early school years (eg, attention problems, reading difficulties) to have KEY POINTS
resolved and so may deny any preexisting school difficulties. A careful history is
● Preexisting conditions
required to uncover these potential contributors to persistent problems. Children can exacerbate symptoms
with premorbid learning difficulties often require increased support at school for 1 and lead to delayed
to 3 months following a concussion. Educational, behavioral, and pharmaceutical recovery.
therapies targeting premorbid learning difficulties should be implemented or

● Preinjury and postinjury
continued in collaboration with the school psychologist and health care provider. psychological factors are
often present in those with
THE INFLUENCE OF PSYCHOSOCIAL FACTORS ON RECOVERY prolonged recovery times.
Psychological and social factors may also be associated with delayed recovery from Psychological support is a
key strategy in healthy
concussion, particularly as the time from the injury becomes more prolonged.36 recovery.
Stress in the child’s life and in the family system may be associated with greater
postconcussion symptoms. Psychological factors such as somatization and ● Avoid overuse of
resiliency have frequently been shown to play a role in the time course of analgesics in posttraumatic
headaches.
recovery.48,49 Further, the tendency exists after mild TBI to remember the past in
an unrealistic more favorable light (ie, a “good old days” bias).50 Cognitive
restructuring and symptom reattribution are an important part of the treatment
approach at any stage in the recovery process.51,52 Cognitive restructuring can
help the adolescent or parent identify and target maladaptive thoughts, known as
09/2022
cognitive distortions. This includes all-or-nothing thinking, overgeneralization,

magnification, and emotional reasoning. The psychotherapist can help the child
or parent recognize these distortions and reframe cognitive reasoning and
thought processes to aid recovery. CASE 15-2 highlights the multiple comorbidities
that are often seen in cases of persistent postconcussion symptoms.
REPEAT INJURY, SECOND-IMPACT SYNDROME, AND CHRONIC

TRAUMATIC ENCEPHALOPATHY
Another potential sequela of TBI is second-impact syndrome, a potentially
devastating rapid accumulation of cerebral edema that is hypothesized to be due
to repeat injury occurring before recovery from the first concussion. This is a
catastrophic but extremely rare injury that appears to affect young student
athletes, with very few cases being described worldwide. Although malignant
cerebral edema secondary to increased cerebral blood flow can be seen more
commonly in children and adolescents with TBI, the role of second injury in this
phenomenon is debated. Nevertheless, concern for this phenomenon has driven
many of the stepwise return-to-play policies in sport.
A prominent focus also exists within the media and public on the effects of repeat
injury from both multiple concussions and exposure to repeated subconcussive
hits and their potential relationship to the development of long-term neurocognitive
and psychological disturbances. A subconcussive hit is a high-energy impact after
which the athlete has no overt symptoms or signs to suggest acutely altered brain
function; it is of particular concern in contact sports, such as American football, hockey,
and boxing. While chronic traumatic encephalopathy (CTE) remains a postmortem
pathologic entity diagnosed primarily in those who have played competitive sports,
concern for the development of CTE is growing among patients and families that
present to the neurologist’s office. Repetitive injuries may lead to chronic learning
deficits long after typical recovery59; in animal studies, they have been shown to
cause distinct pathologic patterns and specific functional deficits in adolescent
mice.60 However, currently no prospective studies have shown the long-term
effects of repeated injury that are sustained during childhood and adolescence.
CONCLUSION
TBI, especially mild TBI, is a significant public health concern. The diagnosis
of mild TBI can be difficult because of confounders, such as intoxication,
stress, attribution bias, and delayed presentation to medical attention, and
warrants careful evaluation. Preinjury history of headache and environmental,
psychological, and cognitive difficulties influence outcome, especially in persistent

postconcussion syndrome. Prolonged periods of rest and social isolation

should be avoided. A collaborative approach with educators, athletic trainers,
and health professionals is needed to facilitate a smooth return to school
and activities. Treatments for prolonged recovery are targeted toward
CASE 15-2 A 16-year-old girl with persistent headaches, mood disturbance, sleep
difficulties, and a decrease in school performance was evaluated in the
concussion clinic 4 months after a concussion that occurred while in
cheerleading practice. She was taking ibuprofen or acetaminophen daily
for her headaches. She found it difficult to fall asleep because of
concerns about her schoolwork, then slept from 3:00 AM to 11:00 AM each
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day and only attended school in the afternoon. She did not drink
caffeinated beverages. She had a previous history of migraine as well as
anxiety that had been managed with cognitive-behavioral therapy and a
family history of anxiety and mood disturbance. Her headaches were
constant and holocephalic. No evidence of psychosis or risk of self-harm
was noted, although she was worried she would “never get back to
normal” and stated she could no longer do “anything.” She was diagnosed
with a medication-overuse component to her headache disorder and an
anxiety disorder. Amitriptyline was started, and analgesics were stopped.
A psychiatric referral was made, and cognitive-behavioral therapy was
restarted. Her sleep and headaches improved over the next 3 months,
and her school performance increased as school attendance increased.
COMMENT This case demonstrates how premorbid difficulties, such as headaches and
mood disturbances, are exacerbated after a concussion. Although these
problems can occur de novo following a mild traumatic brain injury (TBI),
exacerbation of preexisting problems is probably more common. Currently,
no one therapy exists for persistent postconcussion symptoms. The
management of a patient with multiple comorbidities requires a
multifaceted and multidisciplinary approach, targeting the most
problematic areas, as demonstrated in this case. Medication overuse is
common in posttraumatic headaches,53 and amitriptyline can be helpful
when withdrawing analgesics.54 Short-term elevated anxiety levels and
new-onset anxiety disorders are 4 times more likely after a mild TBI than
after an orthopedic injury.55 Cognitive-behavioral therapy or similar
psychotherapies are effective treatments for anxiety in youth.56,57
Sleep problems are common after a mild TBI and are often comorbid with
psychiatric disorders.58 If treatment of psychiatric comorbidities does not
improve sleep, referral to a sleep specialist should be considered.
308 FEBRUARY 2018

symptoms. An urgent need exists for more evidence-based management in
postconcussion syndrome.
USEFUL WEBSITES
AMERICAN ACADEMY OF NEUROLOGY, SPORT AMERICAN ACADEMY OF PEDIATRICS STATE ADVOCACY

CONCUSSION RESOURCES FOCUS, CONCUSSION MANAGEMENT: RETURN TO PLAY
The American Academy of Neurology provides The American Academy of Pediatrics State
sports concussion resources to help physicians, Advocacy Focus provides guidelines on return to
coaches, athletes, and parents better understand, play for student athletes.
prevent, identify, diagnose, and treat aap.org/en-us/advocacy-and-policy/state-
sports concussions. advocacy/Documents/concussion.pdf
aan.com/concussion
NATIONAL CONFERENCE OF STATE LEGISLATURES,
CENTERS FOR DISEASE CONTROL AND PREVENTION, TRAUMATIC BRAIN INJURY LEGISLATION
HEADS UP The National Congress of State Legislatures
The Centers for Disease Control and Prevention website provides information on individual states’
helps parents, coaches, school professionals, and traumatic brain injury legislation.
health care providers know how to recognize, ncsl.org/research/health/traumatic-brain-injury-
respond to, and minimize the risk of concussion and legislation.aspx
other brain injuries.
cdc.gov/headsup/
09/2022
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REVIEW ARTICLE

Evaluation of the Child
C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E With Developmental
VH4kB2Z9EY5jONzaHF6L6BFLKNUIlvpnOmK9o8126tTOuniutr3OwA5Vmj7KGOmPyDdSXOaeh9YV3kmbDv8NVZYfkn50= on 09/
ONLINE
Impairments
By Clara D. M. van Karnebeek, MD, PhD
ABSTRACT
PURPOSE OF REVIEW: Thisarticle discusses the diagnostic evaluation of
intellectual developmental disorder, comprising global developmental
delay and intellectual disability in children.
RECENT FINDINGS:With a prevalence of 1% to 3% and substantial
comorbidity, high lifetime costs, and emotional burden, intellectual
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developmental disorder is characterized by limitations in both intellectual

functioning (IQ less than 70) and adaptive behavior starting before
18 years of age. Pinpointing the precise genetic cause is important, as it
allows for accurate genetic counseling, avoidance of unnecessary testing,
prognostication, and tailored management, which, for an increasing
number of genetic conditions, targets the pathophysiology and
improves outcomes.
SUMMARY: The etiology of intellectual developmental disorder is
CITE AS:
CONTINUUM (MINNEAP MINN) heterogeneous, which mandates a structured approach that considers
2018;24(1, CHILD NEUROLOGY): family situation, test costs, yield, and potential therapeutic tractability of
228–247.
the identified condition. Diagnosis of an underlying genetic cause is
Address correspondence to Dr increasingly important with the advent of new treatments. Still, in many
Clara van Karnebeek, Emma cases, the cause remains unknown, and research is needed to elucidate its
Children’s Hospital, Room complex molecular basis.
H7-224, Academic Medical
Center, Meibergdreef 9, 1105 AZ
Amsterdam, The Netherlands,
c.d.vankarnebeek@amc.uva.nl.
INTRODUCTION
D
RELATIONSHIP DISCLOSURE: evelopmental impairment is the most frequent reason for referral to
Dr van Karnebeek was a
developer of the Treatable
pediatric genetics services, and pediatric neurologists are regularly
Intellectual Disability asked to consult on these cases to assess the type and severity of
application and website impairment and the etiologic diagnosis.1,2 This article discusses the
(treatable-id.org), which are
discussed in this article, but she diagnostic evaluation of intellectual developmental disorder, which
receives no financial comprises both global developmental delay and intellectual disability in children.
compensation resulting from its
Developmental delay is defined as a developmental quotient of less than 70%
development or use.
within a given developmental domain, including gross motor and fine motor,
UNLABELED USE OF expressive language, receptive language, and social/adaptive behaviors. The
USE DISCLOSURE: Dr van
developmental quotient is the developmental age divided by the child’s
Karnebeek reports no chronologic age (adjusted for prematurity). Global developmental delay is defined
disclosure. as a significant delay in two or more developmental domains. A delay in the
© 2018 American Academy of language domains, in particular, is thought to predict a future diagnosis of
Neurology. intellectual disability (applied to children younger than 5 years of age). However,
228 FEBRUARY 2018

not all individuals diagnosed with global developmental delay will have KEY POINTS
lifelong impairment (disability). Intellectual disability is a disability
● Pinpointing the precise
characterized by significant limitations both in intellectual functioning and in
genetic cause of
adaptive behavior as expressed in conceptual, social, and adaptive skills. The intellectual developmental
disability originates before 18 years of age and is applied to children 5 years disorder is important, as it
of age or older.3–5 allows for proper genetic

counseling, avoidance of
The worldwide prevalence of intellectual disability is estimated at 1% to 3%.
unnecessary tests,
Lifetime costs (both direct and indirect) to support individuals with intellectual prognostication, and
developmental disorder exceed those of cardiovascular disease and cancer tailored management,
combined, at approximately $1 million per person.6 which, for an increasing
Individuals with developmental delays are generally identified in early number of genetic
conditions, targets the
childhood. Formal diagnosis is made via IQ testing with a score of less than 70. pathophysiology and
Intellectual developmental disorder can occur either independently or with improves outcomes.
congenital malformations or other neurologic features, including autism
spectrum disorders, epilepsy (CASE 11-1), or sensory impairment. The severity ● The etiology of
intellectual developmental
of intellectual developmental disorder is highly variable, ranging from mild disorder is extremely
(IQ of 55 to 70) or moderate (IQ of 40 to 55) to severe (IQ of 25 to 40) and heterogeneous, which
profound (IQ of less than 25).1 mandates a structured
Pinpointing the precise genetic cause of intellectual developmental disorder is diagnostic approach, taking
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into account family

important, as it allows for proper genetic counseling, avoidance of unnecessary
situation and burden as well
tests, prognostication, and tailored management, which, for an increasing as test costs, yield, and
number of genetic conditions, targets the pathophysiology and improves potential therapeutic
outcomes. However, the heterogeneous etiology of intellectual developmental tractability of the identified
condition.
disorder makes its identification extremely challenging. Causal factors include
maternal alcohol abuse during pregnancy, infections, birth complications,
neglect, and extreme malnutrition. Genetics are also known to play an important
role in the etiology of intellectual developmental disorder, and, in the Western
world, at least 50% of cases are thought to be genetic.9,10
In this article, the focus is on the genetic etiology of intellectual developmental
disorder; rearrangements vary from single-gene mutations to insertions and
deletions with different mendelian modes of inheritance.11 The X chromosome
appears to be enriched with genes mutated in patients with intellectual
developmental disorder, be they syndromic or not (10% of all protein-coding
genes on the X chromosome compared with 4% of the genomic average). In fact,
the total number of X-linked intellectual developmental disorder genes is more
than 100 out of about 800 protein-coding genes on the X chromosome.12
Despite great advances in genomic technologies and costly investigations, at
least half of patients remain undiagnosed.10 A genetic diagnosis can provide
information on the specific type of intellectual developmental disorder, its
prognosis, possible complications, and inheritance. This information can
facilitate family planning, condition-specific support, optimal supportive
management, access to services in the community, and treatment options to
prevent and improve intellectual developmental outcomes.
Until recently, treatments for intellectual developmental disorder have been
largely supportive, with the focus on treating concomitant medical, neurologic,
and behavioral symptoms, thereby enabling the patient to achieve the highest
level of function possible. For example, supportive therapies may include
pharmacotherapy for seizure control; sleep management; psychopharmacology
for maladaptive behaviors; special education programs; and cognitive-behavioral,
occupational, speech, and physical therapy.2,13
DEVELOPMENTAL IMPAIRMENTS
CASE 11-1 A 16-month-old girl was seen in the outpatient clinic for evaluation and
management of her atypical febrile seizures, poorly controlled on
valproic acid. Her psychomotor development was globally delayed; she
was able to sit without support at age 9 months and had just started to
crawl. She made less eye contact than her sister did at that age and did
not say any words. Her vision and hearing were tested and were normal.
A more extensive history revealed an uncomplicated pregnancy and

full-term delivery. During the first weeks of her life, she was hyperalert,
constantly awake and agitated, and since then, she seemed to startle
quickly and was easily frightened.
Physical examination confirmed the delay and hypotonia, in addition to
mild hyperekplexia (exaggerated startle reflex). Sample collection for a
chromosomal microarray and the Treatable Intellectual Disability
Endeavor (TIDE)7 first-tier screening (an explanation of the TIDE protocol
is provided later in this article) was initiated, and neuroimaging was
ordered. Three weeks later, the TIDE results revealed a low plasma serine
level (63 μmol/L, reference 82 μmol/L to 103 μmol/L) and increased
creatine to creatinine ratio in her urine.
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An online application was reviewed and showed that, aside from a

serine biosynthesis defect, the creatine transporter (SLC6A8) deficiency
should also be on the differential diagnosis. Although the latter is an
X-linked disease, it can affect girls as well due to unfavorable skewing of
X-inactivation. Magnetic imaging spectroscopy was added to the brain
MRI to measure cerebral creatine content, as well as a lumbar puncture
during the sedation to measure the serum (CSF glucose ratio [for glucose
transporter 1 (GLUT1) deficiency syndrome], CSF amino acids [for serine
biosynthesis defects], and neurotransmitter monoamine metabolites [for
congenital neurotransmitter diseases]). The MRI showed subtle cortical
migration abnormalities but otherwise normal structures with
unremarkable magnetic imaging spectroscopy findings. The CSF serine
was within normal limits, as was the glucose ratio.
Two weeks later, results were received from the biochemical
geneticist, who noted “peak X” on the CSF analysis, which is a specific
sign for pyridoxine-dependent epilepsy. Pyridoxine 15 mg/kg/d divided in
two doses was immediately prescribed, even before collecting the
urine a-aminoadipic semialdehyde (as this does not impact results) and
DNA for ALDH7A1 molecular analysis, which showed compound
heterozygosity for two known pathogenic missense mutations. After
arranging for genetic counseling, the patient was referred to a specialist in
pediatric metabolic diseases to start triple therapy, a lysine-protein
restricted diet, and arginine supplementation to lower the potentially
toxic metabolites a-aminoadipic semialdehyde and P6C, as this innovative
approach was recently reported to improve neurodevelopmental
outcomes for patients with pyridoxine-dependent epilepsy.8
COMMENT This case illustrates the importance of an etiologic diagnosis, defined as

the determination of the underlying environmental, genetic, or
multifactorial condition with sufficient evidence in the literature to make
a causal relationship with the condition likely.
230 FEBRUARY 2018

Recently, advances in the development and implementation of targeted KEY POINT
treatments that focus on the pathophysiology at a cellular or molecular level have
● The first important step
been made. The goal of these treatments is to affect the underlying etiology to
in evaluating intellectual
either prevent or improve further neurologic manifestations of disease. Inborn developmental disorder is
errors of metabolism constitute the largest group of monogenic conditions confirmation of the type
currently amenable to such therapy.7,14 Concurrently, advances have been made in and severity of
developmental delay (and

the development of treatments for other monogenic conditions, such as fragile X
domains affected),
syndrome and tuberous sclerosis complex, for which trials are under way.15 including intellectual
Notably, despite the individual diseases being rare, the frequency of inborn errors disability. Screening for
of metabolism in aggregate is considerable and, given the opportunity to improve medical and psychological
clinical outcomes, active screening for them should be done. comorbidities should be
performed.
This article outlines the diagnostic approach to the child with unexplained
intellectual developmental disorder, both as the sole presenting feature and in
combination with somatic/psychiatric comorbidity, in accordance with practice
parameters and recent developments.2,7,13
EVALUATION OF INTELLECTUAL DEVELOPMENTAL DISORDER

The process of evaluating intellectual developmental disorder is organized in
several different sequential steps (FIGURE 11-1).
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Step 1: Confirmation of Intellectual Developmental Disorder

Identifying the type of developmental delay is an important preliminary step, as it
influences the course of future investigations.1 Global developmental delay is a
subset of developmental disabilities defined as a significant delay (performance
that is two standard deviations or more below the mean on age-appropriate,
standardized, norm-referenced testing) in two or more developmental domains
(eg, gross/fine motor, speech/language, cognitive, social/personal, or activities of
daily living).3–5 These deficits are evident in comparison with the skills attained by
chronologic peers and are thought to predict a future diagnosis of intellectual
disability. Accurate documentation of these delays is necessary and should be done
using norm-referenced and age-appropriate standardized measures of development
administered by experienced developmental specialists. Cognitive abilities can be
measured using any of a number of psychological tests in which the output is a
numerical value known as IQ. Often this is done by developmental pediatricians or
specialized psychologists.2 Such tests have proven reliable and valid from the age of
5 years and older; if the IQ is below 70, the diagnosis of intellectual disability is
established. The term global developmental delay is used for children aged 5 years or
younger, while the term intellectual disability describes older children. Children
identified as having global developmental delay present with delays in achieving
age-appropriate developmental milestones in two or more developmental domains,
implying deficits in learning and adaptation. In turn, this suggests the delays are
significant and predictive of intellectual disability, especially if speech/language is
affected and the degree is moderate to profound. However, it must be noted that
delays in development, especially those that are mild, may be transient and lack
predictive reliability for intellectual disability or other developmental disabilities.
Pediatric patients with delays in a single developmental domain (eg, with isolated
mild speech or motor delay) are not considered appropriate candidates for the
comprehensive genetic evaluation processes described in this article.
The role of the clinician is to ensure that intellectual developmental disorder and
its severity are confirmed as objectively and formally as possible with the means
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FIGURE 11-1
Schematic illustration of the diagnostic steps in the evaluation of the patient with intellectual
developmental disorder.
FH = family history; MH = medical history; NE = neurologic examination; PE = physical examination;
TIDE = Treatable Intellectual Disability Endeavor; WES = whole-exome sequencing; XLID = X-linked
intellectual disability.
available.1 Recognition of developmental plateauing or regression is absolutely

essential as this requires an expedited diagnostic workup, especially given the
therapeutic amenability of some inborn errors of metabolism, which can present
as a neurodegenerative condition with loss of skills (CASE 11-2); timely
initiation of targeted therapy can halt further decline and improve outcomes.7
Documentation of the clinical course with emphasis on the neurologic findings is
key for follow-up and prognostication, whether it be the natural course or the
response to treatment.
232 FEBRUARY 2018

Step 2: Phenotyping and Screening for Medical Comorbidities KEY POINTS
A complete medical evaluation should be done for every child with intellectual
● Loss of skills is an
developmental disorder,2,13 including testing of vision and hearing and screening
alarming symptom and
for neurologic deficits (hypotonia, movement disorders, seizures, extraocular requires expedited workup.
movements, and swallowing/bulbar abnormalities), behavioral/psychiatric
disturbances, and systemic abnormalities. A clinical history with a ● A complete medical

three-generation pedigree and family history, along with a physical examination evaluation should be done
for every child with
(general, neurologic, dysmorphologic, and dermatologic abnormalities, the latter intellectual developmental
requiring a Wood’s lamp) remain the pillars of the diagnostic workup, not only to disorder.
identify the underlying condition or create a strong differential but also to screen
for potential comorbidities requiring referral to the appropriate specialist ● Chromosomal microarray
and metabolic testing for
physician. According to the American Academy of Neurology, the clinical treatable conditions are
examination should ask the following questions13: first-tier tests for
u Overall, are there features suggesting a specific diagnosis? disorder and should be
considered in all children
u Are there historical or physical findings (eg, dysmorphic features) to suggest
with unexplained
Down, fragile X, or Rett syndrome; other genetic disorders; or hypothyroidism?
u Are there historical (intrapartum asphyxia) or physical findings (microcephaly, disorder. Additional testing
cerebral palsy, focal findings) or focal seizures to suggest central nervous includes neuroimaging,
09/2022
system (CNS) injury or malformation? neurophysiology, single-gene

tests, and specialist
u Does the child have any identifiable risk factors for excessive environmental
evaluations.
lead exposure or other toxins as per established current guidelines?
u Is there loss or regression of developmental milestones (CASE 11-2 ), history of parental ● Inborn errors of
consanguinity, prior unexplained loss of a child, or multiple miscarriages? metabolism constitute a
class of single-gene
Step 3: Additional Investigations disorders involving
When deciding on additional investigations to confirm the diagnosis, the clinician impaired biochemical or
should weigh several factors: available resources, both financial and practical; cellular processes. The
majority are due to defects
availability and cost of a test; expected diagnostic yield; incidental or secondary in genes that typically
findings; and finally, perhaps most important, the risk of missing a potentially affect the synthesis or
treatable condition. Given the variability of all these factors, a standard approach breakdown of molecules,
cannot be prescribed. Rather, a framework is provided here, with emphasis on the leading to accumulation of
toxic molecules or
importance of detailed phenotyping and a differential diagnosis to direct the approach deficiency of cellular
and informed analysis of whole-exome and whole-genome sequencing data. energy or required
If, based on the clinical and physical examination, a diagnosis is immediately substrates for many
apparent (eg, Down syndrome), targeted testing such as a karyotype should be done important intracellular
processes.
for confirmation. If this is not the case, then chromosomal microarray and screening
for treatable inborn errors of metabolism are the next steps and can be done in
parallel. In some centers, whole-exome sequencing might be readily available as a
clinical test; if this is the case, the physician should keep in mind that chromosomal
copy number variants can be missed and should ensure that adequate coverage of
the genes encoding potentially treatable conditions is guaranteed.
CHROMOSOMAL MICROARRAY AS A FIRST-TIER TEST. Chromosomal microarray has

replaced karyotyping as first-tier testing in children with unexplained intellectual
developmental disorder, given the much higher resolution to detect chromosomal
copy number variants and gains or losses of genome material.17 The diagnostic
yield of chromosomal microarray is reported to be at least twice (20% or more)
that of the standard karyotype (10%). For this discussion, chromosomal
microarray encompasses all current types of chromosomal copy number analyses,
including array-based comparative genomic hybridization, single-nucleotide
polymorphism arrays, and fluorescence in situ hybridization (FISH) testing for

patients presenting with intellectual developmental disorder of unknown origin.
However, the standard karyotype and certain FISH tests remain important to
diagnostic testing only in limited clinical situations in which a particular condition
is suspected (eg, Down syndrome, Williams syndrome, Smith-Magenis
syndrome). Pioneering microarray studies in intellectual developmental disorder

showed that pathogenic copy number variants occurred de novo in the germline of
approximately 10% of patients.17 These occurred all over the genome, and
numerous recurrent copy number variants have now been identified in intellectual
disability as autosomal dominant and X-linked causes. Detailed clinical and genetic
characterization of patients with these copy number variants has resulted in the
description of many new intellectual disability syndromes, provided insights into
the genomic architecture underlying these genomic disorders, and revealed many
causative dosage-sensitive genes located in these copy number variant regions.18
In all cases, the interpretation of abnormal chromosomal microarray test
results and variants of unknown significance and the subsequent counseling of
families should be done by a medical geneticist and certified genetic counselor in
collaboration with the reference laboratory and platform used. International
09/2022
CASE 11-2 An 8-year-old boy was seen by a developmental pediatrician for

worsening behavioral issues and the sudden onset of severe tics. Except for
diarrhea during the first year of life, his medical history was unremarkable
until the age of 7 years, when his teacher informed the parents that their son
could not concentrate at school, had trouble reading, and was emotional
and sometimes even aggressive toward other children in the class. The
parents were going through a divorce at the time, so these behavioral
changes were attributed to the upheaval. However, in third grade, problems
continued, and he became more socially withdrawn, not wanting to invite
any friends for his eighth birthday party and frequently making squeaking
sounds and blowing on his palm, with nose rubbing and blinking. During the
clinic visit, a pediatric neurologist was asked to evaluate the child as well;
she noted hyperreflexia of the lower limbs, coordination difficulties, and
possible abnormal visual pursuit. The Treatable Intellectual Disability
Endeavor (TIDE)7 first-tier screen (an explanation of the TIDE protocol is
provided later in this article) showed an elevated lactate (3.4 μmol/L,
reference range 0.2 μmol/L to 1.1 μmol/L) but no other abnormalities; urine
glycosaminoglycans and oligosaccharides were normal, ruling out many, but
not all, storage diseases. A neurodegenerative disease was suspected and
urgent MRI and magnetic resonance spectroscopy of the brain were
requested, with a differential diagnosis of mitochondrial disease and
leukodystrophies. TIDE second-tier testing included plasma oxysterols (for
Niemann-Pick C1 disease because of the abnormal eye movements), plasma
cholestanol (for cerebrotendinous xanthomatosis because of the infantile
diarrhea), plasma very-long-chain fatty acids (for peroxisomal disease),
enzyme activity (galactosylceramidase for Krabbe disease), and
arylsulfatase A (for metachromatic leukodystrophy). He was also seen by
a neuro-ophthalmologist, who noted normal horizontal saccades.
234 FEBRUARY 2018

collaborative efforts are under way to resolve test variability.17 The functional
impact (or lack thereof ) of very rare copy number variants is now better
understood, with increasingly large data sets.10,19
In summary, in every child with intellectual developmental disorder in
whom the etiology remains unknown after a thorough clinical examination, a
chromosomal microarray should be performed simultaneously with metabolic

testing for treatable inborn errors of metabolism, described in the next section. If
these tests are negative or inconclusive, the next step is whole-exome sequencing.
METABOLIC TESTING FOR TREATABLE INBORN ERRORS OF METABOLISM AS

ANOTHER FIRST-TIER TEST. Inborn errors of metabolism constitute a class of
single-gene disorders involving impaired biochemical or cellular processes. The
majority are due to defects in genes that typically affect the synthesis or breakdown
of molecules, leading to accumulation of toxic molecules or deficiency of cellular
energy or required substrates for many important intracellular processes. Many of
these inborn errors of metabolism affect the CNS during infancy or childhood,
presenting as intellectual developmental disorder as well as epilepsy, cerebral
palsy, autism spectrum disorder, and behavioral and psychiatric disturbances.14,20
09/2022
During the presedation consult for the MRI, the anesthesiologist observed
perioral hyperpigmentation, which his mother said had been present since a
sunny summer vacation the past year. His sodium was at the lower limit of
normal and potassium at the upper limit, which prompted an order for an
adrenocorticotropic hormone (ACTH) test, revealing adrenal insufficiency.
MRI showed subtle bilateral demyelination in the parietooccipital regions,
with increased lactate peak on spectroscopy but a normal
N-acetylaspartate (NAA) to choline ratio.The presentation was compatible
with the childhood cerebral form of X-linked adrenoleukodystrophy,16
subsequently confirmed by a typically abnormal very-long-chain fatty acid
profile, as well as a maternally inherited frameshift ABCD1 variant, which had
not previously been reported. The patient was referred to an endocrinologist
to evaluate and monitor adrenal function (as part of the standard protocol
for this condition, which in this case was especially important given the
pigmentation abnormalities compatible with insufficiency) and the
hematopoietic stem cell transplantation team to assess his eligibility for this
lifesaving treatment. His mother was also referred to a neurologist, as the
majority of carrier females have signs of adrenomyeloneuropathy, and to
clinical genetics for general and preconception genetic counseling given the
50% recurrence risk for male offspring.
This case illustrates that thorough phenotyping is important, not only for COMMENT
enhancing diagnostic success but also for proper medical management.
A number of affordable, accessible, and safe treatments are available to treat

inborn errors of metabolism, including (alone or in combination) dietary
restrictions/supplements, cofactors/enzymes, vitamins, substrate inhibition or
reduction (small molecule), enzyme replacement, bone marrow and hematopoietic
stem cell transplantation, and gene therapy. The majority of patients are positively
affected by therapy, with outcomes including improvement or stabilization of

psychomotor/cognitive development (about 20% of inborn errors of metabolism),

behavior/psychiatric disturbances, seizures, and neurologic and systemic
manifestations. The evidence levels for treatments are limited by the small patient
cohorts inherent to rare diseases; however, many are considered standard of care.7,14
A total of 89 inborn errors of metabolism presenting with intellectual
developmental disorder as the predominant phenotypic feature, for which causal
therapy is available, were identified via systematic review and published previously.7,14
These 89 inborn errors of metabolism include disorders of amino acids (n = 12),
cholesterol and bile acids (n = 3), creatine (n = 3), fatty aldehydes (n = 1), glucose
homeostasis and transport (n = 2), hyperhomocysteinemia (n = 7), lysosomes (n = 12),
metals (n = 5), mitochondria (n = 2), neurotransmission (n = 8), organic acids
(n = 19), peroxisomes (n = 1), purines and pyrimidines (n = 3), urea cycle (n = 8),
and vitamins and cofactors (n = 10). Although amenable to treatment, fatty acid
09/2022
oxidation disorders are not included in this list because of their clinical presentation,
which is a metabolic crisis with hypoglycemia (and subsequent neurologic sequelae)
rather than unexplained intellectual developmental disorder. These conditions will
not be missed by the two-tiered protocol outlined in TABLE 11-1, however, as the
acylcarnitine profile is included in the initial metabolic testing as outlined.
While many patients can present with nonspecific intellectual developmental
disorder as the sole feature (eg, creatine transporter deficiency), the majority of
the treatable inborn errors of metabolism listed are associated with additional
neurologic features that may include (as illustrated by CASE 11-1) spasticity,
behavioral disturbance, dementia, episodic encephalopathy, epilepsy, hearing loss,
hypotonia/myopathy, neuroimaging abnormalities (basal ganglia, cerebellum,
cerebrum, white matter, cysts/dysgenesis, or a combination thereof ), neuropathy,
ocular movement abnormality, psychiatric disturbance, sensorineural hearing
loss, spasticity, stroke, vision loss, and various types and degrees of movement
disorders (eg, dystonia, dyskinesia, and ataxia). However, it is important to note
that non-neurologic or systemic features are a prominent phenotype in 57 (64%)
of the 89 treatable intellectual developmental disorders. Other presentations vary
from stable intellectual developmental disorder (ie, without a history of regression
or plateauing) to neurodegenerative, with or without multiorgan involvement.
The timing and nature of onset also varies; some are characterized by acute
decompensations, often in the neonatal or early childhood period, while others
present with a late-onset form of a nonspecific or chronic nature.
A two-tiered metabolic protocol (TABLE 11-1) developed through the
Treatable Intellectual Disability Endeavor (TIDE), a 5-year funded clinical
research project at BC Children’s Hospital, Vancouver, British Columbia, Canada
(tidebc.org), was designed to enhance early diagnosis of treatable inborn errors of
metabolism in children presenting with intellectual developmental disorders.7
The first step involves biochemical testing of blood and urine, which potentially
indicates 60% of the currently known treatable conditions and should be applied
in all patients with unexplained intellectual developmental disorder.7 If these
tests are negative, depending on the results of chromosomal microarray and
236 FEBRUARY 2018

Treatable Intellectual Disability Endeavor Protocol for the Diagnosis of a TABLE 11-1
Treatable Inborn Errors of Metabolism in Intellectual Development Disorder
First Tier: In All Patients With Unexplained Intellectual Disability, Nontargeted Screening
to Identify 54 (60%) of Treatable Inborn Errors of Metabolismb
u Blood
⋄Ammonia, lactate
⋄Plasma amino acids
⋄Total homocysteine
⋄Acylcarnitine profile
⋄Copper, ceruloplasmin
u Urine
⋄Organic acids
⋄Purines and pyrimidines
⋄Creatine metabolites
⋄Oligosaccharides
09/2022
⋄Glycosaminoglycans
Second Tier: Targeted Metabolic Workup to Identify 35 (40%) of Treatable Inborn Errors of
Metabolism Requiring Specific Testingb
u According to patient’s symptomatology and clinician’s expertise
u Utilization of textbooks and digital resources
u Consider the following biochemical/gene tests
⋄Whole blood manganese

⋄Plasma cholestanol
⋄Plasma 7-dehydrocholesterol to cholesterol ratio
⋄Plasma pipecolic acid and urine α-aminoadipic semialdehyde
⋄Plasma very-long-chain fatty acids
⋄Plasma vitamin B and folate
12
⋄Serum and CSF lactate to pyruvate ratio

⋄Enzyme activities (leukocytes): arylsulfatase A, biotinidase, glucocerebrosidase,
fatty aldehyde dehydrogenase
⋄Urine deoxypyridinoline
⋄CSF amino acids
⋄CSF neurotransmitters
⋄CSF to plasma glucose ratio
⋄Coenzyme Q measurement fibroblasts
⋄SLC52A2,
Molecular analyses: CA5A, NPC1, NPC2, SC4MOL, SLC18A2, SLC19A3, SLC30A10,
SLC52A3, PDHA1, DLAT, PDHX, SPR, TH genes
CSF = cerebrospinal fluid.

a
Modified with permission from van Karnebeek CD, et al, Pediatr Neurol.15 © 2016 Elsevier Inc.
b
The first-tier testing comprises group metabolic tests in urine and blood that should be performed in every patient with intellectual developmental disorder
of unknown cause. Based on the differential diagnosis generated by the patient's signs and symptoms, the second-tier tests are ordered individually.
KEY POINTS other testing as well as the clinical phenotype, the clinician should consider at
● In a 2011 practice
low threshold the second step of the TIDE algorithm for the identification of the
parameter, the American remaining 35 treatable intellectual developmental disorders (TABLE 11-1). The
Academy of Neurology and latter conditions require a more targeted and selective approach, including
the Child Neurology Society single-metabolite or primary molecular analysis based on a clinical differential
state that neuroimaging is a

diagnosis (ie, the presence of signs and symptoms). These tests often require more
recommended part of the
diagnostic evaluation, invasive sampling procedures and extensive funding. A free digital application
particularly if there are is available (via treatable-id.org), which supports the clinician in applying the
abnormal findings on two-tiered diagnostic protocol and provides information on the symptoms, tests,
examination (eg, and treatments of these rare diseases.21 Once exome sequencing is established as
microcephaly,
macrocephaly, focal motor the primary diagnostic test rather than biochemical testing, sufficient coverage
findings, pyramidal or of the treatable inborn errors of metabolism genes should be ensured.
extrapyramidal signs).
NEUROIMAGING. In a 2011 practice parameter, the American Academy of
● Whole-exome and Neurology and the Child Neurology Society state that neuroimaging is a
whole-genome sequencing recommended part of the diagnostic evaluation, particularly if there are abnormal
(genomics) are becoming findings on examination (eg, microcephaly, macrocephaly, focal motor findings,
more readily available in
the clinical arena.
pyramidal or extrapyramidal signs).13 One must keep in mind that the brain MRI
rarely provides the precise etiologic diagnosis on its own; more often it provides
09/2022
clues and improves phenotyping. For an MRI, sedation is required in most cases
of intellectual developmental disorder; the inherent risks combined with the
limited diagnostic yield must be considered when ordering this test. Whenever
possible, proton magnetic resonance spectroscopy, a noninvasive MRI technique
that can quantify the concentration of multiple metabolites within the human
brain, should be performed, especially to diagnose the inborn errors of
creatine metabolism.7
OTHER TESTING AND SPECIALIST REFERRALS. Prompted by the clinical features
of the patient and guided by the clinician’s differential diagnosis, further
investigations can be initiated to pursue conditions or screen for medical
comorbidities, which include (but are not limited to) EEG to characterize
seizures and epileptiform activity, EMG, visual evoked potentials, brainstem
auditory evoked response, cardiac evaluation (including echocardiogram and
ECG), skeletal x-rays (to assess for dysostoses or other congenital abnormalities),
abdominal ultrasound (to assess for enlargement or congenital anomalies of
internal organs), referral to a neuro-ophthalmologist (to assess for congenital
abnormalities or signs of metabolic eye disease), and referral to a dysmorphologist
or other specialist required for proper phenotyping and diagnosis. Key is the
presence of a case manager, a specialist who follows up on such referrals and
tests and integrates the information into an efficient diagnostic strategy.
MONOGENIC CONDITIONS. Microdeletion syndromes (eg, Williams,
Prader-Willi, and Angelman syndromes) are now identifiable using
chromosomal microarray; sometimes, however, targeted FISH and methylation
testing are still used. Fragile X syndrome requires FMR1 analysis for CGG repeat
number (full mutation 200 or more repeats). TABLE 11-2 22–30 highlights
monogenic conditions that are often tested for based on the phenotype or
frequency, recent developments in therapeutic approaches, and ongoing trials.
WHOLE-EXOME AND WHOLE-GENOME SEQUENCING. If clinical examination
and the first-tier tests (chromosomal microarray and metabolic screening for
treatable inborn errors of metabolism) do not yield a diagnosis and balanced
238 FEBRUARY 2018

chromosomal aberrations have been excluded, direct searching for
single-nucleotide variants or small insertions/deletions may be performed
using exome or genome analysis.9,10 Whole-exome sequencing is a technique
for sequencing all the expressed genes in a genome (known as the exome) and
is becoming more readily available in the clinical arena. It involves selecting
only the subset of DNA that encodes proteins (known as exons) and then
Monogenic Conditions Often Tested for Based on Phenotype or Frequency TABLE 11-2
and Targeted Treatments in Developmenta
Genetic Treatment in Target From Animal/ Development

Condition Mechanism Phenotype Frequency Development Cellular Models Phase
Fragile X FMR1 CGG Hyperactivity, 1 per 5000 Lithium Inhibits excessive 1
syndrome22 repeat impulsivity, to 4 per 5000 GSK3B signaling and
expansions attention problems, phosphatidylinositol
anxiety, gaze turnover
aversion,
hyperarousal to Mavoglurant mGluR5 NAM; reduces 2b
09/2022
sensory stimuli, (AFQ056) mGluR5-regulated

aggression; activation of dendritic
females less translation
severely affected Basimglurant mGluR5 NAM; reduces 2b
(RO4917523) mGluR5-regulated
activation of dendritic
translation
Arbaclofen GABA-B agonist; 3

reduces presynaptic
glutamate release
Minocycline Reduces excessive 2

activity of MMP9 due
to dysregulation in
absence of FMRP
Ganaxolone GABA-A agonist; 2
increases deficient
GABA signaling
Acamprosate GABA-A/B agonist 2
NNZ-2566 Inhibits excessive 2

ERK/Akt signaling
Metadoxine Inhibits excessive 2

ERK/Akt signaling
Lovastatin Inhibits ERK pathway 1
Down syndrome 23
Trisomy Typical 1 in 650 to RG1662 GABA-A a5 receptor 2b
chromosome dysmorphisms 1 in 1000 subunit inverse
21 of facies and agonist; reduces
extremities, short excessive GABA
stature, hypotonia, signaling
hypermobile joints,
congenital heart
defects, other
CONTINUED ON PAGE 240
sequencing that DNA using any high-throughput DNA sequencing

technology. Humans have about 180,000 exons, constituting about 1% of
the human genome, or approximately 30 million base pairs. Whole-exome
sequencing has revolutionized both diagnosis and discovery of rare mendelian
diseases and has increased our understanding of the genetic basis of
intellectual developmental disorder.31 Whole-genome sequencing analyzes all

our DNA; it is becoming a very powerful method by which to detect both

complex rearrangements as well as intronic and regulatory variants. However,
CONTINUED FROM PAGE 239

Rett syndrome MECP2 In males, epileptic 1 in 10,000 to Mecasermin Activation of Akt 1
09/2022
(MECP2 variants)24 variants encephalopathy; 1 in 15,000 live (rhIGF-1) pathway

in females, normal female births
development up NNZ-2566 Akt pathway effects, 2
to 6–18 months, then reversal of LTP/
regression with dendritic spine
acquired deficits
microcephaly, loss of Fingolimod Increases BDNF 1
purposeful hand use, through binding of
stereotyped S1P receptors
movements
including hand Glatiramer Increases BDNF 2
wringing, gait apraxia acetate
and ataxia, tremor,
Ketamine N-methyl-D-aspartate 1
seizures, apnea,
(NMDA) receptor
hyperventilation,
antagonist
severe intellectual
developmental
disorder and autism
spectrum disorder
Tuberous sclerosis TSC1, TSC2 Autism spectrum 1 in 6000 Everolimus Inhibits excessive 2
complex25 variants disorder, epilepsy, to 1 in 10,000 mTOR activity
behavioral
abnormalities,
epilepsy, benign
tumors, shagreen
patches/
hypopigmentation,
brain tubers, nodules,
astrocytomas
Neurofibromatosis26,27 NF1, NF2 Tumors of the 1 in 3000 to Everolimus Inhibits excessive 2

variants nerve sheath, bone 1 in 4000 mTOR activity
dysplasia, learning
disabilities, high risk
of malignancy
240 FEBRUARY 2018

the size of the data set and effective computational analysis with meaningful
interpretation remain a challenge.10
Either a large panel of candidate or known intellectual disability genes may be
screened, depending on the available resources, including bioinformatic support.
This can be done via selective pull-down or targeted exome analysis (of a
subset of the 20,000 known genes), or, increasingly frequently, whole-exome

sequencing and even whole-genome sequencing is performed. For more

information on whole-exome and whole-genome sequencing, refer to the article

Phelan-McDermid SHANK3 Neonatal hypotonia, Mecasermin Activation of Akt 2

09/2022
syndrome28 heterozygous feeding difficulties, (rhIGF-1) pathway

variants gait disturbances,
physical dysmorphic
features, absent or
delayed speech,
autism spectrum
disorder, seizures,
intellectual
developmental
disorder
Angelman Maternally Autism spectrum 1 in 15,000 Minocycline Increase LTP 2

syndrome29 inherited or disorder,
paternally movement
imprinted E3 disorder, absent
ubiquitin speech, spells of
ligase UBE3A, laughter, seizures
chromosome
15q11–15q13
Prader-Willi Paternally Infantile hypotonia, 1 in 15,000 Oxytocin Deficit in oxytocin 2

syndrome30 inherited or poor suck and to 1 in neurons
maternally failure to thrive, 30,000
imprinted rapid childhood
chromosome weight gain,
15q11–15q13, intellectual
affecting developmental
genes for a disorder,
family of six hypogonadism,
ribonuclear short stature
proteins
BDNF = brain-derived neurotrophic factor; ERK = extracellular signal-regulated kinase; FMRP = fragile X mental retardation protein; GABA =
g-aminobutyric acid; GSK3B = glycogen synthase kinase 3 beta; LTP = long-term potentiation; mGluR5 = metabotropic glutamate receptor 5;
MMP9 = matrix metallopeptidase 9; mTOR = mechanistic target of rapamycin; NAM = negative allosteric modulator; S1P = sphingosine 1-phosphate.
a
Modified with permission from van Karnebeek CD, et al, Pediatr Neurol.15 © 2016 Elsevier Inc.
“Genetic Diagnostics for Neurologists” by Laura Silveira-Moriyama, MD, PhD,

and Alex R. Paciorkowski, MD,32 in this issue of Continuum.
Both whole-exome sequencing and whole-genome sequencing have the
potential to identify “new” genes that cause or result in intellectual developmental
disorder; however, the number of variants that may be identified in each case can
prove difficult to interpret.33,34 Trio analysis, which results from screening of

the patient’s parents (at a minimum), enables variant interpretation, especially

as the majority of intellectual developmental disorder causal variants arise
de novo.10,35
The typical result of untargeted whole-exome/whole-genome sequencing is a
very long list of potentially causative variants in different genes. Identification of
the needle(s) in the haystack requires a close collaboration between the clinical
team and the bioinformaticians with detailed clinical phenotypic information.
Depending on the approach, the gene list might be narrowed down to all
currently known human disease genes listed in the Online Mendelian Inheritance
in Man (OMIM) database versus a broader approach that could include all
20,000 genes and thus include discovery of novel candidate genes.10,35 Also, the
laboratory can choose to broaden the informatics to variants identified in
regulatory and untranscribed or untranslated regions of a specific intellectual
09/2022
developmental disorder gene. These sequence changes, however, are extremely

difficult to identify as they do not fall in the open reading frame, and quantitating
mRNA levels might be the only way to detect their effect. Bioinformatics
pipelines will prioritize variants based on several characteristics: mode of
inheritance, function and topology of the gene (OMIM listing), frequency in
population databases such as Exome Aggregation Consortium, reports of
pathogenicity in other patients with the same phenotype, and predicted impact
on protein function as well as any experimental and model organism data.34,36
The process can be automatized with software packages and programming,
but manual inspection and discussion are almost always needed. Sanger
sequencing confirmation of segregation with disease within a family is an
absolute must.
The American College of Medical Genetics and Genomics and the Association
for Molecular Pathology recently published an important set of standards and
guidelines for the interpretation of sequence variants, with the main goal of
improving and standardizing the pathogenicity classification of genomic variants
by assessing and weighting the strength of the available genetic evidence.37
Sharing of data with entry of variants and phenotypes into open-source
databases is crucial for continued improvement of variant interpretation processes
and understanding of the genetic basis of intellectual developmental disorder.38
Blended phenotypes due to two or more independent genetic defects have been
reported in a subset of patients with intellectual developmental disorder, so one
should not stop analyses of available genomic data prematurely, especially if the
phenotype deviates from reports in the literature for that specific condition.34
A substantial percentage of patients remain for whom a diagnosis is not
established even after applying these novel technologies. Likely at play here are
hitherto-unrecognized intellectual developmental disorder genes, intronic and
regulatory variants, polygenic models with single-nucleotide variants and
chromosomal copy number variants, methylation/imprinting abnormalities,
and multifactorial (gene-environment interactions) etiologies.9,10 Through
integration of functional data sets, such as expression data, functional annotation,
242 FEBRUARY 2018

sequence information, and the biomedical literature, systems biology can KEY POINTS
reconstruct the genetic networks and molecular pathways necessary for
● For meaningful
the different physiologic and pathologic conditions. This accelerates the interpretation of genomic
interpretation of monogenic as well as complex neurodevelopmental data, careful clinical
conditions.10,38,39 phenotyping with a
differential diagnosis or
hypotheses for involved
DIAGNOSTIC YIELD AND MANAGEMENT pathways are essential,

The diagnostic yield for each type of genetic investigation tends to increase along with close
over time, given improvements in specificity and sensitivity as well as the communication between
discovery of novel human disease genes related to intellectual developmental the clinical and
bioinformatics team.
disorder and the availability of detectable biomarkers. Two literature reviews on
this topic elegantly illustrate this change between 2005 and 2016.10,22 Aside from ● If the diagnostic workup
Down syndrome (which represents 6% to 8% of all intellectual developmental is negative, the clinician
disorders), in patients with moderate to severe intellectual developmental should reevaluate the
patient a few years later.
disorders, conventional karyotyping, a routine diagnostic test in the 1970s,
New diagnostic clues may
provided a conclusive diagnosis in 3% to 6.5% of intellectual disability cases. The have arisen, and new
diagnostic yield increased by 6% to 10% after the introduction of both Sanger human disease genes
sequencing and FISH in the 1990s. In the early 2000s, chromosomal microarray related to intellectual
was introduced, increasing the diagnostic yield by another 15% to 23%. The developmental disorder are
09/2022
increasingly being
introduction of whole-exome sequencing in 2010 added a diagnostic yield of 24% identified.
to 33%, and a first pilot study using whole-exome sequencing added a further 26%
in 2014. Taken together, the overall diagnostic yield becomes 55% to 70% for ● The number of rare
moderate to severe intellectual disability. For cases that remain without a conditions underlying
diagnosis, the wait-and-see approach is important for two reasons. First, features disorder that are amenable
evolve over time; particular syndromic phenotypes can become recognizable to treatment is steadily
with age, and new clues may have arisen. Second, reanalysis of whole-exome increasing, and, for many
sequencing data using new pipelines and additional literature cases on novel indications, therapies are
still under development.
phenotypes and human disease genes related to intellectual developmental
disorder is often fruitful.
A 2014 study on neurometabolic gene discovery showed that highly detailed
phenotyping and close teamwork between the clinician, bioinformatician, and
laboratory scientist can provide even higher diagnostic yields and discoveries
(around 90% if candidate genes are included), independent of the severity of the
intellectual developmental disability.34 Importantly, the genomic diagnosis
impacted management beyond genetic counseling in 43% of cases, enabling an
intervention aimed to improve or alleviate pathophysiology (such as initiation
of a medical diet, vitamin supplements, pharmacologic treatment, hematopoietic
stem cell transplantation) or measures to prevent metabolic decompensations
(eg, sick day formula, avoidance disease triggers, malignancy screening).
This kind of personalized medicine, informed by genomic diagnosis and
related pathophysiologic insights, is becoming a reality in intellectual
developmental disorder.
EMERGING THERAPIES
Intellectual developmental disorders have a highly heterogeneous etiology, with
many very low-incidence, high-impact single-gene or contiguous-gene
syndrome causes; also emerging are combinations of common, low-impact
genetic risk factors operating in concert.9 Novel genetic etiologies of intellectual
developmental disorder are increasingly identified based on rapid sequencing
methods. Essential next steps include mapping disorders onto shared cellular
pathways and circuit dysfunctions targetable for novel treatment approaches,

including genetic manipulations such as adenoviral-mediated gene therapy,
protein replacement strategies, small molecule therapies targeted to key
pathways, receptor or channel ligands that alter signaling in specific neurons or
circuits, and microRNAs that can inhibit production of specific key pathway
proteins.15 These could be combined with cellular targeting of therapeutic

molecules through linkage to receptor or transporter into the CNS and individual
neurons or even subcellular organelles.
Monogenic intellectual developmental disorders, such as tuberous sclerosis
complex, fragile X syndrome, and Rett syndrome, have emerged as models in
which extensive preclinical studies of the neurobiology and synaptic mechanisms
of disease in cell lines and animals have identified compounds that target the
underlying disorder (TABLE 11-2). 15 These conditions also serve as clinical
models for translation of such targeted treatments to humans.22 Novel
disease-modifying therapies that reverse the underlying dysfunctional neural
mechanisms, combined with awareness and early diagnosis of the large and
expanding group of inborn errors of metabolism, make this an exciting time in
the treatment of intellectual developmental disorders, providing the prospect of
relief for families dealing with these challenging conditions.
09/2022
However, although many neuronal treatment targets in fragile X syndrome

and other intellectual developmental disorders have been identified and
translational work has begun, early trials (most of which have been performed in
adults) show problems with demonstrating disease modification as considerable
phenotypic heterogeneity exists and many uncertainties remain about how to
show treatment effects optimally in a clinical trial setting. Major trial design
issues regarding relevant outcomes, reliable evaluation methods, and evidence
generation will need to be resolved to demonstrate disease modification in
genetic intellectual developmental disorders. Any outcome measure selected
for a clinical trial in fragile X syndrome must be able to test a broad ability
range, overcome problems of cooperation and variable performance, be
reproducible and quantifiable, and show improvement in quality of life
and function.40
To that end, it has been acknowledged that more objective clinician-
administered and direct observational measures that address cognition and
language and have been validated for intellectual developmental disorder, as well
as biomarkers of CNS function that directly translate from animal models and
track with clinical function, are necessary to reduce placebo effect and establish
that the drug is finding its target. Increasingly, these measures are being
incorporated into new trials. Further, trial design of efficacy studies will likely
need to change focus to younger study populations, with intensive learning
interventions used within the drug and placebo groups to demonstrate comparable
enhancement of synaptic plasticity to those seen in animal models and within a
period compatible to placebo-controlled trials. Therefore, the approach to drug
development in fragile X syndrome must change so that efficacy is no longer
required in adults before being evaluated in children, different methods of global
outcomes analyses over multiple domains are developed and endorsed by
regulatory authorities, and precedents are established for embedding learning
interventions within trial designs. If these problems can be solved, treatment to
reverse the underlying disorders will eventually replace or complement supportive
treatment in intellectual developmental disorders.15
244 FEBRUARY 2018

KEY POINT
CONCLUSION
During the past decade, genetic studies have substantially improved ● Genome sequencing is
understanding of the causes of intellectual disability, and a molecular diagnosis likely to become the first-
can now be provided for most patients with severe intellectual disability. tier diagnostic test for
Further, the number of rare conditions underlying intellectual developmental disorder as soon as it
disorder that are amenable to treatment is steadily increasing, exceeding 100 becomes clinically
already, with therapies still under development for many conditions. Given available and affordable.
the opportunity to improve outcomes, when ordering tests, the diagnostician This genetic testing will
require appropriate
must weigh the diagnostic yield and treatability of potentially identified counseling, and any
conditions with available resources and the burden to the patient and family. incidental findings will
The genetic heterogeneity of intellectual developmental disorder requires need to be assessed
genome-wide approaches, and genome sequencing is likely to become the without compromising a
child’s right to an open
first-tier diagnostic test for intellectual developmental disorder as soon as it future.
becomes clinically available and affordable. This genetic testing will require
appropriate counseling, and any incidental findings will need to be assessed
without compromising a child’s right to an open future. Coverage of the genes
encoding the treatable conditions must be optimal so they are not missed. Most
important, detailed clinical phenotyping and formulation of a strong differential
diagnosis, together with close communication between the clinician and
09/2022
bioinformatics team, are essential for meaningful interpretation of

genomic/exomic data. Much work remains to be done in identifying all genes
causative for intellectual developmental disorder, a process during which data
sharing and collaboration are key. The future generation of diagnosticians
must be trained so that clinical skills are not lost, as big data will not yield
diagnoses on their own, but rather require detailed phenotypic input and clinical
characterization. The patient is so much more than the one gene or chromosomal
variant that is not functioning. Once diagnosis is established, the next chapter
begins, with management, treatment, and prevention. The latter might well be
achieved through expansion of newborn screening programs for early detection
and minimization of disease symptoms in affected children. Given that de novo
mutations are the main cause of severe intellectual developmental disorder,
carrier screening will not be a broadly useful strategy to prevent inherited
mutations. Instead, preventive approaches should focus on promoting early child
bearing to lower the risk of chromosomal abnormalities or freezing of sperm
for future pregnancies.10 The future is bright, with the group of treatable forms
of genetic intellectual developmental disorder steadily expanding through
integrated genomic/exomic technologies, promising therapeutic advances
including gene editing, and innovative trial methodologies for rare diseases.41
These scientific advances are becoming a clinical reality for an increasing number
of affected individuals and families, albeit slowly, further emphasizing the
importance of a timely diagnosis and continued genetic studies in the field of
intellectual developmental disorder.
ACKNOWLEDGMENT
The author gratefully acknowledges the patients and families who inspire and
educate her; Dr Sylvia Stockler-Ipsiroglu (University of British Columbia,
Vancouver, British Columbia, Canada) and Dr E. Berry-Kravis (Rush University,
Chicago, Illinois) for their contributions to previous work on treatable inborn
errors of metabolism and neurodevelopmental conditions, respectively,
summarized here; and Ms Aisha Ghani and Ms Claire Sowerbutt for research
and writing support.
USEFUL WEBSITES
CLINVAR IEMBASE
ClinVar aggregates information about genomic IEMbase is a knowledge base and diagnostic tool
variation and its relationship to human health. for inborn errors of metabolism using clinical or
ncbi.nlm.nih.gov/clinvar/ biochemical features.
iembase.org
EXOME AGGREGATION CONSORTIUM
TREATABLE INTELLECTUAL DISABILITY
The Exome Aggregation Consortium website
The Treatable Intellectual Disability application and
aggregates and harmonizes exome
website provides an interactive tool for the clinician
sequencing data.
focused on treatable inborn errors of metabolism
exac.broadinstitute.org
causing intellectual developmental disorder.
treatable-id.org
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REVIEW ARTICLE
Genetic Diagnostics for
Neurologists

I NT E R V I E W A V AI L A B L E
ONLINE
By Laura Silveira-Moriyama, MD, PhD; Alex R. Paciorkowski, MD
ABSTRACT
PURPOSE OF REVIEW: This article puts advances in the field of neurogenetics
into context and provides a quick review of the broad concepts necessary
for current practice in neurology.
RECENT FINDINGS: The exponential growth of genetic testing is due to its

increased speed and decreasing cost, and it is now a routine part of the
clinical care for a number of neurologic patients. In addition, phenotypic
pleiotropy (mutations in the same gene causing very disparate phenotypes)
and genetic heterogeneity (the same clinical phenotype resulting from
09/2022
mutations in different genes) are now known to exist in a number of

conditions, adding an additional layer of complexity for genetic testing in
these disorders.
SUMMARY: Although the growing complexity of technical knowledge in the

ordering and interpretation of genetic tests makes it necessary for
CITE AS:
CONTINUUM (MINNEAP MINN) neurologists to consult medical geneticists, limitations in the availability of
2018;24(1, CHILD NEUROLOGY):18–36. such professionals often means neurologists will be on the front line
dealing with suspected or confirmed neurogenetic conditions. The growing
Dr Alex R. Paciorkowski,
availability of broad genetic testing through chromosomal microarray and
University of Rochester Medical next-generation sequencing and the expanded phenotypic spectrum of
Center, Child Neurology, 601 many conditions has implications for genetic counseling and medical
Elmwood Ave, Rochester, NY
14642, Alex_Paciorkowski@urmc. management. This article discusses the various forms of genetic variability
rochester.edu. and how to test for each of them. It also provides an update on the most
common forms of neurologic presentations of genetic disease and
RELATIONSHIP DISCLOSURE:
Dr Silveira-Moriyama has a review of testing strategies.
received research/grant support
from Conselho Nacional De
Desenvolvimento E Pesquisa and
Teva Pharmaceutical Industries
Ltd. Dr Paciorkowski receives INTRODUCTION
A
research/grant support from the dvances in genetic testing technologies over the past 2 decades
National Institutes of
Health/National Institute of have revolutionized our ability to make specific molecular
Neurological Disorders and diagnoses in patients presenting with neurologic illness. Although
Stroke (K08 NS078054).
this has brought a wealth of information and has already influenced
UNLABELED USE OF the medical management of many neurologic conditions, it also
PRODUCTS/INVESTIGATIONAL presents a challenge for the practicing neurologist to stay updated in the rapidly
USE DISCLOSURE:
Drs Silveira-Moriyama and
evolving field of neurogenetics.
Paciorkowski report no With the understanding of the surprising scope of variation inherent in the
disclosures. human genome, new technologies have come to the fore that allow clinicians to
© 2018 American Academy of diagnose—and increasingly treat—entire new classes of neurologic disease. With
Neurology. this has come a new vocabulary, and while the basic concepts of human genetics
18 FEBRUARY 2018
may not have changed over the decades, the way we talk about these concepts and KEY POINTS
their relevance to clinical medicine have. The goal of this article is to introduce
● The growing complexity
these concepts, together with the new vocabulary, in the context of practical of technical knowledge
approaches to the use of genetic diagnostic technologies in the care of our patients. involved in ordering and
interpreting genetic tests
NEUROLOGY AND MEDICAL GENETICS makes the opinion of a

medical genetics specialist

While neurologists will see and care for patients with genetic conditions with
desirable in the many cases
regularity, an entire field of medical genetics exists for a reason. Most neurologists of suspected neurogenetic
have no training in genetic diagnostics. Some will be familiar with the more conditions.
common neurogenetic conditions (mainly those within their field of subspecialty)
or with specific genetic conditions they have encountered before. Neurologists ● The shortage of medical
genetics specialists
should not feel pressed to embark upon genetic diagnostic evaluations with little makes it necessary for
ability to explain what results they expect to find and how to interpret the results neurologists to be familiar
when they do arrive. Neurologists do not expect geneticists to determine who with basic concepts in
needs an EEG or EMG, much less to interpret the results. Yet, neurologists medical genetics that will
enable handling some
routinely feel they need to marshal themselves to explore the genome, sometimes cases and referring when
without a road map or compass and often without speaking the local language. appropriate.
Ideally, consultation with a geneticist should be actively pursued when suspecting
or managing a neurogenetic condition, not only to prevent an illogical sequence of ● Before and after genetic
09/2022
testing, it is imperative to
often expensive unnecessary diagnostic evaluations but also to avoid missing the
conduct appropriate
correct diagnosis or appropriate management of patients. But, if a shortage of genetic counseling. It is
properly trained neurologists exists, as occurs in many regions of the world, the ideal to have a specialized
shortage of geneticists is usually even more acute, and many parts of the world genetic counselor provide
this service, but in many
may not have enough medical geneticists for the foreseeable future. This article
limited-resource settings,
cannot solve this problem but tries to mitigate it by providing neurologists with this responsibility lies with
basic tools to communicate with colleagues, quickly get updated on conditions, the neurologist.
and discuss with patients the need for genetics referral and testing.
One essential component involved in all genetic testing is genetic counseling. ● Genetic counseling for
massive gene sequencing
While standards of training for genetic counselors vary widely in different (such as whole-exome
countries, even in developed nations, underserved areas exist in which the sequencing) should include
services of a genetic counselor are not available and either the neurologist or the the expected and
medical geneticist will perform pretest and posttest counseling. Benefits, unexpected outcomes of
testing, the likelihood and
limitations, and potential complications of genetic testing should be discussed type of incidental findings,
with patients, parents, or guardians, and written informed consent should be and which results will or
obtained for specific tests ordered. The benefits of genetic testing may include will not be disclosed.
directly impacting medical management strategies, providing specific
information on recurrence risk and reproductive counseling, providing labels that
enable access to services, and giving access to educational material and support
groups. Limitations of the specific test should be made clear, including the fact
that more targeted testing may miss various differential diagnoses, while broader
testing strategies (eg, chromosomal microarray, exome sequencing) increase the
likelihood of unexpected or unclear results. Incidental findings may have an
impact on family planning, medical screening, and medical management, and
patients should be given the opportunity to waive the disclosure of these results.
The direct impact of genetic results on medical management includes
preventing unnecessary further tests (including invasive and expensive tests),
the organization of appropriate investigations and referrals for potential
comorbidities (eg, specific ophthalmologic, cardiologic, and orthopedic
complications that are frequent in neurogenetic conditions), targeting of medical
therapies based on the genotype, and establishing eligibility for participation in
GENETIC DIAGNOSTICS
KEY POINTS ongoing treatment trials. As genetic disorders are rare, management is often based
on anecdotal reports or small case series. National and international registries are
● Knowledge about the
relationship between
trying to fill this gap, making management guidelines and clinical trials in rare
genotype (what the DNA genetic conditions a reality. In selected instances, already available medical
looks like) and phenotype therapy might be guided by genotype. In epilepsy, for example, the genotype
(what the patient looks like) might suggest that one strategy or medication could be more effective in
has changed dramatically in

controlling seizures (eg, the efficacy of the ketogenic diet in glucose transporter 1
the past decade.
[GLUT1] deficiency1 or avoidance of carbamazepine in Dravet syndrome).2
● Mutations in various Neurotransmitter diseases manifesting with dystonia or parkinsonism might
different genes can cause respond differently to different drugs: patients with mutations in guanosine
very similar phenotypes. triphosphate cyclohydrolase 1 (GCH1) tend to respond to levodopa, while for
This is called genetic
heterogeneity. those with mutations on aromatic L-amino acid decarboxylase (AADC),
levodopa can be detrimental.3 More impressively, while the various attempts at
● Most genes are now genetic therapy for Duchenne muscular dystrophy have shown limited clinical
believed to be associated benefit thus far,4 antisense oligonucleotide therapy is now being implemented
with varied phenotypes
(phenotypic pleiotropy).
for spinal muscular atrophy with dramatic and promising results, with the
possibility that it may be further extended to other neurologic conditions.5
Despite the complexity of genetic tests and the practical limitations of
having them performed, gene testing is currently part of standard care for many
09/2022
neurologic conditions that are discussed later in this article, and it is necessary for
neurologists to push through the existing barriers and try to provide the best
medical care for patients affected by these conditions.
BASIC CONCEPTS OF GENOTYPE-PHENOTYPE CORRELATIONS

Over the past decades, a wealth of information has been obtained that
associates specific genotypes with neurologic disease. With these data, our
understanding of genotype-phenotype correlations has also matured. The
range of genotype-phenotype correlations is summarized in FIGURE 1-1. Down
syndrome, caused by trisomy of chromosome 21, was first reported in 19596 and
is an excellent example of a disorder that often exhibits classic genotype-phenotype
concordance (FIGURE 1-1A ). However, other disorders recognized as hereditary
or familial did not always behave so properly. Before gene sequencing was
widespread, genetic diseases were classified by linkage to certain loci, or general
regions of chromosomes. To search for loci, researchers identified large families in
which members had striking and easily identifiable phenotypes. In these relatively
simple scenarios, the expectation emerged that all genetic disorders would exhibit
classic genotype-phenotype concordance. For some conditions, different loci could
be mapped in different families, and it became clear that the genetic basis for these
phenotypes could be heterogeneous; therefore, these conditions are said to have
genetic heterogeneity (FIGURE 1-1B). The loci for phenotypes with genetic
heterogeneity were often organized by a letter code for the phenotype and then
numbered in order of discovery. For example, the first locus described for
familial dystonia became DYT1, followed by DYT2, DYT3, and so forth; likewise,
for parkinsonism, a series of PARK loci were created (eg, PARK1, PARK2). As
linkage was not based directly upon actual genomic features, some loci were not
confirmed, resulting in discontinuity and confusion in this organization system
and difficulties for the clinicians dealing with it.7 With more specific identification
of genetic causation in larger numbers of patients, most of the vocabulary of the
linkage era has been mercifully replaced with language that is based on genomic
nucleotide sequence and associated features. The ability to rapidly sequence large
20 FEBRUARY 2018
09/2022
FIGURE 1-1
Genotype-phenotype correlations. A, Classic genotype-phenotype concordance. B,
Genetic heterogeneity, when the same or similar phenotype can be caused by mutations
in different genes. C, Phenotypic pleiotropy, when mutations in one single gene can
cause different phenotypes.
numbers of genes in large numbers of patients has allowed phenotypes that at first
seem to be unrelated to be explained by mutations within the same gene. For
example, at least three well-characterized disparate phenotypes have been
associated with sequence variations in ATP1A3: alternating hemiplegia of
childhood, rapid-onset dystonia parkinsonism, and severe infantile epilepsy.
Another example is sequence variations in TUBB4A, causing hypomyelination
with atrophy of the basal ganglia and cerebellum or the completely different
phenotype whispering dysphonia (also known as DYT4). These observations have
become all too common and are termed phenotypic pleiotropy (FIGURE 1-1C).
As clinical neurogenetics progresses and more intermediate phenotypes are
described, a notion is growing that most neurogenetic conditions present with
GENETIC DIAGNOSTICS
KEY POINT a phenotypic spectrum, including classic phenotypes, pleiotropic distinct

phenotypes with marked clinical characteristics, and more intermediate
● Genetic variability may be
normal, predispose the
phenotypes that would not fit into the aforementioned types of presentation.
patient to medical
conditions (risk variants), UNDERSTANDING AND TESTING FOR GENETIC VARIABILITY
cause medical conditions

The human genome has a range of variation, roughly moving from variations large
(pathogenic variants), or
need further studies to enough to be seen on a karyotype to smaller ones consisting of a single nucleotide
clarify its nature (variant of or methylation change. Categories of variation and the appropriate technologies to
unknown significance). identify them are summarized in TABLE 1-1, FIGURE 1-2, and FIGURE 1-3.
Interpretation of variants of
unknown significance
A correlation exists between pathogenicity and the size of genomic variations and
requires the opinion of a population frequency: large and rare variations are more likely to be pathogenic.8
medical genetics specialist. Genomic length is measured in base pairs, one unit consisting of two
TABLE 1-1 Categories of Genomic Variations and the Best Testing

Technology for Their Detectiona
09/2022
Genomic Variation What It Is Best Test Also Detected By
Chromosomal A chromosomal structural Karyotype Chromosomal

aneuploidy abnormality, ie trisomy or microarray
monosomy
Balanced A chromosomal structural Karyotype NA

chromosomal rearrangement in which
translocation no loss or gain of genetic
material occurs
Unbalanced A chromosomal structural Chromosomal Karyotype

chromosomal rearrangement in which microarray
translocation loss or gain of genetic
material occurs
Chromosomal copy A region of a chromosome Chromosomal Karyotype (if >5 Mb)

number variation where genetic material is microarray
duplicated or deleted
Chromosomal Addition of methyl group Methylation- NA

methylation to cytosine; the mechanism sensitive analysis
of imprinting
Gene and exon-level Deletion or duplication of Multiplex Fluorescence in

deletions and entire gene or of specific ligation-dependent situ hybridization
duplication exons within a gene probe amplification (in some cases)
Short tandem repeat Run of repeated DNA Southern blot NA
sequence motifs
Single-nucleotide A single change in the Sequencing NA

variant nucleotide sequence
Indel Insertion or deletion of one Sequencing NA

or more nucleotides into
the DNA sequence
DNA = deoxyribonucleic acid; Mb = megabase; NA = not applicable.

a
Many (but not all) genomic variations can also be detected by other technologies. Please see article text
for discussion of why one modality might be preferred over another.
22 FEBRUARY 2018
FIGURE 1-2
09/2022
Genetic variability at the chromosome level. Summary of the main types of abnormalities at
the chromosome level and how likely they are to be identified by karyotype, chromosomal
microarray (CMA), and fluorescence in situ hybridization (FISH). Deletion or duplication of
an entire chromosome is called chromosomal aneuploidy and can be detected using traditional
karyotype or chromosomal microarray. When parts of one chromosome break off and adhere to
another chromosome, the event is termed translocation, which is balanced when it does not
involve a loss of genomic material or unbalanced when otherwise. Unbalanced translocations
can be identified by karyotype or chromosomal microarray, but balanced translocations will be
missed by chromosomal microarray. Loss or duplication of genomic information can happen at
the end of a chromosome (terminal or subtelomeric deletion/duplication) or from the middle of
a chromosome (interstitial deletion/duplication). Karyotype can only visualize large changes
(greater than 5,000,000 base pairs), while chromosomal microarray has higher resolution (greater
than 100,000 base pairs). FISH is still often used to confirm copy number events found on
chromosomal microarray.
complementary nucleotides in the opposing DNA strands. Deletions (or duplications)

of megabase pairs (Mb), for example, are more likely to be pathogenic than deletions
of a few kilobase pairs (kb). Some regions of the chromosome will be duplicated or
deleted in a large proportion of normal subjects; therefore, even a very large event
is assumed to be nonpathogenic if very common. The largest chromosome-level
events are deletion or duplication of an entire chromosome, resulting in monosomy
(if a deletion) or trisomy (if a duplication). This is called chromosomal aneuploidy
and can be detected using traditional karyotype. But since chromosomal
aneuploidy changes the copy number of an entire chromosome, this event can also
be detected via chromosomal microarray, a technique that detects the dose of
genetic material with high resolution (greater than 100 kb) and would also identify
larger events. Sometimes parts of one chromosome break off and adhere to
another chromosome, an event termed translocation. When this event does not
involve a loss of genomic material, the term balanced chromosomal translocation is
used. Balanced chromosomal translocation can be detected by karyotype because
the translocation changes the chromosome visually, but since no overall
change occurs in the copy number of genomic material and only its location
changes, chromosomal microarray is unable to detect balanced chromosomal
GENETIC DIAGNOSTICS
09/2022
FIGURE 1-3
Genetic variability at the gene level. Summary of the main types of abnormalities at the gene
level and the available genetic tests more likely to identify them. Genes are formed by sequences
of coding regions (exons, represented as thick colored parts) or noncoding regions (introns,
thin lines connecting the exons). An exon can be duplicated or deleted, causing an abnormal
protein to be produced, which is often symptomatic. These events are not detected by sequencing
and require multiplex ligation-dependent probe amplification (MLPA) for detection. Within
an exon, nucleotide-level events can occur, one being an increased number of nucleotides
in the form of an amplification of the number of repeats in a naturally occurring short tandem
repeat sequence. These events are not reliably detected by sequencing techniques and
require DNA Southern blot for diagnosis. When a single nucleotide is changed (single-nucleotide
variant [SNV]) or a deletion or duplication occurs within the exon (indels), the change can
be detected by sequencing techniques such as Sanger sequencing or massive parallel
sequencing (also called next-generation sequencing). Less commonly, the change underlying
the phenotype may be abnormal methylation, in which cytosine methylation inherited from
one of the parents is abnormal, and the diagnosis will require methylation studies.
translocations. This is an important point; balanced chromosomal translocation is

the one chromosome-level event for which karyotype remains superior to
chromosomal microarray in diagnostic performance. Balanced translocations may
be clinically relevant if the chromosomal breakage site is in the middle of
a gene and disrupts function of that gene. If genomic material is lost during
a translocation event, the term unbalanced chromosomal translocation is used.
Unbalanced translocations may be detected both on karyotype and on
chromosomal microarray.
Genomic information can be lost in nontranslocation events as well. If a part of a
chromosome breaks off and is lost at the end of a chromosome, it is a referred to as
a terminal (or subtelomeric) deletion. Alternatively, genomic material can be lost from
the middle of a chromosome, which is referred to as an interstitial deletion. When
genomic material is duplicated at the end of a chromosome or duplicated in the
middle of a chromosome, the terms terminal (or subtelomeric) duplication and
24 FEBRUARY 2018
interstitial duplication are used, respectively. Both deletions and duplications are part KEY POINTS
of normal chromosomal biology and are one type of “copy number events,”
● Multiplex ligation-
which are changes in copy number of genomic material, whether that material is dependent probe
coding or noncoding, or large or small. Larger copy number events are more likely to amplification detects dose
be clinically relevant. Importantly, karyotype can only visualize deletions and changes within a gene,
duplications larger than 5 Mb. Chromosomal microarray is required to identify copy chromosomal microarray
detects dose changes

number variations below 5 Mb down to a resolution of around 100 kb, below
affecting a small part of the
which most clinical laboratories do not call copy number variations as these are chromosome (greater than
inevitably not likely to be clinically relevant and are usually benign variations 100,000 base pairs), while
inherited from unaffected parents. An older technology, fluorescence in situ karyotyping only detects
large changes (greater than
hybridization (FISH) analysis, is an outgrowth of karyotype technology and is still
5,000,000 base pairs).
often used to confirm copy number events found on chromosomal microarray.
Genetic events at the exon level are too small to be detected by karyotype or ● Dosage abnormalities
chromosomal microarray and require a different molecular approach. Genes are can affect only a single
constructed of exons (coding regions) and introns (noncoding), and disease can gene or a whole region of
the chromosome or be in the
result from copy number events at the exon level. Gain of an extra exon is termed an form of an increased number
exon-level duplication, and loss of an exon is termed an exon-level deletion. In of repeats in a given
general, these duplications and deletions require multiplex ligation-dependent sequence that normally is
probe amplification (MLPA) for detection, although, in some cases, FISH probes repeated up to a certain
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number.
may serve the same purpose.
In any healthy subject, the human genome contains many thousands of repeat ● Southern blot detects an
regions made up of units of three, four, or more nucleotide repeats, which are increased number of
called short tandem repeats. Some of these regions are in exons (regions within repeats in a particular
sequence. It is specific for
a gene that are transcribed into mRNA, which is subsequently translated into
the sequence examined, so
protein amino acid sequence), some are in introns (regions within a gene that are if more than one gene with
transcribed into mRNA but are then “spliced out” and not translated into protein repeats can cause the
sequence), some are in untranslated regions of genes (regions at the beginning phenotype observed, a
and end of a gene that are not translated), and many are in intergenic noncoding panel of Southern blot for
various genes can be
regions (regions between known genes, which are not transcribed or translated). requested (eg, testing for
When the cell divides, the number of repeats can increase (expansion) or various spinocerebellar
decrease (contraction) in these short tandem repeats. Many neurologic disorders, ataxias at the same time).
including fragile X syndrome, many spinocerebellar ataxias, myotonic
● In addition to gene
dystrophies, and Huntington disease, are caused by such repeat expansions. sequence and gene dose,
These repeat expansions are usually too small to be detected by karyotype, other factors affect the
chromosomal microarray, or even FISH probes. For technical reasons, they are production of proteins
not reliably identified using sequencing technologies. Therefore, the best test for (epigenetic factors). An
important factor affecting
identifying repeat expansions remains the DNA Southern blot.
gene expression as a
An additional mechanism of genomic variation is methylation. The methylation disease mechanism is
of cytosines usually silences the region of DNA where it occurs, and the pattern of methylation of DNA.
methylation is inherited in a maternal or paternal pattern depending on whether
the chromosome in question comes from the mother or father. This mediates the
curious phenomenon of imprinting, whereby the expression of a given phenotype
is based upon the parental origin of a chromosomal methylation pattern. Patients
have Angelman syndrome if the maternal methylation pattern on chromosome
15q11q13 is missing9 or Prader-Willi syndrome if the paternal methylation pattern
on chromosome 15q11q13 is missing.10 Testing for methylation requires
methylation analysis, which is the test of choice in diagnosing these syndromes as
well as other rarer conditions characterized by imprinting.
Nucleotides can be inserted and deleted within exons in a nonrepeat manner as
well. This can occur as single-nucleotide insertions or as an insertion of two,
GENETIC DIAGNOSTICS
KEY POINTS three, or even more nucleotides. These insertions and deletions are collectively
termed indels and are a very frequent event in the genome. When the number of
● The majority of
neurogenetic conditions
nucleotides inserted or deleted is not a multiple of three, it results in a change
described thus far are in the way the ribosomes read the RNA derived from this DNA and is called a
caused by sequence frameshift mutation: an erroneous sequence of amino acids coded by the DNA
abnormalities that can be downstream of the offending indel. If the indel is a multiple of three, a nonframeshift
detected by DNA
event occurs, and only the amino acids coded by the indel are affected; this may be
sequencing.
tolerated or not depending on the specific biology of the protein produced by the
● Genomic data, including affected gene. Indels of either type are generally detected well by traditional Sanger
the sequence and dose of sequencing, provided the insertion is smaller than 700 bp to 1000 bp, because larger
genes, needs to be analyzed insertions may encumber the polymerase chain reaction (PCR) phase of the
and interpreted to yield
any meaningful clinical technique. Indels smaller than 100 bp are, in general, also detected by massively
result. Interpretation of these parallel sequencing technologies (so called next-generation sequencing) when
results requires combined with the more recent versions of variant detection software.
the expertise of When one single nucleotide is replaced in the DNA sequence, this event is
bioinformaticians and
geneticists.
termed a single-nucleotide variant, which may be benign, pathogenic, or of
uncertain significance. When it is demonstrated scientifically that a
single-nucleotide variant is benign (ie, not associated with any disease and
usually present in a percentage of healthy individuals), the term single-nucleotide
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polymorphism is appropriate. When it is demonstrated scientifically that a

single-nucleotide variant is pathogenic (ie, associated with a disease and usually
absent from healthy individuals) the term mutation has been employed, although
the more currently preferred term is now pathogenic sequence variation. Finally,
there exist single-nucleotide variants that are suspect, which have not yet been
demonstrated scientifically to be benign or pathogenic. These single-nucleotide
variants have been given the label variant of uncertain significance until, with
scientific progress, they are classified as either benign or pathogenic.
Single-nucleotide variants that occur within the coding region of genes may
alter the amino acid codon produced by that sequence of DNA or have no effect
whatsoever. Single-nucleotide variants that alter the amino acid are termed
nonsynonymous variants (also known as missense variants), while those that do not
result in amino acid change are termed synonymous variants. Sometimes a codon is
altered so that a premature stop is introduced. This is termed a nonsense variant
and usually results in an mRNA molecule that is degraded via a process called
nonsense-mediated decay, which results in no protein product or, in some cases,
a truncated protein. Other single-nucleotide variants occur within exon-intron
boundaries and, while they do not produce a change in amino acid sequence, can
disrupt splicing and result in abnormal inclusion or exclusion of an entire exon.
Single-nucleotide variants can also occur within certain untranslated regions of a
gene but alter gene translation. Finally, many single-nucleotide variants occur in
the noncoding intergenic regions of the genome. Analysis of these single-nucleotide
variants is one of the remaining frontiers of genomics. In theory, single-nucleotide
variants (and indels) that alter highly conserved regulatory noncoding regions
may alter expression of specific genes or cause other genomic alterations.
However, this biology is unproven in most cases, and these regions are not
sequenced clinically and are only available through genome sequencing.
Single-nucleotide variants are an ideal class of variation to be detected by
sequencing. Sanger sequencing techniques, in which one gene at a time is generally
amplified and then sequenced, has been largely displaced by massively parallel
sequencing technology. Using massively parallel sequencing technology, total
26 FEBRUARY 2018
genomic DNA is fragmented randomly into roughly 100-bp pieces and then
subjected to a library capture in which molecular baits (short complementary
sequences) pull down the genomic regions of interest for sequencing. In the case of
exome sequencing, which targets only coding regions, the library capture contains
baits for the exons of roughly all 20,000 known genes. Noncoding regions are
therefore not sequenced. Once the pieces of DNA are pulled, they are sequenced by a
huge number of sequencers simultaneously; although this technique is referred to as

massively parallel sequencing, the term next-generation sequencing is also still used.
The many small pieces of sequence produced are like a puzzle that must then
be assembled and mapped to the known sequence of the human genome, with
variations identified and statistical corrections applied. Next, the results must be
annotated so that the end product is a list of all variations in each gene, where the
variant is located, whether it is synonymous or nonsynonymous, whether it is
common or rare, and even whether the variant is predicted to be deleterious or
benign. This analysis requires high-performance computing, and interpretation
requires the expertise of bioinformaticians and geneticists.
TABLE 1-2 summarizes the main sequencing techniques currently used and
their strengths and weaknesses. It is important to understand that massively
parallel sequencing does not detect most classes of genomic variation. In general,
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all genomic variation in which the sequence of DNA is not altered will be invisible
to any sequencing technology. Therefore, chromosomal aneuploidy, translocations,
and chromosomal copy number variants are not detected by current sequencing
technology. Likewise, exon-level deletions and duplications are not visible by
sequencing, since they change the copy number of an exon, not the nucleotide
Practical Aspects of Common Commercially Available Gene TABLE 1-2

Sequencing Testing Methods
Test Main Strengths Main Weaknesses
Single-gene sequencing Cheap, quick, and easy to Not useful for cases with
interpret; as it usually targets atypical phenotype; not
a known disease gene, less practical for phenotypes
likely to return unexpected with genetic heterogeneity
findings
Gene panel sequencing When multiple genes can Coverage and cost of gene
(massively parallel methods) cause similar phenotypes, panels vary significantly, and
panel testing is usually decision to request might
cheaper than testing for require in-depth knowledge
each gene sequentially of genotype-phenotype
correlations for that condition
Exome sequencing Assays approximately 20,000 Targeting of exome analysis

(massively parallel methods) genes simultaneously, making by the testing laboratory is
this test most efficient performed according to
for disorders with genetic clinical information provided,
heterogeneity or for atypical so thorough phenotyping and
phenotypes appropriate interaction with
medical genetics is necessary
Genome sequencing Extends coverage for Currently reserved for

(massively parallel methods) noncoding regions research settings
GENETIC DIAGNOSTICS
sequence. Instead, the remaining (normal) allele will be sequenced, providing a

false-negative sequencing result. Repeat expansions are generally not detectable
by massively parallel sequencing if the repeat expansion is greater than 100 bp.
This is because the newer sequencing technologies work off 100-bp fragments that
must then be mapped back after sequencing to the reference human genome. If
the repeat region is greater than 100 bp, the fragment containing only repeat
sequencing products cannot be mapped to a unique location in the genome.

Therefore, even with the recent advances in sequencing technology, diagnostic
tests such as karyotype, chromosomal microarray, FISH, MLPA, and Southern
blot will remain valuable techniques for the foreseeable future.
Given the rapidity with which new genetic causes of neurologic conditions are
being discovered, exome sequencing is probably the most cost-effective approach
to diagnosis in phenotypes with great genetic heterogeneity, because the coverage
is extensive and data can be reanalyzed at a later date as more genes are discovered
and the significance of variants of unknown significance is clarified. However, one
weakness of exome sequencing is the inability to detect exon-level deletions and
duplications. Deletion/duplication testing is sometimes offered as part of more
focused massively parallel panels, but one may need to determine if a particular
laboratory offers this technique. To optimize cost-effectiveness, it is important to
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consider that genetic causes of more early and dramatic phenotypes (such as global
developmental delay and intellectual disability, epileptic encephalopathy, and
infantile neurodegeneration) are often de novo in inheritance pattern; therefore, it
is relevant to know if parental DNA could be tested to clarify variants of unknown
significance that are difficult to interpret.
NEUROGENETICS IN THE NEUROLOGIC SUBSPECIALTIES

Entire subfields now exist within neurology that barely existed 2 decades ago,
such as genetics of epilepsy, genetics of movement disorders, and genetics of
neuromuscular diseases. A detailed discussion of every genetic cause of every
neurologic presentation is beyond the scope of this article. Instead, very broad
general principles are described that may facilitate organization of the initial
approach to eight key clinical presentations, with the understanding that many
nuances exist within each category of presentation and that workups are best
performed in consultation with domain-specific experts (subspecialists with
discrete training, expertise, and experience with a particular group of
conditions). These notions apply when considering genetic etiologies; therefore,
nongenetic causes should always be excluded when appropriate.
Global Developmental Delay and Intellectual Disability

Global developmental delay is one of the most common reasons for an outpatient
child neurology office visit, and it is defined as delay in at least two of the four
realms of child development (gross motor, fine motor, speech and language, and
social development). If the patient is older than 5 years of age, has impairment in
adaptive functioning, and has a full score of less than 70 on an IQ test, the term
intellectual disability is appropriate. Several classic genetic syndromes have this
presentation, including fragile X syndrome, the most common cause of
intellectual disability in boys. A myriad of other syndromes likewise have this
presentation, and, in younger patients, other sentinel signs/symptoms may not
yet be present. Therefore, a broad screening approach has been recommended by
professional societies, including a survey of genomic architecture with a
28 FEBRUARY 2018
chromosomal microarray, ideally combined with karyotype. Fragile X syndrome KEY POINTS
is caused by triple repeat expansion in the FMR1 gene and is not detected by
● Most pathogenic genetic
chromosomal microarray. Therefore, specific Southern blot testing for this variability is caused by
disorder is usually performed early in the workup. variation of sequence or
If these tests are normal, varied options for further diagnostic testing are dose of the DNA. The
available. Global developmental delay and intellectual disability are prime techniques used to detect
these types of abnormalities

examples of phenotypes with extreme genetic heterogeneity, as literally thousands
are very different, so
of diagnostic possibilities exist with little to differentiate them clinically. ordering the correct test is
Therefore, a massively parallel sequencing strategy (such as neurodevelopmental as important as targeting the
gene panels and exome sequencing) is the best next test to offer. Other right gene.
nongenomic diagnostic tests that may help narrow the field include specific
● Genomic data can be
neurometabolic enzyme testing and N-glycosylation and O-glycosylation stored indefinitely and
screening for congenital disorders of glycosylation. Finally, if Angelman syndrome reanalyzed as the knowledge
or Prader-Willi syndrome are at all suspected, separate methylation-sensitive PCR about genomics evolves.
should be ordered, as this is the best first test to detect the various causes of those
● Given the rapidity with
syndromes. A normal methylation pattern of chromosome 15q11.2-q13 rules out which new genetic causes
Prader-Willi syndrome, and, if clinical suspicion for Angelman syndrome is of neurologic conditions are
strong, sequence analysis of UBE3A should be pursued next. Sequential testing being discovered, exome
with chromosomal microarray/reflex karyotype, fragile X, and exome sequencing sequencing is probably the
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most cost-effective
can approach a diagnostic yield of up to 60%.11
approach to diagnosis in
phenotypes with great
Autism genetic heterogeneity
Autism spectrum disorder is defined by persistent deficits in social communication without a high chance of
chromosomal events, but
and social interaction and restricted or repetitive patterns of behavior, interests,
many exceptions exist.
or activities, usually present in the early developmental period, causing significant
impairment, and not better explained by intellectual disability.12 Despite early ● Global developmental
evidence for a genetic basis for some forms of autism, as seen in fragile X syndrome, delay, intellectual
further advances in testing technologies were required before the breadth of genetic disability, autism spectrum
disorder, and epileptic
causes of autism spectrum disorder became apparent. This means that the encephalopathies are
diagnostic approach to autism spectrum disorder is similar to that for global frequently caused by
developmental delay/intellectual disability: chromosomal microarray with reflex chromosomal-level events,
karyotype (ie, an immediate karyotype if the chromosomal microarray is normal) so chromosomal microarray
and karyotype are likely to
and fragile X testing are indicated as first-line tests. As with intellectual disability, be helpful.
most genetic causes of autism spectrum disorder are de novo in inheritance13 (with
obvious exceptions, eg, fragile X syndrome). If the architecture of the genome has ● Autism, intellectual
been verified as normal, then massively parallel sequencing strategies are indicated, disability, and epileptic
encephalopathy are all
much like in neurodevelopmental disorders, with the same caveat regarding
conditions with great
detection of exon-level deletions and duplications, considering neurometabolic genetic heterogeneity, and
causes, screening for congenital disorders of glycosylation, and specific methylation each can be caused by
testing for Angelman syndrome. The American College of Medical Genetics has mutations in more than
published guidelines for the evaluation of individuals with developmental delay.14 50 known genes.
Epilepsy
Epilepsy is perhaps the most extreme example of genetic heterogeneity
confronting the diagnostician. At present, hundreds of genes are associated with
epilepsy causation, and indications are that thousands may ultimately be
discovered as research advances. However, many of the same principles that
underlie the genetic pathogenesis of global developmental delay/intellectual
disability and autism spectrum disorder also hold true for epilepsy. While a
number of well-described X-linked and autosomal dominant epilepsy disorders
GENETIC DIAGNOSTICS
are known, most causes described (particularly the early-onset epileptic

encephalopathies) are of de novo inheritance. As previously mentioned, the best
first test for molecular diagnosis, independent of the electroclinical epilepsy
syndrome identified, is chromosomal microarray, with karyotype performed if
the microarray is normal. Should chromosomal microarray and karyotype be
normal, some form of massively parallel sequencing approach (with the

aforementioned caveats) would be the most appropriate next step.
Neurodegeneration
Neurodegeneration is a broad category of presentation that can range from
young children with catastrophic loss of developmental milestones and
deterioration of neurologic function to children who initially present with global
developmental delay but over time take on a more ominous clinical course to
older patients who may develop dementing symptoms, ataxia, movement
disorders, or any combination of progressive neurologic signs. Rather than
discuss each of the myriad causes separately, a general approach to genetic
diagnostics in these scenarios is presented here. First, in the event of presentation
of classic signs of a specific disorder to a keen diagnostician (eg, retinal cherry red
spot, increased startle response, and loss of motor skills in an infant is highly
09/2022
suggestive of Tay-Sachs disease; hypotonia, generalized muscle weakness,

respiratory distress, and cardiomyopathy in an infant is suggestive of Pompe
disease; onset of dystonia, hepatitis, psychiatric symptoms, and a
Kayser-Fleischer ring in a young adult are almost pathognomonic of Wilson
disease), the pursuit of specific enzyme or metabolite testing for the suspected
neurometabolic disorder is the best approach. In other cases, the presentation
(such as chorea and declining cognitive performance in a young adult with an
autosomal dominant family history of the same) may suggest a single gene for
immediate testing (in this case Huntington disease, which is diagnosed by
Southern blot testing of the trinucleotide repeat on the HTT gene). Screening
metabolic testing for peroxisomal (very-long-chain fatty acid testing), lysosomal
(lymphocyte lysosomal enzyme panel testing), and mitochondrial (serum or CSF
lactate, pyruvate, plasma and CSF amino acids) disorders as well as other tests,
such as urine organic acids, acylcarnitine profile, skeletal survey, and CSF
neurotransmitters, can be used to detect abnormalities in specific systems. For
more information, refer to the article “Testing for Inborn Errors of Metabolism”
by Jennifer M. Kwon, MD, MPH, FAAN,15 in this issue of Continuum.
Findings from these preliminary forays can then be used to guide subsequent
genetic testing. In many cases, however, the pattern of neurodegeneration is so
nonspecific that no single class of diagnosis is suggested, or it may be associated
with such genetic heterogeneity that a broader approach is indicated. Some cases
may initially present as global developmental delay/intellectual disability, autism
spectrum disorder, or epilepsy until their true neurodegenerative etiology
becomes apparent. As a general rule, autosomal recessive single-gene disorders
and mitochondrial genomic disorders are enriched in this category of
presentation, altering our approach to diagnostics. The more traditional de novo
copy number deletion syndromes are less likely to have a neurodegenerative
course. For this reason, chromosomal microarray may not be the first test
indicated for neurodegeneration. If preliminary metabolic screening has
indicated a particular set of genes, the genes can often be tested by means of a
gene “panel,” with due attention also paid to the possibility of exon-level
30 FEBRUARY 2018
deletions/duplications. If preliminary metabolic screening suggests a disorder of KEY POINT
mitochondrial function, these disorders can be encoded on the mitochondrial
● In neurodegeneration,
genome as well as through a number of nuclear genes (mostly autosomal movement disorders, and
recessive inheritance). Therefore, genetic testing in these cases may involve neuromuscular disorders,
mitochondrial genome sequencing (which often must be ordered separately excluding compatible
from other types of sequencing) and massively parallel sequencing that involves metabolic causes is
paramount. Often, the

a so-called mitochondrial panel on the autosomal genome. Neurodegeneration
opinion of a subspecialist
presenting as ataxia (particularly the spinocerebellar ataxias) may be due to is necessary before
repeat expansions, which are not detected by next-generation sequencing. genetic testing.
Specific Southern blot testing for these disorders would be necessary. If
preliminary metabolic screening does not detect a class of disorder of
peroxisomal, lysosomal, or mitochondrial function, a broader approach through
exome sequencing may be indicated. If these tests are unsuccessful,
chromosomal microarray (with follow-up karyotype if the microarray is normal)
can be offered when neurodegeneration may be due to an unusual presentation
of a disorder of chromosomal copy number.
Microcephaly
Occipital-frontal head circumference two standard deviations or more below the
09/2022
mean can be categorized as prenatal (present at birth) or postnatal in onset, with

markedly different genetic evaluations for each. Some forms of microcephaly are
also associated with specific brain malformation patterns, which are discussed in
the next section. Prenatal microcephaly is associated with mutations in a number
of genes with autosomal recessive inheritance,16 and these can be sequenced in a
massively parallel approach through a panel or exome sequencing (taking caveats
into consideration) followed by chromosomal microarray. Recessive disorders
can feature an inherited pathogenic sequence variation in a gene on one allele
combined with a deletion of the same gene on the other allele.
Postnatal microcephaly presents with normal head size at birth but with
progressive deceleration in head growth, usually through infancy and toddlerhood.
The genetic landscape of postnatal microcephaly disorders is markedly different
than that of prenatal microcephaly; for this reason, a clear charting of head size over
time since birth is the essential first step of the evaluation. In general, postnatal
microcephaly disorders overlap with the previously discussed disorders presenting
with global developmental delay/intellectual disability, epilepsy, and even autism
spectrum disorder, and a similar approach could be followed except for fragile
X syndrome, which is not a common cause of microcephaly.17
Brain Malformations
Over the past decades, detailed knowledge has emerged regarding the genetic
causes and classifications of structural brain malformations.18,19 These include
specific patterns of premigrational, migrational, and postmigrational forebrain
malformations, hindbrain malformations, and syndromes that involve a
combination of these patterns. For more information, refer to the article
“Nervous System Malformations” by John Gaitanis, MD, and Tomo Tarui, MD,20
in this issue of Continuum. Thorough interpretation of the findings on MRI by an
expert in these disorders is a necessary first step in the diagnosis, because what
is needed is not merely the identification of the various findings on the image but
also the insight to put findings together into rare but recognizable patterns.
One must consider that several categories of brain malformations are usually due
GENETIC DIAGNOSTICS
to prenatal insults, such as viral infections or ischemic events, and that some
patterns of brain malformation are so specific as to be associated with a defect in
a single gene. Other brain malformations are associated with specific congenital
anomalies elsewhere in the body that may suggest a diagnosis. However, most
patterns of brain malformation exhibit sufficient genetic heterogeneity that a
broader genome-wide approach to testing is indicated. As with global developmental

delay/intellectual disability and epilepsy (which are frequent copresenting signs with
brain malformations), the best first test is usually chromosomal microarray with
reflex karyotype, followed, when needed, by massively parallel sequencing panels
for brain malformation. Exceptions to this approach abound, making the opinion
of a specialist even more valuable (CASE 1-1).
Neuromuscular Disorders
Hereditary neuropathies may present with motor or sensory peripheral nerve
dysfunction or both. Recognition of whether a neuropathy is axonal or
demyelinating and determination of a clear inheritance pattern are in the realm
of most neurologists, but familiarity with the growing list of genetic conditions
associated with neuromuscular disorders may not be. For this reason, consultation
with a neuromuscular specialist is advisable in suspected genetic cases in addition
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to nerve conduction studies and EMG, which are often an essential component of
the evaluation before a genetic test is ordered. Except for Charcot-Marie-Tooth
disease type 1 (which is largely caused by duplication of PMP22) and X-linked
axonopathies (mostly ascribed to sequence variations in GJB1), other forms of
hereditary neuropathies, such as autosomal dominant axonopathies (eg,
Charcot-Marie-Tooth disease type 2), can be caused by abnormalities in dozens of
different genes. Previous strategies that tested the most common gene in each
CASE 1-1 A 2-year-old boy with a history of hearing loss but no other neurologic
symptoms presented with acute head trauma and underwent a CT scan.
The image showed no acute changes but demonstrated structural
abnormalities, so a follow-up visit was scheduled and an MRI was
ordered. The MRI showed agenesis of the corpus callosum,
polymicrogyria, and ventricular dilation. He had no history suggestive of
prenatal injury and no family history of neurologic abnormalities.
A karyotype was ordered, which disclosed no abnormalities, then a
chromosomal microarray was requested and showed two microdeletions
of unknown significance. A referral to a medical geneticist with an interest
in brain malformations was then requested. The geneticist reported
that the MRI findings were highly suggestive of Chudley-McCullough
syndrome and ordered single-gene testing for GPSM2 mutations, which
showed compound heterozygous mutations of the gene, providing
a definite diagnosis. Since the condition is autosomal recessive, further
reproductive counseling was provided for the parents.
COMMENT This case illustrates how an early opinion of a subspecialist can spare
unnecessary tests and allow for early reproductive counseling.
32 FEBRUARY 2018
phenotype first, followed by sequential testing of the other likely culprits, is
increasingly giving way to panel-based testing for dominant or recessive and
demyelinating or axonal presentations. Some laboratories offer massively parallel
all-inclusive hereditary neuropathy panels, but it should be remembered that the
most common duplication of PMP22 requires copy number testing.
Hereditary neuropathy can also be part of several autosomal recessive

neurometabolic disorders, such as Refsum disease, metachromatic leukodystrophy,

and Krabbe disease, and appropriate testing should be performed if indicated. Other
conditions associated with neuropathy include mitochondrial diseases, Friedreich
ataxia, X-linked adrenomyeloneuropathy, and Pelizaeus-Merzbacher disease.
Primary disorders of muscle are a large and varied group of conditions, with
diverse genetic etiologies. Forms of the same disorder may present at birth, in
infancy or early childhood, or later in adult life. With few exceptions,
consultation with an experienced specialist is indicated to guide genetic testing.
Age of onset, creatine kinase levels, nerve conduction studies and EMG, and
muscle biopsy with specific immunohistochemical and biochemical assays may
yield a pattern suggestive of a diagnosis. In recognizable cases, such as Duchenne
muscular dystrophy, immediate testing of a single gene may be indicated.
Testing of the DMD gene is a prime example of the importance of exon-level
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deletions in pathogenesis, as up to 70% of pathogenic mutations in this gene are

deletions of one or more exons, and genetic testing approaches should take this
into account. Gene panel approaches might be indicated when confronted with a
congenital myopathy, congenital muscular dystrophy, and a limb-girdle
muscular dystrophy. If a mitochondrial etiology is suspected either by the
specifics of the clinical presentation or results from muscle biopsy, mitochondrial
genome sequencing may be helpful.
Movement Disorders
Movement disorders, including tremor, dystonia, myoclonus, chorea, and, less
often, parkinsonism, often accompany neurodegenerative conditions in
children, as discussed earlier in this article. Isolated movement disorders
previously characterized as predominant “pure” movement disorders were often
labeled primary before genomics identified the causes for many of these
conditions. In practical terms, a primary or idiopathic movement disorder is
suspected when no history of brain injury is present, brain imaging through
structural MRI is normal, and laboratory investigations (including testing for
inflammatory or metabolic disease when indicated) are negative. That rules out,
for example, Wilson disease, systemic lupus erythematosus, and anti–N-methyl-
D-aspartate (NMDA) receptor autoimmune encephalitis, to name a few.
Neurotransmitter diseases can be detected by biochemical abnormalities in the
CSF but most often present as primary movement disorders,21 and, in addition to
dopa-responsive dystonia (DYT5), they can present with cerebral palsy–like
phenotypes, which also respond to dopaminergic therapy.
Most primary movement disorders are caused by sequence variations or
small deletions or duplications within the causative gene, although copy number
variants detected through chromosomal microarray have been reported in
association with primary movement disorders and remain a possibility.22 The
genetic heterogeneity and phenotypic pleiotropy of many genes causing
movement disorders make a case for a broad approach to gene testing, either
through a gene panel or exome sequencing. Today, most commercial gene panels
GENETIC DIAGNOSTICS
are targeted to a key phenotype, such as dystonia, juvenile parkinsonism, chorea,

paroxysmal dyskinesia, or ataxia. Nevertheless, with the expanded spectrum of
many conditions, it is becoming clear that a significant overlap exists between
these key phenotypes. Genes causing recessive ataxias, for example, are known to
masquerade as primary choreas,23 and many neurodegenerative conditions with
expanded spectrums can present with movement disorders as their initial

manifestation for months or years. Therefore, it is imperative that the clinician

ordering the tests be familiar with the conditions and their variability as well as
with the testing technologies and their limitations. Often, the opinion of a
movement disorders specialist or a neurogeneticist is advisable, but in the context
of a movement disorder phenotype highly suggestive of a particular condition
(eg, Huntington disease), the testing for a single gene may be the initial choice.
Some idiopathic movement disorders with likely genetic risk factors (ie,
positive family history) with no clear mendelian inheritance have not been
associated with pathogenic sequence variations in any gene despite extensive
studies in past decades. These include Tourette syndrome and essential tremor,
both of which require no genetic testing for diagnosis and management at the
present time.
09/2022
TRENDS AND DIRECTIONS FOR THE FUTURE

Genetics data are unintelligible for clinicians without proper training. To be
interpreted, these data require processing with up-to-date software followed by
interpretation by clinical geneticists and sometimes subspecialists, who match
symptoms with the data (CASE 1-1). Interpretation continuously matures as more
genetic studies are performed, more subjects are tested, and more pathogenic
variants are described. These data are not all localized in one place but are spread
out over different websites and electronic resources, which require professionals
in bioinformatics who are familiar with the analytic environment. Domain
specialists who are very familiar with the clinical manifestations of certain
conditions and are continuously updated on the neurogenetics involved in them
are also an important part of the interpretation process. Many of the exome
sequencing tests or chromosomal microarrays that failed to return known
pathogenic variants a few years ago may need to be reinterpreted, or at least the
variants of unknown significance should be checked, as their significance might
have become clear.
Much genetic testing is performed in research settings, either because of cost or
because of recruitment of patients with specific phenotypes into genetic studies.
An obvious benefit of research sequencing is that domain specialists are often
involved and contribute to the interpretation of findings. Research analyses can be
repeated as more evidence becomes available or when the patient, under
continued follow-up by a research team that includes specialists, presents with
new symptoms that can aid the interpretation. Overall, maintaining a network of
contacts in the field of neurogenetic research can be an ideal way to obtain
valuable clinical advice and sometimes genetic testing on a research basis.
Nevertheless, neurologists with busy and often isolated clinical practices with little
time or opportunity to cultivate these contacts may strive to grow their network of
referrals and use a flexible threshold for referring suspected genetic conditions
that they feel more or less comfortable dealing with. While a network of contacts
might be a temporary solution, it is imperative that the number of medical
geneticists increases to meet the growing demands for referral and genetic testing.
34 FEBRUARY 2018
CONCLUSION
Currently, neurologists dealing with suspected or confirmed neurogenetic
conditions often need the opinion of a medical genetics specialist and a genetic
counselor. These resources may be unavailable in many regions throughout the
world, but with a good network of contacts in the medical genetics field and within
neurologic subspecialties, this shortcoming can be mitigated. In some conditions

in which genetic etiologies are prominent and targeted testing is the first choice,
it may be more practical for the neurologist to order the test and perform pretest
and posttest genetic counseling. With the increased complexity of genetic testing
and genomic data available, the expansion of the field of neurogenetics is inevitable.
ACKNOWLEDGMENT
This work was supported by a grant (K08 NS078054; Dr Paciorkowski) from
the National Institutes of Health/National Institute of Neurological Disorders
and Stroke.
09/2022
USEFUL WEBSITES
CLINVAR ONLINE MENDELIAN INHERITANCE IN MAN
ClinVar is an expertly curated public archive of Online Mendelian Inheritance in Man (OMIM) is a
reports of genomic variations and phenotypes, with comprehensive compendium of genes associated
supporting evidence. with genetic disorders as well as phenotypes
ncbi.nlm.nih.gov/clinvar/ inherited in clear familial patterns for which no
specific genetic mutation has thus far
DEVELOPMENTAL BRAIN DISORDERS DATABASE been described.
The Developmental Brain Disorders Database ncbi.nlm.nih.gov/omim/
provides a repository of genes, phenotypes, and
syndromes specifically targeted at SEQUENCE VARIANT NOMENCLATURE
neurodevelopmental disorders curated by The Sequence Variant Nomenclature website
domain specialists. provides technical information on the description
www.dbdb.urmc.rochester.edu/home of sequence variants.
varnomen.hgvs.org/
ENSEMBL
The Ensembl genome browser is another invaluable UNIVERSITY OF CALIFORNIA SANTA CRUZ GENOME
tool for visualizing regions of interest and their BROWSER
associated annotations. The University of California Santa Cruz Genome
ensembl.org/index.html Browser is an invaluable tool for visualizing
regions of interest and associated annotations
GENEREVIEWS
for these regions.
GeneReviews provides chapter-length information genome.ucsc.edu/
on clinical scenarios and specific single-gene
disorders. It is written by domain experts, with
authoritative recommendations regarding
counseling, testing, and management.
ncbi.nlm.nih.gov/books/NBK1116/
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36 FEBRUARY 2018
Testing for Inborn Errors REVIEW ARTICLE
of Metabolism

C O N T I N U UM A U D I O
VH4kB2Z9EY5jONzaHF6L6BFLKNUIlvpnOmK9o8126tTOuniutr3OwA5Vmj7KGOmPyDdSXOaeh9YV3kmbDFUBN5ROWwyY= on 09/
I NT E R V I E W A V A I L AB L E
ONLINE
By Jennifer M. Kwon, MD, MPH, FAAN
ABSTRACT
PURPOSE OF REVIEW: This article provides an overview of genetic metabolic
disorders that can be identified by metabolic tests readily available to
neurologists, such as tests for ammonia, plasma amino acids, and urine
organic acids. The limitations of these tests are also discussed, as they only
screen for a subset of the many inborn errors of metabolism that exist.
RECENT FINDINGS: Advances in next-generation sequencing and the emerging

use of advanced metabolomic screening have made it possible to diagnose
treatable inborn errors of metabolism that are not included in current
09/2022
newborn screening programs. Some of these inborn errors of metabolism

are especially likely to present with nonspecific neurologic phenotypes,
such as epilepsy, ataxia, or intellectual disability. However, cost may be a
barrier to obtaining these newer tests. It is important to keep in mind that
common metabolic testing may lead to treatable diagnoses. Resources are
available to guide neurologists in diagnosing genetic metabolic conditions.
SUMMARY: This article introduces the clinical presentations of treatable

CITE AS:
inborn errors of metabolism that are important for neurologists to consider
CONTINUUM (MINNEAP MINN)
in patients of all ages. Inborn errors of metabolism are rare, but they can 2018;24(1, CHILD NEUROLOGY):37–56.
present with neurologic symptoms. Newborns are now screened for many
treatable metabolic disorders, but these screening tests may miss milder Address correspondence to Dr
Jennifer M. Kwon, 601 Elmwood
presentations of treatable inborn errors of metabolism that present later in Ave, Box 631, Child Neurology,
life. These patients may present to adult neurologists who may be less Rochester, NY 14642,
likely to consider metabolic genetic testing. Jennifer_kwon@urmc.rochester.
edu.
Dr Kwon has received personal
INTRODUCTION compensation for serving as a
I
nborn errors of metabolism are rare yet numerous and often present with consultant for BioMarin, the
neurologic symptoms. This article provides an overview of genetic metabolic Evidence Review Committee of
the Health Resources and
disorders that can be identified by metabolic tests readily available to Services Administration, and
neurologists, such as tests for ammonia, plasma amino acids, and urine Sanofi Genzyme and receives
research/grant support from
organic acids.
the Hunter’s Hope Foundation.
Newborns in the United States are now screened for many treatable inborn
UNLABELED USE OF
errors of metabolism, but newborn screening tests may miss milder presentations PRODUCTS/INVESTIGATIONAL
of treatable inborn errors of metabolism that can present later in life. These USE DISCLOSURE:
patients may present to adult neurologists who may be less likely to consider Dr Kwon discusses the
unlabeled/investigational use of
metabolic genetic testing. carglumic acid for the treatment
of carbamoyl phosphate
PRESENTATION OF INBORN ERRORS OF METABOLISM synthetase deficiency.
One of the challenges of testing for inborn errors of metabolism is recognizing © 2018 American Academy of
that acute, urgent, and nonspecific presenting symptoms (eg, poor oral intake, Neurology.
INBORN ERRORS OF METABOLISM
KEY POINT lethargy, and seizures) may warrant additional metabolic screening tests to help
identify an inborn error of metabolism with its own specific treatment (CASE 2-1).
● There must be a low
threshold for considering The use of metabolic screening tests (TABLE 2-11) in addition to the standard
an inborn error of laboratory testing of sick patients (ie, complete blood cell count; a comprehensive
metabolism since chemistry panel that includes glucose, liver transaminases, calcium, and uric
presentations are acid; ammonia; lactate; pyruvate; and urinalysis) will identify some treatable
nonspecific.
defects of intermediary metabolism of proteins, carbohydrates, and fats.

Although inborn errors of metabolism are often seen in infants, they can
present at any age. Neurologists should consider these disorders in patients
with (1) recurrent attacks of encephalopathy, vomiting, ataxia, and metabolic
acidosis, especially when the attacks appear to be triggered by illness or changes
in diet (since both catabolism and increased protein intake can provoke
metabolic deterioration); (2) progressive or chronic symptoms of failure to
CASE 2-1 A 10-day-old infant boy was brought to the pediatric emergency
department with new-onset seizures. His prenatal course and delivery
09/2022
had been normal, and he had been discharged home 24 hours after birth.
Initially, he was breast-feeding at regular intervals. After a week, he was
not feeding well and seemed to sleep more frequently. The patient’s
mother brought him to the emergency department because of an episode
in which he stiffened, arched his back, and had a series of jerks. The
event lasted seconds, and he had been lethargic since the event.
On examination, he was difficult to arouse. He was afebrile with a pulse
of 160 beats/min and a respiratory rate of 20 to 30 breaths/min, but
occasionally he had pauses in his breathing. Initial laboratory results showed
a normal complete blood cell count. A chemistry panel showed the
following abnormalities: a bicarbonate level of 16 mmol/L, glucose of
50 mg/dL, aspartate transaminase of 90 U/L, alanine transaminase of 110 U/L,
and an ammonia level of 160 µmol/L. Urinalysis showed ketones but was
otherwise normal. Plasma amino acids and urine organic acids were pending.
COMMENT This is a classic presentation of an organic acid disorder, where an infant

who appears to do well shortly after birth will begin to show lethargy,
poor feeding, respiratory pauses, and seizures the week following
birth. In this setting, heightened concern for sepsis always exists,
although, in this case, the lack of fever and a normal complete blood cell
count are reassuring. The development of symptoms after a week of life
suggests that the infant may not be tolerating feeding. The abnormal
chemistry values and elevated ammonia suggest a primary metabolic
disorder, especially one of amino acid degradation, and this would
significantly alter treatment. Even without a specific diagnosis, the initial
treatment would be IV fluids with a high concentration of glucose to
maintain caloric intake and avoid further catabolism (to minimize stressing
the impaired amino acid degradation system).
38 FEBRUARY 2018
thrive, weakness, or developmental delay; or (3) unusual organ dysfunction such
as cardiomyopathy, hepatomegaly, skeletal findings, or lens dislocation.
CLASSIFICATION OF INBORN ERRORS OF METABOLISM

Metabolic disorders are often subdivided into three groups based on their
clinical and physiologic characteristics (TABLE 2-2).2 Disorders in the first group
lead to excessive accumulation of a substance or compounds with intoxicating

effects (eg, vomiting or obtundation), as seen in organic acid disorders or urea
cycle defects. The second group of disorders directly affect energy metabolism,
causing symptoms in more metabolically active organs such as the brain (eg,
coma, brain malformations), as seen in respiratory chain disorders or pyruvate
dehydrogenase complex deficiency. The third group of disorders involves defects
Common Metabolic Screening Tests Used to Identify Treatable Disorders TABLE 2-1
of Intoxication and Energy Metabolisma
09/2022
Test Name Conditions Screened
Ammonia Urea cycle defects, organic acidurias
Plasma amino acids Aminoacidopathies, urea cycle disorders, some organic acidurias
Urine organic acids Organic acidurias

Plasma acylcarnitine profile Organic acidurias, fatty acid oxidation defects
a 1
Modified with permission from Kwon JM, D’Aco KE, Neurol Clin. © 2013 Elsevier.
Pathophysiologic Effects of Three Categories of Metabolic Disorders TABLE 2-2
Triggers
(Illness, Diagnosis Made by
Pathophysiologic Protein Available Metabolic
Effects Examples Appearance at Birth Load) Screening Tests Treatable
Metabolite Organic acid disorders, Usually normal Often Often Often
accumulation and urea cycle defects,
intoxication aminoacidopathies
Impairment of Mitochondrial Sometimes normal but Often Sometimes; may need Sometimes
energy metabolism disorders, fatty acid may affect metabolically enzyme or DNA testing
oxidation disorders active tissues (eg, brain
malformation)
Disruption of Peroxisomal disorders, Sometimes normal, but Rare Rarely; diagnosis usually Rare
complex molecule lysosomal disorders some present with requires specialized
metabolism dysmorphology enzyme or DNA testing
or organomegaly
DNA = deoxyribonucleic acid.
KEY POINTS in the catabolism of complex molecules in cell organelles, as seen in lysosomal
storage disorders or peroxisomal disorders.
● Inborn errors of
metabolism often present This article discusses disorders in the first and second groups, which are typically
with symptoms that suggest considered small molecule disorders affecting the intermediary metabolism of
sepsis or gastrointestinal proteins, fats, and sugars, while the third group includes large molecule disorders.
illness accompanied by This article emphasizes inborn errors of metabolism with neurologic presentations
weakness, developmental
delay, and poor growth. If in which early diagnosis and treatments can lead to better outcomes. The following
the history suggests decline section begins with an overview of the disorders physicians are most likely to
or an attack of illness identify using commonly available metabolic screening tests, including urea cycle
associated with increased defects, organic acidurias, and aminoacidopathies. The second section continues
catabolism or increased
protein intake, consider
with a discussion of other treatable inborn errors of metabolism that should also be
testing for metabolic considered and that are not readily found using the tests in TABLE 2-1.
disorders.
TREATABLE INBORN ERRORS OF METABOLISM IDENTIFIED BY
● Neurologists should BIOCHEMICAL SCREENING TESTS
recognize the highly Abnormalities in the metabolism of amino acids can lead to urea cycle defects,
specialized nature of
diagnosing and treating organic acid disorders, and other aminoacidopathies (FIGURE 2-1). These
metabolic disorders and disorders of protein intermediary metabolism present in infancy or childhood
involve a metabolic and are characterized by sudden attacks, episodic relapses and remissions, and
09/2022
geneticist in the diagnosis nonspecific physical findings. Metabolic screening tests (TABLE 2-1) in blood and
and care of patients with
inborn errors of
urine are used to detect many of these disorders. Often, a diagnosis is
metabolism. suggested by the pattern of abnormalities on screening, with more specific
diagnoses made through DNA-based or specific enzyme testing. Confirmation
● Almost all inborn errors of diagnoses and management requires the assistance of specialists with
of metabolism are
expertise in metabolic disorders. Most of the disorders discussed are inherited
autosomal recessive
disorders. Genetic as autosomal recessive conditions, so carrier parents are unaffected, and
counseling must be
provided to families
learning of a diagnosis of an
inborn error of metabolism.
● Prior to delivery, infants

are protected from toxic
effects of metabolite
accumulation by placental
clearance, which is why a
symptom-free period often
occurs right after birth.
FIGURE 2-1
Metabolism of amino acids occurs by deamination or removal of the amino group (urea cycle
disorders), metabolism of the carboxyl skeleton of the amino acid (organic acid disorders),
or transformation into other amino acids or compounds (amino acid disorders).
40 FEBRUARY 2018
09/2022
FIGURE 2-2
Urea cycle. Pathways of the urea cycle are shown as solid (one enzymatic step)
or dashed (multiple enzymatic steps) black lines with arrows. Open, double-headed arrows
on dotted lines show amino acids that are transported between cytosol and mitochondrion.
The reactions of the urea cycle remove excess ammonia (NH4) into excretable urea and
synthesize arginine. The first two steps are intramitochondrial, and the rest occur in the
cytoplasm. The enzyme carbamoyl phosphate synthetase I (CPS) incorporates NH4 to make
carbamoyl phosphate in a reaction requiring N-acetylglutamate made from glutamate by
N-acetylglutamate synthetase (NAGS). Carbamoyl phosphate, joined with ornithine via
ornithine transcarbamylase (OTC), makes citrulline. Citrulline moves out of the mitochondria
to the cytosol where argininosuccinate synthetase (ASS) condenses it with aspartate to form
argininosuccinate. This, in turn, is cleaved by argininosuccinate lyase (ASL) to form arginine
and fumarate. As the final step in the cycle, arginine is cleaved by arginase to urea, which is
excreted, and ornithine, which is transported from the cytosol to the mitochondria, to restart
the cycle. Disorders of the urea cycle are caused by deficiencies of enzymes labeled in
hexagons and the jagged lines mark the location of the enzyme defect.
KEY POINTS
siblings are at risk. For this reason, if these diagnoses are considered, genetic
● In the setting of acute counseling should be sought.
encephalopathy (eg,
where a lumbar puncture
Urea Cycle Defects
would be considered an
Excess amino acids are metabolically consumed via the urea cycle (FIGURE 2-2),
appropriate test),
remember to check an which serves to convert ammonia into excretable urea and synthesize arginine,
ammonia level. which is essential for nitric oxide and creatine production.3,4 Neonates with
urea cycle defects generally appear normal for their first 24 hours of life (as
● Elevated ammonia levels
can cause vomiting,
they benefit from the placental clearance of ammonia) and afterward become
encephalopathy, cerebral lethargic and have difficulty feeding (CASE 2-2).4 Vomiting, hypothermia,
edema, and hyperventilation, and cerebral edema with bulging fontanelle can develop early
hyperventilation. in the course of disease and are the result of ammonia intoxication. Respiratory
alkalosis results from this hyperventilation, and, if acidosis develops, it is a late effect
● Urea cycle defects can
present as a catastrophic from respiratory depression and tissue damage. Routine chemistries are often
neonatal illness or during unremarkable or may only show a low blood urea nitrogen (as low as 1 mg/dL).
childhood or teenage years, TABLE 2-3 outlines some of the clinical characteristics of the urea cycle
often after significant disorders as well as the plasma citrulline and urine orotic acid profiles that can
stress (eg, pregnancy,
steroids, excessive protein help distinguish them. Except for arginase deficiency, the other urea cycle
09/2022
ingestion.) defects have similar clinical presentations in the neonatal period: infants may be
asymptomatic in the first 24 to 48 hours and then develop progressive lethargy,
● Although ornithine poor feeding, vomiting, hypothermia, seizures, and hyperventilation. Arginase
transcarbamoylase
deficiency is X-linked, men
deficiency has classically been thought to present with a more slowly progressive
may present later in life. course, resulting in spastic quadriparesis, intellectual disability, and less
abnormal hyperammonemia. Later-onset urea cycle defects may present with
episodic ataxia, progressive cognitive and physical disabilities, or fulminant
progressive encephalopathy. All urea cycle defects are inherited as autosomal
CASE 2-2 A 3-day-old infant girl was brought to the emergency department with a
1-day history of poor feeding and decreased activity. On presentation, she
was lethargic and tachypneic and had developed abnormal movements of
her right arm and leg, which were worrisome for seizures. A sepsis workup
and metabolic tests were performed, and antibiotics and antiepileptic
medications were initiated. Initial investigations showed a high ammonia
(440 μmol/L) level and respiratory alkalosis. She was started on sodium
phenylacetate and sodium benzoate, IV arginine, IV high dextrose, and
continuous insulin infusion, and when her ammonia level continued to rise
to 890 μmol/L, she was prepared for dialysis. Her plasma amino acids
showed elevated glutamine and glycine and undetectable citrulline.
COMMENT The high ammonia and plasma amino acid profile suggest a proximal urea
cycle defect, possibly carbamoyl phosphate synthetase, ornithine
transcarbamylase, or N-acetylglutamate synthase deficiency (FIGURE 2-2).
Subsequent genetic testing confirmed N-acetylglutamate synthase deficiency,
which is the rarest of the urea cycle defects but has a specific treatment
(carglumic acid).
42 FEBRUARY 2018
recessive disorders except for ornithine transcarbamoylase deficiency, which is
X-linked. While this suggests that males are likely to have a more severe
presentation of ornithine transcarbamoylase deficiency, many reports exist of
males who present in adulthood (CASE 2-3).
The principles of treatment3,4 in urea cycle defects, particularly in the acute
state, are to (1) rapidly lower plasma ammonia to normal levels; (2) employ
pharmacologic interventions to enhance nitrogen excretion; and (3) use

nutritional strategies to address the catabolic state by providing essential amino
acids, glucose, and fats.
The long-term management of these disorders requires dietary restriction of
protein, use of nitrogen scavengers such as sodium phenylbutyrate and sodium
benzoate, and replacement of citrulline and arginine as needed. Liver
transplantation can also be used to treat urea cycle defects.
Organic Acid Disorders (Organic Acidemias, Organic Acidurias)

Organic acid disorders are caused by deficiencies of enzymes (often located
in the mitochondria) needed for the metabolism of the activated carbon skeleton
of amino acids (FIGURE 2-1).2 They are characterized by an accumulation of
organic acids proximal to the defective enzyme in the metabolic pathway.
09/2022
Distinguishing Biochemical Findings and Selected Clinical Characteristics TABLE 2-3

of Urea Cycle Disordersa
Enzyme Deficiency Urine Orotic Acid Plasma Citrulline Selected Clinical Characteristics
N-acetylglutamate synthase Low Low Rarest of the urea cycle disorders; N-
(CASE 2–2) acetylglutamate synthase deficiency also has a
specific and effective treatment, carglumic acid
Carbamoyl phosphate Low Low Some patients with carbamoyl phosphate

synthetase synthetase deficiency may also respond to
carglumic acid
Ornithine transcarbamoylase High Low Most common urea cycle defects; X-linked; while
(CASE 2–3) often lethal in boys, girls who present in the
neonatal period may do poorly as well; both
men and women may present later in life with
an episodic ataxia or encephalopathy, often
associated with illness, high protein load, or
steroid-triggered catabolism
Argininosuccinate synthetase High Very high Presentation and management similar to ornithine
transcarbamoylase deficiency
Argininosuccinate lyase High High, with high Episodic hyperammonemia; unique symptoms
argininosuccinate including hypertension, liver fibrosis, and
developmental delay; plasma and CSF show
elevated argininosuccinate
Arginase High Normal Progressive spastic quadriplegia and mental

retardation

a
Data from Ah Mew N, et al, GeneReviews.3
KEY POINTS Accumulation of organic acids leads to metabolic acidosis with an anion gap and
hyperammonemia, which occurs because excess organic acids deplete coenzyme
● Hyperammonemia is
seen in organic acid
A (CoA) and impair urea cycle reactions, which, in turn, leads to encephalopathy
disorders because the and seizures. Accumulating organic acids also have toxic effects on other organs,
leading to bone marrow suppression, cardiomyopathy, renal dysfunction, and
accumulating acids inhibit

the urea cycle. pancreatitis. FIGURE 2-3 contains some of the more important organic acid
disorders likely to present to neurologists.

● Treatable cobalamin
defects may present in
adulthood with brain and METHYLMALONIC ACIDEMIA. Methylmalonic acidemia is relatively common
spinal cord abnormalities compared to other organic acid disorders, with an estimated prevalence of 1 per
suggestive of myelin
disorders.
48,000,6 and is likely to present with neurologic symptoms at all ages, often
without clear metabolic crises. Several genetic defects can result in the increased
production and therefore excretion of methylmalonic acid. The classic and severe
form is due to an absence of methylmalonyl-CoA mutase activity (FIGURE 2-3),
and young infants present with acute encephalopathy including coma, lethargy,
hypotonia, vomiting, and respiratory distress. Later, neurologic sequelae include
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CASE 2-3 A 17-year-old boy was brought to the emergency department after a
new-onset generalized convulsion that lasted 6 minutes and was
associated with urinary incontinence. Prior to this, he had been healthy
but had begun experiencing intermittent nausea and vomiting for 1 week
without diarrhea or fever, coincident with starting a new fitness program
and the intake of high-protein supplements. On arrival in the emergency
department, he was afebrile with normal vital signs. He was lethargic but
arousable to pain.
Initial laboratory results were notable for an elevated alanine
aminotransferase level of 166 U/L (normal range less than 42 U/L) and an
ammonia level of 787 μmol/L (normal range 16 μmol/L to 60 μmol/L). The
rest of his comprehensive chemistry panel (including bicarbonate level),
coagulation profile, and complete blood cell count were normal.
Ultrasound of his abdomen was normal. He was started on lactulose, but
after 24 hours his ammonia level did not improve, and he became less
responsive. He was intubated, and a head CT showed diffuse cerebral
edema. Prior to being started on dialysis, plasma amino acids and
quantitative urine organic acids were obtained, which showed a low
plasma citrulline level of 7 μmol/L (normal range 19 μmol/L to 62 μmol/L),
and his urine orotic acid was elevated at 27.7 mmol/mol creatinine
(normal range 0 mmol/mol to 1.3 mmol/mol creatinine).
COMMENT Neurologists should consider obtaining an ammonia level when faced with
acute encephalopathy.3 The history of taking in a high protein load just prior
to decompensation is suggestive of a disorder of amino acid metabolism,
and the very high ammonia level with no metabolic acidosis (based on
normal bicarbonate level) suggests a urea cycle defect.5 The additional
finding of low citrulline and elevated urine orotic acid suggests that the
defect is in ornithine transcarbamoylase (FIGURE 2-2).
44 FEBRUARY 2018
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FIGURE 2-3
Intermediary metabolism of amino acids leads to adenosine triphosphate production via the
Krebs cycle. Pathways of intermediary metabolism of glucose and selected amino acids are
shown with one or two arrowheads to indicate one or multiple enzymatic steps. All pathways
lead to the Krebs cycle, which, in turn, drives oxidative phosphorylation to make adenosine
triphosphate. Disorders are labeled in parallel lines, which are placed to mark the enzymatic
block. Vitamin cofactors are shown as ovals and include biotin, pyridoxine, folate,
adenosylcobalamin (Ado-Cbl), and methylcobalamin (Me-Cbl). Cobalamin, or vitamin B12,
is transported across the cell membrane and metabolized to Ado-Cbl. Methylmalonic
acidemia is therefore caused by defects in the pathway making cobalamin or by
methylmalonyl-CoA mutase deficiency.
ATP = adenosine triphosphate; CoA = coenzyme A; PC = pyruvate carboxylase complex deficiency;
PDHD = pyruvate dehydrogenase deficiency.
extrapyramidal symptoms, such as dystonia, associated with basal ganglia

(globus pallidus or putamen) injury. Chronic renal dysfunction is another late
complication. The laboratory findings show severe metabolic acidosis, ketonuria,
hyperammonemia, neutropenia, and thrombocytopenia. Urine organic acids
include marked accumulation of methylmalonic acid, 3-hydroxypriopionate,
2-methylcitrate, and tiglylglycine.
Abnormalities of intracellular cobalamin processing can also present with
methylmalonic acidemia and may respond to cobalamin supplementation
(FIGURE 2-3 and CASE 2-4). These disorders may present in adulthood with
mental status changes, dementia, and myelopathy. Imaging may show
demyelinating lesions in the brain and spinal cord.
PROPIONIC ACIDEMIA AND ISOVALERIC ACIDEMIA. Propionic acidemia and isovaleric

acidemia have similar presentations to methylmalonic acidemia in infants
(TABLE 2-48–13). Of the three, propionic acidemia tends to be associated
with more long-term neurologic sequelae, including basal ganglia and white
KEY POINT matter lesions. Isovaleric acidemia is generally less severe in presentation
● Serum methylmalonic
and outcome.
acid and homocysteine, Acute management of methylmalonic acidemia, propionic acidemia, and
commonly used to identify isovaleric acidemia includes correcting the acidosis, hypoglycemia, and
vitamin B12 and folate hyperammonemia.6,8–10 In methylmalonic acidemia, parenteral cobalamin
deficiency, will also help

screen for treatable
may help nonclassic presentations of disease. In propionic acidemia, biotin
cobalamin defects. administration may enhance the defective enzyme function. Chronic
management of methylmalonic acidemia, propionic acidemia, and isovaleric
CASE 2-4 An 8-year-old boy was brought to the emergency department for a
new-onset seizure and a 3-month history of behavior changes. His seizure
was a generalized convulsion lasting 1 minute that had begun while he was
eating breakfast. A few weeks prior to this event, he had become
increasingly irritable, with aggressive outbursts, agitation, and visual
hallucinations, but he had been healthy previous to these symptoms. He
had been started on risperidone a week before presentation to the
emergency department. In the emergency department, about an hour
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after his seizure, he seemed tired but could talk and walk.
His physical examination was unremarkable. His neurologic examination
was notable for limited cooperation, slow responses, increased tone of his
arms and legs, stiff gait, and brisk reflexes. He had no dysmetria.
His initial laboratory evaluation showed a normal comprehensive
chemistry panel, ammonia level, and complete blood count. His CSF
showed normal protein and glucose and no evidence of infection. His
EEG (awake) showed a slow background and no epileptiform discharges.
Brain MRI showed scattered small patches of periventricular signal
abnormalities on T2-weighted images (that were nonenhancing on
postcontrast T1-weighted images), prominent in the centrum semiovale
and basal ganglia.
The radiologic findings prompted admission for observation and
additional testing. Thyroid, cortisol, lysosomal storage enzymes,
very-long-chain fatty acids, and vitamin E, vitamin B12, and folate levels
were normal. Plasma homocysteine was 200 μmol/L (normal less than
20 μmol/L), plasma methylmalonic acid was 1013 μmol/L (normal less than
30 μmol/L), and his plasma amino acid studies confirmed elevations in
homocystine as well as a low methionine. Urine organic acids also showed
excretion of high amounts of methylmalonic acid.
COMMENT Based on the MRI, neurologists would consider a diagnosis of an acquired

white matter disorder or an early presentation of hereditary disorders of
white matter such as metachromatic leukodystrophy or X-linked
adrenoleukodystrophy. Small molecule disorders such as organic acidurias
may also present in this way, and prompt specific treatment may be
lifesaving. This boy’s metabolic profile was consistent with a cobalamin
processing defect that results in elevated levels of methylmalonic acid
and homocysteine.7 He showed improvement once he began receiving
cobalamin injections.
46 FEBRUARY 2018
acidemia includes protein restriction, and some have benefited from
liver/kidney transplantation.
TABLE 2-4 also mentions two other organic acid disorders. Multiple
carboxylase deficiency caused by either biotinidase deficiency or
holocarboxylase synthetase deficiency can be treated with biotin. Multiple
carboxylase deficiencies should therefore be considered in any young child with

nonspecific neurologic findings, such as spasticity or myelopathy with upper

motor neuron findings, especially if skin abnormalities are present.11,12 Children
with glutaric aciduria type I may be seen by neurologists for their macrocephaly.
Their imaging, which shows widened sylvian fissures and prominent
subarachnoid spaces, may be misinterpreted as showing cortical atrophy.13
Prompt recognition of this disorder can prevent progressive brain (especially,
basal ganglia) injury. Management protocols for glutaric aciduria type I,
Selected Organic Acid Disorders TABLE 2-4

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Organic Acid Urine Organic Acid

Disorders Defective Enzyme (Cofactor) Findings Selected Clinical Findings
Propionic Propionyl-CoA carboxylase 3-Hydroxypropionate, Classic presentation in infancy with

acidemia8 (biotin) methylcitrate, tiglylglycine, encephalopathy, severe metabolic acidosis,
and propionylglycine hyperammonemia, and neutropenia; central
nervous system white matter and basal
ganglia abnormalities may develop
Isovaleric Isovaleryl-CoA dehydrogenase Isovaleryl glycine and Like methylmalonic acidemia and propionic
acidemia9,10 isovaleric acid acidemia, presents with encephalopathy
and metabolic acidosis; urine has a “sweaty
feet” odor; about one-half of patients
have a later-onset, more chronic form of
the disease
Multiple Four biotin-requiring 3-Hydroxypropionate, Biotinidase and holocarboxylase synthetase

carboxylase carboxylase enzymes, including 3-hydroxyisovalerate, and deficiency are associated with hypotonia,
deficiency11,12,a propionyl CoA carboxylase and 3-methylcrotonylglycine seizures, lethargy, irritability, alopecia, rash,
pyruvate carboxylase and laryngeal stridor,11 but biotinidase
deficiency is milder and presents later;
urine may have a strong (“tomcat”) odor;
myelopathy with or without vision loss is
one presentation of biotinidase deficiency;12
treatment with biotin is effective for both
disorders
Glutaric Glutaryl-CoA dehydrogenase Glutaric acid and After a period of normal development,
aciduria type I13 3-hydroxyglutarate infants present with metabolic crises
associated with dystonia, opisthotonus,
and seizures; may have macrocephaly and
involuntary movements; central nervous
system imaging shows widened sylvian
fissures and increased subarachnoid
spaces
CoA = coenzyme A.
a
Multiple carboxylase deficiency is due to biotinidase deficiency and holocarboxylase synthetase deficiency.
KEY POINTS including supportive care during illness and infection, will prevent catabolism
and the onset of metabolic crises.
● The organic acid
disorders methylmalonic
acidemia and propionic Amino Acid Disorders (Aminoacidopathies)
acidemia can selectively Amino acid disorders are due to enzyme defects in amino acid metabolism and
damage basal ganglia and are identified with plasma amino acid assays.2 (Urine amino acid assays are not
white matter.
usually indicated and should only be ordered by a metabolic specialist.) Amino

● Late-onset organic acid acid disorders are often characterized by early encephalopathy, usually without
disorders may be treatable metabolic acidosis, but the nature of the encephalopathy and clinical
and are relatively easy to presentation vary. Some of the better-known aminoacidopathies are discussed in
screen for with urine
studies; their identification
this article. All are inherited as autosomal recessive traits.
may prevent permanent
brain injury. PHENYLKETONURIA. Phenylketonuria is caused by defects in phenylalanine
hydroxylase (FIGURE 2-3), which converts phenylalanine to tyrosine in the
● Elevated phenylalanine
presence of the cofactor tetrahydrobiopterin. Elevated phenylalanine interferes
acts as a neurotoxin, which
is why the phenylalanine- with transport of tryptophan and tyrosine into the brain and also has direct toxic
restricted diet for effects on the brain. During early development, high levels of phenylalanine
phenylketonuria is a diet cause severe irreversible mental retardation. The devastating effects of
for life. phenylketonuria can be prevented by initiation of a phenylalanine restricted
09/2022
● Untreated
diet within the first weeks of life. Thanks to newborn screening, infants with
homocystinuria is phenylketonuria can be identified shortly after birth and treated early, thereby
associated with strokes, avoiding permanent cognitive impairment. However, because phenylalanine has
lens dislocation, and toxic effects even in the adult brain, patients with phenylketonuria are advised to
skeletal abnormalities.
stay on their diet for life. Phenylketonuria is the most common treatable
● The clinical presentation aminoacidopathy, with an incidence of approximately 1 per 11,000.14
of maple syrup urine
disease, with metabolic HOMOCYSTINURIA. Homocystinuria is caused by a deficiency in cystathionine
crisis and coma, is similar to
$-synthase, which catalyzes the metabolism of homocysteine to cystathionine.
the organic acid disorders,
but there may be no Some patients with homocystinuria respond to pharmacologic doses of
metabolic acidosis or pyridoxine. The reason for this is not quite clear since pyridoxine is not a
hypoglycemia. cofactor, although pyridoxal 50 -phosphate is a ligand for cystathionine
$-synthase. Since pyridoxine responsiveness only occurs when residual
cystathionine $-synthase activity is present, it is not surprising that those who are
unresponsive to pyridoxine have more severe presentations.15 Homocystinuria is
associated with the childhood onset of cognitive impairment, skeletal
abnormalities including lens dislocation, marked myopia, and vascular disease
with strokes and pulmonary embolism.
Other signs include bony abnormalities including scoliosis, anterior chest
deformities, and disproportionately long legs that are similar to those seen in Marfan
syndrome. Diagnosis is suggested by elevated plasma levels of homocysteine,
homocystine (measured in plasma amino acid assays), and methionine. Those who
do not respond to pyridoxine are placed on a methionine-restricted and cysteine-
supplemented diet and may also receive pyridoxine and betaine, a methyl donor
that remethylates homocysteine to methionine. These treatments appear to lower
the risk of intravascular thrombosis.16
MAPLE SYRUP URINE DISEASE. Maple syrup urine disease is a rare disorder
(incidence of approximately 1 per 185,000) caused by defects in the enzyme
branched chain a-keto acid dehydrogenase.17 Patients typically present in the
first 1 to 2 weeks of life when infants develop feeding difficulties and decreased
48 FEBRUARY 2018
responsiveness, after which stupor, respiratory abnormalities, myoclonus,
posturing, and spasms may occur. The characteristic odor of burnt sugar may
be detected at this time. The fontanelle may be full or bulging, and imaging studies
may show cerebral edema. Routine laboratory evaluation may show ketonemia/
ketonuria, metabolic acidosis, and hypoglycemia, or these findings may be absent,
requiring a high index of suspicion to make this diagnosis. Plasma amino acids (as
well as urine and CSF) will show elevations in leucine, isoleucine, valine, and their
keto acid derivatives; some of these compounds appear to be highly neurotoxic.
Less common presentations of maple syrup urine disease include neonatal
ophthalmoplegia (with or without other cranial nerve palsies), hypotonia,
episodic decompensations (CASE 2-5) (including coma and signs of raised
intracranial pressure), or more chronic failure to thrive and slowed development.17
The acute effects of maple syrup urine disease need to be treated with
aggressive supportive measures, including IV fluid hydration, dextrose
administration, and branched-chain amino acid–free total parenteral nutrition.9
Chronic maintenance treatment includes use of branched-chain amino acid–free
formulas and low-protein diets. Thiamine, a cofactor for branched-chain a-keto
acid dehydrogenase, may be used as an additional treatment in some cases. These
measures can significantly improve neurologic outcome when instituted promptly.
09/2022
Summary and the Role of Newborn Screening

Defects of intermediary protein metabolism (urea cycle disorders, organic acid
disorders, and aminoacidopathies) are relatively easy to diagnose using the
metabolic tests described in TABLE 2-1, and they have serious neurologic sequelae
A 5-year-old girl was admitted with a high fever, vomiting, and worsening CASE 2-5
somnolence. Her developmental history was normal. Encephalitis or
meningitis was suspected, and she was given acyclovir and cefotaxime.
A full septic evaluation was performed. Her lumbar puncture was normal,
and her other laboratory tests were remarkable only for mild hyponatremia
with a sodium level of 130 mmol/L and a low bicarbonate level of
11 mmol/L. Her plasma ammonia, glucose, and lactate were normal. The
patient’s head CT and later MRI were normal.
She had experienced a similar episode, also with a febrile illness,
2 years previously, also with similarly inconclusive screening tests.
However, during the current admission, she had more metabolic testing,
and her plasma amino acids showed elevations of leucine, isoleucine,
and valine, consistent with maple syrup urine disease. She was treated with
protein restriction and received parenteral glucose, nonbranched-chain
amino acids, and lipids to lower her branched-chain amino acid levels.
Clinical recovery followed.
This is a case of intermittent maple syrup urine disease, which can present COMMENT
18
with intermittent attacks of lethargy and ataxia, especially during illness.
Prevention of these attacks allows children with the intermittent form of
maple syrup urine disease to have normal development.
if unrecognized and untreated. Disorders of fatty acid and carbohydrate

metabolism (eg, medium-chain acyl-CoA dehydrogenase deficiency,
galactosemia) will not receive similar attention in this article, and the reader is
directed to other excellent resources.2,19 The disorders described above as well as
other important and treatable conditions arising from defects in the intermediary
metabolism are currently screened for in newborns in the United States so

that affected infants can be promptly recognized and receive appropriate

treatment.20 Still, it is important for the neurologist to keep in mind that
screening programs may still miss milder presentations of these disorders, so the
metabolic tests outlined in TABLE 2-1 remain important to consider. The next
section describes treatable inborn errors of metabolism seen by neurologists that
require additional tests to identify.
TREATABLE INBORN ERRORS OF METABOLISM NOT DETECTED ON COMMON

METABOLIC SCREENING
Many treatable inborn errors of metabolism that present to neurologists are
not readily identified by common metabolic screening tests nor do they
reliably present with metabolic acidosis or hyperammonemia. In the case of
09/2022
pyridoxine-dependent seizures and glucose-transporter deficiency syndrome,

these diagnoses are generally considered in the evaluation of a neonate with
refractory seizures, and it is in this setting that the additional tests, such as the
pyridoxine challenge or CSF glucose, are obtained. These diagnoses are less
frequently considered after early infancy, so a high index of suspicion is needed
to embark on screening and diagnostic testing. TABLE 2-5 lists some inborn errors
TABLE 2-5 Additional Metabolic Tests to Consider When Screening for

Treatable Inborn Errors of Metabolism
Treatable Inborn Errors Of Metabolism

Biochemical Assay/Test Identified Treatment
Blood and CSF lactate, Pyruvate dehydrogenase complex Ketogenic diet, thiamine
pyruvate deficiency
Few treatments; some may respond to biotin21
Pyruvate carboxylase deficiency
Blood copper, Wilson disease Chelation

ceruloplasmin
Menkes syndrome (X-linked) No treatment except in presymptomatic boys22,23
CSF glucose (compared Glucose transporter 1 deficiency Ketogenic diet

with serum glucose)
CSF amino acids Nonketotic hyperglycinemia No treatment for severe, early-onset form; in late-onset
disease, treatment includes glycine restriction, sodium
benzoate, N-methyl-D-aspartate (NMDA) receptor
antagonists24
Urine creatine Creatine deficiency syndromes (including Creatine, possibly with ornithine supplementation and
metabolites guanidinoacetate methyltransferase arginine restriction
deficiency)
50 FEBRUARY 2018
of metabolism in which additional biochemical assays may lead to KEY POINTS
treatable diagnoses.21–24
● Pyridoxine-dependent
epilepsy used to be a
Pyridoxine-Dependent Epilepsy clinical diagnosis but now
The classic presentation of pyridoxine-dependent epilepsy is an infant with biochemical (plasma and
severe neonatal seizures refractory to standard anticonvulsant therapy in urine α-aminoadipic

semialdehyde) and
whom the seizures respond both clinically and electrographically to large daily
molecular (ALDH7A1 gene)
supplements of pyridoxine (vitamin B6). Although neurologists have been aware tests are available.
of this disorder for some time, only recently has the exact defect been shown to
be mutations in the ALDH7A1 gene.25 Prior to having a true biochemical or ● Diagnosis of glucose
genetic test for the condition, the diagnosis had traditionally been a clinical one, transporter type 1 deficiency
requires documentation of
made by administering 100 mg to 500 mg of IV pyridoxine (pyridoxine low CSF glucose values in
challenge) while monitoring the EEG and looking for significant improvement the setting of normal blood
and cessation of seizures. Now, direct DNA testing is available, and the diagnosis glucose. Mutational testing
can also be confirmed by finding elevations in plasma and urine a-aminoadipic of the SLC2A1 gene can also
be performed.
semialdehyde. Later-onset forms or atypical cases include late-onset seizures (up
to 2 years of age); seizures that initially respond to anticonvulsants and then ● Patients with glucose
become intractable; seizures during early life that do not respond to pyridoxine transporter type 1 deficiency
but that are then controlled with pyridoxine several months later; and prolonged can be treated with the
09/2022
ketogenic diet.
seizure-free intervals (up to 5.5 months) that occur after pyridoxine
discontinuation. Cognitive impairment is common.
Pyridoxine-dependent seizures are treated with high doses of daily
pyridoxine. In the past, before specific testing was available, many children with
intractable early-onset epilepsy were continued on empiric pyridoxine treatment
for at least several months. It is also known that another form of neonatal
encephalopathy and seizures is caused by abnormalities in the pyridoxal
pathway. The related disorder is caused by recessive mutations in pyridoxal 50 -
phosphate oxidase,26 and this condition is treated with pyridoxal phosphate,
although some cases are responsive to pyridoxine.27
Glucose Transporter Type 1 Deficiency Syndrome

Glucose transporter type 1 deficiency syndrome is caused by impaired transport
of glucose across the blood-brain barrier, which causes a wide range of clinical
phenotypes, the most typical of which are early-onset seizures, developmental
delay, and movement disorders.28 This condition can also present with cognitive
impairment with fluctuating ataxia, motor incoordination, or altered
consciousness. Other children may have more normal developmental trajectories
but may have early-onset generalized epilepsy. The diagnosis is made by
documenting a low CSF glucose in the setting of normal blood glucose levels.
Mutation analysis of the SLC2A1 gene can also be performed. The evaluation of
the CSF glucose should be accompanied by a CSF lactate evaluation. In glucose
transporter type 1 deficiency syndrome, CSF lactate is low to normal, while it is
often elevated in other inborn errors of metabolism or infections.29 Without
glucose, the only other source for brain energy is through ketones, so treatment
with the ketogenic diet is recommended as it will likely stop the seizures and may
prevent other neurologic sequelae.
Creatine Deficiency Syndromes

Creatine deficiency syndromes are composed of three disorders that lead to
low creatine levels in the brain.30,31 They are caused by defects in creatine
biosynthesis due to a deficiency of either the enzyme arginine:glycine

amidinotransferase deficiency or guanidinoacetate methyltransferase deficiency
or caused by creatine transport defects due to mutations in the X-linked
transporter gene SLC6A8. In all cases, a nonspecific syndrome of developmental
and cognitive impairment, global delays, and epilepsy may occur. In
guanidinoacetate methyltransferase deficiency due to mutations in GAMT

(CASE 2-6), the epilepsy may be intractable, and patients may also develop a
CASE 2-6 A 30-month-old boy with a history of developmental delay presented

with a several-week history of brief eye-rolling episodes. In the past
week, the episodes had become more frequent and had been occurring
throughout the day, often lasting minutes at a time. His prior history was
notable for developmental delay after an unremarkable pregnancy and
birth. He began rolling at age 5 months, sitting at age 8 months, and taking
independent steps at 15 months of age. He was a quiet and content infant
who did not start using syllables or babbling until he was 10 months of age,
09/2022
and currently, at age 2 years, only said “uh oh” and “mo.” He repeated
other words when prompted but had limited spontaneous speech, did not
follow simple commands, and tended to get objects he wanted rather
than point to them. The patient had no history of regression and was
otherwise healthy. His growth parameters (stature, weight, and head
circumference) had been proceeding along the 50th to 60th percentiles.
His family history was unremarkable for developmental delays,
intellectual disabilities, autism, or seizures.
Video-EEG monitoring over 2 days showed a slow-waking background
and frequent epileptiform discharges with complex morphology lasting 1
to 5 seconds. Discharges lasting more than 3 seconds had clear clinical
correlates, including eye rolling and, occasionally, myoclonic jerks of his
head and shoulders. His head MRI with contrast was normal. He was
started on clobazam, then levetiracetam was added, but after several
months, his seizures continued. Metabolic testing, including all tests listed
in TABLE 2-2 (performed for ketogenic diet initiation), was normal. Because of
his history of delays and his refractory epilepsy, chromosomal microarray
testing and a next-generation sequencing epilepsy panel were ordered.
The microarray was normal, but the next-generation sequencing
epilepsy panel showed two pathogenic variants in the guanidinoacetate
N-methyltransferase (GAMT) gene, predicted to cause a creatine deficiency
syndrome. When appropriate treatment was instituted, his seizures resolved
within days, and within weeks he began speaking.
COMMENT This boy’s impressive recovery after diagnosis and initiation of disease-
specific treatment shows the value of thinking about treatable causes of
neurologic presentations such as developmental delay and epilepsy. The
use of next-generation sequencing epilepsy panels or the newer
metabolomics panel offers hope that these potentially treatable diagnoses
will not be missed.
52 FEBRUARY 2018
movement disorder with basal ganglia abnormalities on MRI. Magnetic
resonance spectroscopy will demonstrate a deficient creatine peak. However,
this testing is not always feasible in routine clinical practice. Diagnosis is
generally made by measurement of guanidinoacetate, creatine, and creatinine
in urine and plasma, but these tests may not be straightforward to obtain. The
creatine depletion and clinical effects of guanidinoacetate methyltransferase

and arginine:glycine amidinotransferase deficiency (but not the X-linked

transporter defect) may be partially reversed with creatine supplementation.
Guanidinoacetate methyltransferase deficiency is also treated with ornithine
supplementation and dietary arginine restriction.
Pyruvate Dehydrogenase Complex Deficiency

The pyruvate dehydrogenase complex converts pyruvate into acetyl-CoA, one
of the first crucial steps of the tricarboxylic acid cycle. The excess pyruvate is
converted to lactate, and pyruvate dehydrogenase complex deficiency is the most
common disorder leading to lactic acidemia.32 This complex consists of three
enzymes, the complicated reactions of which depend on a number of coenzymes,
including thiamine. Defects in pyruvate dehydrogenase complex limit
carbohydrate metabolism and decrease energy production. Most cases of
09/2022
pyruvate dehydrogenase complex deficiency are caused by defects in the E1

a-subunit gene PDHA1 on Xp22. Although X-linked, both males and females
with mutations in PDHA1 can present with severe or milder symptoms. The most
severe presentation includes brain malformation with neonatal lactic acidosis.
Seizures, apnea, worsening weakness, and ataxia are also reported. MRI findings
with basal ganglia and brainstem abnormalities are common. While the diagnosis
is suggested by elevated lactate in blood and CSF, mutational analysis (eg, genetic
mitochondrial next-generation sequencing panel) is useful. Some, but not all,
patients benefit from a ketogenic diet33 and thiamine supplementation.
Wilson Disease
Wilson disease is a disorder of copper transport caused by mutations in a
copper-transporting ATPase gene (ATP7B) that causes gradual copper
accumulation in the liver, brain, kidney, and cornea.34 The presentation may be
with hepatic disease (jaundice, hepatitis, rapidly progressive liver failure) or a
neuropsychiatric disorder (tremor, dysarthria, irritability, psychosis). The
diagnosis is suggested by low serum copper and ceruloplasmin with increased
urinary copper excretion. Treatment consists of copper chelation with
penicillamine or trientine, zinc to interfere with copper absorption, and avoidance
of high copper-containing foods. Liver transplant may also be indicated. For more
information on Wilson disease, refer to the article “Wilson Disease” by Ronald F.
Pfeiffer, MD, FAAN,35 in the August 2016 issue of Continuum.
APPROACHES TO TESTING FOR INBORN ERRORS OF METABOLISM

The treatable disorders of metabolism described in this article are individually
rare but, as a group, are likely to be seen in neurology practices. While readily
available and relatively inexpensive screening tests such as those listed in TABLE 2-1
may be useful in some cases, this approach will identify only a small portion
of the inborn errors of metabolism likely to present to neurologists. TABLE 2-5
lists a few more tests that may be useful in metabolic screening. However,
metabolic assays can be challenging to interpret with their own false positives
and risks for missed diagnoses. Often, these assays are repeated multiple times
when results are ambiguous, which increases the costs of screening.
A more comprehensive approach to metabolic testing might involve
whole-exome sequencing or phenotype-driven next-generation sequencing
panels (eg, comprehensive epilepsy panels, ataxia panels). The yield of
next-generation sequencing epilepsy panels in epileptic encephalopathy is

relatively high,36,37 and they not only help make diagnoses but provide assurance
that a treatable inborn error of metabolism has not been missed. The cost of this
technology is a barrier to widespread use, but this may change as the costs go
down and as the burdens of repeated metabolic (especially CSF) testing are
recognized. Metabolomics profiling is a small molecule screening approach that
promises to provide a much more comprehensive survey of metabolic
derangements than can currently be assessed using other available metabolic
tests.38,39 While these platforms are cheaper than next-generation sequencing
panels, they still require additional confirmatory biochemical and molecular
diagnostic testing. If metabolomics profiling detects two or three potential
targets, then the costs of following up with additional testing may begin to
approach that of whole-exome sequencing.
Several of the small molecule disorders discussed in this article are screened in
09/2022
newborns to ensure that treatment is provided promptly. It should also be kept in

mind that newborn screening programs in the United States are regulated and
managed by each state, leading to regional variations in clinical follow-up and
care. Furthermore, some forms may present later in life, and some older children
and adults will not have had an opportunity to be screened for these disorders.
For these reasons, it is preferable to repeat metabolic screening tests, even if the
newborn screen was known to be normal, if testing appears clinically indicated.
The best strategies for performing an extended metabolic screening
evaluation will vary with clinical presentation. While this article is meant
to serve as an introduction to more familiar treatable inborn errors of
metabolism, additional resources can help clinicians interested in refining
their metabolic screening strategy for particular patients (refer to the
section on useful websites).
CONCLUSION
This article discusses testing for inborn errors of metabolism, specifically those
disorders of small molecules that are relatively easy to screen for, are treatable,
and for which effective treatment leads to improved neurologic outcomes.
Yet, many of these defects in intermediary metabolism, so readily screened for
using plasma amino acids, urine organic acids, and acylcarnitine profiling, are
not ones that practicing neurologists are likely to diagnose in practice. In fact,
many of the more important and treatable conditions are already screened for in
newborns in the United States.20 The list of other inborn errors of metabolism
that cause epilepsy,40 weakness,41 or leukodystrophies,42 for example, is
extensive and should be considered by the clinician in the appropriate clinical
scenario. Newer technologies such as metabolomics screening improve the
sensitivity of existing biochemical assays, but whole-exome sequencing remains
a powerful, although still expensive, tool for diagnosing rare but potentially
treatable inborn errors of metabolism.
54 FEBRUARY 2018
USEFUL WEBSITES
TREATABLE INTELLECTUAL DISABILITY: AN INTERACTIVE NATIONAL MEABOLIC BIOCHEMISTRY NETWORK
TOOL FOR THE CLINICIAN The United Kingdom’s National Metabolic
This website summarizes more than 80 treatable Biochemistry Network website contains useful
inborn errors of metabolism that are related to guidelines and basic training videos for metabolic
intellectual disability. testing.

treatable-id.org metbio.net/metbioTraining.asp
GENETIC METABOLIC CENTER FOR EDUCATION

This website provides a four-part tutorial video
series, Metabolism 101, that reviews basic
information about metabolic disease identification
and management.
geneticmetabolic.com
REFERENCES
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31(4):1031–1035. doi:10.1016/j.ncl.2013.04.005. Vogelstein B, et al, eds. The online metabolic and
molecular bases of inherited disease. New York, NY:
2 Saudubray JM, van den Berghe G, Walter J. Inborn McGraw-Hill, 2014. ommbid.mhmedical.com/
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27 Plecko B, Paul K, Mills P, et al. Pyridoxine
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28 Pearson TS, Akman C, Hinton VJ, et al. Phenotypic 40 Pearl PL. Amenable treatable severe pediatric
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13(4):342. doi:10.1007/s11910-013-0342-7.
41 Angelini C. Spectrum of metabolic myopathies.
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fluid analysis in the workup of GLUT1 deficiency 10.1016/j.bbadis.2014.06.031.
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56 FEBRUARY 2018
Hypoxic-Ischemic REVIEW ARTICLE

Encephalopathy C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
and Other Neonatal

Encephalopathies
By Hannah C. Glass, MDCM, MAS
ABSTRACT
PURPOSE OF REVIEW: Neonatal encephalopathy is the most common condition
in neonates encountered by child neurologists. The etiology is most often
global hypoxia-ischemia due to failure of cerebral perfusion to the fetus
caused by uterine, placental, or umbilical cord compromise prior to or
09/2022
during delivery. Other etiologies of neonatal encephalopathy include

ischemic stroke and intracranial hemorrhage, infection, developmental
anomalies, and inborn errors of metabolism. CITE AS:
2018;24(1, CHILD NEUROLOGY):
RECENT FINDINGS: Therapeutichypothermia is standard of care for the 57–71.
treatment of neonatal encephalopathy presumed to be caused by
hypoxia-ischemia. The number needed to treat is approximately 6 to 7 to Address correspondence to
prevent one child from either death or disability at age 18 to 22 months. EEG Dr Hannah C. Glass, 675 Nelson
Rising Ln, Box 0663, San
monitoring and MRI are important tools in determining the etiology of Francisco, CA 94158, Hannah.
encephalopathy and prognosis of the infant. Glass@ucsf.edu.
SUMMARY: Neonatal encephalopathy is a heterogeneous disorder that is Dr Glass has served on the
characterized by alterations in mental status, hypotonia, seizures, and editorial board of Pediatric
Neurology and has given expert
abnormalities in feeding and respiration. The most common cause of medical testimony related to
neonatal encephalopathy is hypoxic-ischemic encephalopathy, for which medicolegal proceedings.
treatment with 72 hours of therapeutic hypothermia is associated with Dr Glass receives research/grant
support from the Cerebral Palsy
reduced death or disability. Alliance, National
Institutes of Health (grant
numbers 1P01NS082330,
1UG3OD023272, and
INTRODUCTION R03HD090298), Patient-Centered
N
eonatal encephalopathy is a heterogeneous condition that can be due Outcomes Research Institute,
and Pediatric Epilepsy
to any disorder that disrupts the central nervous system in the first Research Foundation.
days of life. The characteristic signs of neonatal encephalopathy are
UNLABELED USE OF
altered mental status (eg, irritability, decreased responsiveness,
coma), seizures, hypotonia, abnormal primitive reflexes, apnea, USE DISCLOSURE:
feeding disturbance, and abnormal cry.1 Neonatal encephalopathy may be Dr Glass discusses the
transient and reversible or may be the first sign of a brain injury, intracranial fosphenytoin, levetiracetam, and
infection, or brain malformation that leads to a lifelong disability. phenobarbital for the treatment
Neonatal encephalopathy that is caused by an intrapartum event leading to of neonatal seizure disorders.
perinatal hypoxia-ischemia (sometimes called perinatal asphyxia) has historically © 2018 American Academy
been called hypoxic-ischemic encephalopathy (HIE); however, some prefer the term of Neurology.
HYPOXIC-ISCHEMIC ENCEPHALOPATHY
neonatal encephalopathy given that the exact pathogenesis is often not known.2,3
In this article, the term neonatal encephalopathy will be used as an umbrella term
that encompasses HIE (or encephalopathy that is presumed to be caused by
hypoxia-ischemia).
EPIDEMIOLOGY
The incidence of neonatal encephalopathy in the developed world is estimated

at 2 to 6 per 1000 live term births, with HIE occurring in approximately 1.5 per
1000 live term births.4–6 Neonatal encephalopathy that is due to suspected or
confirmed HIE is among the most common diagnoses encountered by a child
neurologist and accounts for approximately 40% of new consults in the neonatal
intensive care unit.7,8
CLINICAL PRESENTATION
Clinical signs of encephalopathy include changes in consciousness and tone
and depressed primitive reflexes as well as seizures. Sarnat and colleagues9
classified the severity of encephalopathy in the setting of presumed HIE as
mild, moderate, or severe based on the worst degree of encephalopathy as
observed on serial examinations. Importantly, the severity of encephalopathy
09/2022
is associated with mortality. Children with severe encephalopathy have a high

rate of mortality, and survivors have a very high likelihood of permanent
neurologic disability, whereas those with mild encephalopathy survive, and
those with moderate encephalopathy have intermediate rates of death
or disability.
ETIOLOGY
Neonatal encephalopathy may be due to a variety of conditions that can impair
the central nervous system. While a well-defined hypoxic-ischemic event (eg,
placental abruption, uterine rupture, cord prolapse) is the cause of encephalopathy
in many infants, other causes of altered mental status or seizures in a neonate
include ischemic or hemorrhagic stroke, infection, brain malformation, genetic
conditions, and inborn errors of metabolism (TABLE 3-1 10). Often, the exact
etiology remains unexplained.
In many neonates with encephalopathy, the initial encephalopathy and
seizures may resolve in the neonatal period. However, if the child has
experienced a brain injury, neurologic deficits can emerge as the child ages.
EVALUATION OF THE NEONATE WITH ENCEPHALOPATHY

Since the etiology of encephalopathy is broad, a careful evaluation is warranted,
especially in cases where the risk of perinatal asphyxia is low or where no sentinel
event occurred.
History and Physical Examination

Maternal history should focus on an evaluation for antecedents of neonatal
encephalopathy, including maternal medical history (eg, history of thromboembolic
disorders and pregnancy loss) and use of medications or substance abuse, obstetric
history (eg, results of prenatal screening and fetal ultrasounds), intrapartum events
(including fetal heart rate monitoring), and placental pathology (to evaluate for
placental abruption, vascular lesion, infection, or umbilical cord thrombosis). A
family history of epilepsy and congenital neurologic and neuromuscular conditions
may be a clue to a diagnosis other than HIE.
58 FEBRUARY 2018
The infant’s history must detail the onset, timing, and progression of KEY POINTS
encephalopathy and seizures. The presence of oliguria, hypotension, transaminitis,
● The hallmark signs of
or coagulopathy suggests multiorgan failure and can support the occurrence of a neonatal encephalopathy
global hypoxic event and a diagnosis of HIE. are altered mental status
In addition to a comprehensive neurologic examination, neonates should be (eg, irritability, lethargy,
carefully evaluated for signs of abnormal fetal development, including coma), seizures, hypotonia,
abnormal primitive reflexes,
dysmorphic craniofacial features, birthmarks, and congenital anomalies of the apnea, feeding disturbance,
internal organs and skeleton. A single or absent palmar crease, micrognathia, and and abnormal cry.
joint contractures can indicate a long-standing decrease in fetal movements,
suggesting prenatal onset of encephalopathy. ● Neonatal encephalopathy
that is caused by an
intrapartum event leading to
Laboratory Evaluation perinatal hypoxia-ischemia
Umbilical artery pH and base excess provide important clues regarding fetal (sometimes called perinatal
perfusion. A comprehensive laboratory evaluation also includes newborn blood asphyxia) has historically
been called hypoxic-ischemic
gas and lactate levels; a complete blood cell count, C-reactive protein, calcitonin,
encephalopathy; however,
and blood cultures to look for signs of infection; glucose; electrolyte panel; tests some prefer the term
for liver enzymes; creatinine and blood urea nitrogen; bilirubin levels; and a neonatal encephalopathy
coagulation profile. If central nervous system infection is suspected, lumbar given that the exact
pathogenesis is often
puncture should be performed for cell count, cultures, and viral studies (eg, herpes
09/2022
not known.
simplex virus, Parechovirus, and rotavirus, among others). In areas without a
comprehensive newborn screen to test for inborn errors of metabolism or in cases ● While a well-defined
where an inborn error of metabolism is suspected, additional evaluation including hypoxic-ischemic event (eg,
serum ammonia, serum amino acids, and urine organic acids may be warranted. placental abruption, uterine
rupture, cord prolapse) is
Genetic evaluation, including single-nucleotide polymorphism array, is the cause of
important to evaluate for the cause of congenital anomalies (including isolated encephalopathy in many
brain malformations) and suspected syndromic diagnoses. infants, other causes of
altered mental status or
seizures in a neonate
Neurophysiologic Monitoring include ischemic or
According to the American Clinical Neurophysiology Society, neurophysiologic hemorrhagic stroke,
brain monitoring using continuous video-EEG or, if continuous EEG is not infection, brain
available, an adapted montage and trending such as amplitude-integrated EEG is malformation, genetic
conditions, and inborn
important to assess the degree of encephalopathy and recovery, as well as the
errors of metabolism.
presence of seizures.11 Clinical evaluation alone without neuromonitoring can both
overestimate and underestimate the burden of seizures. Clinical observation ● In addition to a
is unreliable, as movements that are not seizures may be interpreted as such comprehensive neurologic
by the bedside staff.12,13 In addition, neonates frequently have seizures examination, neonates with
encephalopathy should be
without clinical correlate (subclinical seizures), and so seizures may go carefully evaluated for signs
undetected or underrecognized in neonates who do not receive monitoring.14–16 of abnormal fetal
Amplitude-integrated EEG is a limited channel recording that is displayed as a development, including
compressed tracing at the bedside (FIGURE 3-1).17 The advantage of this tool is dysmorphic craniofacial
features, birthmarks, and
that it is easy to apply and interpret by bedside nursing and medical staff. The congenital anomalies of the
primary disadvantage is that it has lower accuracy for seizure detection. internal organs and skeleton.
Neurophysiologic brain monitoring should continue for at least 24 hours or until
24 hours after the last seizure.11
Neuroimaging
MRI is recommended for all neonates with encephalopathy or seizures to assist
with identifying the etiology of encephalopathy and to assist with prognosis.
Head ultrasound is useful as a bedside tool to determine the presence of
hemorrhage or ventriculomegaly; however, after a hypoxic-ischemic event,
head ultrasound is often normal in the acute setting.18 CT is rarely used in

infants because of the need for high radiation doses to achieve adequate
resolution of brain parenchyma.
MRI can be performed safely (and often without sedation) in critically ill
children with appropriate monitoring and training. In addition to conventional
imaging (T1- and T2-weighted MRI), diffusion-weighted imaging (DWI) and

magnetic resonance spectroscopy are important to identify acute injury, whereas

susceptibility-weighted imaging (SWI) can improve identification of small areas
TABLE 3-1 Differential Diagnosis of a Neonate With Altered Mental Status or Seizures
Hypoxic-Ischemic Encephalopathy (Global Hypoxia-Ischemia)

u Sentinel hypoxic or ischemic event occurring immediately before or during labor and delivery
(eg, placental abruption, uterine rupture, cord prolapse)
u Heart rate monitor patterns consistent with an acute peripartum or intrapartum event
u Apgar score of less than 5 at 5 minutes and 10 minutes
09/2022
u Fetal umbilical artery pH of less than 7.0 or base deficit of 12 mmol/L or greater
u Onset of encephalopathy within the first 24 hours of life
u Presence of multiorgan failure consistent with hypoxia-ischemia (eg, elevated transaminases,
hypotension/cardiomyopathy, renal failure, bone marrow failure)
Bacterial or Viral Sepsis or Intracranial Infection
u Set up for infection (eg, prolonged rupture of membranes, maternal fever, and chorioamnionitis)
u Mother positive for group B streptococcus
u Temperature instability
u Apnea/bradycardia
u Hypotension
u Hepatic dysfunction including hyperbilirubinemia
u Disseminated intravascular coagulopathy
Ischemic Perinatal Stroke
u Neonate who appears otherwise healthy with focal motor seizures is the most common
clinical presentation
u Focal arterial ischemia on MRI
Intracranial Hemorrhage
u Small subdural hemorrhages are rarely symptomatic
u Intraventricular hemorrhage and periventricular or cerebellar hemorrhages due to fragile
germinal matrix are a common cause of encephalopathy and seizures in preterm neonates
u Intraventricular hemorrhage/thalamic hemorrhage in a term neonate should prompt search for
cerebral sinovenous thrombosis
u Parenchymal hemorrhages in a term neonate may be due to sinovenous thrombosis, trauma,
coagulopathy, vascular malformation, or genetic cause (eg, collagen type IV alpha 1 chain
[COL4A1] mutation), although the cause is often not found
60 FEBRUARY 2018
of hemorrhage. Conventional T1 and T2 images must be evaluated for structural
developmental malformations, as these lesions may cause early encephalopathy
or seizures and may also predispose to secondary hypoxic-ischemic injury during
the birth process.19 DWI can be used to detect anatomic areas of injury in the
acute phase (approximately the first 7 to 10 days after injury). Magnetic
resonance spectroscopy may show a lactate peak (a sign of abnormal metabolism

most often due to acute injury) or low N-acetylaspartate (NAA) (indicating

decreased neuronal integrity).
Brain Malformation
u Abnormal fetal or neonatal ultrasound or MRI
u Associated craniofacial dysmorphisms or organ anomalies
09/2022
u Genetic abnormality
Inborn Error of Metabolism
u Cerebral edema or symmetric pattern of injury
u Persistent lactic acidosis
u High ammonia
u Feeding intolerance/vomiting
u Unusual odor
Neonatal-Onset Epileptic Encephalopathy
u Persistent clinical and/or EEG seizures despite medication escalation
u Prominent tonic symptomatology
u EEG with persistent burst suppression

u Worsening clinical status or EEG patterns
u MRI in the first week of life without acute injury
u Gene mutation (eg, KCNQ2, KCNQ3, SCN1A, SCN2A, SLC13A5, STXBP1, KCNT2, GDLC,
CDKL5, CHD7)10
Transient Encephalopathy
u Maternal use of selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine

reuptake inhibitors (SNRIs), drugs of abuse
u Electrolyte abnormality
u Hypoglycemia
EEG = electroencephalogram; MRI = magnetic resonance imaging.
09/2022
FIGURE 3-1
Concurrent EEG and amplitude-integrated EEG in two neonates with presumed hypoxic-ischemic
encephalopathy. Neonatal EEG montage is displayed at 15 mm/sec and with sensitivity of
7 µV/mm (A) and 15 µV/mm (B). Amplitude-integrated EEG time scale is noted with each
compressed trace, representing more than 3 hours of recording. A, Upper panel of normal
continuous EEG and amplitude-integrated EEG shows normal continuous voltage with cycling
in a neonate with encephalopathy presumed to be caused by hypoxic-ischemic encephalopathy
who is status post–therapeutic hypothermia. B, Lower panel showing neonate with
encephalopathy presumed due to be caused by hypoxic-ischemic encephalopathy. The
seizure arising from T4 on the EEG is evident as a sudden rise in the lower and upper margins
of the suppressed amplitude-integrated EEG.
62 FEBRUARY 2018
MRI is an important prognostic tool, as the pattern and severity of injury KEY POINTS
are helpful in predicting later deficits. For neonates who receive therapeutic
● The American Clinical
hypothermia, the burden of injury apparent on MRI is lower, particularly in basal Neurophysiology Society
ganglia and thalamus but also in the white matter and watershed regions.20–22 recommends
neurophysiologic monitoring
MANAGEMENT OF THE ENCEPHALOPATHIC NEONATE using continuous EEG or
amplitude-integrated EEG to
Neonates with encephalopathy should be cared for in a neonatal intensive care determine the presence of
unit with capacity to provide neuromonitoring, neuroimaging, and subspecialty electrographic seizures and
neurologic care. to establish the severity of
encephalopathy.
Neurocritical Care
● MRI is recommended
Advances in basic cardiopulmonary support, favorable evidence from the adult for all neonates with
neurocritical care literature, and improved understanding of the impact of encephalopathy or seizures
critical illness on the developing brain have led to the emergence of neonatal to assist with identifying the
neurocritical care (also called neonatal neurointensive or brain-focused care) as etiology of encephalopathy,
as well as for assisting
an important approach that can potentially improve developmental outcomes in with prognosis.
neonates with encephalopathy.23 The focus of neonatal neurocritical care
involves a culture change for the entire neonatal intensive care unit toward ● Optimized care involves
brain-focused care, such that all care providers are continually aware of the active management of
09/2022
temperature (including
neurologic implications of critical illnesses and the impact of management therapeutic hypothermia
strategies on the developing brain.24,25 For example, optimized care involves for neonates with
active management of temperature (including therapeutic hypothermia for encephalopathy due to
neonates with encephalopathy due to hypoxia-ischemia and avoiding hyperthermia hypoxia-ischemia and
avoiding hyperthermia for all
for all brain-injured neonates),26 blood pressure (to avoid fluctuations in brain
brain-injured neonates),
perfusion in the setting of critical illness and pressure passive circulation), oxygenation/ventilation,
oxygenation/ventilation, and glucose (especially avoiding hypoglycemia, which and glucose (especially
can cause de novo injury and may exacerbate underlying hypoxic-ischemic avoiding hypoglycemia,
which can cause de
injury).27–29 This attention to physiologic homeostasis is especially important
novo injury and may
during resuscitation and the so-called “golden” first hour after delivery.30 exacerbate underlying
In addition to medical management, application of advanced technologies such hypoxic-ischemic injury).
as digital EEG with bedside trending (such as amplitude-integrated EEG) and
remote review allow bedside assessment of brain function in real time. Furthermore, ● Therapeutic hypothermia
to 33.5°C (92.3°F) for
safe, high-resolution brain imaging using MRI is widely available as an important 72 hours is standard of care
tool to assess the impact of critical illness on brain structure and development. for neonates who are at least
A focus on the brain during the period of critical illness allows for medical 36 weeks gestational age
interventions, including application of therapeutic hypothermia and treatment and who have neonatal
encephalopathy that is due
of seizures in real time, developmentally supportive care, compassionate to suspected or confirmed
communication with families, and, if appropriate, early decision making hypoxia-ischemia.
regarding goals of care. According to the literature on acute brain injury in adults,
a neurocritical care approach leads to higher rates of favorable outcomes by the
following mechanisms: (1) earlier recognition and treatment of neurologic
conditions; (2) prevention of secondary brain injury through attention to
maintenance of physiologic homeostasis of factors such as temperature, blood
pressure, and glucose; (3) consistent management using guidelines and protocols;
and (4) use of experienced specialized teams at dedicated referral centers.31
Therapeutic Hypothermia for Neonatal Encephalopathy

Therapeutic hypothermia to 33.5°C (92.3°F) for 72 hours is standard of care
for neonates at least 36 weeks gestational age at birth who have neonatal
encephalopathy that is due to suspected or confirmed hypoxia-ischemia.32 The
proposed mechanisms of neuroprotection by hypothermia include suppression

of apoptosis, reduced inflammation and cytotoxic edema, lowered cerebral
metabolism, and modulation of seizure severity.33 Several randomized controlled
trials and meta-analyses demonstrated reduced death or disability at 18 to
24 months of age (relative risk 0.75, 95% confidence interval, 0.68–0.83), a higher
number of children with a normal outcome, and sustained benefits to children

from infancy until they reach school age (although loss to follow-up has been a
significant issue in the large trials).34–36 The number needed to treat to prevent
death or disability is, on average, about 6 to 7. A trial of longer (120 hours) or
deeper (32.0°C [89.6°F]) cooling was terminated early when a futility analysis
determined that the likelihood of benefit of longer or deeper cooling (or both) for
neonatal death was less than 2%.37
Eligibility criteria varied slightly between the clinical trials and typically
involved some combination of gestational age (generally 36 weeks or more,
although one study cooled neonates at 35 weeks), indicator of perinatal distress
(an Apgar score of less than 5 at 10 minutes, blood gas pH of less than 7.00 or
base excess of −12 mmol/L to −16 mmol/L or more from the umbilical cord or
within the first hour of life, or more than 10 minutes of resuscitation), and
moderate to severe encephalopathy. Some regional systems have implemented
09/2022
screening criteria for when to call a cooling center to improve identification of

eligible neonates.
Therapeutic hypothermia should be implemented within 6 hours after birth, and
evidence from preclinical studies and the randomized controlled trials suggests
that earlier implementation leads to lower rates of death or moderate/severe
disability.38–40 Disability is variably defined depending on the trial and is typically
some combination of low scores on standardized cognitive testing, functionally
disabling cerebral palsy, epilepsy, and vision or hearing impairment.41
Passive cooling can be safely initiated prior to transport; servo-controlled
devices that help to maintain stable temperature and avoid overcooling are
available for use during transport.42 Both head cooling and whole-body cooling
appear equally effective.34 Whole-body cooling has been preferentially adopted due
to the ready availability of cooling blankets at many centers, as well as better access
to the infant’s head for brain monitoring using EEG. Many centers use sedation
(eg, with morphine sulfate) to prevent discomfort, cold stress, and shivering.
Continuous brain monitoring, preferably with continuous video-EEG, is
recommended for all neonates undergoing hypothermia.11 The risk of seizures in
neonates undergoing hypothermia is approximately 50%.43–45 Seizures most
commonly arise within the first 24 hours of life and should be treated as rapidly
as possible after detection using adequate doses of antiseizure medications.
Phenobarbital (20 mg/kg initial dose) and phenytoin (or preferably fosphenytoin
at 20 mg/kg of phenytoin equivalents) have similar efficacy; however, approximately
one-half of children have recurrent seizures after the initial bolus of either
medication.46 Levetiracetam is also used to treat seizures in neonates (40 mg/kg
to 60 mg/kg initial dose); however, limited data exist regarding efficacy. In the
case of recurrent seizures, escalating doses of antiseizure medications are warranted
to abolish electrographic seizures (including those without clinical correlate).
Recurrent (or rebound) seizures have been reported during the rewarming phase
of therapeutic hypothermia, although this phenomenon appears to be relatively
uncommon.47 In the setting of acute symptomatic seizures due to HIE, prolonged
treatment is rarely warranted. Although limited evidence exists to guide duration
64 FEBRUARY 2018
of treatment, in almost all cases, KEY POINTS
antiseizure medications can safely
● Eligibility criteria in
be discontinued once the acute clinical trials for therapeutic
symptomatic seizures hypothermia for neonatal
have resolved.48,49
encephalopathy varied
EEG is prognostic for brain slightly between trials and
typically involved some
injury and developmental combination of gestational

outcomes in neonates undergoing age, indicator of perinatal
hypothermia. Normal or mildly distress, and moderate to
abnormal EEG (eg, mild excess severe encephalopathy.
discontinuity) or early recovery
● Therapeutic hypothermia
from severe abnormalities within should be implemented
the first 24 to 36 hours after birth within 6 hours after birth,
portends good prognosis, whereas and evidence from
severe (and especially persistently preclinical studies and the
randomized controlled trials
severe) abnormalities (eg, burst suggests that earlier
suppression, depressed and implementation leads to
FIGURE 3-2
undifferentiated tracing, extremely Apparent diffusion coefficient map on the fourth better outcomes.
low voltage) are associated with
09/2022
day after birth in a full-term neonate born by

● Continuous brain
moderate to severe brain injury, cesarean delivery after maternal uterine rupture
monitoring, preferably
50–52 shows reduced diffusion in the ventrolateral
death, and disability. with continuous video-EEG,
thalamus, basal ganglia, motor cortex,
MRI is recommended for all hippocampus, and brainstem.
is recommended for all
neonates undergoing neonates undergoing
hypothermia.
hypothermia to assist with
determining etiology of ● The risk of seizures in
encephalopathy, timing of injury, and prognosis. The predominant patterns of neonates undergoing
injury in neonates with HIE are (1) basal ganglia/thalamus (with extension to hypothermia is
rolandic cortex, hippocampus, and brainstem in severe cases), which is seen approximately 50%.
predominantly in the setting of acute profound disruption in placental ● Normal or mildly

perfusion FIGURE 3-2, and (2) watershed areas (with injury to the watershed abnormal EEG (eg, mild
zones of the anterior, middle, and posterior cerebral arteries), which occurs in excess discontinuity) or
the setting of partial prolonged disruption of placental perfusion (CASE 3-1 and early recovery of severe
abnormalities within the first
CASE 3-2).
53
24 to 48 hours after birth
Hypothermia is associated with reduced extent of injury on MRI, especially portends good prognosis,
injury to the thalamus and basal ganglia.20,21 MRI is useful to ensure that whereas severe (and
the diagnosis of HIE is, in fact, correct given that children with underlying especially persistently
severe) abnormalities
anomalies are at higher risk for peripartum asphyxia and imaging may reveal
(eg, burst suppression,
unexpected findings such as brain malformations.19,54 In addition, the MRI depressed and
provides useful prognostic information (TABLE 3-255–60).20,59 Children undifferentiated tracing,
with injury to the thalamus or basal ganglia typically develop cerebral palsy, extremely low voltage) are
associated with brain injury,
whereas outcome for children with the watershed pattern of injury is
death, and disability.
variable, and outcome may be favorable even in children with severe injury.57,60
Alternative and Adjuvant Neuroprotective Agents

Multiple alternative and adjuvant agents that target various mechanisms in
the cascade of events that lead to neuronal necrosis and apoptosis are under
investigation in preclinical and clinical studies.61,62 Examples of target mechanisms
and agents include (1) preventing free radical–induced injury (eg, antioxidants
such as melatonin, allopurinol, and N-acetylcysteine), (2) reducing excitotoxicity
(eg, xenon, magnesium sulfate, cannabinoids), (3) anti-inflammation, and
(4) repair and regeneration (eg, erythropoietin, stem cells). These agents are
currently being evaluated in preclinical or clinical trials and are not in widespread
clinical use.
Prognosis
Neonates with encephalopathy are at risk for long-term disabilities, including

cerebral palsy, epilepsy, and cognitive impairment. The predictors of unfavorable

outcomes are indicated in TABLE 3-2. Therapeutic hypothermia does not prevent
adverse outcomes in all patients. The rate of death or disabilities in the
randomized controlled trials was approximately 50%.63 Similarly, the rates of
cerebral palsy and developmental delay are lower among cooled neonates; however,
they remain approximately 19% for cerebral palsy and 23% for developmental delay.
CASE 3-1 An infant girl was born at 39 weeks gestation by emergent cesarean
delivery due to maternal placental abruption. Apgar scores were assigned
as 0 at 1 minute, 2 at 5 minutes, 2 at 10 minutes, and 5 at 15 minutes. Cord
09/2022
arterial pH was 6.90 with base deficit 17 mmol/L. The initial neurologic
examination 60 minutes after birth was remarkable for decreased
responsiveness, absent suck/gag, generalized hypotonia, and
stereotyped response to noxious stimuli.
Therapeutic hypothermia was initiated for treatment of suspected
hypoxic-ischemic encephalopathy (HIE) due to placental abruption. The
target temperature was achieved by 2 hours after birth. The initial EEG
was discontinuous with interburst intervals of up to 17 seconds and
without obvious state changes. Fourteen hours after birth, the infant
experienced four focal seizures lasting 45 to 60 seconds each that
stopped following a single dose of IV phenobarbital (20 mg/kg).
By the day after birth, the infant had spontaneous eye opening and was
more responsive. The EEG had improved, showing only mild excess
discontinuity with interburst intervals of up to 8 seconds during sleep.
Phenobarbital was discontinued. MRI performed the fourth day after
birth was normal, including diffusion-weighted imaging (DWI) and
magnetic resonance spectroscopy with a voxel placed in the left basal
ganglia. The child was taking full oral feeds via breast-feeding by the fifth
day after birth and was discharged home on the seventh day after
showing adequate oral intake. Prior to discharge home, the parents were
counseled regarding a cautiously optimistic prognosis based on early
improvement of EEG and neurologic examination as well as the normal
MRI. At age 2, the child had normal development and had not had
recurrent seizures.
COMMENT This case demonstrates the importance of implementing therapeutic

hypothermia at the earliest possible time after recognition of HIE. This case
also demonstrates the prognostic value of early improvement of the EEG
and of normal MRI, as well as the possibility of good outcomes after HIE
even in children with severe acidosis and low Apgar scores.
66 FEBRUARY 2018
Reasons for absent or incomplete effect of hypothermia may be delayed onset of KEY POINT
cooling, injury that is too severe, or incorrect diagnosis.
● The predominant
patterns of injury in
MANAGEMENT OF ENCEPHALOPATHY NOT DUE TO HYPOXIC-ISCHEMIC neonates with hypoxic-
ENCEPHALOPATHY ischemic encephalopathy
If HIE is not the cause of the encephalopathy, then the general neurocritical care are (1) basal ganglia/
thalamus (with extension to
principles discussed above (eg, maintaining normal glucose, temperature, blood rolandic cortex,
pressure) apply; however, therapeutic hypothermia is not indicated. Neonates hippocampus, and
with suspected infection as the cause of encephalopathy should be treated with brainstem in severe cases,
antimicrobial agents (or antiviral agents if herpes simplex virus is suspected). which is seen predominantly
in the setting of acute
Neonates with arterial stroke should have a careful cardiac examination to assess profound disruption in
for congenital heart defects and a family history taken to assess for risk factors for placental perfusion), and (2)
thrombophilia. Neonates with bland or hemorrhagic venous infarcts should be watershed areas (with injury
reimaged within 1 week and consideration given for anticoagulation if an acute to the watershed zones of
the anterior, middle, and
clot is identified.64,65 In the setting of neonatal encephalopathy due to brain posterior cerebral arteries),
malformation, a suspected or confirmed inborn error of metabolism, or which occurs in the setting
neonatal-onset epileptic encephalopathy, a specific genetic diagnosis should of partial prolonged injuries.
be sought.
09/2022
A 37-year-old woman with gestational diabetes mellitus and CASE 3-2

hypertension who was pregnant with a 41-week-gestation male fetus
presented to obstetric triage because of decreased fetal movements
during the previous 12 hours. Labor was induced, and after 24 hours of
induction, the fetal heart monitor showed bradycardia to 60 beats/min,
and the child was delivered emergently by cesarean delivery. The child
was limp, apneic, and bradycardic at birth. Apgar scores were assigned as
1 at 1 minute, 2 at 5 minutes, and 4 at 10 minutes. The child was intubated
and transferred to a regional cooling center. During transport, the child
had several episodes of asymmetric tonic stiffening with changes in vital
signs and was treated with 20 mg/kg of IV phenobarbital followed by
maintenance dosing for presumed seizures.
Cooling was initiated at 5 hours after birth. EEG initiated at 10 hours
after birth showed status epilepticus without clinical correlate. The child
received an additional 20 mg/kg of phenobarbital, after which he was
unresponsive, and the background EEG pattern showed no definite
cerebral activity. This EEG pattern persisted throughout cooling and
rewarming. An MRI on the fifth day after birth showed injury to the
thalamus, basal ganglia, and much of the cerebral cortex and subcortical
white matter. Magnetic resonance spectroscopy showed a large lactate
peak and low N-acetylaspartate (NAA) in the basal ganglia. The parents
were counseled regarding expected poor prognosis, and they chose to
discontinue life support and provide the child with palliative care.
This case exemplifies several key indicators of a poor prognosis in neonates COMMENT
with hypoxic-ischemic encephalopathy: status epilepticus, persistently
severely abnormal EEG, and severe injury on MRI.
KEY POINTS LONG-TERM MANAGEMENT

Once the neonate with encephalopathy has recovered from the critical illness, the
● Developmental care by
occupational and physical
focus turns toward establishing oral feeding and readiness for discharge home.
therapists and lactation Developmental care by occupational and physical therapists and lactation
experts can begin during the inpatient admission to assess and manage
experts can begin during the

inpatient admission to assess positioning, oral feeding readiness and preparation, and behavioral state
and manage positioning, oral
feeding readiness and

regulation and to optimize tone, strength, and ability to deal with environmental
preparation, and behavioral stimuli.24 Developmentally appropriate exercises (eg, upright positioning,
state regulation and to “tummy time,” language exposure, and early exposure to fine motor tasks) can
optimize tone, strength, and be initiated in the hospital and taught to the parents for practice at home.
ability to deal with
Since survivors of neonatal encephalopathy are at high risk for long-term
environmental stimuli.
disabilities, children should be followed longitudinally by a high-risk program or
● Since survivors of a child neurologist as recommended by the American Academy of Pediatrics.32
neonatal encephalopathy Close monitoring ensures appropriate and timely referrals to developmental
are at high risk for long-term therapies such as occupational and physical therapy. Follow-up should be at
disabilities, children should
be followed longitudinally least until 18 to 24 months of age; however, follow-up until school age is preferred.
by a high-risk program or
a child neurologist as
recommended by the
09/2022
American Academy
CONCLUSION
of Pediatrics. Neonatal encephalopathy is a heterogeneous disorder marked by altered mental
status, altered muscle tone, and depressed primitive reflexes, as well as
seizures. Therapeutic hypothermia is standard of care for neonates with
encephalopathy that is presumed to be caused by hypoxia-ischemia and who
would have fulfilled entry criteria into the large randomized trials. Brain-focused
TABLE 3-2 Predictors of Outcome in Neonates Treated With Therapeutic Hypothermia
Indicators of Poor Prognosis Indicators of Good Prognosis

Clinical examination Unresponsive, minimally responsive, or stereotyped responsiveness No or mild encephalopathy at
persisting beyond 24–36 hours after birth 24 hours55
EEG/amplitude- Severe abnormality (burst suppression, depressed and Early normalization of EEG/
integrated EEG undifferentiated tracing, extremely low voltage on continuous EEG; amplitude-integrated EEG
burst suppression or flat tracing on amplitude-integrated EEG), (within 24–36 hours)
especially if it persists beyond 24–36 hours after birth50–52
Early return of sleep-wake
Seizures that are refractory to initial loading doses of antiseizure cycling
medications or multifocal56
Seizures that respond to
first-line medication
MRI Moderate to severe injury (and especially near-total injury) Children with focal or
Injury to the ventrolateral thalamus or basal ganglia57 watershed pattern of injury,
even with high injury burden,
Absent myelination of the posterior limb of the
may have a favorable outcome60
internal capsule58
Magnetic resonance spectroscopy lactate: N-acetylaspartate

that is greater than 1/359
EEG = electroencephalogram; MRI = magnetic resonance imaging.
68 FEBRUARY 2018
management includes neurophysiologic monitoring and imaging with MRI to
help determine diagnosis, prognosis, and neurologic complications, as well as
careful attention to maintenance of normal homeostatic mechanisms (eg, glucose,
blood pressure) to help prevent secondary brain injury. While outcomes have
improved since the widespread use of hypothermia, risk of death or disability in
the clinical trials was almost 50%. Emerging adjuvant therapies such as
erythropoietin hold promise for further improving outcomes.
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a multicenter cohort study. Neurology 2014;82(14): 2011;76(24):2055–2061. doi:10.1212/
1239–1244. doi:10.1212/WNL.0000000000000282. WNL.0b013e31821f442d.
44 Low E, Boylan GB, Mathieson SR, et al. Cooling and 59 Thayyil S, Chandrasekaran M, Taylor A, et al. Cerebral
seizure burden in term neonates: an observational magnetic resonance biomarkers in neonatal
study. Arch Dis Child Fetal Neonatal Ed 2012;97(4): encephalopathy: a meta-analysis. Pediatrics 2010;
F267–F272. doi:10.1136/archdischild-2011-300716. 125(2):e382–e395. doi:10.1542/peds.2009-1046.
70 FEBRUARY 2018
60 Harteman JC, Groenendaal F, Toet MC, et al. 63 Tagin MA, Woolcott CG, Vincer MJ, et al.
Diffusion-weighted imaging changes in cerebral Hypothermia for neonatal hypoxic ischemic
watershed distribution following neonatal encephalopathy: an updated systematic review and
encephalopathy are not invariably associated with meta-analysis. Arch Pediatr Adolesc Med 2012;
an adverse outcome. Dev Med Child Neurol 2013; 166(6):558–566. doi:10.1001/archpediatrics.2011.1772.
55(7):642–653. doi:10.1111/dmcn.12122.
64 Moharir MD, Shroff M, Pontigon AM, et al. A
61 Johnston MV, Fatemi A, Wilson MA, Northington F. prospective outcome study of neonatal cerebral
Treatment advances in neonatal neuroprotection sinovenous thrombosis. J Child Neurol 2011;26(9):
and neurointensive care. Lancet Neurol 2011;10(4): 1137–1144. doi:10.1177/0883073811408094.
372–382. doi:10.1016/S1474-4422(11)70016-3. 65 Kersbergen KJ, Groenendaal F, Benders MJ,

62 Davidson JO, Wassink G1, van den Heuij LG, et al de Vries LS. Neonatal cerebral sinovenous
Therapeutic hypothermia for neonatal hypoxic-ischemic thrombosis: neuroimaging and long-term
encephalopathy—where to from here? Front Neurol follow-up. J Child Neurol 2011;26(9):1111–1120.
2015;6:198. doi:10.3389/fneur.2015.00198. doi:10.1177/0883073811408090.
09/2022
REVIEW ARTICLE
Nervous System
Malformations

ONLINE
By John Gaitanis, MD; Tomo Tarui, MD
ABSTRACT
PURPOSE OF REVIEW: This article provides an overview of the most common
nervous system malformations and serves as a reference for the latest
advances in diagnosis and treatment.
RECENT FINDINGS:Major advances have occurred in recognizing the genetic

basis of nervous system malformations. Environmental causes of nervous
system malformations, such as perinatal infections including Zika virus, are
also reviewed. Treatment for nervous system malformations begins prior
09/2022
to birth with prevention. Folic acid supplementation reduces the risk of

neural tube defects and is an important part of health maintenance for
pregnant women. Fetal surgery is now available for prenatal repair of
myelomeningocele and has been demonstrated to improve outcomes.
SUMMARY: Each type of nervous system malformation is relatively

uncommon, but, collectively, they constitute a large population of
CITE AS:
neurologic patients. The diagnosis of nervous system malformations begins
2018;24(1, CHILD NEUROLOGY):72–95. with radiographic characterization. Genetic studies, including
chromosomal microarray, targeted gene sequencing, and next-generation
Address correspondence to sequencing, are increasingly important aspects of the assessment. A
Dr John Gaitanis, Tufts Medical
Center, Floating Hospital for genetic diagnosis may identify an associated medical condition and is
Children, 800 Washington St, necessary for family planning. Treatment consists primarily of supportive
Boston, MA 02111, therapies for developmental delays and epilepsy, but prenatal surgery for
JGaitanis@tuftsmedicalcenter.
org. myelomeningocele offers a glimpse of future possibilities. Prognosis
depends on multiple clinical factors, including the examination findings,
Dr Gaitanis reports no
imaging characteristics, and genetic results. Treatment is best conducted
disclosure. Dr Tarui receives in a multidisciplinary setting with neurology, neurosurgery, developmental
research/grant support from pediatrics, and genetics working together as a comprehensive team.
the National Institutes of Health
Eunice Kennedy Shriver National
Institute of Child Health and
Human Development
(K23HD079605) and the Susan
Saltonstall Award, which played INTRODUCTION
T
a primary role in preparing this
manuscript.
he nervous system undergoes rapid developmental changes
throughout gestation and continues to evolve after birth and into
UNLABELED USE OF early adulthood. Disruption of the developing nervous system can
PRODUCTS/INVESTIGATIONAL USE
DISCLOSURE:
occur at any stage. The timing and nature of disruptions account for
Drs Gaitanis and Tarui report no the specific malformations that result, which include a myriad of
disclosures. conditions such as spina bifida, hydrocephalus, holoprosencephaly,
© 2018 American Academy lissencephaly, and focal cortical dysplasia. Resulting signs may include cognitive
of Neurology. impairment, epilepsy, autism spectrum disorders, and motor and sensory
72 FEBRUARY 2018
impairment. Since brain malformations are defined by structural changes, KEY POINTS
neuroimaging is the fundamental diagnostic test. With improvements in
● Ambulation is one of the
ultrasound and prenatal MRI, accurate diagnosis can now occur prenatally. most important clinical
Prompt diagnosis allows for interventions sooner, in some cases prior concerns in patients with
to delivery. myelomeningocele.
This article reviews common alterations of nervous system development and Antigravity function of the
iliopsoas and quadriceps
discusses them according to the embryologic stage in which the abnormality muscles is required for
has its origin.1 Emphasis is given to the clinical presentation and imaging walking, but ambulation
characteristics of the known conditions. can be impaired in all
children with spina bifida,
even those with low
BRIEF OVERVIEW OF EMBRYOLOGY neurosegmental lesions.
Brain and spinal cord development begins with neurulation, which is the process
of neural tube formation that occurs in the third and fourth weeks of gestation. In ● Hydrocephalus is seen in
the fifth and sixth weeks, prosencephalic development occurs, giving shape to approximately 90% of
patients with
the developing brain. Cortical development is divided into stages of cell
myelomeningocele
proliferation, neuronal migration, and postmigrational cortical organization.1–3 affecting the lumbar region.
Myelination and cortical organization are the final steps of brain development Newborns can be
and continue well beyond birth.4 asymptomatic without
recognizable clinical signs
09/2022
of increased intracranial
DISORDERS OF NEURULATION pressure.
Fusion of the neural tube begins at the level of the hindbrain (medulla and pons)
and at least one other site and proceeds rostrally and caudally.5 Failure of rostral
fusion disrupts brain development, resulting in anencephaly or encephalocele.
Incomplete caudal fusion causes the spinal disorder myelomeningocele.
Anencephaly occurs no later than day 24 of gestation. Encephalocele and
myelomeningocele occur around day 26 of gestation.
Myelomeningocele
Myelomeningocele is the most common disorder of neurulation with which
fetuses and infants can remain viable. Its incidence in the United States is
approximately 0.2 to 0.4 per 1000 live births.6 The neurologic features of
myelomeningocele relate to the level of involvement, presence of hydrocephalus,
and other associated brain malformations.
Impairment of motor, sensory, and sphincter function relates to the level of
involvement. Ambulation is one of the most important clinical concerns.
Antigravity function of the iliopsoas and quadriceps muscles is required for
walking. Ambulation can be impaired in children with spina bifida, even those
with low neurosegmental lesions. Some children who learn to walk can lose
ambulation in later childhood; this is particularly true in those with high-level
lesions.7
Hydrocephalus is seen in approximately 90% of patients with lumbar lesions.
Hydrocephalus develops later in gestation or postnatally. Newborns with
myelomeningocele can be asymptomatic without recognizable clinical signs of
increased intracranial pressure (lethargy, irritability, limited upward gaze, and
rapidly expanding head circumference). Infants can become symptomatic up to
6 weeks after birth. Clinical signs are frequently absent; thus, neuroimaging is
necessary for the prompt diagnosis of hydrocephalus. Infants demonstrating
hydrocephalus require shunt placement immediately following myelomeningocele
closure, as the closure stops CSF leakage and thus possibly worsens hydrocephalus
unless CSF flow is diverted. Shunt placement at the time of myelomeningocele
NERVOUS SYSTEM MALFORMATIONS
closure can reduce surgical morbidities such as wound dehiscence and CSF
leaks in the area of the myelomeningocele repair without increasing
shunt complications.8
Myelomeningocele combined with inferior displacement of the cerebellar tonsils
through the foramen magnum is termed the Arnold-Chiari malformation (Chiari
type II). Of note, Chiari type I refers to displacement of the cerebellar tonsils
through the foramen magnum without dysraphism. Other features of Chiari type
II malformation include elongation and thinning of the upper medulla and pons
and bony defects of the foramen magnum, occiput, and upper cervical vertebrae.
Myelomeningocele may be associated with brainstem malformations, with
resulting brainstem dysfunction such as apnea, stridor, cyanotic spells, and
dysphagia, which can become significant causes of morbidity and mortality.
Periventricular nodular heterotopia is associated with Arnold-Chiari
malformations in roughly one-third of patients.9 It is seen more commonly in
patients with a low pontomesencephalic junction.
Diagnosis of myelomeningocele and Arnold-Chiari malformation begins prior
to birth, and, increasingly, treatment also can begin prenatally. Associated brain
and non–central nervous system (CNS) malformations can be detected by fetal
sonography or MRI, which influences postnatal outcome. The rationale for fetal
09/2022
surgery was proposed by animal models and is intended to prevent progressive

intrauterine damage of neural tissue exposed to the myelomeningocele lesion.10
A randomized trial of prenatal versus postnatal repair of myelomeningocele was
stopped early because of the efficacy of prenatal surgery.11 In that trial, prenatal
surgery was associated with lower rates of shunt placement (40% versus 82%) and
improvements in mental development and motor function. Complications of
prenatal surgery included an increased risk of preterm delivery and uterine
dehiscence at delivery.
In postnatal surgery, the myelomeningocele is closed as early as possible
to prevent infection (usually within the first 48 hours of life). Brainstem dysfunction
(which presents with intermittent apnea, bradycardia, swallowing dysfunction,
nystagmus, or vocal cord paralysis) may require decompressive upper cervical
laminectomy to reduce brainstem and cerebellar tonsillar compression due to Chiari
II malformation. Such surgery is best performed within the first weeks after birth.
Urinary dysfunction may necessitate daily catheterization to prevent urinary
tract infections. Orthopedic follow-up is also needed for prevention and
management of scoliosis and contractures. Given the wide range of systems affected
in myelomeningocele, multidisciplinary clinics are helpful for coordinating care.
Ideally, treatment begins with prevention of the condition. The British
Medical Research Council Vitamin Study Group conducted a randomized
prevention trial that found daily oral supplementation with folic acid before
conception and during early pregnancy substantially reduced the recurrence of
neural tube defects in children of women who previously had a child with such a
condition.12 Currently, the US Public Health Service and Centers for Disease
Control and Prevention (CDC) recommend that all women of childbearing age
consume 0.4 mg of folic acid daily to prevent neural tube defects. Women who
previously had a child with neural tube defects are recommended to consume
4 mg of folic acid daily to prevent recurrence of a neural tube defect.13 Yet, even
with folate fortification, myelomeningocele still occurs. In addition to folate
deficiency, genetic and nongenetic etiologies are implicated, including
gestational diabetes mellitus and medications (eg, valproic acid).14
74 FEBRUARY 2018
DISORDERS OF PROSENCEPHALIC DEVELOPMENT KEY POINTS
The forebrain takes shape during prosencephalic development beginning in the
● Prenatal surgery for
fifth week and continuing through the second and third months of gestation. myelomeningocele is
Forebrain development can be divided into three stages: formation, cleavage, associated with lower rates
and midline development.15 Anomaly of prosencephalic formation of shunt placement and
(aprosencephaly, atelencephaly) is not viable and extremely rare, thus this improvements in mental
development and motor
article focuses on the latter two stages. function.
Disorders of Prosencephalic Cleavage ● Oral supplementation

The rostral end of the neural tube expands to create the forebrain and with folic acid before
prosencephalon. After development of the prosencephalon, the midline of the conception and during
structure indents and cleaves into the telencephalon primordia of the bilateral early pregnancy
substantially reduces the
cerebral hemispheres. recurrence of neural tube
defects in women who
HOLOPROSENCEPHALY. Included among disorders of prosencephalic cleavage is
previously had a child with
holoprosencephaly, in which the absence of hemispheric separation results in such a condition. All
a single, large forebrain ventricle that can be first recognized on the prenatal women of childbearing age
ultrasound and fetal MRI (FIGURE 4-1). Alobar holoprosencephaly is the most are recommended to
consume 0.4 mg of folic
severe form, in which the brain is a single spherical structure with a common acid daily to prevent neural
09/2022
ventricle and a malformed cortical mantle. Malformation may involve the tube defects. Women who
dysplastic optic nerves and the olfactory bulbs and tracts. The thalamus and have had a child with a
hypothalamus do not separate normally and may accompany hypopituitarism. neural tube defect are
recommended to consume
Facial anomalies, when present, can range from as severe as cyclopia to as subtle
4 mg of folic acid daily.
as a single central incisor. Semilobar and lobar holoprosencephaly are less severe
forms of the same anomaly (FIGURE 4-1). ● The etiology of
Associated cortical malformations frequently cause epilepsy. Careful attention holoprosencephaly is
to the neuroimaging features is therefore necessary in providing an heterogeneous with both
genetic and environmental
accurate prognosis.16 causes. Gestational
The etiology of holoprosencephaly is heterogeneous with both genetic and diabetes mellitus is the
environmental causes. Gestational diabetes mellitus is the most common most common
environmental cause and carries a 1% risk of holoprosencephaly (200 times environmental cause and
carries a 1% risk of
greater than in the healthy population). Chromosomal abnormalities account for holoprosencephaly.
approximately 25% to 50% of holoprosencephaly cases, with trisomy 13 Chromosomal
syndrome and trisomy 18 syndrome being the most common. Thus, karyotype abnormalities account for
and chromosomal microarray analysis can be the first genetic tests ordered.17 approximately 25% to 50%
of holoprosencephaly
Single-gene mutations are found in roughly 25% of patients. Several genes are cases.
known to be causative (SHH, SIX3, ZIC2). The first gene discovered, the sonic
hedgehog (SHH) gene at 7q36, is also the most common.17 SHH plays an
important role in dorsal-ventral patterning.18 Assuming a clear environmental cause is
not found, the evaluation typically begins with a chromosomal microarray followed
by targeted gene sequencing if the chromosomal microarray is unremarkable.17
Genetic counseling is important given the heterogeneity of these disorders.
Abnormalities of Midline Prosencephalic Development

Abnormalities of midline prosencephalic development are typically less severe
than holoprosencephaly and include agenesis of the corpus callosum19 and
septooptic dysplasia.
AGENESIS OF THE CORPUS CALLOSUM. Agenesis of the corpus callosum can be

either partial or complete (FIGURE 4-2). With partial agenesis, the posterior
portion is more affected. Agenesis of the corpus callosum can be isolated or
KEY POINTS
● Both partial and

complete isolated agenesis
of the corpus callosum
can have broad
neurodevelopmental
presentations from mild to

severe impairments.
● Septooptic dysplasia
presents with visual
impairment in infancy
(congenital nystagmus or
poor visual engagement),
hypopituitarism, or both.
09/2022
FIGURE 4-1
Semilobar holoprosencephaly. Coronal (A) and axial (B) fetal MRI at 20 weeks gestational age show
a single ventricle, absence of the septum pellucidum, and incompletely formed interhemispheric
fissure (absence of cleavage of frontal lobes [B, arrow]) consistent with holoprosencephaly.
Coronal (C) and axial (D) MRI of a male newborn shows rudimental temporal and occipital
lobes consistent with semilobar holoprosencephaly. Partial fusion of thalamus (D, arrowhead)
and incomplete hippocampal formation are additionally recognized.
complex based on absence/presence of associated CNS malformations. Both

partial and complete isolated agenesis of the corpus callosum can have broad
neurodevelopmental presentations from mild to severe impairments (CASE 4-1).
According to a meta-analysis of 16 case series of prenatally diagnosed “isolated”
agenesis of the corpus callosum, approximately 70% of patients have normal
outcomes, 15% have mild to moderate neurodevelopmental disabilities, and 15%
have severe disabilities such as speech delays, impaired comprehension,
attention disorders, hypotonia, dyscoordination, or dysphagia.20 Associated
brain anomalies that are relevant to prognosis may be found in 15% of cases of
isolated agenesis of the corpus callosum.21 Even in patients with normal
intelligence, deficits of social cognition22 and executive functioning are observed.23
Prognosis is therefore extremely difficult to predict in early infancy.24
76 FEBRUARY 2018
09/2022
FIGURE 4-2
Agenesis of the corpus callosum. Fetal brain MRI (A, coronal; B, axial; C, sagittal) at 31 weeks
gestational age showing complete agenesis of the corpus callosum. Characteristic findings
are shown, including vertical (coronal) and parallel (axial) orientation of anterior horns of
lateral ventricles and ventriculomegaly, especially of the posterior horns (colpocephaly).
Full-term neonatal brain MRI (D, coronal; E, axial; F, sagittal) of the same patient with findings
remnant to fetal MRI, such as parallel alignment of the bodies of lateral ventricles. Sagittal
image shows abnormal radiant orientation of sulci (F). Late gestational development after
31 weeks, including gyrification, appears to have normally occurred without associated
central nervous system anomalies, consistent with isolated agenesis of the corpus callosum.
SEPTOOPTIC DYSPLASIA. Septooptic dysplasia is characterized by optic nerve

hypoplasia in combination with pituitary dysfunction and absence of the septum
pellucidum. The clinical presentation is visual impairment in infancy (congenital
nystagmus or poor visual engagement), hypopituitarism, or both. Occasionally,
the infant may be prenatally diagnosed with absence of the septum pellucidum
and later diagnosed with septooptic dysplasia during postnatal follow-up
including ophthalmologic and endocrinologic follow-up. The causes are highly
heterogeneous, including both environmental and genetic etiologies. Identified
genes associated with septooptic dysplasia are HESX1, OTX2, PROKR2, SOX2,
and SOX3. HESX1, OTX2, SOX2, and SOX3 are homeobox genes essential for
pituitary and forebrain development.25–27
DISORDERS OF NEURONAL PROLIFERATION

In the human fetus, neuronal proliferation (neurogenesis) takes place between
the second and fourth months of gestation.28,29 Neurons and glia are generated in
the margin of cerebral ventricles (ventricular and subventricular zones). In the
earliest phases, neuronal proliferation mostly generates neuroprogenitor cells

themselves30,31; then, in later phases, more cells exit from their proliferative cycle
to become postmitotic neurons while the others remain stem cells. Eventually,
the ratio of cells leaving the proliferative cycle increases until all the neurons
within the proliferative unit become postmitotic.32 Abnormal neuronal
proliferation results in conditions characterized by quantitative and qualitative

anomalies of neurons and glia such as decreased proliferation, disordered

proliferation, or abnormal differentiation/maturation.
Decreased Proliferation
Decreased neuronal proliferation results in microcephaly with or without
abnormal cerebral morphology.
MICROCEPHALY/MICROLISSENCEPHALY. Primary microcephaly is a condition of

small head size and is defined when the birth head circumference is three or more
CASE 4-1 A 36-year-old woman presented for a fetal neurology consultation at

09/2022
31 weeks of gestation regarding a possible brain malformation in her

female fetus. She had three healthy boys from previous pregnancies. At
30 weeks gestation, a routine obstetric ultrasound found her fetus had
enlarged lateral ventricles (ventriculomegaly). Subsequent level II
ultrasound by maternal fetal medicine additionally found an absent
septum pellucidum and raised concern of agenesis of the corpus
callosum. Fetal MRI found complete agenesis of the corpus callosum.
Maternal serum testing for cytomegalovirus and toxoplasma titers were
negative. Fetal echocardiogram was unremarkable. Amniocentesis to test
chromosomal microarray was declined. Based on a presumed diagnosis of
isolated agenesis of the corpus callosum, a broad spectrum of possible
neurodevelopmental impairments was discussed with the woman. The
remainder of the pregnancy was uneventful, and the infant girl was born
via uncomplicated delivery at 39 weeks gestational age.
Her physical and neurologic examination were unremarkable. Postnatal
MRI confirmed the diagnosis of complete agenesis of the corpus
callosum. Chromosomal microarray testing of the child was negative. A
diagnosis of isolated agenesis of the corpus callosum was confirmed.Her
early development was normal, and at 18 months of age, the Bayley Scales
of Infant and Toddler Development, Third Edition, found mild expressive
language delay but otherwise age-appropriate cognitive, motor,
socioemotional, and general adaptive development.
COMMENT This case exemplifies the difficulty in prognosticating neurodevelopmental

outcomes of agenesis of the corpus callosum prenatally and even
postnatally. The case represents a milder end of the spectrum, with
agenesis of the corpus callosum being the only recognizable malformation
in this patient as well as having a normal chromosomal microarray study.
However, more severe neurodevelopmental impairments can also occur in
the same context.
78 FEBRUARY 2018
standard deviations below normal. Primary microcephaly is a heterogeneous KEY POINTS
condition and can be caused by destructive processes (eg, hypoxia-ischemia,
● Primary microcephaly is
intrauterine infections) or from a genetically determined reduction in neuronal a heterogeneous condition
proliferation. Most genetic forms are recessively inherited. Mutations associated and can be caused by
with primary microcephaly alter neuroprogenitor cell proliferation through cell destructive processes
cycle regulation (MCPH1, CENPJ, CDK5RAP2), centrosome function (NDE1), (hypoxia-ischemia,

intrauterine infections) or
cell proliferation (ASPM, STIL), mitotic spindle formation (WDR62), or DNA
from a genetically
repair (PNKP, PCNT). One of the most common genetic causes is microcephaly determined reduction in
5, caused by mutations in the abnormal spindlelike microcephaly-associated neuronal proliferation.
gene (ASPM).33,34 ASPM is essential for normal mitotic spindle activity in Mutations associated with
primary microcephaly alter
neuroprogenitor cells, and its disruption therefore affects neuronal proliferation.35
neuroprogenitor cell
Intellectual disability and a generalized simplification of the gyral pattern are proliferation through cell
common, but more severe gyral abnormalities have not been described. cycle regulation,
A simplified gyral pattern is sometimes recognized in cases of microcephaly centrosome function, cell
proliferation, mitotic
with a spectrum of severity, which, on the severe end, is termed
spindle formation, or DNA
microlissencephaly.36,37 Microlissencephaly may be associated with cerebellar and repair.
callosal anomalies38 and clinically manifests with global developmental delay,
intellectual disabilities, and seizures.39 Thus, microlissencephaly is considered to ● All patients with
be a distinct clinical entity from the more common microcephaly with a hemimegalencephaly
09/2022
have epilepsy.
simplified gyral pattern.40 Hemispherectomy is often
Intrauterine infections, such as cytomegalovirus or Zika virus, have been required to treat
associated with microcephaly as well as more extensive injuries or intractable epilepsy,
malformations. Five clinical features are particularly associated with Zika virus: although some patients’
seizures may be controlled
(1) severe microcephaly with a partially collapsed skull (resembling anencephaly medically.
but with preserved skin overlying the skull), (2) thin cerebral cortices with
subcortical calcifications, (3) macular scarring and pigmentary retinal mottling,
(4) congenital contractures, and (5) early hypertonia or extrapyramidal
symptoms (CASE 4-2).41
Disordered Proliferation
Malformations in this group are characterized by significantly abnormal
neuroprogenitor cell proliferation as well as other malformations and
occasionally abnormal growth outside the CNS.
HEMIMEGALENCEPHALY. Hemimegalencephaly is the unilateral enlargement of just

one cerebral hemisphere and is associated with unilateral overgrowth of the
body, which is likely caused by disturbances in cellular differentiation,
proliferation, and organization.42 Neuropathology extends beyond the size of the
hemisphere and includes abnormal gyration, ventriculomegaly, and abnormally
increased T2 signal of the white matter.42,43 Histology shows disorganized
cortical lamination, subcortical heterotopia, and large dysmorphic neurons
termed balloon neurons.44–46 The opposite hemisphere may be normal or have
mild dysplasia and heterotopia.47 Although most cases of hemimegalencephaly
are nonsyndromic, it can be rarely associated with tuberous sclerosis complex,48
hypomelanosis of Ito,45 and linear nevus sebaceous syndrome.49 All patients have
epilepsy; hemispherectomy is often required to treat intractable epilepsy,
although some patients’ epilepsy may be controlled medically.42,50
Abnormal Neuronal Differentiation or Maturation
In abnormalities of maturation or differentiation, neurons exhibit immature or
glial features. In cortical dysplasia or cortical hamartoma of tuberous sclerosis
complex, dysplastic or characteristic balloon neurons can be seen,51,52 along with

evidence of disrupted neuronal migration such as disorganized or absent
lamination and malpositioned or heterotopic neurons in both gray and white
matter.47 Therefore, its pathology is combined with abnormalities in migration
and differentiation or maturation. Dysplastic and balloon neurons may lack the
cellular machinery to migrate properly through the cortical plate.47

TUBEROUS SCLEROSIS COMPLEX. Tuberous sclerosis complex53 is a multisystem

dominantly inherited condition. It has a high rate of spontaneous mutations, and
approximately one-half of all patients do not have an affected parent. Two genes
are causative for tuberous sclerosis complex, both of which result in similar
clinical features. The TSC1 gene, located on chromosome 9q34, encodes for the
protein hamartin, which indirectly links the cell membrane to the cytoskeleton.54
The TSC2 gene, located at chromosome 16p13.3, encodes for the protein tuberin,
CASE 4-2 A 29-year-old woman presented at her 35th week of pregnancy to

09/2022
establish obstetric care. She had moved from the Dominican Republic to
the United States when her fetus was 11 weeks gestational age, and she
had not received further prenatal care until the current presentation, at
which time a fetal ultrasound detected significant fetal anomalies of
severe microcephaly, small forebrain, scalloped parietal bones, and
bilateral ventriculomegaly, as well as a dilated third ventricle. Fetal
echocardiogram found levorotation and tricuspid valve thickening. She
denied any symptoms of illness during the pregnancy.
An infant boy was born at 37 weeks gestation with severe microcephaly
(head circumference of 29 cm), generalized hypotonia, poor suck,
single palmar crease, rocker bottom feet, and respiratory distress in
addition to the findings that had been seen on ultrasound. Chest
x-ray showed right-sided diaphragmatic paralysis that required
supplemental oxygen viacontinuous positive airway pressure and
later nasal cannula.
Neonatal echocardiogram found a patent ductus arteriosus, patent
foramen ovale, and right atrial and ventricular dilatation. Neonatal brain
MRI identified agenesis of the corpus callosum (FIGURE 4-3A), pachygyria
(FIGURE 4-3B), and parenchymal subcortical calcification (FIGURE 4-3C). The
newborn was diagnosed with congenital Zika virus infection by serum IgM
and real-time reverse transcription polymerase chain reaction. At
2 months of age, the child had marked microcephaly (head circumference
of 32 cm), scalloped parietal bone, slanted occiput (FIGURE 4-3D and 4-3E),
diffuse spasticity (FIGURE 4-3F), bilateral hearing loss, and cortical visual
impairment.
COMMENT This case exemplifies severe microcephaly and abnormalities in migration,

neurodegeneration, and calcification characteristic of congenital Zika virus
infection occurring in the early stage (before 11 weeks) of pregnancy.
80 FEBRUARY 2018
which functions in cellular signaling pathways.54 Hamartin and tuberin interact KEY POINT
as part of a larger protein complex controlling cell growth and size.54 Diagnosis
● In the brain,
of tuberous sclerosis complex is mostly clinical owing to the large size of TSC1
characteristic features of
and TSC2 genes. Clinically, tuberous sclerosis complex is classified into three tuberous sclerosis include
subcategories: definite, probable, and suspect, based on the type and number of cortical and subcortical
abnormalities characteristic of the disease.55 The disease is primarily recognized hamartomas, subependymal
nodules, and subependymal

by lesions in the skin, kidneys, heart, and CNS.
giant cell astrocytomas.
In the brain, the characteristic features include cortical and subcortical
hamartomas (FIGURE 4-4A, 4-4B, and 4-4C), subependymal nodules (FIGURE 4-4D),
and subependymal giant cell astrocytomas. On MRI, cortical tubers appear as
enlarged, atypically shaped gyri with abnormal signal intensity in the subcortical
white matter (FIGURE 4-4A).56 Microscopically, they resemble focal cortical
dysplasia57 with disorganized lamination and balloon neurons.47 Cortical tubers
may contribute to the pathogenesis of epilepsy. Infants with tuberous sclerosis
09/2022
FIGURE 4-3
Imaging and photographs of the patient in CASE 4-2. Neonatal brain MRI identifying agenesis of the corpus callosum
(A, sagittal T1-weighted image), pachygyria (B, axial T2-weighted image), and parenchymal subcortical calcification
(C, axial T1-weighted image). Photographs showing marked microcephaly (head circumference of 32 cm), scalloped
parietal bone, slanted occiput (D, E), and diffuse spasticity (overlapping fingers) (F).
complex predominantly develop infantile spasms. For further discussion on

infantile spasms and their management, refer to the article “Epileptic
Encephalopathies” by Shaun A. Hussain, MD, MS,58 in this issue of Continuum.
Patients with tuberous sclerosis complex may develop progressive cognitive
impairment. Seizures in children younger than 2 years of age, infantile spasms,
and a high burden of cortical tubers are associated with a high risk for cognitive
impairment. Autism is commonly seen in patients with tuberous sclerosis complex,

especially in patients with temporal tubers, seizure onset before 3 years of age, or
infantile spasms.59 For more information on tuberous sclerosis complex, refer to the
article “Neurocutaneous Disorders” by Tena Rosser, MD,60 in this issue of Continuum.
FOCAL CORTICAL DYSPLASIA. Focal cortical dysplasia strongly resembles the

cortical tubers of tuberous sclerosis complex. Macroscopically, the lesions display
wider-than-normal gyri and blurring of the gray-white junction.61 Focal cortical
dysplasia is highly associated with medically refractory epilepsy and often
requires epilepsy surgery to control the seizures.62
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FIGURE 4-4
Tuberous sclerosis complex. MRI of a 4-month-old female infant with tuberous sclerosis
complex. Arrowheads in T2 axial (A, B) and T1 coronal (C) images point to T2 high signal (and
T1 low, not shown) cortical/subcortical (A) and cortical (B, C) tubers, and expanding gyri (A).
T2 axial image (D) shows a subependymal nodule (arrow), as seen in approximately 98% of cases.
82 FEBRUARY 2018
Microscopically, features of focal cortical dysplasia are characterized as KEY POINTS
abnormal cortical lamination, dysmorphic cells (cytomegalic dysmorphic
● Patients with tuberous
neurons and balloon cells), and abnormal cellular polarity.63 The recent sclerosis complex may
consensus classification proposed by the International League Against Epilepsy develop progressive
subclassifies focal cortical dysplasia into types I, II, and III.64 Focal cortical cognitive impairment.
dysplasia type I is characterized by abnormal radial or tangential migration. Cells Seizures in children younger
than 2 years of age, infantile
observed in type I appear to be less dysmorphic or small dysmorphic cells spasms, and a high burden
(hypertrophic pyramidal neurons) in contrast to type II. Focal cortical dysplasia of cortical tubers are
type II has disrupted cortical lamination and characteristic dysmorphic cells such associated with a high risk
as cytomegalic dysmorphic neurons and balloon cells. Type IIa only has for cognitive impairment.
Autism is commonly seen in
cytomegalic dysmorphic neurons, and type IIb has balloon cells (CASE 4-3). Type patients with tuberous
II is relatively well visualized by MRI. Focal cortical dysplasia type III is sclerosis complex,
associated with an additional brain lesion and subclassified as follows: IIIa especially in patients with
(hippocampal sclerosis), IIIb (tumor), IIIc (vascular malformations), or IIId temporal tubers, seizure
onset before 3 years of age,
(acquired lesions in early life such as gliosis). On MRI, focal cortical dysplasia or infantile spasms.
may be found to be funnel-shaped and slightly hyperintense lesions on
T2-weighted images (FIGURE 4-5). Typical funnel lesions have their bases ● Focal cortical dysplasia
oriented toward the pial surface and the tip into the white matter.62 Focal cortical is highly associated with
medically refractory
dysplasia is increasingly detected along with advances in MRI techniques,
09/2022
epilepsy and often requires

especially in 3T images. Yet, focal cortical dysplasia type I may be epilepsy surgery to control
radiographically occult as its anatomic alterations are so subtle and can only be the seizures.
detected on a microscopic level. Focal cortical dysplasia type I may be found in
nonlesional specimens resected in epilepsy surgery. ● Focal cortical dysplasia
type I may be
radiographically occult as its
DISORDERS OF NEURONAL MIGRATION anatomic alterations are so
During the third through fifth months of gestation, neurons and glia produced subtle and can only be
from ventricular and subventricular zones migrate radially or tangentially to their detected at the microscopic
level. Focal cortical dysplasia
final sites within the cerebral cortex.28 Anomalies during this process result in a type I may be found in
variety of cortical malformations with characteristic anatomic and nonlesional specimens
pathologic features. resected in epilepsy surgery.
● Most patients with

Heterotopia
periventricular nodular
Heterotopia refers to collections of ectopic neurons located outside the cortex.65 heterotopia have normal
Unlike cortical dysplasia, the neurons within heterotopias have a normal intelligence, and some
morphology. Thus, on MRI, a heterotopia appears isointense to normal gray patients may develop
matter, in contrast to dysplasia, which usually has abnormal signal intensity. The epilepsy, commonly in the
middle teenage years.
cortex overlying a heterotopia may appear normal or thinner with shallow sulci.56
Periventricular nodular heterotopia is characterized by clusters of ectopic
neurons forming periventricular nodules within the periventricular region.
Cerebral cortex overlying these nodules is otherwise normal-appearing
(FIGURE 4-6).66 The nodules are rounded, irregular in shape, and dispersed
within myelinated fibers. In periventricular heterotopia, some neurons migrate
toward the cortex to formulate a normal-appearing six-layer cortex, while
ectopic neurons fail migration and remain within the subependymal region to
form heterotopias. Most patients with periventricular nodular heterotopia have
normal intelligence. Some patients may develop epilepsy, commonly in the
middle teenage years.67 Periventricular nodular heterotopia most often results
from a mutation of the filamin A (FLNA) gene on chromosome Xq28.Ref6467,68
Mutations of ARFGEF2, ERMARD, FAT4, DCHS1, and LRP2 are also associated
with periventricular heterotopias, although they usually have other features such
CASE 4-3 A 6-year-old girl presented with seizures that had suddenly developed
1 day prior to initial neurologic evaluation. She had no significant past
medical history, and her development had been normal. Her seizures
involved head and eye deviation to the right with full extension of the right
arm and flexion of the left arm at the elbow, which was followed by
right-sided clonic activity. During some seizures, she appeared

partially responsive. During the year following presentation, her seizures

remained refractory, and with a high frequency of more than 20 per day,
despite multiple trials of antiepileptic medications including oxcarbazepine,
levetiracetam, gabapentin, and phenytoin. A phase I epilepsy surgery
evaluation was performed and revealed that her seizures localized to
central leads without a clear distinction between sides. Brain MRI
demonstrated a linear band of T2/fluid-attenuated inversion recovery
(FLAIR) hyperintense signal emanating from the base of the left
supplementary motor cortex and extending toward the ventricle (FIGURE 4-5).
Based on these findings, the patient underwent a phase II epilepsy
surgery evaluation with electrocorticography. The interictal recording
demonstrated slow rhythmic
09/2022
spike waves over the left

frontal-central region. The
ictal recording demonstrated
paroxysmal fast activity with
repetitive spike waves over
the left frontal-central region
in the area of the supplementary
motor cortex. A focal cortical
resection was performed over
the region of the ictal onset.
Pathology revealed focal
cortical dysplasia type IIb.
The patient developed
transient right arm weakness
for 1 month following surgery.
FIGURE 4-5
Imaging of the patient in CASE 4-3 with focal cortical
The weakness subsequently
dysplasia. Axial fluid-attenuated inversion recovery fully resolved, and the patient
(FLAIR) MRI shows hyperintense signal in the left no longer had seizures and
frontal cortical/subcortical region (arrow). Affected was able to successfully
gyri appear to be wider, and their gray-white
matter boundary is blurred with a thin band of T2/
taper off of her antiepileptic
FLAIR hyperintensity extending from the cortex medications following the
to the ventricular margin. procedure.
COMMENT This case demonstrates how focal cortical dysplasia can be the responsible
epileptogenic lesion in refractory epilepsy. The seizures are often
refractory to multiple pharmacologic treatments, and many patients are
therefore appropriate epilepsy surgery candidates. If the lesion is fully
resected, complete seizure cessation is possible.
84 FEBRUARY 2018
KEY POINT
● Patients with classic

lissencephaly have severe
reduction in gyral formation
manifesting either as agyria
(a total absence of gyri) or

pachygyria (a reduced
number of abnormally
large gyri).
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FIGURE 4-6
Periventricular nodular heterotopia. A 27-week fetus was initially referred for ventriculomegaly
and found to have nodular heterotopia (A, B, arrows). Newborn MRI of this patient
confirmed bilateral ventriculomegaly and periventricular nodular tissues with signal isointense
to cortex suggestive for ectopic gray matter, notable in coronal (C) and axial (D) images.
as microcephaly (ARFGEF2),69 agenesis of the corpus callosum, polymicrogyria

(ERMARD),70 or other syndromic features (FAT4, DCHS1,71 and LRP272).
Lissencephaly
Lissencephaly refers to a paucity of normal gyri and sulci resulting in a “smooth
brain.” It is a heterogeneous condition and was previously divided into two
pathologic subtypes: classic (type I) and cobblestone (type II). More recently,
however, cobblestone malformations have been recognized as a distinct category
of diseases associated with dystroglycanopathies.
CLASSIC LISSENCEPHALY. Patients with classic lissencephaly have severe reduction

in gyral formation manifesting either as agyria (a total absence of gyri) or
pachygyria (a reduced number of abnormally large gyri). Radiographically,
agyria appears as a smooth brain surface with diminished white matter and
shallow, underopercularized sylvian fissures.56 The gyri in pachygyria are
reduced in number and have an abnormally broad and flat morphology.56
Genetic investigations have been most fruitful in this malformation, and many
responsible genes and molecular mechanisms have been discovered. Pachygyria
has a posterior greater than anterior gradient in LIS1, TUBA1A, and TUBB2B
mutations (FIGURE 4-7) and an anterior greater than posterior gradient in DCX,
ACTB, and ACTG1 mutations. Most children with lissencephaly have relatively
severe cognitive and motor disabilities and seizures. Clinical severity is related
to the degree of structural abnormality, with greater gyral simplification resulting
in greater clinical impairment. Epilepsy is universal, and infantile spasms are a
particularly common seizure type. EEG reveals characteristic, high-voltage beta
activity.73 Neurodevelopmental disabilities are severe, with intellectual disability,
spastic quadriparesis, and microcephaly all occurring commonly.
Classic lissencephaly has a markedly thickened smooth cortex with a relatively
unaffected cerebellum and brainstem. Mutations of the platelet-activating factor
acetylhydrolase gene (PAFAH1B1 [LIS1]) located on chromosome 17p13.3 is
commonly seen, especially in cases with a posterior greater than anterior gradient.74
The LIS1 gene product interacts with microtubules functioning in intracellular
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FIGURE 4-7
Lissencephaly and TUBA1A mutation. A fetal MRI at 21 weeks gestational age was ordered
because of microcephaly. Axial (A) and coronal (B) images show shallow operculum, abnormally
box-shaped temporal lobes suggesting diffuse cerebral malformation. Follow-up fetal MRI
at 29 weeks gestational age (C, axial; D, coronal) show persistent shallow operculum
(under-undulation) and absence of normal sulcations in frontal lobes consistent with anterior
dominant lissencephaly. Abnormal hypoplastic temporal lobes were also persistent. Postnatal
MRI (E and F, axial; G, coronal; H, sagittal) continued to show the same features consistent with
anterior dominant lissencephaly. Genetic investigation determined a TUBA1A mutation.
86 FEBRUARY 2018
molecular transport. Almost all patients have de novo heterozygous mutations of KEY POINTS
LIS1. Therefore, the recurrence risk of having a second affected child is very ● Most children with
low. A microdeletion syndrome affecting this region manifests as Miller-Dieker lissencephaly have
syndrome, with other congenital anomalies (craniofacial, renal, cardiac, or relatively severe cognitive
gastrointestinal malformations).75 Mutations of TUBA1A76 and TUBB2B77 are and motor disabilities and
seizures. Clinical severity is

also categorized as tubulinopathies, which affect isotypes of tubulin, one of the
related to the degree of
components of microtubules. Tubulinopathies may be associated with structural abnormality, with

lissencephaly, polymicrogyria, microcephaly, or any combination of greater gyral simplification
these conditions. resulting in greater clinical
impairment. Epilepsy is
Abnormalities of the doublecortin (DCX or XLIS) gene, located on the X
universal, and infantile
chromosome, are also known to cause classic lissencephaly with an anterior spasms are a particularly
greater than posterior gradient.78 In affected hemizygous males, the phenotype is common seizure type.
nearly indistinguishable from LIS1. However, carrier heterozygous females
present with a disorder termed double cortex, also known as subcortical band ● LIS1 mutations are
commonly seen in cases
heterotopia (FIGURE 4-8). In double cortex, heterotopic accumulations of with a posterior greater
than anterior gradient of
agyria. Almost all patients
have de novo heterozygous
mutations of LIS1. The
09/2022
recurrence risk of having a

second affected child is
very low. A microdeletion
syndrome affecting this
region manifests as
Miller-Dieker syndrome,
with other congenital
anomalies (craniofacial,
renal, cardiac, or
gastrointestinal
malformations).
FIGURE 4-8
DCX mutation causing double cortex. Fetal MRI at 28 weeks gestational age showed smooth gyri
and subcortical band heterotopia (A, axial; B, coronal; arrowheads), suggestive of lissencephaly.
The image contrast was adjusted to accentuate T2 low-signal band in the subcortical
region (arrowheads). Postnatal MRI (C, axial; D, coronal) of this patient confirmed subcortical
band heterotopia (low-intensity signal in T2-weighted image band in subcortical white matter).
The child developed global developmental delay and infantile spasms.
TABLE 4-1 Etiologic Summary of Brain and Spine Malformations and Their Investigation
Relatively Common
Disorder Incidence Genetic Causes Genetic Workupa Notes
Neurulation
Myelomeningocele 4.6/10,00080 Copy number variants Chromosomal Increased risk with

microarray gestational diabetes
mellitus, folate deficiency,
maternal medications
(valproic acid)
Prosencephalic Development
Holoprosencephaly 1/10,00081 25% to 50% chromosomal First: chromosomal Increased risk with
abnormalities; syndromic microarray gestational diabetes
holoprosencephaly (eg, autosomal mellitus82
dominant, autosomal recessive); Second: SHH, SIX3,
nonsyndromic holoprosencephaly and ZIC2
(eg, SHH, ZIC2, SIX3, TGIF1)
Septooptic dysplasia 1/10,00083 HESX1 HESX1 Look for visual impairments

09/2022
and hypopituitarism
Younger maternal age
Neuronal Proliferation
84
Microcephaly 1.5/10,000 Primary: MCPH1, CENPJ, May choose individual Look for nongenetic
CDK5RAP2, NDE1, PNKP, PCNT gene sequencing or causes such as
available panel cytomegalovirus, Zika
Microcephaly plus sequencing test infections, intrauterine
polymicrogyria: NDE1, WDR62 injuries
Megalencephaly Not known Though not common, postzygotic No practical approach

(mosaic) mutations of FLNA, LIS1, Look for associated
DCX, and genes in the PI3K-AKT Panel sequencing test extra-CNS anomalies
pathway (AKT3, PIK3CA, PIK3R2 in for PI3K-AKT pathway
megalencephaly-capillary may be considered,
malformation-polymicrogyria although yield is
syndrome) are reported unknown
Focal cortical dysplasia Not known Focal cortical dysplasia type I: No practical approach Focal cortical dysplasia
NPRL2 type I: prenatal, perinatal
May consider individual insults; focal cortical
Focal cortical dysplasia type II:
genes at left based on dysplasia
DEPDC5, MTOR, NPRL3, PIK3CA
subtypes
Focal cortical dysplasia type II: Focal cortical dysplasia
DEPDC5, MTOR, NPRL3, PIK3CA type II: mTOR pathway;
focal cortical dysplasia
Focal cortical dysplasia with
megalencephaly: PTEN Focal cortical dysplasia
type III: acquired pathology
88 FEBRUARY 2018
Relatively Common
Genetic Workupa
Disorder Incidence Genetic Causes Notes

Axonal Development
Agenesis of the 1.8/10,00085 Copy number variants Chromosomal microarray See if it is isolated or
corpus callosum (17.3%)85 syndromic
Look for associated

brain malformations
Neuronal Migration
Heterotopia Not known Periventricular nodular heterotopia: FLNA, chromosomal
FLNA, copy number variants microarray
Lissencephaly Not known Lissencephaly plus agenesis of the First: LIS1 (posterior
corpus callosum: ARX reelin type greater than anterior), DCX
plus anterior greater than (anterior greater than
posterior gradient: RELN, VLDLR; posterior)
09/2022
anterior greater than posterior

gradient: ACTB, ACTG1, DCX,86 Second: TUBA1A, TUBB2B
DCX (female subcortical band (posterior greater than
heterotopia), posterior greater anterior); ACTB, ACTG1
than anterior gradient: eg, LIS1, (anterior greater than
PAFAH1B1, TUBA1A, TUBB2B posterior)
Cobblestone Not known FCMD, FKRP, POMT1, POMT2, Based on clinical features, O-glycosylation of
malformations LARGE1, POMGNT1 may consider individual a-dystroglycan mutations
genes listed at left Look for associated
anomalies (eye
anomalies, myopathies)
Disorders of Postmigrational Development
Polymicrogyria Not known Bilateral frontoparietal, perisylvian Bilateral: ADGRG1 Look for
polymicrogyria: ADGRG1 (also cytomegalovirus,
known as GPR56) Asymmetric: based on vascular injuries
clinical features, may
Asymmetric polymicrogyria: consider panel
TUBA8, TUBB2B, TUBB3 sequencing test
May seen in syndromes such as Also look for nongenetic
Zellweger syndrome causes, schizencephaly
Schizencephaly Not known EMX2 Nongenetic causes, look Look for
for polymicrogyria cytomegalovirus,
vascular injuries
Postmigrational Not known CASK, MECP2 (Rett syndrome), Depending on clinical

microcephaly UBE3A (Angelman syndrome), features, may consider
TSEN54 individual genes listed at left
CNS = central nervous system; mTOR = mammalian target of rapamycin.

a
Selections of genetic tests are based on the authors’ personal preference. References are included if relevant articles support selection of
genetic tests.
neurons occur in the subcortical white matter, forming band heterotopia. The
overlying cortex displays a relatively normal six-layered architecture. Random
inactivation of the X chromosome accounts for this pattern. Neurons expressing
a normal copy of DCX undergo normal migration, whereas those expressing a
mutant copy remain arrested in the subcortical white matter. Since males have
only one X chromosome, they develop classic lissencephaly.

COBBLESTONE MALFORMATIONS. In contrast, cobblestone malformations develop

from an overmigration of neurons beyond the disrupted basal membrane and the
pial surface and onto the overlying subarachnoid tissue. Cobblestone
malformations are sometimes associated with congenital muscular dystrophy
and eye abnormalities (eg, Fukuyama type congenital muscular dystrophy,
Walker-Warburg syndrome, and muscle-eye-brain disease). These disorders
result from an impairment of glycosylation of a-dystroglycan,79 affecting the
80–86 87
brain, nerve, and skeletal muscle (TABLE 4-1 ).
DISORDERS OF POSTMIGRATIONAL DEVELOPMENT

Disorders of postmigrational development are caused by impairments of cortical
organization after migration has taken place.
09/2022
Polymicrogyria
Polymicrogyria is thought to develop at the latest stages of neuronal migration or
the earliest phases of cortical organization.3 It often results from external
(nongenetic) causes such as intrauterine cytomegalovirus infection88 or placental
perfusion failure.89 Patients with genetic etiologies may present with focal but
symmetric lesions such as bilateral perisylvian polymicrogyria. Polymicrogyria
can occur in any conceivable region, and frontoparietal, perisylvian, and
parietooccipital regions have all been observed. Common clinical presentations
include epilepsy and cognitive impairment. More specific symptoms are
associated with a specific region or regions involved, as is the case in bilateral
perisylvian polymicrogyria.
Bilateral frontoparietal polymicrogyria is characterized by bilateral,
symmetric polymicrogyria in the frontoparietal regions, with an anterior greater
than posterior gradient.90 MRI shows thin white matter with areas of T2
prolongation, ventriculomegaly, and hypoplastic pons and cerebellar vermis.90
Reflecting broadly localizing pathology, the clinical manifestations are relatively
severe and include motor disability, seizures, and global developmental delays.65,90
Cerebellar abnormalities and dysconjugate gaze are also common.90 The causative
gene is ADGRG1 (also known as GPR56),91 which forms part of the adhesion
G protein–coupled receptor family.
Bilateral perisylvian polymicrogyria results in a clinical syndrome manifested
by mild cognitive impairment, epilepsy, and pseudobulbar palsy.92 In childhood,
the pseudobulbar palsy results in expressive speech delay and feeding difficulty.
Bilateral perisylvian polymicrogyria is often a sporadic condition but has also
been described in association with neurofibromatosis type 193 and Kabuki
make-up syndrome.94 Phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2)
is a kinase that is involved in cell growth, survival, proliferation, motility, and
morphology and is associated with bilateral perisylvian polymicrogyria.53
These polymicrogyria syndromes are the most commonly described.
Polymicrogyria can be also seen in association with other brain malformations,
90 FEBRUARY 2018
genetic syndromes, or fetal brain injuries such as perinatal infection. Genes KEY POINTS
associated with polymicrogyria are increasingly being identified.
● Cobblestone
malformations are
PRENATAL DIAGNOSIS AND COUNSELING OF BRAIN MALFORMATIONS sometimes associated with
With advances in obstetric ultrasound, brain malformations have been congenital muscular
increasingly recognized in the fetal period, especially in the second trimester, dystrophy and eye
abnormalities. These
when a routine fetal anatomic evaluation has been offered to pregnant women disorders result from an
in the United States. Open neural tube defects may be diagnosed even earlier, impairment of glycosylation
with maternal serum screening of a-fetoprotein in the first trimester. Concerning of a-dystroglycan,
findings are further investigated with fetal MRI and genetic tests. Child affecting the brain, nerve,
and skeletal muscle.
neurologists play a central role in providing prenatal diagnosis and counseling
to pregnant women and families in collaboration with a multidisciplinary ● Bilateral perisylvian
team consisting of maternal fetal medicine, radiologists, neurosurgeons, polymicrogyria results in a
geneticists, and neonatologists.95 Child neurologists are essential in formulating clinical syndrome
manifested by mild
a diagnostic plan, assessing prognosis, and providing postnatal care to
cognitive impairment,
affected children.95 epilepsy, and
Lately, significant advances have been made in prenatal genetic diagnosis and pseudobulbar palsy. In
fetal surgery, which is changing practice. Genotyping of fetal cells via chorionic childhood, the
pseudobulbar palsy results
villi sampling and amniocentesis (amniocytes) remains the gold standard of
09/2022
in expressive speech delay

fetal genetic diagnosis. Chromosomal microarray and targeted sequencing have and feeding difficulty.
regularly been used for prenatal diagnosis of structural fetal anomalies including
brain malformations. The detection rate of pathognomonic copy number ● Child neurologists play a
variants of CNS anomalies remains low (approximately 15%), which makes central role in providing
prenatal diagnosis and
prenatal diagnosis and counseling challenging.96 Noninvasive prenatal testing counseling to pregnant
has been introduced to detect fetuses with aneuploidies such as trisomies 21, 18, women and families in
and 13 as well as sex chromosome aneuploidies by quantifying changes in the collaboration with a
amount of cell-free DNA circulating in plasma of high-risk pregnant women. multidisciplinary team
consisting of maternal fetal
When applied to high-risk pregnant women, noninvasive prenatal testing has a medicine, radiologists,
high average sensitivity (trisomy 21 [99.4%], trisomy 18 [96.6%], trisomy 13 neurosurgeons, geneticists,
[86.4%], and sex chromosome aneuploidies [89.5%]) and a low average false- and neonatologists. Child
positive rate (trisomy 21 [0.16%], trisomy 18 [0.05%], trisomy 13 [0.09%] and neurologists are essential in
formulating a diagnostic
sex chromosome aneuploidies [0.20%]).97 However, the test is still considered a
plan, assessing prognosis,
screening tool, and further confirmation is recommended with gold standard and providing postnatal
testing such as amniocentesis or chorionic villi sampling. Although noninvasive care to affected children.
prenatal testing can be used to identify certain syndromic brain malformations
such as Dandy-Walker malformation with the abovementioned trisomies, the
implication to prenatal diagnosis of brain malformations is relatively limited.
Detection of other microdeletion syndromes has been reported in research, but
clinical application is still under investigation in terms of cost, amount of
labor, and clinical validity.98 Using next-generation sequencing technology,
whole-exome sequencing has been introduced, although technical,
informational, and ethical controversies exist in the use of these advanced
genome sequencing methods in prenatal diagnosis.98
Fetal surgery of myelomeningocele is the first successful fetal therapy for
prenatal neurologic disorders.11 Fetuses with myelomeningocele that fulfill
surgical criteria may benefit from fetal surgery (intrauterine closures of open
neural tube defects by open fetal surgery in pregnant women). Fetal surgery
may result in improved motor and cognitive outcomes. The procedures still
have concerning risks for premature birth. Long-term outcome studies
are ongoing.
CONCLUSION
Disorders of nervous system development can be a devastating diagnosis, particularly
given their association with intellectual impairment, motor dysfunction, and epilepsy.
Although patients benefit from therapeutic interventions, such as physical,
occupational, and speech therapy, the magnitude of improvement is limited.
Likewise, epilepsy treatments are limited in their response, and many patients remain
refractory to multiple medication trials. Clearly, improved therapeutic options are

needed for this group of conditions. It is hoped that advances in genetics will provide
insight into novel treatment avenues. With detailed prenatal imaging and prenatal
diagnosis, the potential also exists for initiating therapy prior to delivery.
Counseling and guidance remain important duties of the treating physician. In
newly diagnosed children, a thoughtful and compassionate approach to the
radiographic and genetic assessment offers parents insight into their child’s
condition. The genetics evaluation is particularly important for purposes of
family planning.
ACKNOWLEDGMENT
09/2022
Dr Tarui acknowledges grant support from the National Institutes of

Health Eunice Kennedy Shriver National Institute of Child Health and Human
Development (K23HD079605) and the Susan Saltonstall Award, which played a
primary role in the preparation of this manuscript.
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REVIEW ARTICLE

Neurocutaneous
I NT E R V I E W A V AI L A B L E Disorders
ONLINE
By Tena Rosser, MD
ABSTRACT
PURPOSE OF REVIEW: This article presents an up-to-date summary of the
genetic etiology, diagnostic criteria, clinical features, and current
management recommendations for the most common neurocutaneous
disorders encountered in clinical adult and pediatric neurology practices.
RECENT FINDINGS: The

phakomatoses are a phenotypically and genetically
diverse group of multisystem disorders that primarily affect the skin and
central nervous system. A greater understanding of the genetic and
09/2022
biological underpinnings of numerous neurocutaneous disorders has led to

better clinical characterization, more refined diagnostic criteria, and
improved treatments in neurofibromatosis type 1, Legius syndrome,
neurofibromatosis type 2, Noonan syndrome with multiple lentigines, tuberous
sclerosis complex, Sturge-Weber syndrome, and incontinentia pigmenti.
SUMMARY: Neurologists require a basic knowledge of and familiarity with a

wide variety of neurocutaneous disorders because of the frequent
involvement of the central and peripheral nervous systems. A simple
CITE AS: routine skin examination can often open a broad differential diagnosis and
2018;24(1, CHILD NEUROLOGY):96–129.
lead to improved patient care.
Dr Tena Rosser, Children’s
Hospital of Los Angeles, 4650 INTRODUCTION
T
Sunset Blvd, Mailstop 82, Los he phakomatoses are a heterogeneous group of disorders that primarily
Angeles, CA 90027, trosser@
chla.usc.edu.
affect the skin and central nervous system (CNS). While phenotypically
and genetically diverse, they are united by their origins in defects of
RELATIONSHIP DISCLOSURE: the developing primitive embryonic ectodermal tissue, which gives
Dr Rosser receives
rise to both the skin and nervous system. Most neurocutaneous
Novartis AG and the US syndromes are classified as single-gene disorders, but they have autosomal
Army/US Department of Defense dominant, autosomal recessive, or X-linked inheritance patterns (TABLE 5-1).
(NF100612) and publishing royalties
from Lippincott Williams & Wilkins. Neurologists require a basic knowledge of and familiarity with a wide variety of
Dr Rosser has provided expert neurocutaneous disorders because of the frequent involvement of the central and
legal testimony on a variety of
peripheral nervous systems in these conditions. A simple routine skin examination
neurologic disorders in childhood.
can often open a broad differential diagnosis and lead to improved patient care in
UNLABELED USE OF these cases. Recent advances in genetic technologies have furthered our
USE DISCLOSURE:
understanding of the specific genetic defects and protein functions responsible for
Dr Rosser reports many neurocutaneous disorders, moving the field forward such that biologically
no disclosure. based, targeted therapies are being developed for many associated complications.
© 2018 American Academy of Several neurocutaneous disorders have now been categorized as RASopathies,
Neurology. a group of related disorders caused by mutations in genes that regulate the
96 FEBRUARY 2018
RAS–mitogen-activated protein kinase (MAPK) pathway. This important
biological pathway governs functions such as cell growth, proliferation,
differentiation, and apoptosis.1 Significant phenotypic overlap exists among the
RASopathies, which manifest with characteristic dysmorphic facial features as
well as with abnormalities of the dermatologic, cardiac, ophthalmic,
musculoskeletal, and gastrointestinal systems. Many of these disorders also carry

a predisposition to both benign and malignant tumors. Almost all are associated
with a range of mild to severe developmental disabilities.1
RASopathies with neurocutaneous features include neurofibromatosis type 1
(NF1), Legius syndrome, Noonan syndrome with multiple lentigines (previously
called LEOPARD syndrome), and capillary malformation-arteriovenous
malformation syndrome. While Noonan syndrome, cardiofaciocutaneous
Neurocutaneous Disorders Most Commonly Encountered by Neurologists TABLE 5-1
Syndrome Inheritance Pattern Chromosome Gene Protein

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Hereditary hemorrhagic Autosomal 12q1, 9q34, 18q21.1, ACVRL1, ENG, Multiple

telangiectasia dominant 10q11.22 SMAD4, GDF2
Legius syndrome Autosomal 15q13.2 SPRED1 SPRED1

dominant
Neurofibromatosis Autosomal 17q11.2 NF1 Neurofibromin

type 1 dominant
Neurofibromatosis Autosomal 22q12.2 NF2 Merlin/schwannomin
type 2 dominant
Nevoid basal cell Autosomal 9q22.3-31, 1p32.2-p32.1 PTCH1 Sonic hedgehog

carcinoma syndrome dominant
Noonan syndrome with Autosomal 12q24, 3p25.2, 7q34 PTPN11, RAF1, BRAF Multiple
multiple lentigines dominant
Tuberous sclerosis Autosomal 9q34.3, 16p13.3 TSC1, TSC2 Hamartin, tuberin

complex dominant
Von Hippel-Lindau Autosomal 3p26-p25 VHL pVHL
syndrome dominant
Ataxia telangiectasia Autosomal 11q22.3 ATM ATM

recessive
Incontinentia pigmenti X-linked dominant X IKBKG NEMO/IKBKG
Blue rubber bleb nevus Sporadic Unknown Unknown Unknown

syndrome
Congenital melanotic Sporadic Unknown Unknown Unknown

nevi/neurocutaneous
melanosis
Sturge-Weber syndrome Sporadic 9q21 GNAQ Guanine nucleotide-binding

protein G(q) subunit alpha
Hypomelanosis of Ito Mosaic Multiple Multiple Multiple
Epidermal nevus Multiple Multiple Multiple Multiple

syndromes
NEUROCUTANEOUS DISORDERS
syndrome, and Costello syndrome also share the RAS-MAPK pathway, they
generally do not have the characteristic hyperpigmented lesions seen in the other
RAS-MAPK pathway disorders.1,2 Tuberous sclerosis complex is caused by
dysregulation of the mammalian target of rapamycin (mTOR) pathway, which
lies downstream but is an integral part of the complete RAS-MAPK pathway. As
demonstrated in FIGURE 5-1, many other well-known neurocutaneous disorders

are linked through this web of biological connections.3

While a comprehensive list of neurocutaneous disorders is long, the most
common neurocutaneous disorders encountered in neurologic clinical practice
are reviewed in this article, including NF1, Legius syndrome, neurofibromatosis
type 2 (NF2), Noonan syndrome with multiple lentigines, tuberous sclerosis
complex, Sturge-Weber syndrome, and incontinentia pigmenti. The genetic
basis, diagnostic criteria, clinical features, and relevant management issues are
discussed for each disorder.
NEUROFIBROMATOSIS TYPE 1
NF1 is the most common and well-known neurocutaneous disorder, occurring in
approximately 1 in 3000 to 1 in 4000 individuals.4,5 NF1 is an autosomal
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dominant disorder caused by a mutation in the NF1 gene that lies on
FIGURE 5-1
RAS–mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin
(mTOR) pathways in neurocutaneous disorders.
CFC = cardiofaciocutaneous syndrome; NSML = Noonan syndrome with multiple lentigines; NF1 =
neurofibromatosis type 1.
Modified with permission from Wataya-Kaneda M, J Dermatol Sci.3 © 2015 Japanese Society for
Investigative Dermatology.
98 FEBRUARY 2018
chromosome 17q11.2.6,7 Approximately 50% of cases of NF1 are familial, and the
remaining cases occur sporadically.4,5,7 The NF1 gene encodes the protein
neurofibromin, which acts as a guanine triphosphatase (GTPase)-activating
protein (GAP) and is important in cell growth and signaling pathways,
participating in downregulating the tumor-suppressing RAS-MAPK pathway.7
NF1 is a multisystem disorder primarily affecting the skin, CNS, peripheral

nervous system, eyes, and musculoskeletal system.4,5
Diagnosis
In 1987, the National Institutes of Health (NIH) Consensus Development Panel
established NF1 diagnostic criteria that still remain the gold standard for making
a clinical diagnosis (TABLE 5-2).8 In most cases, an NF1 diagnosis can be made on
a clinical basis by an experienced physician using the diagnostic criteria, but
genetic testing may be required in atypical cases. In addition, the discovery of the
clinically milder Legius syndrome (described later in this article) has increased
the need to perform genetic testing to differentiate it from NF1.9 Since NF1
clinical features develop over time, it may also be difficult to confirm a diagnosis
in young children with multiple café au lait spots and no other NF1-related
findings, so genetic testing may also be appropriate in these cases. However, a
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clinical diagnosis can be confirmed by the NIH diagnostic criteria for NF1 in as
many as 75% of children by 6 years of age and almost all by 10 years of age.10 Of
note, some individuals may have a mosaic or segmental form of NF1 that involves
only a segment of the body and does not place them at risk for the numerous
medical complications that can be seen in the population with generalized NF1.10
Clinical Features
NF1 primarily affects the skin, CNS, peripheral nervous system, eyes, and
musculoskeletal system, but rarer complications can occur involving other
organ systems.
SKIN. Café au lait spots are the hallmark clinical feature in NF1 and are identified
in almost all affected individuals. These are macular hyperpigmented lesions that
National Institutes of Health Neurofibromatosis Type 1 Diagnostic Criteriaa TABLE 5-2
The diagnostic criteria require the presence of two of seven clinical features, including:
u Six or more café au lait spots >5 mm in diameter in prepubertal children and >15 mm in
postpubertal children
u Two or more neurofibromas or one plexiform neurofibroma
u Axillary or inguinal freckling
u Optic pathway glioma

u Two or more Lisch nodules
u A distinctive osseus lesion (long bone thinning, sphenoid wing dysplasia)
u A first-degree relative with neurofibromatosis type 1 meeting the above criteria
a Data from Neurofibromatosis Conference Statement, Arch Neurol.8
are typically present at birth and grow in number and size over the first few
months to years of life. Freckling with 1 mm to 3 mm hyperpigmented macular
lesions in the axillary and inguinal areas is seen in almost 90% of cases
(FIGURE 5-2). Freckling most often arises in the toddler years and can help
confirm an NF1 diagnosis in young children with multiple café au lait spots.5,8,10
PERIPHERAL NERVOUS SYSTEM. Neurofibromas are benign nerve sheath tumors

that occur along the length of peripheral nerves. They typically develop in the
preteen and adolescent years and are present in almost all affected individuals
by adulthood (FIGURE 5-3). Neurofibromas are often classified into cutaneous
and subcutaneous groups. They
have no malignant potential but
can be cosmetically disfiguring
and cause pruritus.5,11,12
Plexiform neurofibromas are
found in approximately 30% of
individuals with NF1 and
represent more complex nerve
sheath tumors that arise from
09/2022
bundles of nerve fascicules or

nerve plexuses.4,5,12 They are
thought to be congenital and can
occur in any location, internally
or externally, on the body. When
visible externally, they may be
covered with an irregular area of
hyperpigmentation either with or
without hypertrichosis. Internal
plexiform neurofibromas may be
only identifiable on imaging
studies such as MRI. Plexiform
neurofibromas are a significant
FIGURE 5-2 cause of morbidity in NF1. As they
Café au lait spots and axillary freckling in a girl progress over time, plexiform
with neurofibromatosis type 1.
neurofibromas become intricately
involved with the surrounding
tissues. Thus, their presence often
results in significant cosmetic
disfigurement, organ
compression, erosion of
neighboring bone, vascular
compromise, and neurologic
deficits such as weakness, sensory
change, and pain (FIGURE 5-4).12
Unlike dermal neurofibromas,
plexiform neurofibromas have a
risk of malignant transformation,
FIGURE 5-3
becoming malignant peripheral
Dermal neurofibromas in an adult with nerve sheath tumors.
neurofibromatosis type 1. Epidemiologic studies have
100 FEBRUARY 2018

KEY POINTS
● Plexiform
neurofibromas occur in
approximately
30% of individuals with
neurofibromatosis type 1
and are the cause of

significant morbidity.
● The lifetime risk of

malignant transformation
of plexiform neurofibromas
is approximately 10%.
● Warning signs of
malignancy include rapid
plexiform growth,
significant pain, new
neurologic deficit, and
change to a hard texture.
FIGURE 5-4 ● Optic pathway gliomas

09/2022
Neurofibromatosis type 1. A, An extensive left facial and neck plexiform neurofibroma in are present in 15% to 20%
an adolescent with neurofibromatosis type 1. B, Axial T2-weighted MRI demonstrates the of young children with
complexity of this lesion, with almost complete obliteration of her airway. Her clinical course neurofibromatosis type 1
was also complicated by a transient ischemic attack, likely due to involvement of the but often have an indolent
left carotid artery. course, becoming
symptomatic in only 33%
to 50% of those affected.
determined the lifetime risk of malignant transformation to be approximately
10%.13 Malignant peripheral nerve sheath tumors can occur sporadically in ● Children under 6 years
individuals without NF1, but they occur at a younger age and at a higher frequency of age are most at risk
when associated with NF1. Clinical warning signs of malignancy include rapid for developing optic
pathway gliomas.
plexiform growth, severe pain, new neurologic deficits, and change in plexiform
texture to a more solid hard mass. Malignant peripheral nerve sheath tumors are
challenging to treat as they often cannot be fully resected and are resistant to
chemotherapy. The 5-year survival rate is poor at 20% to 50%.13,14
CENTRAL NERVOUS SYSTEM. Optic

pathway gliomas are a pediatric
phenomenon, occurring in 15% to
20% of children with NF1. The
population under 6 years of age is
most at risk of developing optic
pathway gliomas, with a
median age of detection of
approximately 3 years
(FIGURE 5-5).14,15 Classified
as World Health Organization
(WHO) grade I pilocytic
astrocytomas, optic pathway
gliomas most often have an
FIGURE 5-5
indolent course but become Axial T2-weighted fat-saturated brain MRI
symptomatic in one-third to demonstrates a left optic pathway glioma in a
one-half of affected patients.14 4-year-old boy with neurofibromatosis type 1.
They can occur in any portion of the optic pathway, including the prechiasmatic
optic nerves, optic chiasm, optic tracts, and optic radiations. Several studies have
demonstrated that chiasmatic and postchiasmatic lesions are the most likely to
progress, while prechiasmatic lesions have a more benign course.15 Findings may
include optic atrophy, proptosis, pupillary abnormalities, decreased visual acuity,
and decreased color vision. Additional involvement of the hypothalamus is not

uncommon and can result in endocrinopathies such as precocious puberty.

Treatment with chemotherapeutic agents is typically based on the development of
visual symptoms but is sometimes undertaken when progressive growth is seen on
serial neuroimaging.14,15
Brain MRIs in the pediatric NF1 population also often reveal T2-hyperintense
lesions, which are now known to be benign and should not be confused with brain
tumors. MRI T2 hyperintensities occur in approximately 60% to 80% of pediatric
patients with NF1 and are found in typical areas, including the brainstem, basal
ganglia, thalami, and cerebellum.16 They are nonenhancing and, by definition,
do not cause mass effect or neurologic deficits. Their presence waxes and wanes
throughout childhood, with many resolving by adulthood.16 There have been
few pathologic studies of these interesting lesions, but they are hypothesized to
09/2022
represent areas of myelin edema because of their histologic appearance with

spongiotic or vacuolar tissue changes.17 A large body of literature exists from
research efforts to define the relationship between MRI T2 hyperintensities and the
neurocognitive deficits in children with NF1. While general agreement exists that
such a relationship is likely, the exact nature and pathogenesis are still unclear.16,17
Neurocognitive and behavioral deficits are well-known neurologic
complications of NF1. Learning disabilities are found in 30% to 70% of affected
children.17 Compared to unaffected siblings, a general lowering of IQ is seen in
children with NF1, but intellectual disability (IQ less than 70) is uncommon in
this population. A wide range of cognitive domains are affected, including verbal
learning, visuospatial skills, and executive functions such as attention and
working memory.16,17 In addition, approximately 30% to 50% of children with
NF1 meet the diagnostic criteria for attention deficit hyperactivity disorder
(ADHD), which can further impact academic and social outcomes.18 More recent
research has shown an increased prevalence of features of autism and social
impairments in children with NF1.19
EYE. Lisch nodules (hamartomatous lesions of the iris) are identified in

approximately 95% of patients older than 20 years of age. An ophthalmologic
slit-lamp examination is often required to visualize them. They are markers of
NF1 but do not cause vision or other ocular problems.5
MUSCULOSKELETAL SYSTEM. Specific musculoskeletal features of NF1 are part

of the diagnostic criteria and are often easily identified at birth. The most
common findings include sphenoid wing dysplasia, anterior chest wall
deformities (pectus carinatum and excavatum), bowing of the tibia/fibula,
osteopenia, and osteoporosis. Pseudarthrosis, or a “false joint,” occurs when
fragile NF1-related long bone thinning leads to fractures, which often heal
poorly and require stabilization surgeries.20 Vertebral scalloping and spinal
neurofibromas can result in dystrophic scoliosis, which appears at a young age,
is more severe, and progresses more rapidly than idiopathic scoliosis.20 In
addition, individuals with NF1 have lower bone mineral density and a higher
102 FEBRUARY 2018

fracture rate than the general population, which may be due to alterations in KEY POINTS
NF1-related osteoblast or osteoclast function.21
● Optic pathway gliomas
present with decreased
OTHER. Vasculopathy is a less common but important potential complication of visual acuity, pupillary
NF1. Research has demonstrated that the expression of abnormal neurofibromin abnormalities, color
and dysregulation of the RAS-MAPK pathway in vascular epithelial cells vision abnormalities,
and proptosis.
promotes proliferative changes and altered vascular morphogenesis.22 The scope

Endocrinopathies may
of vascular abnormalities seen in the NF1 population includes renal artery signal associated
stenosis, moyamoya syndrome, cerebral aneurysms, and stenotic or tortuous chiasmatic and
cerebral vessels (FIGURE 5-6).23 Renal artery stenosis can result in primary hypothalamic involvement.
hypertension (CASE 5-1). Recent literature has shown that, compared to the
● While still a controversial
general population, the odds of having any type of stroke are significantly issue, evidence-based
elevated in both children and adults with NF1. Adults and children have an medicine does not support
increased risk for hemorrhagic stroke, while children are particularly at risk for the use of screening
ischemic strokes.23 Finally, as NF1 is caused by an aberration of tumor-suppressing brain MRIs for optic
pathway gliomas in
biological pathways, an increased incidence of brain and systemic tumors exists pediatric patients with
in NF1. Pheochromocytomas, gastrointestinal stromal tumors, leukemia, brain neurofibromatosis type 1, but
tumors, and breast cancer are all more common in patients with NF1 than in the regular vision screening is
general population.5 imperative.
09/2022
● Any child with

Management neurofibromatosis type 1
NF1 is best managed by experienced clinicians familiar with the disorder in a who has vision
multidisciplinary setting with access to subspecialists with the expertise to care deterioration, endocrine
abnormalities, significant
for NF1-related complications. Published guidelines exist for health supervision headaches, seizures,
recommendations for children with NF1 and are in the process of being updated, marked increase in head
but such recommendations are lacking for adult patients with NF1.24 size, or other concerning
As the signs and symptoms of neurologic symptoms
should undergo a brain MRI
NF1 develop over time, with and without contrast.
longitudinal monitoring is
necessary and specific
management recommendations
are age-related. Genetic counseling
is an integral part of patient care
and is most important at the time
of diagnosis and with family
planning. Throughout childhood,
annual skin examinations and
monitoring of vision, skeletal
growth, blood pressure, and
neurocognitive development
is important.24
Ophthalmologic examinations
are recommended annually until
8 years of age and every 2 years FIGURE 5-6
thereafter until 18 years of age Vascular abnormalities in neurofibromatosis type 1.
to assess for changes associated Time-of-flight brain magnetic resonance angiogram
with optic pathway gliomas. (MRA) demonstrates occlusive stenosis of the origin
of the M1 segment of the left middle cerebral artery
While still a controversial issue, and extensive associated vessel collateralization
evidence-based medicine does in a 3-year-old girl with asymptomatic
not support the use of screening neurofibromatosis type 1 and moyamoya syndrome.
brain MRIs for optic pathway gliomas, but any child with vision deterioration,
signs of endocrine abnormalities, significant headaches, seizures, marked increase
in head size, or other concerning neurologic symptoms should undergo a brain
MRI.15,24 Appropriate referrals to developmental specialists should be considered
for children with evidence of learning disabilities, ADHD, or features of autism.24
Management of adults with NF1 focuses on monitoring for benign tumors,

malignancies, bone health, and vasculopathy as well as for progression of any

complications identified earlier in life.24 There should be a low threshold for
evaluating any individual with NF1 for stroke if presenting with new
neurologic deficits.23
As our understanding of the functions of neurofibromin and the RAS-MAPK
pathway have expanded, biologically targeted therapies have focused on
treatment of the most severe NF1 complications. Numerous phase 1 and phase 2
clinical trials have been performed for the treatment of optic pathway gliomas,
plexiform neurofibromas, malignant peripheral nerve sheath tumors, and
NF1-related cognitive deficits.25,26
LEGIUS SYNDROME
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Legius syndrome was first described in 2007 in a group of individuals who met
the NIH diagnostic criteria for NF1 but who had no identifiable mutation in the
NF1 gene.8,27 A heterozygous germline mutation in the SPRED1 gene on
chromosome 15q13.2 was identified as causing this NF1-like syndrome, and, as
with the NF1 gene, this gene codes for a protein that acts as a tumor suppressor to
downregulate the RAS-MAPK pathway.27,28 An autosomal dominant inheritance
pattern with complete penetrance has been established.28
CASE 5-1 A 25-year-old man was brought to the emergency department by ambulance
after having his first seizure. He had no known underlying medical condition
and was in his usual state of good health when the seizure occurred.
On examination, he was afebrile with a heart rate of 100 beats/min and a
blood pressure of 180/96 mm Hg. He appeared to be healthy but was
postictal. On skin examination, he had multiple café au lait spots in addition
to axillary freckling and dermal neurofibromas consistent with a diagnosis
of neurofibromatosis type 1 (NF1). His neurologic examination was normal.
Head CT revealed hypodensities in the parietooccipital regions. Brain MRI
was consistent with a diagnosis of posterior reversible encephalopathy
syndrome (PRES). Further workup for an etiology of his hypertension
revealed right-sided renal artery stenosis.
COMMENT This case highlights the fact that neurocutaneous disorders often go
undiagnosed, particularly when individuals are otherwise healthy. In this
case, a skin examination facilitated confirmation of the diagnosis and led to
appropriate patient management. In addition, the vascular manifestations
of NF1 can be clinically silent for many years, and it is important for
individuals with NF1 to be monitored by experienced clinicians for potential
complications throughout their lifetime.
104 FEBRUARY 2018

Clinical Features KEY POINTS
Research studies have shown that approximately 5% of individuals with Legius
● Legius syndrome is
syndrome meet the NIH diagnostic criteria for NF1, which has called into caused by a mutation in the
question the specificity of the clinical criteria used by clinicians for decades to SPRED1 gene.
confirm an NF1 diagnosis.28 Legius syndrome presents with features including
café au lait spots and macrocephaly either with or without axillary and inguinal ● Approximately 5% of
individuals with Legius

freckling. However, notably absent are other findings common to NF1, including
syndrome will meet the
Lisch nodules, optic pathway gliomas, neurofibromas, tibial dysplasia, and National Institutes of Health
malignant peripheral nerve sheath tumors. Lipomas have been identified in diagnostic criteria for
several families with SPRED1 mutations and should not be confused clinically neurofibromatosis type 1.
with neurofibromas. Dysmorphic facial features similar to those seen in Noonan
● Individuals with Legius
syndrome, including hypertelorism, down-slanting palpebral fissures, and syndrome do not have many
low-set posteriorly rotated ears, were noted in the first five families reported of the clinical features
with Legius syndrome and have been found in other study populations.27,29 seen in neurofibromatosis
Learning disabilities and ADHD may also be present but are often less severe type 1, including dermal or
plexiform neurofibromas,
than in NF1.29 Rare malignancies, including leukemia, breast cancer, and dermoid Lisch nodules, optic
tumor of the ovary, have been reported in single cases of Legius syndrome but pathway gliomas, or tibial
are not unexpected given the involvement of the RAS-MAPK pathway.28,29 dysplasia.
09/2022
Management ● Adults with

neurofibromatosis type
Genetic testing for Legius syndrome should be considered in postpubertal
2 typically present in the
individuals with multiple café au lait spots and no neurofibromas or Lisch second or third decade of
nodules as well as in cases where the NF1 phenotype is less clear.28 Distinguishing life with hearing loss,
between NF1 and Legius syndrome has significant implications for an tinnitus, or disequilibrium.
individual’s long-term medical prognosis and family genetic counseling. For
● Children with
example, with few exceptions, there should be no need for the brain and spinal neurofibromatosis type
MRIs and ophthalmologic evaluations that are often part of routine NF1 care.24 2 commonly present with
nonvestibular-related
symptoms due to other
NEUROFIBROMATOSIS TYPE 2 brain tumors, spinal cord
NF2 is an autosomal dominant multisystem disorder that predisposes to the tumors, and ophthalmic
development of multiple benign nerve sheath tumors, CNS tumors, ophthalmic abnormalities.
abnormalities, and neurocutaneous lesions. The NF2 gene maps to chromosome
22q12 and encodes the protein merlin (also known as schwannomin), a tumor
suppressor.30–32 Merlin has numerous functions involving the interactions
between cell membrane and cytoskeletal proteins but, like neurofibromin in NF1,
ultimately regulates downstream cell signaling through the RAS-MAPK
pathway.32 Epidemiologic studies show an incidence of NF2 of approximately 1 in
33,000 to 1 in 40,000 live births.25,33
Diagnosis
The diagnostic criteria for NF2 have evolved over the years to improve sensitivity
as the genetic basis and defining clinical features have been elucidated. The
Manchester criteria34 are still frequently used, but in 2011, Baser and colleagues
built upon current knowledge to create criteria that can be used to reliably make
an earlier diagnosis than prior criteria (TABLE 5-3).33,35 While vestibular
schwannomas are the hallmark of NF2, additional clinical features are often
required to confirm the diagnosis.33
NF2 most often presents in the second or third decade of life with hearing
loss, tinnitus, or disequilibrium, which are attributable to vestibular
schwannoma involvement. Children with NF2 are more likely to come to
KEY POINTS medical attention because of nonvestibular etiologies, such as other brain
tumors, spinal cord tumors, skin lesions, visual disturbances, and
● Schwannomatosis is a
rare third form of
mononeuropathy (CASE 5-2).30,35,36
neurofibromatosis with NF2 is now rarely confused with NF1, but schwannomatosis should be
clinical and genetic overlap included in the differential diagnosis of any patient with suspected NF2.
with neurofibromatosis Schwannomatosis is a rare third form of neurofibromatosis, with clinical,

type 2.
genetic, and imaging overlap with NF2. Mutations in the SMARCB1 gene account
● Individuals with for 40% to 50% of the cases of familial schwannomatosis and 10% of sporadic
schwannomatosis typically cases.25 More recently, associated mutations in the LZTR1 gene, which maps to
present in their twenties to chromosome 22 in the region of the NF2 and SMARCB1 genes, have also been
thirties with chronic pain
identified in some cases. Individuals with schwannomatosis often present in their
and symptoms relatable to
nerve sheath tumors in the twenties to thirties with chronic pain and symptoms relatable to nerve sheath
central and peripheral tumors. While other cranial nerves can be involved, individuals with
nervous systems. schwannomatosis can be distinguished from those with NF2 because they do not
develop vestibular schwannomas.25
● Schwannomatosis does
not cause vestibular
schwannomas as seen in Clinical Features
neurofibromatosis type 2, The clinical manifestations of NF2 involve the skin, CNS, peripheral nervous
but other cranial nerves can system, and eyes.
09/2022
be involved.
SKIN. The cutaneous findings of NF2 are much less prominent than in other
neurocutaneous disorders. Skin tumors are identified in approximately 70% of
affected individuals.36 Plaquelike, raised, intracutaneous, hyperpigmented
areas with occasional hypertrichosis occur most frequently. Subcutaneous
nodular palpable lesions can also often be identified. Café au lait spots are
found in approximately 40% of cases but are atypical and much less numerous
than those seen in NF1.35,36
TABLE 5-3 Manchester Criteria for the Diagnosis of Neurofibromatosis Type 2a
Individuals who meet the following criteria can be diagnosed with neurofibromatosis
type 2 by:
A Bilateral vestibular schwannomas
B First-degree relative with neurofibromatosis type 2 AND:
1 Unilateral vestibular schwannoma OR
2 Any two of the following: meningioma, glioma, neurofibroma, schwannoma, posterior
subcapsular lenticular opacities
C Unilateral vestibular schwannoma AND any two of the following: meningioma, glioma,
neurofibroma, schwannoma, posterior subcapsular lenticular opacities
D Multiple meningioma (two or more) AND
1 Unilateral vestibular schwannoma OR
2 Any two of the following: meningioma, glioma, neurofibroma, schwannoma, posterior
subcapsular lenticular opacities
a
Modified with permission from Baser ME, et al, Neurology.33 © 2002 American Academy of Neurology.
106 FEBRUARY 2018

A 10-year-old girl presented to the emergency department with a 2-week CASE 5-2
history of progressively worsening headaches, nausea, and vomiting. She
had initially been diagnosed with a viral syndrome, but the family brought
her to the emergency department after she developed intermittent right
face and arm numbness with slurred speech. She had no history of
weakness or seizure activity. Two years previously she underwent removal

of a right congenital cataract.

In the emergency department, her neurologic and general examinations
were normal. Head CT showed a hyperdense mass in the left frontoparietal
region with associated hyperostosis of the adjacent calvaria and a 2-mm
midline shift concerning for a meningioma. Brain MRI showed a large left
hemispheric enhancing extraaxial mass with central areas of necrosis and
surrounding edema consistent with a meningioma (FIGURE 5-7 ). Bilateral
cranial nerve VII and VIII schwannomas were also identified. An MRI of
the spine was normal. A diagnosis of neurofibromatosis type 2 (NF2) was
subsequently clinically confirmed.
09/2022
FIGURE 5-7
Coronal postcontrast T1-weighted MRI of the
patient in CASE 5-1 shows a left hemispheric
enhancing mass with central necrosis and
surrounding edema consistent with a meningioma
in a 10-year-old girl with neurofibromatosis type 2.
This case highlights the fact that while adults with NF2 typically present COMMENT
with symptomatology related to vestibular schwannomas, children with NF2
are more likely to present with ophthalmic findings, meningiomas,
nonvestibular schwannomas, and spinal tumors.
CENTRAL AND PERIPHERAL NERVOUS SYSTEMS. Vestibular schwannomas are

benign tumors of the eighth cranial nerve and the hallmark of NF2. They arise
from within the internal auditory canal and expand into the cerebellopontine
angle. They may initially develop and become symptomatic unilaterally but
frequently become bilateral over time. Vestibular schwannomas are the primary
cause of NF2-associated morbidity, causing sensorineural hearing loss, tinnitus,

balance problems, and brainstem compression that progress over time

(FIGURE 5-8).25,30 Several studies on the natural history of vestibular schwannomas
have shown a growth rate of 1 mm/y to 1.8 mm/y.25 Interestingly, the degree of
hearing loss does not necessarily correlate with the tumor size or growth rate.25
Additional benign intracranial neoplasms also frequently develop in NF2.
After vestibular schwannomas, oculomotor and trigeminal nerves are the next
most commonly involved cranial nerves.30 Meningiomas occur in approximately
50% of affected individuals and may be multiple.30 They are found at the
convexities, at the skull base, along the falx, and around the optic nerves. Like
other tumors in NF2, they have variable growth rates and periods of relative
quiescence. Meningiomas resulting in brain edema are more aggressive than
those without edema and require more immediate intervention. Headaches,
seizures, balance problems, and visual deterioration can result, depending on
09/2022
their location and the degree of compression of local tissues. One study found
that the presence of NF2-associated meningiomas raised the relative risk of
mortality by 2.5 times compared to those without meningiomas.25
Spinal cord tumors are seen in almost 70% of NF2 cases.37 Spinal schwannomas
and extramedullary meningiomas occur most frequently. Weakness, sensory
changes, pain, and bowel/bladder difficulties can result when these lesions cause
spinal cord and nerve compression.37 Intramedullary ependymomas occur in
33% to 53% of patients and have a
predilection for the cervical spine
and the cervicomedullary
junction.38 They can cover
multiple spinal cord segments and
often contain cystic components.
Most NF2-associated spinal
ependymomas have an indolent
course, remain asymptomatic,
and do not require intervention.38
A distinct NF2-associated
polyneuropathy is a less
well-known feature of this
disorder, with one study
reporting clinical features of
neuropathy in almost 50% of
patients with NF2 evaluated.39
While axonal neuropathies are
more common, demyelinating
changes have also been
FIGURE 5-8 identified on nerve conduction
Axial postcontrast T1-weighted MRI demonstrates
bilateral vestibular schwannomas with brainstem
studies. Interestingly, NF2
compression in a 23-year-old man with polyneuropathy occurs in the
neurofibromatosis type 2. absence of associated nerve
108 FEBRUARY 2018

sheath lesions. Thus, a patient with NF2 with loss of deep tendon reflexes not KEY POINTS
explained by associated peripheral nerve schwannomas may need an evaluation
● Intracranial
for an underlying neuropathy.39 Children and adults with NF2 may also develop neurofibromatosis type
a mononeuropathy, most often affecting the facial nerve. In addition, an 2–related tumors include
underrecognized poliolike illness resulting in irreversible lower extremity vestibular schwannomas,
monoplegia has been reported in pediatric NF2 and is rarer in adults.35 other cranial nerve
schwannomas, and
EYES. Approximately 80% of individuals with NF2 have ocular involvement. meningiomas.
Subcapsular lenticular opacities, a type of cataract, are included in the
31 ● The spinal tumors
diagnostic criteria and are seen in 60% to 80% of patients. Additional most often found in
ophthalmologic findings include epiretinal membranes, retinal hamartomas, neurofibromatosis type 2
childhood cortical wedge opacities, optic disc gliomas, and optic nerve sheath include schwannomas,
extramedullary
meningiomas. Unexplained amblyopia and strabismus are well-documented
meningiomas, and
findings in early childhood NF2. Identification and ongoing monitoring of intramedullary
31,35
these abnormalities is important as they can potentially threaten vision. ependymomas.
Management ● A high rate of mosaicism

Like many multisystem disorders, management of NF2 ideally involves specialists exists in neurofibromatosis
from numerous disciplines, including medical genetics, otolaryngology, type 2, which can
complicate confirmation of
09/2022
neurosurgery, neurology, oncology, ophthalmology, and audiology. Evaluation at a diagnosis and screening
the time of diagnosis should include neuroimaging of the brain/internal auditory of family members.
canals and spine with and without contrast, ophthalmologic examination,
neurologic examination, and audiology. Depending on the lesions and symptoms ● If genetic testing in blood
lymphocytes is negative for
identified, follow-up neuroimaging, audiology, and clinical evaluations are required
the NF2 mutation, testing of
on a regular basis in addition to monitoring by the appropriate subspecialists.30 a tumor sample can be
Genetic testing and counseling are important components in the management helpful, particularly in
of individuals with NF2. A high rate of mosaicism exists in NF2, which can sporadic cases.
complicate confirmation of an NF2 diagnosis and assessment of the risk of family
● Noonan syndrome with
members developing NF2. As an autosomal dominant disorder, individuals with multiple lentigines is a rare
two generations of affected family members with a confirmed NF2 diagnosis multisystem RASopathy
have a 50% risk of inheriting the disorder. However, over 50% of NF2 cases arise with three known causative
de novo with no family history, and children of these individuals may have a genes (PTPN11, RAF1, BRAF).
less than 50% risk of having NF2, as some of these cases may be mosaic. Genetic
studies have shown 25% to 33% of de novo cases are mosaic, with an NF2
mutation identifiable only in tumors and not in blood lymphocytes.40 A mutation
can be identified in lymphocytes in only approximately 60% of individuals
who meet the NF2 diagnostic criteria but do not have a family history.40
Of note, while traditional treatment has focused on surgical interventions,
over the past decade, attention has turned to the development and use of
chemotherapeutic agents, such as bevacizumab, that target the biological
pathways involved in tumor growth. These studies have thus far produced mixed
results on outcome measures of tumor shrinkage and hearing restoration, but
newer agents are in the pipeline.25,35 Surgery has remained the mainstay of
treatment for other NF2 brain and spinal cord tumors, including schwannomas,
meningiomas, and ependymomas. Oncologic intervention with chemotherapy
and radiation is reserved for the more aggressive lesions, which are less common
in NF2.25,35
NOONAN SYNDROME WITH MULTIPLE LENTIGINES

Noonan syndrome with multiple lentigines is an autosomal dominant
RASopathy. The incidence of this rare condition is currently unknown.2,41,42
KEY POINTS Noonan syndrome with multiple lentigines is genetically heterogeneous, and
mutations in three genes are responsible for approximately 95% of cases.41 A
● Hypertrophic
cardiomyopathy is the most
missense mutation in the PTPN11 gene on chromosome 12q24 is identified in 85%
common cardiac anomaly in of patients. However, mutations in the RAF1 gene on chromosome 3p25.2 and the
Noonan syndrome with BRAF gene on chromosome 7q34 are also seen in some individuals.1,41,42
multiple lentigines and can

be a cause of morbidity and
mortality. A variety of
Clinical Features
cardiac arrhythmias and No specific diagnostic criteria have been identified for Noonan syndrome with
valvular defects are also multiple lentigines. Noonan syndrome with multiple lentigines was previously
frequently identified. known as LEOPARD syndrome, with the mnemonic describing the clinical
features: lentigines (FIGURE 5-9), electrocardiographic conduction defects,
● In tuberous sclerosis
complex, mutations in the ocular hypotelorism, pulmonic stenosis, abnormal genitalia, retardation of
TSC1 and TSC2 genes map to growth, and sensorineural deafness.2,42 Noonan syndrome with multiple
different chromosomes but lentigines has become the preferred name for this disorder because of the clinical
produce essentially the
and genetic similarities overall with Noonan syndrome, which is associated with
same clinical syndrome with
variable expressivity. a similar facial appearance, cardiac abnormalities, and skin findings.43 The
clinical features of Noonan syndrome with multiple lentigines are highlighted in
● TSC1 mutations occur TABLE 5-4.
more often with a familial
09/2022
inheritance pattern and

produce a milder
Management
phenotype, while TSC2 When Noonan syndrome with multiple lentigines is suspected, prompt evaluation
mutations arise more by a geneticist is recommended, including a thorough clinical assessment and
frequently in sporadic cases appropriate genetic testing to confirm the diagnosis. A baseline clinical
and result in more severe
clinical manifestations.
examination should evaluate for associated neurologic, cardiac, genitourinary,
and hearing abnormalities. Noonan syndrome with multiple lentigines is
inherited in an autosomal dominant fashion, so genetic counseling is necessary
for patients and families as well.41,44
A thorough cardiac evaluation, including
a clinical examination, ECG, and
echocardiogram, is warranted in all patients
with Noonan syndrome with multiple
lentigines beginning at a young age. It is also
important for patients to have serial cardiac
evaluations since hypertrophic
cardiomyopathy and arrhythmias may
develop over time.44,45 In addition,
newborn hearing screening should be done
in all affected individuals. Hearing
screening may need to be repeated annually
as hearing loss has been reported to develop
at older ages.41,44
TUBEROUS SCLEROSIS COMPLEX

Tuberous sclerosis complex is a multisystem
FIGURE 5-9 autosomal dominant disorder that occurs in
Multiple lentigines on the trunk of an approximately 1 in 6000 individuals,
adolescent with Noonan syndrome with causing hamartomatous lesions that
multiple lentigines.
Reprinted with permission from
primarily affect the brain, skin, heart, eyes,
Martinez-Quintana E, Rodriguez-González F, kidneys, and lungs.46,47 Approximately
Mol Syndromol.41 © 2012 S. Karger AG. 70% of tuberous sclerosis complex cases
110 FEBRUARY 2018

occur sporadically, while the remaining cases are familial.47 Mutations in
tumor-suppressing genes causing tuberous sclerosis complex occur on two different
chromosomes but result in essentially the same clinical features with highly variable
expressivity. TSC1 lies on chromosome 9q34, while the locus for TSC2 maps to
chromosome 16p13.3.47 The protein products of the TSC1 and TSC 2 genes
(hamartin and tuberin, respectively) cooperate as part of a protein complex to

downregulate cell proliferation and differentiation through the mTOR pathway.3

Important genotype-phenotype correlations exist in tuberous sclerosis complex.
Analysis of large familial populations of individuals with tuberous sclerosis complex
have revealed that TSC1 cases tend to occur more often with a familial inheritance
pattern and result in a milder clinical phenotype, while TSC2 cases occur most
often sporadically and are characterized by more severe clinical complications.47
Diagnosis
The diagnostic criteria for tuberous sclerosis complex were published in 1998
after the first International Tuberous Sclerosis Complex Consensus Conference
and were updated in 2012 to incorporate the identification of a pathologic
mutation in the TSC1 or TSC2 gene as confirmation of a tuberous sclerosis
complex diagnosis (TABLE 5-5).46 Both major and minor criteria have been
09/2022
established and are the basis of a clinical diagnosis. Identification of a pathologic

mutation in the TSC1 or TSC2 gene is now sufficient to confirm the diagnosis,
regardless of the clinical features present. However, molecular genetic testing is
positive in 75% to 90% of cases, thus normal genetic testing does not exclude a
tuberous sclerosis complex diagnosis.46
Clinical Features
Tuberous sclerosis complex affects multiple organs of the body, including the
skin, CNS, eyes, heart, and kidneys.
Clinical Features of Noonan Syndrome With Multiple Lentigines TABLE 5-4
Organ System Clinical Features

Skin Lentigines: darkly pigmented, small lesions clustering in head, neck, and trunk regions but sparing mucosa;
present at birth and increase with age (FIGURE 5-9 )
Facies Overlap with Noonan syndrome and other RASopathies; hypertelorism, flat nasal bridge, dysmorphic
ears in most patients; may also have thin lips, low-set ears, ptosis, and redundant neck skin
Central nervous Learning disabilities seen in 30%, but intellectual disability is rare; hypotonia, seizures, autism spectrum
system disorder, and general delays are less common
Heart Hypertrophic cardiomyopathy is the most commonly seen defect and can be life-threatening; right bundle
branch block is the most common arrhythmia but other conduction abnormalities can occur; pulmonary
stenosis is reported in 23%
Hearing Sensorineural hearing loss is found in 25%; it is often bilateral and can be profound
Skeletal Pectus carinatum or pectus excavatum found in 75%; scoliosis, scapular winging, syndactyly, joint hypermobility,
rib anomalies, and cervical spine fusion can be seen
Other Dental anomalies can occur; growth retardation found in 25%; suspected association with malignancies of
varying types
TABLE 5-5 Tuberous Sclerosis Complex Diagnostic Criteriaa
Genetic Diagnostic Criteria
The identification of either a TSC1 or TSC2 pathogenic mutation in DNA from normal tissue is
sufficient to make a definite diagnosis of tuberous sclerosis complex (TSC). A pathogenic

mutation is defined as a mutation that clearly inactivates the function of the TSC1 or TSC2
proteins (eg, out-of-frame indel or nonsense mutation), prevents protein synthesis (eg, large
genomic deletion), or is a missense mutation whose effect on protein function has been
established by functional assessment. Other TSC1 or TSC2 variants whose effect on function
is less certain do not meet these criteria and are not sufficient to make a definite diagnosis of
TSC. Note that 10% to 25% of patients with TSC have no mutation identified by conventional
genetic testing, and a normal result does not exclude TSC or have any effect on the use of
clinical diagnostic criteria to diagnose TSC.
Clinical Diagnostic Criteria
Definite diagnosis: Two major features or one major feature with two minor features
Possible diagnosis: Either one major feature or two minor features
09/2022
u Major Features
1 Hypomelanotic macules (>3, at least 5-mm diameter)

2 Angiofibromas (>3) or fibrous cephalic plaque
3 Ungual fibromas (>2)
4 Shagreen patch
5 Multiple retinal hamartomas

6 Cortical dysplasiasb
7 Subependymal nodules
8 Subependymal giant cell astrocytoma
9 Cardiac rhabdomyoma
10 Lymphangioleiomyomatosisc
11 Angiomyolipomas (>2)c
u Minor Features
1 “Confetti” skin lesions

2 Dental enamel pits (>3)
3 Intraoral fibromas (>2)
4 Retinal achromic patch

5 Multiple renal cysts
6 Nonrenal hamartomas

a Reprinted with permission from Northrup H, Krueger DA, Pediatric Neurol.46 © 2013 Elsevier.
b
Includes tubers and cerebral white matter radial migration lines.
c A combination of the two major clinical features (lymphangioleiomyomatosis and angiomyolipomas)
without other features does not meet criteria for a definite diagnosis.
112 FEBRUARY 2018

SKIN . The cutaneous features of tuberous sclerosis complex are numerous and KEY POINT
represent hallmark findings of the disorder that often prompt a diagnostic
● The most common
workup. Hypomelanotic macules are the most common skin finding, present in cutaneous findings in
approximately 90% of affected individuals. They are most often present at birth or tuberous sclerosis complex
develop during infancy and remain stable through the lifetime (FIGURE 5-10).46,48 include hypomelanotic
A Wood’s lamp can be helpful in macules, facial

angiofibromas, fibrous
identifying hypopigmented
cephalic plaques, shagreen
macules on light-colored skin. patches, confetti lesions,
The clinical criteria require three and ungual fibromas.
or more of these lesions measuring
at least 5 mm in diameter to be
present to fulfill a major
criterion.46,48 Hypomelanosis
of hair (poliosis) is also considered
to be a hypopigmented macule in
the 2012 diagnostic criteria.
Confetti lesions are small (1 mm
to 3 mm) collections of
hypopigmented lesions that occur
09/2022
on the arms and legs and represent FIGURE 5-10

A hypomelanotic macule on the arm of an
a minor feature.46,48
adolescent with tuberous sclerosis complex.
Facial angiofibromas develop
in approximately 75% of cases and
have their onset in early childhood,
between 2 and 5 years of age.46
They present most often as papular
lesions in a malar distribution but
can also involve the perioral facial
areas (FIGURE 5-11).48 Forehead
plaques, now called fibrous cephalic
plaques, are present in 25% of the
tuberous sclerosis complex
population and appear as elevated
erythematous lesions on the
forehead or scalp.46,48
Shagreen patches, a major
criterion, are relatively specific
for a tuberous sclerosis complex
diagnosis and are observed in
50% of cases. They develop in
the first decade of life and present
as plaquelike “orange-peel”
lesions, typically in the lumbosacral
region (FIGURE 5-12).46 Rarely
present in childhood, ungual FIGURE 5-11
fibromas (bumpy lesions that Prominent facial angiofibromas are seen in a malar
originate from the nail bed on and perioral distribution in an adolescent girl
with tuberous sclerosis complex. She experienced
the fingers and toes) develop in a dramatic improvement when placed on
approximately 80% of adults with everolimus for treatment of a subependymal
tuberous sclerosis complex.46,48 giant cell astrocytoma.
CENTRAL NERVOUS SYSTEM. CNS

involvement affects almost all
individuals with tuberous
sclerosis complex and clinically
manifests with significant
neurologic complications,
including epilepsy, autism,

developmental delays, and
intellectual disability. The
brain MRI in tuberous sclerosis
complex reveals three primary
findings: tubers, subependymal
FIGURE 5-12 nodules, and subependymal
An extensive shagreen patch in the lumbosacral giant cell astrocytomas
region of a 21-year-old man with tuberous
sclerosis complex who had also undergone
(SEGAs) in a subset of
spinal fusion for scoliosis. patients.46,49
Tuberous sclerosis complex
derives its name from tubers
that represent areas of congenital
09/2022
cortical dysplasia and are caused by failure of neuronal migration during fetal
development. These lesions are most often multiple and occur in approximately
90% of affected individuals (FIGURE 5-13).46 Cerebral white matter radial
glial migration lines are often associated with cortical tubers, and the
two are now considered together as a major tuberous sclerosis
complex feature.46,49
Subependymal nodules are benign lesions that develop along the surface
of the ependymal lining of the lateral ventricles and are found in 80% to
90% of individuals with
tuberous sclerosis complex.
They can be detected in utero
and are often present at birth,
calcifying over time
(FIGURE 5-14).46,49
Subependymal nodules are
thought to be the origin of
SEGAs, which are benign
neoplasms arising adjacent to
the foramen of Monro in 10%
to 20% of young patients
with tuberous sclerosis complex.49
As such, subependymal
nodules and SEGAs have
similar histopathology with
mixed glioneuronal cells.
As hamartomatous brain
FIGURE 5-13 lesions, tubers are responsible
Numerous hyperintense cortical tubers are seen for the impairing clinical
on axial fluid-attenuated inversion recovery
(FLAIR) MRI, most prominent in the right
neurologic features of tuberous
hemisphere in a patient with tuberous sclerosis sclerosis complex, such as
complex. medically refractory epilepsy,
114 FEBRUARY 2018

while stable subependymal KEY POINTS
nodules remain asymptomatic.46,49
● Subependymal giant cell
SEGAs are a pediatric astrocytomas occur in
phenomenon, presenting at the approximately 5% to 20% of
average age of 11 years and rarely young patients with
developing de novo after 20 to tuberous sclerosis

complex.
25 years of age.49,50 Debate
currently exists as to how ● Subependymal giant cell
subependymal nodules transform astrocytomas are a
to SEGAs and how to categorize pediatric phenomenon and
SEGAs on neuroimaging. rarely develop de novo
after 20 to 25 years of age.
However, despite the
controversies, SEGAs are typically ● Subependymal giant cell
defined by their location, size of astrocytomas are benign
5 mm to 10 mm, contrast tumors that arise from
subependymal nodules
enhancement, and progressive located at the foramen of
growth, while subependymal Monro and can cause acute
nodules appear to be nonenhancing FIGURE 5-14 and chronic obstructive
static lesions.49,50 hydrocephalus as they
09/2022
Axial fluid-attenuated inversion recovery (FLAIR)

enlarge.
SEGA growth is usually slow, MRI demonstrates bilateral subependymal
measured to be approximately nodules (arrow) in a 10-year-old girl with tuberous
sclerosis complex. Several hyperintense cortical ● Epilepsy with multiple
50
2 mm to 5 mm per year. While tubers are also visible and most prominent in the different seizure types
SEGAs are benign lesions, their right posterior parietal lobe. occurs in 80% of individuals
location at the foramen of Monro with tuberous sclerosis
complex.
is problematic and can result in
obstructive hydrocephalus ● Infantile spasms present
(FIGURE 5-15). When presenting acutely, patients may report headache, nausea, in 40% to 50% of infants
vomiting, ataxia, irritability, lethargy, increased seizures, or visual disturbance. with tuberous sclerosis
complex.
These lesions can be life-threatening because of severe increased intracranial
pressure or hemorrhage. SEGAs with an indolent course can be monitored on
serial neuroimaging every 1 to 3 years, according to the published guidelines.51
While surgical intervention with gross total resection can be curative, mTOR
inhibitors such as everolimus have shown significant efficacy at stabilizing and
shrinking SEGAs, although they frequently reoccur when therapy
is discontinued.49,50
Epilepsy occurs in approximately 80% of individuals with tuberous sclerosis
complex, with multiple seizure types seen in over 50% of patients.52 In one
large retrospective study, 62.5% of patients developed refractory epilepsy,
while 33.5% ultimately achieved epilepsy remission.52 Almost 40% to 50% of
infants with tuberous sclerosis complex develop infantile spasms, which are a
risk factor for the development of refractory epilepsy and Lennox-Gastaut
syndrome.52 Numerous studies have correlated poor neurologic, cognitive, and
behavioral outcome with the development of infantile spasms, early-onset
epilepsy, and refractory epilepsy.52,53 Treatment options for tuberous sclerosis
complex–associated epilepsy include the typical modalities of anticonvulsants,
the ketogenic diet, vagus nerve stimulation, and epilepsy surgery under
appropriate circumstances.51,52 Several studies have demonstrated a superior
response to vigabatrin in infants with tuberous sclerosis complex and
infantile spasms; thus, it is recommended as the first-line treatment over
adrenocorticotropic hormone (ACTH) in this population.51,53 Vigabatrin has
been associated with retinal

toxicity and potentially
permanent visual field
constriction, so monitoring with
electroretinograms is
recommended for
these patients.53
The majority of individuals
with tuberous sclerosis complex
experience intellectual,
behavioral, and psychosocial
impairments, which are now
described with the
comprehensive term tuberous
sclerosis–associated
neuropsychiatric disorders
(TAND). Autism spectrum
disorders occur in
FIGURE 5-15 approximately 40% to 50% of
09/2022
Axial postcontrast T1-weighted MRI of an individuals with tuberous

8-year-old girl with tuberous sclerosis complex
shows a subependymal giant cell astrocytoma at sclerosis complex, while a wide
the right foramen of Monro with right more than range of intellectual disabilities
left ventricular enlargement. A smaller with developmental delays occur
subependymal giant cell astrocytoma is also in over 50%.54 ADHD is also
visualized at the foramen of Monro on the left.
common, reported in 30% to
50% of affected individuals.51,54
Behavioral symptoms may
include aggression, temper tantrums, sleep disturbance, and self-injury.
Depression and anxiety are also not uncommon. A TAND checklist has been
validated, and placebo-controlled double-blind clinical trials are currently
addressing the efficacy of everolimus in the treatment of TAND-related
symptoms.51,54
EYES. Tuberous sclerosis complex–associated lesions of the eye rarely affect

vision. The presence of multiple retinal hamartomas is considered a major
tuberous sclerosis complex diagnostic feature; they are found in 30% to 50% of
individuals with tuberous sclerosis complex.46 Retinal achromic patches are areas
of hypopigmentation of the retina. They are relatively common and are a minor
diagnostic feature.46
HEART. Cardiac rhabdomyomas are hamartomatous lesions involving the cardiac

myocytes and are present in approximately 50% of children with tuberous
sclerosis complex.55 Cardiac rhabdomyomas can be detected as early as 20 to
30 weeks of gestation by fetal ultrasound and may increase in size later in
gestation, possibly because of the influence of maternal hormones. They are
multiple in 90% of cases. The majority of cardiac rhabdomyomas remain
asymptomatic, but they can be clinically significant depending on their size
and location.46,55 Ventricular rhabdomyomas are most common and can cause
outflow obstruction, valvular dysfunction, and arrhythmias, leading to
hemodynamic compromise and congestive heart failure in severe cases.
116 FEBRUARY 2018

Cardiac rhabdomyomas spontaneously regress in the first year of childhood KEY POINTS
and are less problematic in adolescence and adulthood.46,55
● Vigabatrin has shown
A variety of cardiac arrhythmias are also relatively common in children and superior efficacy to
adults with tuberous sclerosis complex. Irregular, slow, and fast heart rhythms adrenocorticotropic
have all been reported and can be clinically significant. A cardiac rhabdomyoma hormone in infants with
underlying the conduction pathways is a frequent and well-known cause. An tuberous sclerosis complex
and infantile spasms; thus,

increased incidence of Wolff-Parkinson-White syndrome also exists in the
it is recommended as
tuberous sclerosis complex population.55 first-line treatment.
Patients taking vigabatrin
KIDNEYS. Renal manifestations are central to the diagnostic criteria and represent require regular monitoring
for potential retinal toxicity
a major cause of morbidity and mortality in tuberous sclerosis complex.
and associated vision loss.
Angiomyolipomas are rare in the general population but occur with a prevalence
of 55% to 90% in individuals with tuberous sclerosis complex.56 They are benign ● The comprehensive term
tumors that develop within the renal parenchyma and are composed of smooth tuberous sclerosis–
muscle spindle cells, adipocytes, and abnormal vasculature. While often associated neuropsychiatric
disorders is now used to
asymptomatic, angiomyolipomas may result in flank pain, hematuria, and describe the numerous
spontaneous hemorrhage, which can be life-threatening.46,56 behavioral and psychiatric
Multiple renal cysts are another common finding in tuberous sclerosis symptoms that can arise in
complex and, in conjunction with angiomyolipomas, have the potential to impair individuals with tuberous
09/2022
sclerosis complex.
renal function (FIGURE 5-16). Of note, a subset of individuals with TSC2
mutations may have cysts due to a contiguous gene deletion syndrome involving ● Lymphangioleiomyomatosis
the TSC2 gene and the adjacent polycystic kidney gene (PKD1) on chromosome occurs both in tuberous
16p13.3.46 Renal cell carcinoma also occurs more frequently and at younger ages sclerosis complex and
sporadically.
in tuberous sclerosis complex than in the general population, with an incidence
of 2% to 4%.57 ● The incidence of tuberous
sclerosis complex–
LUNGS . Lymphangioleiomyomatosis is characterized by abnormal proliferation of associated
smooth muscle cells (lymphangioleiomyomatosis cells) in the lungs and can occur lymphangioleiomyomatosis
is 1% to 4%, and it primarily
in association with tuberous affects women.
sclerosis complex or sporadically.
The prevalence of
lymphangioleiomyomatosis in
patients with tuberous sclerosis
complex is 1% to 4%,58 but cystic
lung changes may be seen in as
many as 80% of women with
tuberous sclerosis complex by
40 years of age.46 Although
cystic lung changes are found in
10% to 12% of men with tuberous
sclerosis complex, symptomatic
lymphangioleiomyomatosis
rarely occurs in males.46,48,57
Histologically, interstitial
proliferation of smooth muscle
cell bundles and thin-walled
well-circumscribed cystic FIGURE 5-16
pulmonary parenchymal changes Renal cysts in tuberous sclerosis complex. Coronal
T2-weighted MRI of the abdomen demonstrates
occur. Lymphangioleiomyomatosis markedly enlarged kidneys with multiple renal
cells are considered to be cysts in a 4-year-old girl with a TSC2 mutation.
neoplastic and, while low grade, have malignant and metastatic potential.
Circulating lymphangioleiomyomatosis cells can be found in many bodily
fluids, such as blood and urine, and the lymphatics, which supports their
metastatic qualities.57 Clinically, lymphangioleiomyomatosis may present with
pulmonary symptomatology, including dyspnea, hemoptysis, recurrent
pneumothorax, and chylothorax, in addition to extrapulmonary features

such as renal angiomyolipomas, chylous ascites, lymphatic tumors

(lymphangioleiomyomas), and abdominal/thorax lymphadenopathy. The
diagnosis of lymphangioleiomyomatosis is best made by high-resolution
TABLE 5-6 Surveillance Recommendations in Tuberous Sclerosis Complexa
Organ System or Surveillance and

Specialty Area Health Maintenance Treatment of Complications
Genetics Offer genetic testing and counseling when Not applicable
appropriate
09/2022
Skin Perform an annual detailed skin examination Facial angiofibromas: treatment options include
pulse dye laser and ablative laser therapy; topical
mammalian target of rapamycin (mTOR) inhibitors
have been studied in clinical trials and have shown
promise in case studies but are not yet approved
by the US Food and Drug Administration
Central Subependymal giant cell astrocytoma: Perform a Symptomatic subependymal giant cell astrocytoma:
nervous brain MRI every 1–3 years in patients younger than acute resection or ventriculoperitoneal shunt may
system 25 years of age who are asymptomatic; individuals be required
with known or growing subependymal giant cell
Enlarging but asymptomatic subependymal giant
astrocytomas need neuroimaging more often
cell astrocytoma: mTOR inhibitors and surgical
Epilepsy: Routine or video-EEG is indicated with resection are both options
suspected seizure activity; management of epilepsy
with options including anticonvulsants, ketogenic
diet, vagus nerve stimulator, and epilepsy surgery
Developmental delays and autism: Perform
annual screening for tuberous sclerosis
complex–associated neuropsychiatric disorders;
comprehensive evaluations recommended in infancy,
preschool, pre–middle school, adolescence, and
adulthood; refer for appropriate developmental and
psychiatric support
Heart Perform an echocardiogram every 1–3 years in Symptomatic rhabdomyomas and conduction
children with asymptomatic cardiac rhabdomyomas abnormalities should be managed by an
until regression demonstrated; symptomatic experienced cardiologist on an individual case
individuals require more frequent monitoring basis; ECG, echocardiogram, and Holter monitoring
may be required
Perform an ECG every 3–5 years in asymptomatic
individuals of all ages to screen for conduction
abnormalities; symptomatic individuals require
more frequent or detailed assessments
118 FEBRUARY 2018

chest CT, which typically demonstrates round cystic changes throughout the lungs. KEY POINT
Lymphangioleiomyomatosis is slowly progressive but, if untreated, ultimately
● Lymphangioleiomyomatosis
leads to respiratory failure and can be fatal.57,59 commonly presents with
pulmonary symptoms,
Management including dyspnea,
hemoptysis, recurrent
Guidelines for the clinical evaluation at suspected diagnosis, surveillance, and
pneumothorax, and
management in tuberous sclerosis complex were published in 2013 to accompany chylothorax, but
the revised diagnostic criteria.51 As tuberous sclerosis complex is a multisystem extrapulmonary features
disorder, management typically includes many subspecialist services and also occur.
Organ System or Surveillance and

Specialty Area Health Maintenance Treatment of Complications
Kidneys Obtain MRI of the abdomen every 1–3 years Asymptomatic angiomyolipomas >3 cm: treatment
09/2022
throughout the lifetime of the patient with an mTOR inhibitor is the recommended
first-line therapy; selective embolization followed
Assess renal function and blood pressure
by steroids, ablative therapy, or kidney-sparing
annually
resection are second-line therapies
Angiomyolipoma with acute hemorrhage:
embolization followed by corticosteroids is the
recommended first-line therapy
Eyes Annual ophthalmologic examination should be Treatment as per ophthalmology

performed with previously identified retinal lesions
or visual symptoms
Lung Perform clinical screening for Moderate to severe lymphangioleiomyomatosis
lymphangioleiomyomatosis at every clinic visit or rapidly progressing: mTOR inhibitors are
(take a history about any respiratory symptoms and recommended as first-line treatment; for further
perform auscultation of the lungs) progression, lung transplantation can be considered
Provide counseling to avoid estrogens and smoking
at every clinic visit
Perform high-resolution chest CT every 5–10 years in
asymptomatic individuals with unremarkable baseline
high-resolution CT
Perform annual pulmonary function tests and
high-resolution CT every 2–3 years for individuals
with known lung cystic changes
Teeth Perform detailed dental examination every 6 months Treatment as per dentistry
CT = computed tomography; ECG = electrocardiogram; EEG = electroencephalogram; MRI = magnetic resonance imaging.
a Modified with permission from Krueger DA, Northrup H, Pediatr Neurol.51 © 2013 The Authors.
requires coordinated care.46,51 At the time of suspected diagnosis, a thorough

survey for potential involvement of many organ systems is warranted, including
the skin, teeth, brain, heart, kidneys, lungs, and eyes. A three-generation family
history should also be obtained, and genetic testing can be offered when the
diagnosis cannot be clinically confirmed.51
The discovery of the effectiveness of mTOR inhibitor medications, such as

rapamycin and everolimus, in tuberous sclerosis complex has significantly

improved treatment options and the clinical outcome in this patient population.
mTOR inhibitors have been used effectively in numerous tuberous sclerosis
complex–associated complications, including SEGAs, angiomyolipomas, and
lymphangioleiomyomatosis.49–51,56,59 Tuberous sclerosis complex surveillance
and treatment recommendations are outlined in TABLE 5-6 .
STURGE-WEBER SYNDROME
Sturge-Weber syndrome is a vascular malformation syndrome involving the skin,
brain, and eyes. It occurs sporadically, with an estimated prevalence of 1 in 20,000
to 1 in 50,000 live births, and is the third most common neurocutaneous
syndrome after NF1 and tuberous sclerosis complex.58,60 Sturge-Weber syndrome
is caused by a somatic mosaic mutation in the GNAQ gene located on chromosome
09/2022
9q21, which plays an important role in vascular development.58 The recent

discovery of the GNAQ gene in 2013 clarified that Sturge-Weber syndrome
represents the severe end of a clinical spectrum that also includes more benign
isolated port-wine birthmarks (previously known as port-wine stains) in the
mildest form.58
Diagnosis
A facial port-wine birthmark is usually present at birth and raises suspicion of the
diagnosis. The term Sturge-Weber syndrome is usually not assigned to individuals
who have an isolated port-wine birthmark, but, rarely, individuals who have
involvement of the skin and eye are included within the spectrum of those
considered to have Sturge-Weber syndrome.61 In rare cases, an intracranial
leptomeningeal angioma may be present without a facial port-wine birthmark
or glaucoma.60
The diagnosis of Sturge-Weber syndrome is confirmed with a contrast-enhanced
brain MRI that identifies the characteristic abnormal enhancing leptomeningeal
blood vessels. Neuroimaging in the neonatal period may not be sufficient to
rule out these findings because of the sensitivity of MRI in this young age
group, so repeat imaging after 1 year of age is recommended. A child with a
facial port-wine birthmark who is older than 1 year of age with a normal
contrast-enhanced brain MRI is highly unlikely to develop brain involvement.60,61
Clinical Features
Sturge-Weber syndrome manifests with changes in the skin, brain, and eye.
SKIN. Clinically, Sturge-Weber syndrome is characterized by a constellation of

symptoms, including a facial port-wine birthmark, abnormal intracranial
leptomeningeal blood vessels, and a choroid angioma of the eye. A port-wine
birthmark is a cutaneous capillary malformation that most commonly occurs
in the distribution of the ophthalmic branch of the trigeminal nerve but can
extend to other branches or occur bilaterally (FIGURE 5-17). For children
born with a facial port-wine birthmark involving the forehead or upper eyelid,
120 FEBRUARY 2018

10% to 35% will have brain KEY POINTS
involvement and, thus, will be
● Discovery of the GNAQ
diagnosed with Sturge-Weber gene has clarified that
syndrome. In addition, a 50% Sturge-Weber syndrome
risk of developing glaucoma represents the severe end of
exists when both the upper and a clinical spectrum that also
includes more benign

lower eyelid are involved.61 isolated port-wine
birthmarks.
CENTRAL NERVOUS SYSTEM.
The abnormal leptomeningeal ● A facial port-wine
vascular malformation birthmark and an intracranial
typically occurs in the leptomeningeal angioma
(often in the parietooccipital
parietooccipital region and is region) are typically
ipsilateral to the port-wine required to make a diagnosis
birthmark.60 However, of Sturge-Weber syndrome.
intracranial involvement can
● A child with a facial
be bilateral, and these
port-wine birthmark who
individuals often manifest a is older than 1 year of age
more severe neurologic and
09/2022
with a normal contrast-

developmental phenotype enhanced brain MRI is
(FIGURE 5-18). The unlikely to develop brain
FIGURE 5-17 involvement.
leptomeningeal vascular A 9-year-old girl with Sturge-Weber syndrome and a
lesions disrupt normal cerebral right facial port-wine birthmark in the distribution of ● In Sturge-Weber
the first and second divisions of cranial nerve V,
blood flow and ultimately syndrome, a facial port-wine
causing facial hemihypertrophy. birthmark is usually
cause stasis as well as chronic
ipsilateral to the intracranial
insufficient tissue perfusion, lesion.
resulting histologically in local
brain atrophy due to gliosis, neuron loss, and calcification development.60,61 ● The most common
As such, Sturge-Weber syndrome is a progressive disorder and can result in neurologic complications of
Sturge-Weber syndrome
significant neurologic deficits over time, including hemiparesis and visual
include epilepsy, strokelike
field cuts. The most common neurologic complications of Sturge-Weber episodes, headaches, and
syndrome include epilepsy, strokelike episodes, migraines, and developmental developmental disabilities.
delays with intellectual disability.60,61
Epilepsy is very common in Sturge-Weber syndrome, occurring in 80% of ● Hemiparesis and visual
field cuts can develop over
affected individuals.62,63 Seizures usually begin early in life, with a median age time in Sturge-Weber
of onset of 6 months.63 Seventy-five percent of children with Sturge-Weber syndrome and are thought to
syndrome and epilepsy will have their first seizure by their first birthday, and be due to chronic ischemia
90% will present with seizures within the first 2 years of life.60,62 Focal seizures associated with the
leptomeningeal vascular
with or without evolution to bilateral involvement are most common, but malformation.
infantile spasms as well as atonic and absence seizures have been reported in
this population.63 In addition, evidence exists that some individuals have a
pattern of extended seizure-free periods for as long as 6 to 12 months mixed with
episodes of seizure clusters that can occur over 1 to 2 days.63 In one study, a
younger age of seizure onset was not associated with worsening seizure control
or neurocognitive development over time but did correlate with more
profound hemiparesis.63
Strokelike episodes are an important neurologic complication of Sturge-Weber
syndrome, but little is known about their prevalence. They present with
transient neurologic deficits, including hemiplegia and visual field cuts.
Clinically, they can be difficult to differentiate from episodes of Todd paralysis
when comorbid epilepsy exists,

but they are typically
longer lasting and can become
permanent. They can develop in
association with seizures as well
as migraines. Young children

and toddlers are particularly

vulnerable, as strokelike episodes
can also be caused by minor head
trauma.61 Little is understood
about the pathophysiology
of these strokelike episodes,
but regional cerebral
hypoperfusion is suspected
based on small case series and
neuroimaging studies.61
Headaches, often with
migrainous features, are also
commonly reported in
09/2022
FIGURE 5-18
Bilateral intracranial involvement in Sturge-Weber individuals with Sturge-Weber
syndrome. Axial postcontrast T1-weighted MRI syndrome and can be quite
demonstrates diffuse left (arrow) more than right
occipital lobe leptomeningeal enhancement with
impairing. These headaches
associated volume loss in a 21-year-old man with are treated with the typical
Sturge-Weber syndrome. Clinically, he has bilateral interventions of
facial port-wine birthmarks, left hemiparesis, over-the-counter analgesics and
glaucoma, and poorly controlled epilepsy.
headache prophylactic
medications with
variable efficacy.61
The developmental delays and neurocognitive deficits associated with
Sturge-Weber syndrome range from mild to severe and show correlation with
the presence of epilepsy, age of epilepsy onset, and seizure control.60,61
Children with later onset of seizures may have less intellectual disability. In one
population of children with Sturge-Weber syndrome without seizures, only
6% had developmental delay and 11% required special education classes.62
However, it must be recognized that the etiology of neurocognitive dysfunction
in Sturge-Weber syndrome is likely multifactorial and related not only to
epilepsy but also to other factors, such as the degree of cortical involvement
(unilateral, bilateral, anterior, posterior), history of strokelike episodes, and
severity of neurologic deficits.64
EYE. Glaucoma has a prevalence of 30% to 60% in patients with Sturge-Weber
syndrome.65 Glaucoma can present with conjunctival injection, buphthalmos, or
excessive tearing of the eye. The incidence of glaucoma peaks in infancy and
again in young adulthood. Glaucoma can occur unilaterally or bilaterally and
does not always correspond to the trigeminal distribution of the port-wine
birthmark.60
MANAGEMENT. The presence of a facial port-wine birthmark at birth should
prompt an evaluation with a pediatric neurologist and ophthalmologist who
can initiate a thorough workup and counsel the family.60,61 A variety of laser
treatments have been used for cosmesis with facial port-wine birthmarks with
122 FEBRUARY 2018

variable efficacy. However, no standard guidelines exist on how or when to KEY POINTS
manage these cosmetically challenging lesions.61
● Glaucoma associated
Management of epilepsy in Sturge-Weber syndrome involves the use of with Sturge-Weber
traditional anticonvulsants, but more aggressive measures are often required syndrome does not always
when medical management fails. Placement of a vagus nerve stimulator and the correspond to the
use of the ketogenic or Atkins diet have been used in patients with refractory trigeminal distribution of
the facial lesion.

epilepsy.61 In the most severe cases, hemispherectomy may be an additional
option; it is considered most appropriate for patients with unilateral involvement ● The use of low-dose
and a preexisting hemiparesis or visual field cut.61 aspirin has been used to
The use of low-dose aspirin (3 mg/kg/d to 5 mg/kg/d) to prevent strokelike prevent seizures and
strokelike episodes in
episodes and seizures has been studied by several groups and remains
Sturge-Weber syndrome
controversial.66 Improvement in both strokelike episodes and seizure control has but remains controversial.
been reported in retrospective and survey studies, but larger prospective studies
are needed to better understand the impact daily aspirin may have on long-term ● Incontinentia pigmenti is
neurologic outcome.66 a rare X-linked dominant
disorder that primarily
For infants with brain involvement, several studies have also evaluated the affects females.
utility of presymptomatic treatment with the early use of a combination of
anticonvulsants and low-dose aspirin, but additional data are needed before these ● Central nervous system,
interventions are widely adopted for the whole Sturge-Weber population.66,67 dental, nail, hair, and ocular
09/2022
anomalies are commonly

They may be more appropriate for the highest-risk group with bilateral and seen in incontinentia
extensive brain involvement.60 pigmenti.
Prompt referral to an ophthalmologist shortly after birth is recommended to
avoid any preventable complications from glaucoma. Screening for glaucoma is
recommended every few months through infancy and early childhood. Lifelong
annual eye examinations are also recommended, even when early assessments
do not detect eye involvement.60,61
Clinical genetic testing for a mutation in the GNAQ gene is not generally
indicated. The mutation is rarely detected in the blood, and confirmatory testing
would likely require more invasive testing of affected tissue. In addition, the
same mutation is found in individuals with isolated port-wine birthmarks and in
patients with Sturge-Weber syndrome, so genotype-phenotype correlations have
not yet been established.58,61
INCONTINENTIA PIGMENTI
Incontinentia pigmenti is a rare X-linked dominant condition affecting
females; it is hemizygous lethal in most males. It is caused by mutations in the
IKBKG gene, which was previously known as the NEMO gene. The IKBKG gene
localizes to Xq28, where a deletion in the IKBKG exon 4 to exon 10 causes the
majority of cases of incontinentia pigmenti. Nuclear factor-kappa B (NF-kB)
transcription factor is activated by the protein product of the IKBKG gene and
plays an important role in inflammatory, immune, and cellular apoptotic
pathways.68–70
Clinical Features
The clinical findings in individuals with incontinentia pigmenti are highly
variable and likely secondary to skewed X-chromosome inactivation in this
predominantly female population. The skin, CNS, eyes, dentition, nails, and hair
are most often affected.68–71
The original diagnostic criteria for incontinentia pigmenti were determined
in 1993 before the discovery of the causative gene and were based on major and
minor criteria.71 Because of the discovery of the causative gene and improved
phenotypic characterization of incontinentia pigmenti, an update of the
original diagnostic criteria has recently been proposed (TABLE 5-7).68
The major criteria describe the typical dermatologic findings associated with
incontinentia pigmenti, and the minor criteria review other associated
anomalies.6,71
Additional conditions for establishing an incontinentia pigmenti diagnosis

have been proposed and are dependent on identifying major and minor
criteria in the presence or absence of an affected first-degree female
TABLE 5-7 Proposed Revision of Incontinentia Pigmenti Diagnostic Criteriaa
Major Criteria
u Typical incontinentia pigmenti skin changes distributed on the lines of Blaschko
⋄Vesiculobullous stage
09/2022
⋄Verrucous stage
⋄Hyperpigmented stage
⋄Atrophic/hypopigmented stage
Minor Criteria
u Dental anomalies
u Ocular anomalies
u Central nervous system anomalies
u Alopecia
u Hair abnormalities
u Nail abnormalities
u Palate abnormalities
u Nipple and breast abnormalities

u Multiple male miscarriages
u Typical skin histopathologic findings
Additional Conditions to Confirm an Incontinentia Pigmenti Diagnosis

u No evidence of incontinentia pigmenti in a first-degree female relative:
⋄Ifonenominor
IKBKG mutation data available, require two or more major criteria OR one major and
criterion to confirm diagnosis
u Confirmed IKBKG mutation with any major or minor criterion confirms diagnosis
u Evidence of incontinentia pigmenti in a first-degree female relative:
⋄Requires one major criterion OR two minor criteria

u Eosinophilia and skewed X-chromosome inactivation support the diagnosis in all cases
a
Modified with permission from Minić S, et al, Clin Genet.68 © 2013 John Wiley & Sons A/S.
124 FEBRUARY 2018

relative and the presence or absence of a mutation in the IKBKG gene KEY POINTS
(TABLE 5-7).68
● In incontinentia pigmenti,
cutaneous hyperpigmented
SKIN. The dermatologic manifestations of incontinentia pigmenti begin at birth or
markings follow the lines of
shortly thereafter and evolve sequentially in four stages through adulthood along Blaschko and develop in
the lines of Blaschko (lines of normal cell development in the skin). These four stages.
stages include:
● Rare cases of acute
u Stage 1: vesiculobullous stage; erythematous and vesicular lesions that often have a linear disseminated
distribution and present at birth or in the first few weeks of life encephalomyelitis have
u Stage 2: verrucous stage; hyperpigmented crusted pustules develop and last for been reported in infants
several months with incontinentia pigmenti.
u Stage 3: hyperpigmented stage; whorls of macular hyperpigmentation that can persist
into adulthood
u Stage 4: atrophic/hypopigmented stage; pale or hairless patches develop on the skin as
hyperpigmented lesions fade in late adolescence or early adulthood
Stage 4 is not present in all patients (FIGURE 5-19).68,69,71
CENTRAL NERVOUS SYSTEM. Neurologic complications are found in approximately

30% of individuals with incontinentia pigmenti and can be the cause
09/2022
of significant morbidity associated with the disorder.68,72 Most neurologic

problems present in the neonatal
or infancy periods and rarely
manifest later in life. Ischemic
strokes affecting deep and
subcortical white matter and
larger vascular territories
(middle cerebral artery,
anterior cerebral artery) have
been seen. Cerebral dysgenesis
can also occur, with cerebellar
hypoplasia, cerebral atrophy,
corpus callosum hypoplasia,
and hemorrhagic change as
well as periventricular and
subcortical white matter
disease.72
Approximately 20% to 40%
of patients develop epilepsy,
likely secondary to brain
malformations and cortical
strokes.68,72 Of note, in one case
series, two infants (ages 6
and 7 months) developed
acute disseminated
encephalomyelitis (ADEM);
thus ADEM should be included
in the differential diagnosis of FIGURE 5-19
Incontinentia pigmenti. A, A 5-day-old infant with
any infant with incontinentia
incontinentia pigmenti and rash in the
pigmenti presenting with vesiculobullous phase. B, Same infant at 6 weeks of
acute neurologic symptoms.72 age, demonstrating the verrucous stage of the rash.
KEY POINT Intellectual disability, developmental delay, cerebral palsy, and microcephaly
are common.72 Microvascular occlusion, inflammation, or disrupted cellular
● Neurologic complications
of incontinentia pigmenti
apoptosis during development are the proposed causative mechanisms for the
include ischemic stroke and CNS damage seen in incontinentia pigmenti.72
cerebral dysgenesis, which
can clinically result in Management

epilepsy, cerebral palsy, The IKBKG gene is the only known causative gene in incontinentia pigmenti,
developmental delays, and and approximately 80% of affected individuals have a deletion in exon 4 to
intellectual disability.
exon 10.68 Genetic confirmation with targeted mutational analysis in early
infancy can be helpful in determining the diagnosis, developing a care plan,
and assessing prognosis. However, negative genetic testing in a clinically
convincing case does not completely rule out the diagnosis.68,73
Management of the medical complications of incontinentia pigmenti is
symptomatic. As a multisystem disorder, involvement of genetic, dermatologic,
neurologic, dental, and ophthalmologic specialists early in the medical course is
important.68,71 The dermatologic manifestations typically do not require any
intervention. Any child with epilepsy or obvious neurologic deficits should
undergo neuroimaging with a brain MRI. A brain magnetic resonance angiogram
(MRA) should be done in cases where stroke is suspected.72,73 Monitoring for
09/2022
visual complications is often necessary throughout the lifetime of affected

individuals. More severe ophthalmologic complications, such as retinal
detachment and avascular retina, are commonly treated with laser
photocoagulation or cryotherapy.73
CONCLUSION
While often rare individually, as a group, the neurocutaneous disorders
represent a broad spectrum of genetically and clinically heterogeneous
syndromes that are frequently encountered by neurologists. Involvement of
the central and peripheral nervous systems in neurocutaneous disorders results
in diverse neurologic symptoms, including cerebral dysgenesis, brain/spinal
tumors, epilepsy, cerebrovascular disease with stroke, cerebral palsy,
developmental delays, intellectual disability, and peripheral neuropathy.
Advancements in genetic technologies have helped define clinical features,
hone diagnostic criteria, and inform treatment options for these complex
disorders. It is now understood that several of the more common neurocutaneous
disorders are biologically linked through the RAS-MAPK pathway, which
modulates tumor-suppressing functions; this knowledge has provided an
opportunity for the development of novel interventions. The use of everolimus
in multiple tuberous sclerosis complex complications and bevacizumab for
vestibular schwannomas in NF2 are examples of how biologically targeted
therapies can have a significant impact on patient outcome. All neurologists are
encouraged to incorporate a thorough skin evaluation into their routine clinical
assessment of patients as dermatologic clues may provide a unique
diagnostic opportunity.
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pigmenti diagnostic criteria update. Clin Genet 2014; findings in incontinentia pigmenti: a review. Eur J Med
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ejmg.2012.04.007.
69 Poziomczyk CS, Bonamigo RR, Santa Maria FD,

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70 Minić S, Trpinac D, Gabriel H, et al. Dental and 2015;46(6):650–657. doi:10.3928/
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09/2022
REVIEW ARTICLE

Leukodystrophies
C O N T I N UU M A UD I O By Amy T. Waldman, MD, MSCE
VH4kB2Z9EY5jONzaHF6L6BFLKNUIlvpnOmK9o8126tTOuniutr3OwA5Vmj7KGOmPyDdSXOera88TePS0Kw/LUA1vcWMc= on 09/
ONLINE
ABSTRACT
PURPOSE OF REVIEW: The leukodystrophies, typically considered incurable
neurodegenerative disorders, are often diagnosed after irreversible central
and peripheral nervous system injury has occurred. Early recognition of
CITE AS:
these disorders is imperative to enable potential therapeutic interventions.
CONTINUUM (MINNEAP MINN) This article provides a summary of the symptoms of and diagnostic
2018;24(1, CHILD NEUROLOGY): evaluation for leukodystrophies, along with the currently available
130–149.
therapies and recent advances in management.
Dr Amy T. Waldman, Children’s RECENT FINDINGS: The leukodystrophies are a rapidly expanding field because
Hospital of Philadelphia, CTRB
of advances in neuroimaging and genetics; however, recognition of the
10th Floor, Room 10012, 3501 Civic
Center Blvd, Philadelphia, PA clinical and biochemical features of a leukodystrophy is essential to
09/2022
19104, waldman@email.chop. accurately interpret an abnormal MRI or genetic result. Moreover, the
edu.
initial symptoms of leukodystrophies may mimic other common pediatric
RELATIONSHIP DISCLOSURE: disorders, leading to a delay in the recognition of a degenerative disorder.
Dr Waldman serves on the
board of directors of the Child
Neurology Foundation and has SUMMARY: This article will aid the clinician in recognizing the clinical features
received personal compensation of leukodystrophies and providing accurate diagnosis and management.
for speaking engagements from
Johns Hopkins University, St.
Christopher’s Hospital for
Children, St. Peter’s University,
and SUNY Downstate Medical INTRODUCTION
T
Center. Dr Waldman receives he leukodystrophies are inherited disorders that predominantly affect
Biogen, Elise’s Corner, the the white matter of the central nervous system (CNS). Leukodystrophy
National Institutes of Health is a unifying term for diseases that affect glial cells, resulting in
(K23NS069806, R01NS071463), myelin sheath and axonal damage; approximately 30 distinct
and the National Multiple
Sclerosis Society and receives disorders have been classified as leukodystrophies (TABLE 6-1). 1
publishing royalties from Leukodystrophies are distinguished from genetic leukoencephalopathies, which
UpToDate, Inc.
may also have significant white matter involvement but whose pathology does
UNLABELED USE OF not primarily affect glia. Such conditions include systemic inborn errors of
PRODUCTS/INVESTIGATIONAL metabolism and primary neuronal disorders (such as neuronal ceroid
USE DISCLOSURE:
Dr Waldman discusses published
lipofuscinoses, which are also lysosomal storage disorders). Altogether, more
clinical trial results presenting a than 91 leukodystrophies and genetic leukoencephalopathies have been
lentiviral vector in combination defined based on clinical, radiographic, and genetic data.
with hematopoietic stem cell
transplantation for Clinically, a leukodystrophy is generally suspected in a child with regression in
metachromatic leukodystrophy developmental skills or failure to acquire new skills. Peripheral nervous system
and X-linked
disease also occurs in some of the leukodystrophies and may be a presenting feature;
adrenoleukodystrophy. These
data are presented to therefore, a high index of suspicion is necessary to ensure a prompt diagnosis.
demonstrate advances in MRI is a key tool in differentiating leukodystrophies. On T2-weighted images,
potential treatments for this
disorder and also help to
symmetric hyperintensities occur in various regions depending upon the
understand the pathology and underlying disorder.2 Typically the affected white matter is significantly
need for newborn screening. hypointense on T1-weighted images; however, a distinct subgroup, the
© 2018 American Academy hypomyelinating leukodystrophies, are isointense or hyperintense (or sometimes
of Neurology. mildly hypointense) on T1-weighted images. The MRIs of patients with
130 FEBRUARY 2018

suspected leukodystrophies should be systematically reviewed to differentiate KEY POINTS
hypomyelinating from demyelinating disorders (using T1-weighted images),
● The leukodystrophies
determine the extent of white matter abnormality (confluent, isolated, comprise a heterogeneous
multifocal), categorize confluent disease by primary area of involvement group of disorders
(frontal, frontotemporal, parietooccipital, periventricular, subcortical, diffuse predominantly affecting
cerebral, or posterior fossa), and observe for the presence of MRI features unique the glial cell or myelin
sheath.
to certain disorders (eg, cysts, contrast enhancement, calcifications).2 Together,
these factors aid the clinician in narrowing the differential diagnosis. ● Genetic
Generally, the treatment of the leukodystrophies is supportive, with a leukoencephalopathies
multidisciplinary team to assist in managing the symptoms. Briefly, medications include metabolic
are used to treat seizures, spasticity, dystonia, autonomic dysfunction, and other disorders and primary
neuronal diseases that affect
symptoms, while equipment is used to optimize comfort, tone, and safety. Most the white matter through
children need further assistance with respect to nutrition and gastrointestinal mechanisms other than glial
function as well as pulmonary clearance and reserve. pathology.
The field of leukodystrophies is rapidly changing through gene discovery,
● X-linked
newborn screening, and novel therapy programs. This article focuses on a few adrenoleukodystrophy
of the leukodystrophies that highlight these advances, particularly those with should be considered in
recent clinical trials and treatment trials planned in the near future. Improved school-aged boys with the
neurologic outcomes occur with early treatment, which is predicated on prompt recent onset of attention
09/2022
and behavioral difficulties,

recognition of the disorder.
especially for those who
demonstrate regression in
X-LINKED ADRENOLEUKODYSTROPHY cognition, fine motor skills,
X-linked adrenoleukodystrophy is a peroxisomal disorder caused by mutations or speech. While MRI may
be helpful in confirming
in ABCD1 on Xq28. ABCD1 encodes a peroxisomal membrane protein cerebral involvement, the
(ATP-binding cassette, subunit D) that is necessary for b-oxidation of saturated test of choice to confirm
unbranched very-long-chain fatty acids. As a result, very-long-chain fatty or exclude X-linked
acids accumulate in the brain, adrenal gland, and testes.3 adrenoleukodystrophy is
measurement of plasma
very-long-chain fatty acids.
Clinical Symptoms
Multiple phenotypes exist in X-linked adrenoleukodystrophy, with varying ● The adrenal function of
severity and clinical manifestations (TABLE 6-2 4 ). The earliest symptom in boys with X-linked
X-linked adrenoleukodystrophy is adrenal insufficiency, with affected boys adrenoleukodystrophy
should be monitored
coming to medical attention during an adrenal crisis. For approximately 10% of routinely by an
males, adrenal insufficiency is the only manifestation of disease (known as endocrinologist.
Addison only). The childhood cerebral form occurs in approximately 31% to 35%
of affected males and typically presents between 4 and 8 years of age with
attention difficulties, cognitive decline, and behavioral problems (CASE 6-1).
Changes in speech and handwriting occur, and school performance is affected.
Many children are initially thought to have attention deficit hyperactivity
disorder, and the delay in diagnosis precludes them from potential therapy. The
attention and behavioral problems may be present for several months, followed
by progressive loss of ambulation, speech, vision, and hearing over 6 months to
2 years. Adrenomyeloneuropathy (40% to 46% of affected males) occurs later in
life, manifesting as a distal axonopathy. Some females can develop symptoms in
adulthood, making the term carrier a misnomer.
Neuroimaging
Children with childhood cerebral X-linked adrenoleukodystrophy experience
inflammatory demyelination in the brain (confluent T2-hyperintense and
T1-hypointense lesions), typically beginning in the parietooccipital lobes (85% of
LEUKODYSTROPHIES
cases) and posterior corpus callosum (FIGURE 6-1), although anterior

presentations can also occur. The Loes scoring system5,6 is universally applied to
quantify the extent of cerebral involvement. Regions of the brain (such as
parietooccipital white matter, anterior temporal white matter, visual pathway,
corpus callosum, auditory pathway, basal ganglia, projection fibers, and cerebellum)
are subdivided and scored based on the extent of disease (with a score of 0 if normal,
0.5 if unilateral involvement is present, and 1 if the lesion or atrophy is bilateral).

Global atrophy is also assessed. A normal MRI scan has a score of 0, and the
maximum severity score is 34. An enhancing rim is often seen at the border of the
T2-hyperintense area. Younger boys identified through newborn screening or
presentation with adrenal insufficiency have a normal brain MRI but require frequent
TABLE 6-1 The Leukodystrophiesa
Inborn Errors of Metabolism

09/2022
u X-linked adrenoleukodystrophy
u Krabbe disease (globoid cell leukodystrophy)

u Metachromatic leukodystrophy
u Cerebrotendinous xanthomatosis
u Canavan disease
u Fucosidosis
u Peroxisomal biogenesis disorders (including Zellweger syndrome, neonatal
adrenoleukodystrophy, and infantile Refsum disease)
u Polyglucosan body disease

u Sialic acid storage disorders (Salla disease, infantile sialic acid storage disease, and
intermediate form)
u Single-bifunctional enzyme deficiencies of peroxisomal fatty acid b-oxidation (including

D-bifunctional protein deficiency, sterol carrier protein X [SCPx] deficiency, peroxisomal
acyl-coenzyme A [CoA] oxidase deficiency)
u Sjögren-Larsson syndrome
Disorders of RNA/DNA Transcription/Translation
u Aicardi-Goutières syndrome
u POL3-related disorders (hypomyelination, hypogonadotropic hypogonadism, and

hypodontia [4H syndrome])
u EIF2B-related disorder (vanishing white matter disease or childhood ataxia with central
nervous system hypomyelination [CACH])
u Hypomyelination with brainstem and spinal cord involvement and leg spasticity (HBSL)
u Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL)
u Leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL)
u RNAse T2–deficient leukoencephalopathy
132 FEBRUARY 2018

MRI surveillance scans (every 6 months between 3 and 10 years of age) to promptly
recognize those who develop the cerebral form who may benefit from treatment.
Diagnosis
The diagnosis of X-linked adrenoleukodystrophy is confirmed by the presence of
elevated saturated unbranched very-long-chain fatty acids in plasma, red blood

cells, or cultured fibroblasts. The biochemical abnormalities among the

very-long-chain fatty acids include elevations in hexacosanoic acid (C26), the
hexacosanoic acid to docosanoic acid ratio (C26:C22), and the hexacosanoic
acid to tetracosanoic acid ratio (C26:C24). Variations in these three
measurements overlap with values for healthy controls; however, a

Genes Related to Proteins Critical for Myelin Development

09/2022
u Pelizaeus Merzbacher disease (PMD)
u Pelizaeus Merzbacher–like disease (PMD)

u SOX10-associated peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy,
Waardenburg syndrome, and Hirschsprung disease (PCWH)
Cytoskeletal
u Alexander disease
u Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC)
u Autosomal dominant leukodystrophy with autonomic disease (ADLD)
Myelin Water Maintenance

u Chloride ion channel 2 (ClC2)–related leukoencephalopathy with intramyelinic edema
u Megalencephalic leukoencephalopathy with subcortical cysts (MLC)
Mechanism Not Yet Elucidated
u 18q deletion syndrome

u Adult-onset leukodystrophy with neuroaxonal spheroids and pigmented glia (including
hereditary diffuse leukoencephalopathy with spheroids [HDLS] and pigmentary type of
orthochromatic leukodystrophy with pigmented glia [POLD])
u Hypomyelination with congenital cataract (HCC)
u Oculodentodigital dysplasia
DNA = deoxyribonucleic acid; RNA = ribonucleic acid.

a
Data from Vanderver A, et al, Mol Genet Metab.1
LEUKODYSTROPHIES
TABLE 6-2 X-linked Adrenoleukodystrophy Phenotypes and Frequenciesa
Phenotype Description Estimated Relative Frequency

Phenotypes in males with
X-linked adrenoleukodystrophy
Childhood cerebral Onset at 3–10 years of age; progressive behavioral, 31–35%

cognitive, and neurologic deficits, often leading to total
disability within 3 years; inflammatory brain
demyelination
Adolescent cerebral Like childhood cerebral; onset at 11–21 years of age; 4–7%
somewhat slower progression
Adrenomyeloneuropathy Onset 28 ± 9 years, progressive over decades; distal 40–46%

axonopathy that involves spinal cord mainly; inflammatory
response mild or absent; approximately 40% have or
develop cerebral involvement with varying degrees of
inflammatory response and more rapid progression
Adult cerebral Dementia, behavioral disturbances; sometimes focal 2–5%

09/2022
deficits, without preceding adrenomyeloneuropathy;

white matter inflammatory response present;
progression parallels that of childhood cerebral form
Olivopontocerebellar Mainly cerebellar and brainstem involvement in 1–2%

adolescence or adulthood
“Addison-only” Primary adrenal insufficiency without apparent Varies with age; up to 50%
neurologic involvement; onset common before in childhood
7.5 years; most eventually develop
adrenomyeloneuropathy
Asymptomatic Biochemical and gene abnormality without Diminishes with age; common
demonstrable adrenal or neurologic deficit; detailed <4 years; very rare >40 years
studies often show adrenal hypofunction or subtle signs
of adrenomyeloneuropathy
Phenotypes in female X-linked

adrenoleukodystrophy carriers
Asymptomatic No evidence of adrenal or neurologic involvement Diminishes with age; most

women <30 years
neurologically uninvolved
Mild myelopathy Increased deep tendon reflexes and distal sensory Increases with age;
changes in lower extremities with absent or approximately 50% >40 years
mild disability
Moderate to severe Symptoms and pathology resemble Increases with age;
myeloneuropathy adrenomyeloneuropathy but milder and later onset approximately 15% >40 years
Cerebral involvement Rarely seen in childhood and slightly more common in Approximately 2%
middle age and later
Clinically evident adrenal Rare at any age Approximately 1%
insufficiency
a
Modified with permission from Kemp S, et al, Hum Mutat.4 © 2001 Wiley-Liss, Inc.
134 FEBRUARY 2018

discrimination function is applied that accurately distinguishes those with KEY POINT
X-linked adrenoleukodystrophy from healthy controls or those with
● Very-long-chain fatty
nonperoxisomal disorders.3 In a patient with elevated very-long-chain fatty acids, especially C26:0 and
acids, genetic sequencing of ABCD1 is performed. the ratios of C26:C22 and
Newborn screening for X-linked adrenoleukodystrophy has been implemented C26:C24, are elevated in
in some US states using various methodologies, such as the detection of all clinical phenotypes
of X-linked
1-hexacosanoyl-2-lyso-sn-3-glycero-phosphorylcholine (26:0-lyso-PC) in dried adrenoleukodystrophy,

blood spots using liquid chromatography–tandem mass spectrometry.7–9 The and these abnormalities
diagnosis of X-linked adrenoleukodystrophy through the newborn screening may be detected at birth,
program allows for proactive monitoring of adrenal function and neurologic facilitating a diagnosis prior
to symptom onset.
disease for affected boys and has further enabled the diagnosis of X-linked
adrenoleukodystrophy in family members (such as older siblings) who also
benefit from screening programs.
Disease-specific Therapy
The primary treatable manifestation of X-linked adrenoleukodystrophy is
adrenal insufficiency, which is the most common symptom of the disorder and
present in multiple phenotypes. Biochemical abnormalities in cortisol production
09/2022
occur in 85% of all males with X-linked adrenoleukodystrophy; screening for

this should begin during infancy, with regular testing throughout the life of an
affected male. The need for cortisol supplementation and stress-dosed steroids or
both is determined in partnership with an endocrinologist.
A 6-year-old boy presented with attention and behavioral difficulties. CASE 6-1
According to his teachers, he had difficulty responding when his name
was called, following along during class activities, and following
directions, requiring reminders. His mother believed that he was often
lost in his thoughts and described him as a daydreamer. These symptoms
were first noted approximately 9 months before presentation.
Previously, he had no issues in preschool and was on target with his
peers. His brother died at 7 months of age “of an infection.”
On examination, he had difficulty with comprehension, often asking
for commands to be repeated, and abnormal expressive language. His
neurologic examination was also notable for difficulty with tandem gait,
brisk patellar reflexes, and extensor plantar responses. Brain MRI
revealed T2 hyperintensities in the parietooccipital lobes bilaterally with
an enhancing rim. Very-long-chain fatty acids revealed an elevation in
hexacosanoic acid (C26:0), an elevated hexacosanoic acid to docosanoic
acid ratio (C26:C22), and an elevated hexacosanoic acid to tetracosanoic
acid ratio (C26:C24).
This case illustrates the clinical variability of the presenting manifestations COMMENT
of X-linked adrenoleukodystrophy. This patient has childhood cerebral
adrenoleukodystrophy, whereas his brother likely died of an unrecognized
adrenal crisis in the setting of an illness.
LEUKODYSTROPHIES
Hematopoietic stem cell

transplantation has been
successful in arresting or slowing
the progression of the cerebral
disease if initiated early in the
disease course (ie, Loes score less

than 10, no or minimal neurologic

symptoms, and preserved
cognition [Wechsler
Performance IQ higher than 80]).
In an experienced X-linked
adrenoleukodystrophy transplant
center, the 5-year survival rate
was 89% in those with a Loes
score of less than 10 (N = 30)
compared to 60% in boys with a
Loes score higher than 10
(N = 30). However, it is
important to note that even after
09/2022
FIGURE 6-1
Childhood cerebral X-linked adrenoleukodystrophy. successful engraftment, the
Axial fluid-attenuated inversion recovery (FLAIR) neurologic progression may
MRI demonstrates confluent white matter signal continue for 12 to 18 months
abnormality in the bilateral parietal white matter
posttransplant, with disability
with involvement of the splenium of the corpus
callosum, posterior aspect of the thalami, progression occurring during this
and posterior limbs of the internal capsules. time. Therefore, many boys with
minimal evidence of neurologic
disease prior to transplant
develop worsening symptoms, such as visual and cognitive impairment or
behavioral problems, after the transplant. In addition, the transplant itself
confers significant morbidity. Hematopoietic stem cell transplantation is only
performed for the cerebral form of the disease and is not indicated in males
without evidence of active cerebral disease (detected by MRI). Active research
programs are investigating biomarkers of neurologic dysfunction and other
strategies (including reduced-intensity conditioning) to improve
transplantation outcomes.10
Gene therapy using a lentiviral vector in combination with hematopoietic
stem cell transplantation was performed in 17 boys with early cerebral X-linked
adrenoleukodystrophy who did not have a suitable match for transplant.11
Although MRI disease progression was evident in some participants 12 to
18 months posttransplant, 14 out of 17 participants had no (or minimal) clinical
symptoms at a median of 29.4 months posttransplant. One participant had a
seizure; thus, he did not meet predefined criteria for minimal disease progression
but otherwise did well. Two participants demonstrated disease progression, one
within 2 weeks of transplant, indicating a rapidly progressive course. The other
participant withdrew from the study and underwent an allogeneic transplant,
later dying from complications related to a viral infection. In summary, males
with early cerebral disease should be referred for an urgent hematopoietic stem
cell transplant; gene therapy in combination with transplant may be an option in
the future for those individuals without a sibling match. Males diagnosed
through newborn screening undergo serial neurologic examinations and imaging
136 FEBRUARY 2018

protocols as toddlers to identify cerebral disease early, which enables prompt KEY POINT
treatment and improved outcomes.
● Infantile Krabbe disease
Aside from transplant, dietary therapy has been explored for X-linked should be considered in a
adrenoleukodystrophy, with a reduction in fat intake and the use of Lorenzo’s oil child 6 months of age or
(4:1 mix of glyceryl trioleate to glyceryl trierucate). While this combination may younger with irritability,
correct the measurement of very-long-chain fatty acids in the blood, reduction in sterile pyrexia, and
elevated CSF protein. Other
dietary fat and supplementation with Lorenzo’s oil have not been effective in symptoms in this age group
alleviating symptoms of cerebral X-linked adrenoleukodystrophy (or other include extremity stiffness,
symptoms) once present.12 fisted hands, and
decreased oral intake.
GLOBOID CELL LEUKODYSTROPHY (KRABBE DISEASE)

Globoid cell leukodystrophy, or Krabbe disease, is an autosomal recessive lysosomal
storage disorder caused by mutations in GALC on chromosome 14q31. GALC
encodes the enzyme galactosylceramidase, which is essential in the degradation
of lipids (galactosylceramide and psychosine) during myelin turnover.
Clinical Symptoms
Four classic phenotypes are associated with galactosylceramidase deficiency
(TABLE 6-3). The most common is the early-onset infantile phenotype (85% to
09/2022
90%), which presents prior to 6 months of age, with irritability, stiffness, arrest
Krabbe Disease (Globoid Cell Leukodystrophy) Phenotypes and Frequencies TABLE 6-3
Phenotype Description Frequency

Early-onset infantile Onset prior to 6 months, regression occurs over several months 85–90%a
Stage 1: Irritability; failure to thrive (decreased intake, vomiting), developmental arrest

and regression (decreased head control, loss of smiling); hypersensitivity to auditory,
tactile, or visual stimuli; stiffness and clenched fists; episodes of sterile hyperpyrexia;
seizures
Stage 2: Rapid neurologic regression with arm flexion, leg extension, and scissoring;
opisthotonos; seizures; hyperreflexia; optic atrophy; and abnormal pupillary responses
Stage 3: The “burnt-out” stage, characterized by decerebrate posturing, blindness,

deafness, and the absence of voluntary movement
Late-onset infantile Onset between 6 months and 3 years of age; early milestones are achieved, followed by 10–15%
psychomotor regression, notably affecting gross motor skills; ataxia, stiffness, and visual
impairment; disease progression is slower than the early-onset infantile form
Juvenile onset Onset between 3 and 8 years of age; initial presentation is visual impairment, followed Unknown
by hemiparesis and ataxia; initial symptoms occur rapidly, followed by a plateau or slow
progression with improved survival over other forms
Adult onset Heterogeneous group combining those who are asymptomatic in childhood and Unknown
develop neurologic symptoms (such as spastic paraparesis) as adults (typically older
than 20 years of age) and those who are mildly symptomatic in childhood but for whom
the disease was not recognized
a
Newborn screening results and longitudinal data will impact our understanding of GALC mutations, galactosylceramidase enzyme activity, and
the frequency of these clinical phenotypes in the future.
LEUKODYSTROPHIES
of development, and failure to

thrive.13 Older patients generally
present with spasticity,
paraparesis, visual impairment,
and ataxia (TABLE 6-3). A
peripheral neuropathy is also

present in Krabbe disease, and a

loss of reflexes may be the
presenting symptom.14 The
clinical course is not determined
by the genotype; however, a few
variants have some predictive
value. A 30-kb deletion of GALC
(either homozygous or in
combination with another severe
variant) causes early-onset
infantile disease.
FIGURE 6-2
Krabbe disease. Axial T2-weighted MRI Neuroimaging
09/2022
demonstrates confluent diffuse T2 high signal Krabbe disease is a demyelinating

involving the central white matter and corpus disorder (T1 hypointense) with
callosum. The white matter has a striated
and speckled appearance. confluent T2 hyperintensities
with a periventricular or
parietooccipital predominance
(FIGURE 6-2). 2 Of note, MRI abnormalities in early-onset infantile disease are
not always appreciated because of the myelination pattern of a newborn. For
example, bilateral symmetric T2-weighted hyperintensity is present in the
dentate hilum, surrounded by hypointensity in the peridentate area and
hyperintensity in the cerebellar white matter.15 This pattern may not be
appreciated as it is similar to the normal variability of these structures present in
a newborn.
Diagnosis
The diagnosis of Krabbe disease is confirmed by low galactosylceramidase
(0% to 5% of normal values) in white blood cells or cultured fibroblasts,
followed by GALC sequencing for mutations. Of note, deletions (and
duplications) are not detected through sequencing; therefore, anyone
presenting with clinical features consistent with Krabbe disease for whom a
heterozygous mutation is detected should have further testing for a deletion.
For an irritable infant presenting to medical attention, a lumbar puncture may
be performed to exclude infection or other etiologies. While not specific for
Krabbe disease, CSF protein is frequently elevated in early-onset infantile
disease (with a normal CSF cell count).16
Newborn screening for Krabbe disease is under way in several US states
to identify early-onset infantile disease for possible treatment.
Galactosylceramidase activity, which is measured in dried blood spots using
various methodologies, is typically employed as an initial screen; however,
significant overlap exists between affected patients, carriers, and healthy
individuals. Moreover, the lack of genotype-phenotype correlations precludes
the ability to accurately predict the onset of neurologic symptoms in an affected
138 FEBRUARY 2018

individual; thus later-onset forms of the disease are identified through newborn KEY POINT
screening.17 As they may be asymptomatic for many years, these patients do
● The biochemical
not need an emergent transplant in the neonatal period. Some states use abnormality in Krabbe
psychosine as a second-tier test as elevated levels correlate with early-onset disease is an abnormal
infantile disease.18–20 Alternatively, some laboratories screen for the 30-kb galactosylceramidase level
deletion in GALC to identify early-onset infantile disease. In a child with a (typically 0% to 5% of

normal values) in white
positive newborn screen for Krabbe disease, the diagnosis is confirmed by low blood cells or cultured
galactosylceramidase followed by GALC sequencing/deletion analysis. fibroblasts.
Hematopoietic stem cell transplantation may alter the neurologic progression in
asymptomatic early-onset infantile Krabbe disease, but the overall impact
on morbidity in this disorder remains in question. The outcomes of umbilical
cord blood transplantation for 11 children with asymptomatic disease (identified
prenatally or in the neonatal period through previously affected siblings) were
compared to 14 children diagnosed between 4 and 9 months of age.21 In the
asymptomatic group, the transplant occurred between 12 and 44 days of life,
compared to between 142 and 352 days in the symptomatic group. Survival was
100% in the asymptomatic group at a median of 36 months compared to 43%
09/2022
of the symptomatic group (P=.01). In the asymptomatic group, brain MRIs

showed normal maturation of myelin, with decreased hyperintensity of affected
areas. In addition, transplant outcomes were significantly improved for the
asymptomatic children with respect to gross motor, fine motor, language, and
cognitive function. Many achieved developmental milestones; however, all
ultimately developed gross motor impairments of varying degrees (spasticity,
gait abnormalities, or needing assistance to stand or walk). In comparison, the
symptomatic children who survived lost all gross and fine motor skills. The
outcomes for many of these children were included in a subsequent publication
with longitudinal follow-up data (range 4 to 15 years). Of the 18 children with
Krabbe disease who were transplanted within 7 weeks of life, five ultimately
died (three died of transplant-related complications, one died of a surgical
complication unrelated to Krabbe disease, and one died of disease progression).
Surviving children had variable deficits in gross motor function, neurocognitive
skills, language, and adaptive behavior.22 These results, while encouraging for
early transplantation, suggest that additional modalities of therapy will likely be
necessary in Krabbe disease to achieve symptomatic control.
The state of New York has published its experience in screening over 2 million
infants for Krabbe disease and other disorders as part of its newborn screening
program since 2006.17 On the initial screen, approximately 10,200 infants were
identified with galactosylceramidase activity less than or equal to 20% of normal
activity. On repeat testing, 620 newborns who had galactosylceramidase activity
less than or equal to 12% of normal subsequently underwent genetic sequencing,
and 348 infants had at least one pathogenic GALC mutation. Ultimately, 14
children had very low galactosylceramidase activity (0 nmol/h/mg to
0.15 nmol/h/mg protein, considered high-risk), but only five were confirmed
through further evaluations (MRI, lumbar puncture, nerve conduction studies,
and brainstem auditory evoked response) to have early-onset infantile Krabbe
disease. One family declined treatment, and that child is deceased. Four of the
patients underwent umbilical cord blood transplantation: two died of
transplant-related complications, one is unable to walk independently and has
LEUKODYSTROPHIES
KEY POINTS failure to thrive but receptive language appropriate for age, and one has severe
delays and failure to thrive.
● Metachromatic
leukodystrophy should be For older individuals, the assessment of transplantation outcomes is
considered in a toddler with challenged by differences in phenotypes, unpredictable disease onset, and
regression in gross motor variability in disease duration. Transplantation does not improve peripheral
skills, a peripheral nervous system disease for most patients.

neuropathy, or gall
bladder polyps.
METACHROMATIC LEUKODYSTROPHY
● Gall bladder disease Metachromatic leukodystrophy is also an autosomal recessive lysosomal storage
should be considered in disorder caused by an enzyme deficiency of arylsulfatase A, which is encoded on
patients with metachromatic
leukodystrophy who
the ARSA gene on chromosome 22q13.3-qter. Sulfatides accumulate in the central
experience feeding and peripheral nervous systems, kidneys, testes, and visceral organs (gall bladder).
intolerance.
Clinical Symptoms
●Arylsulfatase A
pseudodeficiency is The clinical phenotypes and frequencies of metachromatic leukodystrophy are
common; therefore, the presented in TABLE 6-4. Of note, the peripheral neuropathy may present prior
diagnosis of metachromatic to the onset of speech or other CNS abnormalities (CASE 6-2). In fact, several
leukodystrophy is confirmed patients with metachromatic leukodystrophy have been diagnosed with other
by low arylsulfatase A
09/2022
activity along with an

disorders (eg, Guillain-Barré or spastic diplegia) because of the perceived
elevation in the urinary absence of CNS disease (clinically and radiographically).23,24 Any child with
excretion of sulfatides. normal early milestones followed by a decline in motor skills at any age should be
evaluated for metachromatic leukodystrophy through leukocytes and
urine sulfatides.
Unique to metachromatic leukodystrophy, the gall bladder is also involved,
likely due to sulfatide accumulation and irritation of the epithelium.25 Gall
bladder disease may be asymptomatic, detected through an ultrasound revealing
a polyp or thickening of the wall, or cause abdominal pain, vomiting, or biliary
colic. Asymptomatic gall bladder polyps were detected incidentally in two
patients (undergoing trauma evaluations) who later exhibited neurologic
symptoms 12 to 15 months after the polyps were detected.26,27 Neuroimaging was
available (as part of the trauma evaluation) for one of these patients, and the
TABLE 6-4 Metachromatic Leukodystrophy Phenotypes and Frequencies

Late infantile Onset <30 months; early milestones are often achieved, followed by regression in gross motor 50–60%
skills (especially gait) and speech; weakness and hypotonia evolve to spasticity, tonic spasms,
and decerebrate posturing; a peripheral neuropathy may be present prior to central nervous
system symptoms
Juvenile Onset between 30 months and puberty; early milestones are achieved, followed by 20–30%
psychomotor regression, mental status changes, and behavioral disturbances; declining
school performance, personality changes, or gait abnormalities may prompt medical attention
Adult Onset >12–14 years; psychiatric manifestations (such as behavioral changes and emotional 15–20%
lability or substance abuse) may lead to diagnoses of bipolar disorder and dementia prior
to the recognition of motor and cognitive symptoms; other adults may present with a
peripheral neuropathy
140 FEBRUARY 2018

brain MRI was normal at the time of the trauma. Fifteen months later, the MRI
was repeated because of regression in motor skills and was consistent with
metachromatic leukodystrophy.26
Neuroimaging
Metachromatic leukodystrophy is a demyelinating disorder (T1 hypointense)

with confluent T2 hyperintensities surrounding the frontal and parietal

periventricular white matter (FIGURE 6-3). 2 In patients with diffuse disease,
a striped (tigroid) appearance may be seen, in which normal white matter
alternates with hyperintense lesions (also seen in other leukodystrophies, such
as Pelizaeus-Merzbacher disease).28
Diagnosis
The diagnosis is suspected if a low arylsulfatase A level (less than 10% of normal
values) is detected in white blood cells or cultured fibroblasts; however,
arylsulfatase A pseudodeficiency is relatively common. Individuals with
arylsulfatase A pseudodeficiency have arylsulfatase A levels ranging from 5% to
20% of normal values without clinical or radiographic disease. Therefore, a
diagnosis of metachromatic leukodystrophy in individuals with low arylsulfatase A
09/2022
must be confirmed by the detection of elevated sulfatides in the urine and ARSA
sequencing for mutations.29
A full-term infant boy was noted to have slow development of motor CASE 6-2
milestones. He walked around 18 months but continued to be unsteady.
He was referred for early intervention, and hypotonia was suspected. His
speech and cognition were normal for his age. At 2 years, he had
persistent gait unsteadiness and was referred to neurology. An EMG was
consistent with a demyelinating polyneuropathy. Subsequently, his gait
further regressed and a walker was needed. He could not push up into a
prone position or crawl. His speech regressed with decreased speech
production. His examination was notable for increased tone in the lower
extremities, decreased dorsiflexion, and absent patellar reflexes. He was
only able to walk with assistance. Brain MRI was performed at 2 years,
7 months, and diffuse T2 hyperintensities were seen throughout the white
matter. Arylsulfatase A level in leukocytes was low, and urine sulfatides
were elevated.
This case illustrates a delay in the diagnosis of metachromatic leukodystrophy. COMMENT

Late infantile metachromatic leukodystrophy typically presents between 1 and
3 years of age with gross motor delay or regression. In this patient, a peripheral
neuropathy, rather than symptoms localizing to the central nervous system,
was the initial manifestation of disease. Metachromatic leukodystrophy
should be considered in any child presenting with a peripheral neuropathy.
As the typical central nervous system involvement may develop later,
brain MRI findings may be subtle or unremarkable. Biochemical testing
(arylsulfatase A, urine sulfatides) is the diagnostic test of choice.
LEUKODYSTROPHIES
A high index of suspicion for

metachromatic leukodystrophy
must exist for children presenting
with a peripheral neuropathy or
gall bladder abnormality in the
absence of other neurologic

features. The MRI may not reveal

pathology early in the disease
course; therefore, a normal MRI is
not sufficient to exclude
metachromatic leukodystrophy.
The diagnosis of metachromatic
leukodystrophy should be
excluded through a normal
arylsulfatase A level and the
absence of urinary sulfatides.
Legislation mandating newborn
screening for metachromatic
leukodystrophy has not been
09/2022
FIGURE 6-3
Metachromatic leukodystrophy. Axial MRI in approved at the state or federal
metachromatic leukodystrophy demonstrates level. The required methodology
confluent diffuse T2 hyperintense signal involving for metachromatic leukodystrophy
the central white matter and corpus callosum, similar
newborn screening is still under
to Krabbe disease. The striped “tigroid” appearance
is not specific for metachromatic leukodystrophy development30 and is further
but characteristic of leukodystrophies. challenged by the frequency of
arylsulfatase A pseudodeficiency
in the population.
Hematopoietic stem cell transplantation may be beneficial in asymptomatic
children with metachromatic leukodystrophy (diagnosed because of an affected
sibling) or early symptomatic juvenile-onset disease. Cohorts have included
those receiving bone marrow–derived cells,31 umbilical cord blood,32 or both.33
For late-infantile disease, four of ten in one cohort32 and two of four in a different
cohort died.33 Of the six children who died, five of the deaths occurred within the
first year posttransplant. One patient in each group was asymptomatic at the
time of transplant. In patients with juvenile disease, the 5-year survival
posttransplant is estimated to be 59% (N = 27),33 79% (N = 24),31 and 82.4%
(N = 17)32 across various studies. While disease stability may occur, many
patients experience decline posttransplant with respect to MRI involvement,
gross motor function, cognitive skills, nerve conduction velocities, and other
metrics, although outcomes are frequently better compared to affected siblings
or natural history cohorts.32,33
In a phase 1/2 clinical trial, gene therapy in combination with autologous
hematopoietic stem cell transplantation was performed in 20 children with
metachromatic leukodystrophy (asymptomatic late-onset infantile disease,
juvenile disease, and early-onset juvenile disease [less than 6 months from
symptom onset]).34,35 For this open-label study, hematopoietic stem cells were
removed from the patient, transduced with a lentiviral vector encoding ARSA
ex vivo, and returned to the patient after myeloablative conditioning. Two
142 FEBRUARY 2018

publications describe the outcomes of the first nine patients enrolled in the KEY POINTS
study.34,35 The onset of MRI abnormalities in asymptomatic individuals was
● Aicardi-Goutières
delayed compared to sibling controls, and many showed age-expected gains syndrome should be
in gross motor function and cognition. However, not all children remained considered in young
asymptomatic, and some disease progression occurred. The unique aspect of children with developmental
regression, acquired
this therapy is the ability of the transduced cells to make supranormal levels of
microcephaly, spasticity,
arylsulfatase A, which was detected as early as 1 month in blood and 6 months in and dystonia. Chilblains,
CSF. Data from the trial are still being analyzed to determine the future role of glaucoma, cardiomyopathy,
gene therapy for this disorder. stroke, and comorbid
autoimmune conditions are
present, with variability in
AICARDI-GOUTIÈRES SYNDROME the presence and frequency
of these symptoms by
Aicardi-Goutières syndrome is an inflammatory disorder caused by mutations genetic mutation.
in any one of seven genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C,
SAMHD1, ADAR, or IFIH1), all of which encode proteins involved in nucleic ● In Aicardi-Goutières
acid metabolism and signaling.36 The pathophysiology involves the accumulation syndrome, a CT scan may
be performed to
of nucleic acids (for all genes except ADAR and IFIH1) that activate the innate demonstrate calcium
immune response with increased expression of type I interferon–stimulated deposits in the basal
genes. The symptoms and imaging features of Aicardi-Goutières syndrome ganglia and other areas of
09/2022
mimic TORCH (toxoplasmosis, other infections, rubella, cytomegalovirus the brain.

infection, and herpes simplex) and other in utero infections.
● Patients with
Aicardi-Goutières
Clinical Symptoms syndrome may have a CSF
lymphocytic pleocytosis,
In 1984, Jean Aicardi and Françoise Goutières described the syndrome that elevated interferon alfa, or
now bears their names.37 Among five families, eight infants had a progressive elevated neopterin or
encephalopathy presenting shortly after birth with feeding difficulties or biopterin.
manifesting as subacute neurologic deterioration after a period of normal
development, typically before 1 year of age. Ultimately, the affected children
developed appendicular spasticity and dystonia, truncal hypotonia, and acquired
microcephaly. These children were all found to have basal ganglia calcifications
on head CT and a persistently elevated CSF white blood cell count (lymphocytic
predominance) on serial measurements. Since the initial description, the clinical
phenotypes (TABLE 6-5) have evolved.
In addition to the neurologic manifestations, other symptoms provide clues to
the diagnosis of Aicardi-Goutières syndrome, and some trends in clinical
manifestations based on genetic mutations have been identified among 374
patients with Aicardi-Goutières syndrome.36 Chilblains, which are small purple-red
or white blistering lesions on the toes, fingers, helix, or pressure areas, occur in
approximately one-third of all patients with Aicardi-Goutières syndrome
(FIGURE 6-4 38 ). 39,40 They are most common after 1 year of age and increase in
cold weather.41 Chilblains have been reported with mutations of each of the seven
genes; however, they most frequently occur in children with SAMHD1 mutations
(approximately 54%, or 26 of 48 children) and rarely occur in ADAR mutations.
Glaucoma also occurs in approximately 20% of children (10 of 48) with SAMHD1
mutations, typically in the first 6 months of life, although it can occur at an older
age. Stroke due to large vessel disease has also been reported in SAMHD1
mutations (9 of 9 children). While infrequent, infantile-onset hypertrophic
cardiomyopathy may occur, especially in infants with a TREX1 mutation (9 of 12
infants with cardiomyopathy had mutations in the TREX1 gene). These
relationships may inform genetic testing of single genes but should not be used to
LEUKODYSTROPHIES
exclude a diagnosis of Aicardi-Goutières syndrome, as overlap of genetic

syndromes does occur.
Although rare, other autoimmune diseases, including hypothyroidism,
diabetes mellitus, autoimmune gastritis, autoimmune hepatitis, panniculitis,
Crohn disease, systemic lupus erythematosus, and antiphospholipid antibody
syndrome, have been described in patients with Aicardi-Goutières syndrome.

Neuroimaging
The pathognomonic feature of Aicardi-Goutières syndrome on neuroimagingis
intracerebral calcifications, which are present in approximately 90% of
individuals (N = 121) using MRI (FIGURE 6-5) and CT.42 The calcium deposits
are frequently present in the basal ganglia, deep white matter, thalamus, and
dentate nuclei of the cerebellum. They can be visualized on MRI using
T1-weighted, gradient recalled echo (GRE), or susceptibility-weighted images;
however, a head CT may be necessary to confirm their presence. The cerebral
white matter is also affected (present in 120 of 121 children), with T2
hyperintensities or white matter rarefaction with a frontotemporal predominance or
diffuse involvement.42 In the same study, one patient had isolated bilateral striatal
09/2022
necrosis, which has been reported in ADAR1 mutations.43 Other distinguishing MRI
features in infants with Aicardi-Goutières syndrome (median age 0.7 months)
include cerebral atrophy (with ventricular enlargement), temporal lobe swelling,
temporal horn dilation, and temporal cysts.44 A normal brain MRI and nonspecific
white matter changes have been reported in children with severe dystonia (but
preserved cognition) who have mutations in various Aicardi-Goutières syndrome
genes. As such, a normal or nondiagnostic brain MRI does not exclude the
diagnosis of Aicardi-Goutières syndrome.
Diagnosis
A diagnosis of Aicardi-Goutières syndrome should be considered in young
children with the clinical or radiographic features described. A lumbar puncture
TABLE 6-5 Aicardi-Goutières Syndrome Phenotypes and Frequenciesa

Prenatal Presents at birth with poor feeding, irritability, abnormal tone and movements, seizures; 11.4%
onset thrombocytopenia and hepatosplenomegaly at birth support the prenatal onset
Perinatal Presents at birth with similar features to the prenatal onset form but without the systemic 11.4%
involvement
Infancy Onset <1 year of age; may meet early milestones, followed by psychomotor regression, spasticity, 68.6%
dystonia, and acquired microcephaly; seizures and visual impairment may also occur
Childhood Variable symptoms and disease onset, although the oldest known age at symptom onset is 8.6%
5 years of age (subacute dystonia); glaucoma developed in a 6-year-old patient with
known disease
a
Data from Crow YJ, et al, Am J Med Genet.36
144 FEBRUARY 2018

may provide supportive evidence. The KEY POINT
CSF may reveal a lymphocytic pleocytosis.
● Infants with persistent
Elevated CSF neopterin and biopterin and jaundice or chronic diarrhea
reduced folate have been reported in and children with bilateral
patients with normal CSF profiles cataracts should be tested
(including cell counts, interferon, and for cerebrotendinous

xanthomatosis, even in the
interleukin levels).45 absence of neurologic

symptoms, through
Disease-specific Therapy measurement of serum
cholestanol and urine and
No therapies are currently approved for
serum bile alcohols.
Aicardi-Goutières syndrome; however,
active research studies and clinical trials
are investigating treatments that
target the interferon pathway and
autoantibody production in children with
Aicardi-Goutières syndrome.46
CEREBROTENDINOUS XANTHOMATOSIS
09/2022
Cerebrotendinous xanthomatosis is an
autosomal recessive disorder caused by
mutations in the CYP27A1 gene, which
encodes sterol 27-hydroxylase. The
deficiency of this enzyme results in the
accumulation of cholesterol and cholestanol
and the formation of xanthomas in
tendons, CNS, skin, and other organs.
Clinical Symptoms
The earliest manifestation of
cerebrotendinous xanthomatosis is
neonatal cholestatic jaundice,47 which
persists beyond the first week of life with
chronic diarrhea and is associated with FIGURE 6-4
elevated transaminases and bilirubin. In Chilblains in Aicardi-Goutières
syndrome. Chilblains are vasculitis
childhood and adolescence, juvenile lesions (purple-red discolorations) of
bilateral cataracts occur, but they are often the skin typically located on the fingers,
thought to be “idiopathic,” and most toes, or other dependent areas (such
clinicians do not appreciate the possibility as elbows or earlobes); necrosis of these
lesions can occur.
of cerebrotendinous xanthomatosis. Reprinted with permission from Abe J, et al,
Xanthomas occur in the Achilles and other Rheumatology (Oxford).38 © 2013 The Authors.
tendons, especially over extensor surfaces,
in adolescence or adulthood. They can also
develop in the brain, lungs, and bones. The neurologic symptoms develop
predominantly in adulthood, with cognitive impairment, ataxia, and pyramidal
features (such as spasticity). Psychiatric symptoms can also occur.
Neuroimaging
The cerebellum is preferentially affected in cerebrotendinous xanthomatosis;
notably, T1 hypointense and T2 hyperintense lesions are seen in the bilateral
LEUKODYSTROPHIES
dentate nuclei as well as T2

hyperintensities in the cerebellar
white matter.48 Cerebellar and
cerebral atrophy are also present.
The periventricular white matter,
globus pallidus, posterior limb of

the internal capsule, substantia

nigra, and cerebral peduncles
may also be affected.49
Diagnosis
A high index of suspicion is
needed for the diagnosis of
cerebrotendinous xanthomatosis
as serum cholesterol levels and
hepatic function testing are
normal. The diagnosis is
confirmed through elevated
FIGURE 6-5
serum cholestanol, which
09/2022
Aicardi-Goutières syndrome. Axial T1-weighted

MRI demonstrates hyperintensity in the bilateral is 5 to 10 times normal values, and
basal ganglia, predominantly the putamen (arrows), the excretion of bile alcohols in
representing mineralization in a patient with the urine and serum.
Aicardi-Goutières syndrome.
Testing for cerebrotendinous
xanthomatosis has not been
incorporated into newborn
screening programs in the United States; however, a methodology
to detect a bile acid precursor in dried blood spots has successfully differentiated
infants with cerebrotendinous xanthomatosis from unaffected controls.50 In
Victoria, Australia, urine bile alcohols have been added to a urine metabolic
screening panel (including amino acids, organic acids, and others) and enabled
the diagnosis of four patients with cerebrotendinous xanthomatosis among
23,000 urine samples.51,52
Chenodeoxycholic acid inhibits cholesterol and cholestanol synthesis by
downregulating CYP7A transcription.53 Treatment with chenodeoxycholic acid
does not improve neurologic deficits once present but, if started early, prevents
neurologic deterioration. For example, patients whose treatment with
chenodeoxycholic acid began before 25 years of age (N = 10) had improved
ambulation with significantly less pyramidal involvement and fewer cerebellar
deficits compared to those who started after 25 years of age (N = 6).54 Dysarthria
was not noted in any of the treated younger patients. Cholic acid is FDA approved
for children and adults with cerebrotendinous xanthomatosis and has fewer side
effects than chenodeoxycholic acid, especially in infants and children, whose
diarrhea worsens on chenodeoxycholic acid.55
TRENDS
Newborn screening programs for leukodystrophies are being implemented
for Krabbe disease and X-linked adrenoleukodystrophy, while testing for
146 FEBRUARY 2018

metachromatic leukodystrophy and cerebrotendinous xanthomatosis are under KEY POINT
development. Such programs are providing new challenges for disease prediction
● Cholic acid is a US Food
models. Genotype-phenotype correlations for many disorders do not predict age and Drug Administration–
of onset or functional decline; therefore, it is not clear when to introduce a approved treatment for
therapy, such as hematopoietic stem cell transplantation, or how to determine its cerebrotendinous
efficacy. Gene therapy trials in some of the leukodystrophies provide hope for xanthomatosis and, when
initiated early, delays the
families; however, more data are needed on their efficacy and safety profiles. onset of neurologic
Novel therapeutic strategies are needed for peripheral nervous system symptoms.
involvement of leukodystrophies such as Krabbe disease and metachromatic
leukodystrophy, as hematopoietic stem cell transplantation has a limited benefit
in the treatment of these symptoms.
CONCLUSION
The leukodystrophies are a group of complex disorders with variable
clinical features and presentations by age. Many of these disorders have
extra-CNS manifestations before the onset of neurologic symptoms
or MRI abnormalities, such as adrenal insufficiency in X-linked
09/2022
adrenoleukodystrophy or chronic diarrhea and cataracts in cerebrotendinous

xanthomatosis. Both metachromatic leukodystrophy and Krabbe disease can
present with a peripheral neuropathy, and, in such cases, the brain MRI is
often normal or reveals subtle findings. Therefore, knowledge about the
typical disease presentations and a high index of suspicion are crucial to
confirming the diagnosis before the worsening of CNS symptoms and disease
progression on MRI. Biochemical testing, such as enzyme levels in Krabbe
disease and metachromatic leukodystrophy; very-long-chain fatty acids in
X-linked adrenoleukodystrophy; CSF cell counts, neopterin, and biopterin in
Aicardi-Goutières syndrome; and serum cholestanol in cerebrotendinous
xanthomatosis, are the tests of choice to screen suspected individuals for
these disorders.
ACKNOWLEDGMENT
This work was supported by a career training grant (K23NS069806) from the
National Institutes of Health.
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01.WNL.0000082726.08631.E7.
REVIEW ARTICLE

Evaluation and Acute
C O N T I NU U M A UD I O
I NT E R V I E W A V AI L A B L E Management of Ischemic
ONLINE
Stroke in Infants
and Children
By Catherine Amlie-Lefond, MD
ABSTRACT
PURPOSE OF REVIEW: This article provides an overview of stroke in neonates,
infants, and children.
09/2022
RECENT FINDINGS: Arterial ischemic stroke and cerebral venous sinus

thrombosis are increasingly recognized in childhood as important causes
of lifelong morbidity and mortality. Diagnosis of arterial ischemic stroke
is frequently delayed, as acute neurologic deficits can be challenging
to detect in the young child, and stroke is often not considered in the
differential diagnosis. Neurologic sequelae following stroke are common,
and strategies to minimize stroke size and optimize recovery are being
developed. Recurrent arterial ischemic stroke is not uncommon,
particularly in children with cerebral arteriopathy. Cerebral venous sinus
CITE AS:
thrombosis causes obstruction of venous outflow leading to venous
CONTINUUM (MINNEAP MINN) infarcts. Complications include hemorrhagic conversion of infarcts and
2018;24(1, CHILD NEUROLOGY): increased intracranial pressure. Without treatment, thrombus extension
150–170.
with increased symptoms is common. Robust guidelines of care that exist
Address correspondence to Dr for adults do not exist for children, particularly for children with arterial
Catherine Amlie-Lefond, Seattle ischemic stroke.
Children’s Hospital, 4800 Sand
Point Way NE, PO Box 5371,
Seattle, WA 98145, SUMMARY: The approach to stroke in infants and children can be informed
calefond@seattlechildrens.org. by clinical experience in pediatric stroke and cerebral venous sinus
thrombosis, the extensive literature on pediatric thrombosis, and
Dr Amlie-Lefond has received extrapolation from data from adult patients.
the National Institutes of Health
StrokeNet.
INTRODUCTION
I
UNLABELED USE OF schemic stroke in neonates and children can occur because of interruption of
USE DISCLOSURE: arterial blood flow (arterial ischemic stroke) or obstruction of venous flow
Dr Amlie-Lefond discusses the (cerebral venous sinus thrombosis). Prompt diagnosis and early treatment
are necessary to minimize complications and limit brain injury, including
recombinant tissue plasminogen
activator and thrombectomy preventing stroke extension and recurrence.
for the treatment of childhood
stroke. PERINATAL ISCHEMIC STROKE
© 2018 American Academy Perinatal ischemic stroke, estimated to occur in 1 in 2500 births, is defined as
of Neurology. pathologic or radiologic evidence of focal arterial or venous infarction
150 FEBRUARY 2018

occurring or presumed to have occurred between 20 weeks gestation and
28 days of age.
Presentation
Perinatal stroke may be diagnosed in the immediate newborn period, most
typically when an infant with an acute middle cerebral artery stroke develops
recurrent seizures, usually focal, within the first few days of life.1 Other infants
are diagnosed with presumed perinatal ischemic stroke during the first year of
life when they develop hemiplegia, developmental delays, or epilepsy. These
children usually present at 4 to 6 months of age, when hemiparesis or
developmental delay becomes apparent, but may present earlier with
encephalopathy or epilepsy. A small percentage of children with perinatal
ischemic stroke present with acute stroke beyond the immediate newborn period
but within the first 28 days of life. These infants may represent very early
childhood arterial ischemic stroke rather than late neonatal arterial ischemic
stroke in terms of risk factors, recurrence risk, and secondary stroke prevention
strategies. Very rarely, stroke will be diagnosed in utero on prenatal imaging.
The vascular distribution of perinatal ischemic stroke can be arterial or
venous.2 Arterial distribution is more common in term infants, and venous
09/2022
distribution infarcts involving the periventricular region resulting in presumed

periventricular venous infarction are believed to occur earlier in utero than
arterial strokes and are more common in infants born prematurely.3
Etiology
Studies identifying risk factors for perinatal ischemic stroke have historically
focused on perinatal arterial stroke, particularly those presenting acutely in
the newborn period. Conclusions are limited as data from studies are often
inconsistent, associations are often weak, and causative associations are difficult
to prove.4,5
Diagnosis
Diagnosis is confirmed by the presence of focal arterial or venous infarction on
neuroimaging. Although cranial ultrasound is the modality of choice for preterm
periventricular hemorrhagic infarction, cranial ultrasound has low sensitivity
for term ischemic perinatal stroke. Head CT is more sensitive than cranial
ultrasound but requires radiation and should only be used if other modalities
are not available.
Brain MRI, including diffusion-weighted imaging (DWI), is the most sensitive
test to confirm perinatal arterial stroke and should be obtained as soon as the
infant is adequately stable. Newborns who are fed and swaddled can often
tolerate head MRI without sedation, particularly if rapid protocols limiting the
time of the scan are used.
Investigations
Debate exists as to the optimal timing and extent of thrombophilia workup in
patients with perinatal arterial stroke. Routine thrombophilia testing in perinatal
arterial stroke is unlikely to change management.6 Blood loss due to blood draws
in the neonate should be minimized. Maternal history of autoimmune disorder,
thrombosis, or recurrent pregnancy loss should be sought. An echocardiogram is
indicated if concern exists for congenital heart disease or cardiac thrombus.
ISCHEMIC STROKE
Acute Care
In acute symptomatic perinatal arterial stroke presenting with seizures, EEG,
including continuous EEG, can be used to assess the efficacy of antiepileptic
medications. Use of anticoagulation or aspirin is not recommended in the
absence of an ongoing cardioembolic source.7 Evaluation prior to feeding is
important, and close neurodevelopmental follow-up is indicated at

hospital discharge.
Outcome
Infants with perinatal stroke are at risk for epilepsy, including intractable
epilepsy and infantile spasms. Studies report variable rates of epilepsy following
ischemic perinatal stroke, ranging from less than one-fourth to one-half of
children,8 likely reflecting the difference in patient ascertainment and follow-up.
Most infants with perinatal arterial stroke will have neurocognitive sequelae.8
Normal IQ is frequently seen, particularly in children without other risk factors
for developmental sequelae.9 Neuromotor outcome and hemiplegia largely
depend on the area of infarction: involvement of the basal ganglia, thalamus, or
posterior limb of the internal capsule is associated with motor incoordination
or hemiplegia.10,11
09/2022
CHILDHOOD ARTERIAL ISCHEMIC STROKE

The true incidence of childhood arterial ischemic stroke is not known, but it is
estimated at 5 to 10 per 100,000 children annually. Following childhood arterial
ischemic stroke, 6% to 10% of children die, 20% experience recurrent stroke, and
more than 75% are left with long-term neurologic deficits.12–17 Arterial ischemic
stroke differs significantly in children compared to adults, and the differences
include the presenting signs and symptoms, differential diagnosis, risk factors,
developmental hemostasis (age-related changes in hemostasis during
childhood), and paucity of patient-specific outcome data. Consequently, care
recommendations are primarily based on extrapolation from experience treating
adult patients and expert consensus.
Presentation
Most children with acute arterial ischemic stroke will have focal neurologic
deficits, although recognition of such deficits can be challenging in the ill or very
young child. Diagnosis of arterial ischemic stroke is often delayed because of the
infrequency of stroke in children relative to adults and the frequency of stroke
mimics, such as seizure, migraine, encephalitis, demyelination, and functional
neurologic disorders.18,19 Early recognition of childhood arterial ischemic stroke
may be facilitated by use of screening protocols similar to those used to detect
stroke in adults,20 although full neurologic assessment will be necessary to
confirm stroke and exclude mimics. The most common stroke mimics in
childhood are seizure, migraine, psychogenic presentation, mass lesion,
infection, methotrexate toxicity, posterior reversible encephalopathy syndrome
(PRES), and metabolic stroke.18,19
The most common cause of sudden-onset focal neurologic deficits in adults is
acute stroke, and treatment for presumed arterial ischemic stroke in adults can be
instituted based on head CT imaging that excludes the presence of intracranial
hemorrhage and assesses early ischemic signs. In contrast, because of the high
frequency of stroke mimics in childhood, neuroimaging is necessary not only to
exclude hemorrhagic stroke (which accounts for one-half of all strokes in
152 FEBRUARY 2018

childhood) but also to confirm the presence of arterial ischemic stroke and to rule KEY POINTS
out urgent mimics prior to treatment. Cerebral arteriopathy is a common risk
● Diagnosis of arterial
factor in childhood arterial ischemic stroke.21 Stroke associated with cerebral ischemic stroke is often
arteriopathy is often preceded by transient ischemic attacks of focal neurologic delayed because of the
deficit,22 and transient neurologic deficit is an indication for urgent cerebral arterial infrequency of stroke in
imaging as treatment may prevent further transient or permanent ischemic injury. children relative to adults
and the frequency of stroke

mimics, such as seizure,
Etiology migraine, encephalitis,
Arterial ischemic stroke can result from an embolus to the artery, such as from the demyelination, and
heart or large artery, or from thrombosis in situ, frequently in the setting of functional neurologic
disorders.
arteriopathy. Congenital and acquired cardiac diseases account for approximately
30% of cases of childhood arterial ischemic stroke, presumably due to ● Congenital and acquired
cardioembolic events.23 Children who have required cardiac surgery are at highest cardiac diseases account for
risk for stroke, not only in the perioperative period, but for years following surgery approximately 30% of cases
as well. Indeed, most childhood strokes associated with congenital heart disease of childhood arterial
ischemic stroke, presumably
occur outside the hospital.24 Stroke recurrence in congenital heart disease can due to cardioembolic
occur even in children on anticoagulation (CASE 7-1).25 events.
Up to one-half of all childhood arterial ischemic stroke is associated with
cerebral arteriopathy,21 which is also a risk factor for recurrent stroke.14 Stroke ● Up to one-half of all
09/2022
childhood arterial ischemic

due to arteriopathy often presents with a subacute or stuttering onset, frequently
stroke is associated with
following a history of transient ischemic attacks (CASE 7-226).22,27 Other risk cerebral arteriopathy, which
factors for childhood arterial ischemic stroke include infection, acute head and is also a risk factor for
neck disorders, acute and chronic systemic conditions, and prothrombotic states recurrent stroke.
(TABLE 7-1). One-half of children presenting with acute arterial ischemic
● Approximately one-
stroke will have more than one risk factor identified, while only 9% will have fourth of arteriopathies in
no risk factors identified.23 childhood arterial ischemic
Despite the importance of cerebral arteriopathy in patients with childhood stroke are focal cerebral
stroke, diagnosis is challenging, and nomenclature continues to evolve. Cerebral arteriopathy, which is a
narrowing of the artery that
arteriopathies associated with childhood arterial ischemic stroke include focal usually involves large- and
cerebral arteriopathy, moyamoya, dissection, vasculitis, sickle cell arteriopathy, medium-sized arteries.
and postvaricella angiopathy.28 Approximately one-fourth of arteriopathies in
childhood arterial ischemic stroke are focal cerebral arteriopathy, which is a
narrowing of the artery usually involving large- and medium-sized arteries.
Cerebral arteriopathy, particularly when progressive, is a risk factor for recurrent
ischemia.28 Transient cerebral arteriopathy is a subset of focal cerebral arteriopathy
in which no progression is seen on vascular imaging at 6 months. Both conditions
are believed to occur as a sequela of infection or inflammation.29 Focal cerebral
arteriopathy is well associated with varicella-zoster virus infection.30
Moyamoya is a progressive steno-occlusive arteriopathy of the distal internal
carotid arteries, proximal middle cerebral arteries, and, not infrequently, the
anterior cerebral arteries. Moyamoya is associated with the development of basal
lenticulostriate collaterals, or moyamoya (Japanese for “puff of smoke”). Although
many children with moyamoya have a history of transient ischemic attacks
with signs of anterior circulation ischemia, diagnosis often does not occur
until the child has an overt stroke.31 Idiopathic moyamoya disease is
likely genetic.32,33
Moyamoya occurring in association with underlying syndromes (moyamoya
syndrome) is well associated with sickle cell disease, trisomy 21, neurofibromatosis
type 1, and as a sequela of radiation therapy to the head. Given the high risk of
stroke in patients with moyamoya, particularly in young children who are more
ISCHEMIC STROKE
CASE 7-1 A 6-month-old girl with complex heart disease and known cardiac
thrombosis on anticoagulation was brought to the emergency
department after 4 days of rash and 1 day of emesis and irritability. On
examination, she was noted to have difficulties using her right arm and to
have a right facial droop. Head CT performed 3 hours after symptoms

were noticed already showed edema, with loss of gray-white matter

differentiation in the area of the left middle cerebral artery distribution
(FIGURE 7-1A) as well as a possible thrombus in the left proximal middle
cerebral artery (FIGURE 7-1B). Over the next day, she developed recurrent
tonic-clonic movements of the right hand, consistent with partial
seizures, which were initially refractory to treatment.
Follow-up head CT performed at age 2 years after a fall while on
anticoagulation showed encephalomalacia in the distribution of the prior
left middle cerebral artery infarct with mild ex vacuo dilatation of the
posterior horn of the left lateral ventricle (FIGURE 7-1C ).
09/2022
FIGURE 7-1
Imaging of the patient in CASE 7-1. Head CT 3 hours after symptoms were noticed shows
edema with loss of gray-white matter differentiation in the area of the left middle
cerebral artery distribution (A) and possible thrombus (B, arrow) in the left proximal
middle cerebral artery. Follow-up head CT at age 2 years after a fall while on
anticoagulation (C) shows encephalomalacia in the distribution of prior left middle
cerebral artery infarct with mild ex vacuo dilatation of the posterior horn of the left
lateral ventricle.
COMMENT This case exemplifies stroke in the setting of congenital heart disease.
Congenital heart disease is a significant risk factor for childhood arterial
ischemic stroke, and ischemic stroke can occur even in the setting of full
anticoagulation.23,25
154 FEBRUARY 2018

A 5-year-old boy who had been previously healthy was roughhousing with CASE 7-2
friends when he developed a headache, confusion, and right facial
weakness, followed by an inability to stand. Head CT completed 3.5 hours
after symptom onset was normal except for sinusitis and middle ear
effusions. Diffusion-weighted MRI 5 hours after symptom onset

showed acute ischemia in the distribution of the left middle cerebral

artery (FIGURE 7-2A), with changes seen on fluid-attenuated inversion
recovery (FLAIR) imaging (usually present 4 to 6 hours after stroke onset)
as well (FIGURE 7-2B). Time-of-flight magnetic resonance angiography
(MRA) showed irregularity of the distal left internal carotid artery and
proximal left middle cerebral artery (FIGURE 7-2C). Thrombophilia
workup was unrevealing except for mildly elevated lipoprotein (a),
and investigations into etiologies of focal cerebral arteriopathy (other
than sinusitis and middle ear effusions), including varicella-zoster
virus antibodies in CSF, were unrevealing.
09/2022
FIGURE 7-2
Imaging of the patient in CASE 7-2. Axial diffusion-weighted MRI (A) and axial
fluid-attenuated inversion recovery (FLAIR) MRI (B) performed 5 hours after symptom
onset show acute ischemia in the distribution of the left middle cerebral artery.
Time-of-flight magnetic resonance angiogram (MRA) shows irregularity of the distal
left internal carotid artery and proximal left middle cerebral artery (C, arrow).
This case exemplifies stroke in the setting of focal cerebral arteriopathy. COMMENT
Focal cerebral arteriopathy may show early progression, with most cases
stabilized or improved by 6 months following stroke; however,
approximately 6% of cases show ongoing progression.26
ISCHEMIC STROKE
TABLE 7-1 Risk Factors for Childhood Arterial Ischemic Stroke
Cardiac
u Congenital heart disease
u Acquired heart disease

u Cardiac intervention or surgery

Cerebral Arteriopathy
u Focal/transient cerebral arteriopathy
u Moyamoya
u Cervicocephalic arterial dissection

u Varicella-zoster virus—associated vasculopathy
u Primary/secondary central nervous system vasculitis
Hypercoagulable State
u Homocystinemia
u Anticardiolipin antibodies
09/2022
u Elevated lipoprotein (a)
u Hematologic malignancy
u Protein C deficiency
u Protein S deficiency
u Factor V Leiden
u Factor II (prothrombin mutation G20210A)
Hematologic Disorders
u Sickle cell disease
u Iron deficiency anemia
u Thrombocytosis
u Malignancy
Infection
u Bacterial meningitis
u Varicella—primary and reactivation
u Fungal meningitis
u Tuberculous meningitis
Drugs
u Asparaginase
u Exogenous estrogen
u Illicit drugs (eg, cocaine, methamphetamine)
Inflammatory/Autoimmune
u Systemic lupus erythematosus

u Rheumatoid arthritis
u Systemic vasculitis
156 FEBRUARY 2018

likely to have rapidly progressive arteriopathy with recurrent strokes,34 surgical
revascularization is recommended to decrease the risk of ischemic stroke, as well
as hemorrhagic stroke, which tends to occur in adulthood (CASE 7-3).35
Approximately 25% of patients with sickle cell disease have cerebral
arteriopathy, including moyamoya, which is a risk factor for primary and
recurrent stroke. Without treatment, 11% of patients with sickle cell disease will
have a clinically evident stroke by 20 years of age36 and 37% will have clinically
silent strokes by age 14 years.37 The risk of recurrent stroke is decreased by
A 3-year-old girl, who had been previously healthy, presented with CASE 7-3
new-onset right-sided seizures, followed by right hemiparesis, which
improved over 2 hours. During the previous 6 months, she had a history of
two episodes of right hemiparesis with crying, without seizure activity. On
axial T2-weighted MRI, multiple hyperintense foci were seen bilaterally,
consistent with ischemic injury (FIGURE 7-3A). Time-of-flight magnetic
resonance angiography (MRA) showed occlusion of the terminal internal
carotid arteries, proximal middle cerebral arteries, and anterior cerebral
09/2022
arteries consistent with moyamoya (FIGURE 7-3B). This was confirmed on

cerebral catheter angiogram, showing occlusion of the supraclinoid left
internal carotid artery (FIGURE 7-3C). Examination showed multiple café au
lait spots, and she was subsequently diagnosed with neurofibromatosis
type 1. Bilateral pial synangiosis was performed, and she remained free of
seizures or transient ischemic attacks over the subsequent 3 years.
FIGURE 7-3
Imaging of the patient in CASE 7-3. A, Axial T2-weighted MRI shows multiple small hyperintense
foci bilaterally (arrows), consistent with ischemic injury. B, Time-of-flight magnetic
resonance angiogram (MRA) shows no flow-related signal in the left internal carotid artery,
proximal middle cerebral arteries, and anterior cerebral arteries. C, Cerebral catheter
angiogram shows occlusion of the supraclinoid left internal carotid artery.
This case exemplifies moyamoya presenting with transient ischemic COMMENT

attacks. Moyamoya often presents with transient ischemic attacks, which
may not be recognized until completed stroke occurs.31
ISCHEMIC STROKE
regular red blood cell transfusions38,39 or, alternatively, if transfusions are not
feasible, hydroxyurea therapy.40 Elevated transcranial Doppler velocity in the
middle cerebral artery is strongly associated with stroke risk in sickle cell
disease, and the incidence of the first overt stroke is markedly decreased in
children with increased velocities by regular red blood cell transfusions41,42
or hydroxyurea.43
Cervicocephalic arterial dissection accounts for up to 20% of childhood arterial

ischemic stroke28,44,45 and one-half of posterior circulation childhood arterial
ischemic stroke.46 Cervicocephalic arterial dissection can occur spontaneously or
following trauma. Trauma may be more likely to trigger dissection in a susceptible
individual; for example, dissection is more likely to occur in patients with a
connective tissue disorder. Vertebral artery dissection is particularly challenging
to diagnose, as it can present with ataxia and vomiting, which are not infrequent
complaints in childhood. Timely diagnosis is important because of the significant
risk of recurrent stroke (which can be decreased with antithrombotic treatment) as
well as subarachnoid hemorrhage and recurrent dissection. Following cervical
artery dissection, avoidance of potential triggering events, such as contact sports
and other activities where rapid movement of the head and neck can occur,
is recommended.
09/2022
Childhood primary angiitis of the central nervous system (CNS), in which

arterial inflammation is limited to the CNS, is divided into large-medium artery
disease, in which arteriopathy can be detected on a cerebral catheter angiogram,
and small vessel artery disease, in which arteriopathy is not visible on a catheter
angiogram. Inflammatory markers are frequently uninformative in large-medium
childhood primary angiitis of the CNS.47 In small vessel childhood primary angiitis
of the CNS, MRI imaging of the brain parenchyma is usually abnormal, but findings
are nonspecific; many, but not all, patients have elevated inflammatory markers.
Biopsy, even nonlesional, has a significant yield in children with small vessel
primary angiitis.48 However, biopsy may be negative even in children believed to
have vasculitis,49 and diagnosis can be particularly challenging in these cases.
CNS vasculitis can also occur secondary to a systemic cause, most commonly in
systemic rheumatologic diseases such as Takayasu arteritis and polyarteritis
nodosa but also infection or malignancy. The arteriopathy associated with
secondary CNS vasculitis often involves vessels of multiple sizes.
Congenital and acquired thrombophilias are associated with childhood arterial
ischemic stroke, especially if multiple thrombophilias or other risk factors are
present.23,50 A meta-analysis of observational studies of thrombophilia in childhood
ischemic stroke reported an association with protein S deficiency, protein C
deficiency, factor V Leiden, prothrombin mutation G20210A, antithrombin III
deficiency, antiphospholipid antibodies, and methylenetetrahydrofolate reductase
(MTHFR) C677T.50 Homocysteine levels, rather than MTHFR mutation genetic
testing, should be used to screen for hyperhomocysteinemia, as not all patients
with MTHFR mutations have abnormally elevated homocysteine levels and
elevated homocysteine can occur in other disorders.
Diagnosis
Because of the high incidence of stroke mimics in childhood, diagnosis requires
confirmatory neuroimaging. Urgent imaging is indicated to address the possible
need for immediate intervention, including malignant infarction and consideration
of acute reperfusion strategies, and for conditions associated with a high risk of
158 FEBRUARY 2018

recurrent or progressive stroke without treatment, including craniocervical artery KEY POINTS
dissection and cardiac thrombus.
When possible, MRI is the optimal study for diagnosis of acute childhood ● Cervicocephalic arterial
dissection accounts up to
arterial ischemic stroke. Diffusion-weighted imaging (DWI), which is highly
20% of childhood arterial
sensitive for ischemia, can be performed early in the study to inform further ischemic stroke and
study sequences. A rapid stroke MRI protocol that can be performed in one-half of posterior
approximately 20 minutes can be useful in children who would require sedation circulation childhood
arterial ischemic stroke.
for a longer study or if imaging resources are limited. Ideally, this protocol should
include axial T2-weighted or axial fluid-attenuated inversion recovery (FLAIR) ● Congenital and acquired
sequences, susceptibility weighted imaging (SWI) or gradient recalled echo thrombophilias are
(GRE) for detection of blood, DWI/apparent diffusion coefficient for detection associated with childhood
of ischemia, and time-of-flight MRA of the head and neck to evaluate for cerebral arterial ischemic stroke,
especially if multiple
arteriopathy. Increasingly, vessel wall imaging is being used to evaluate arterial thrombophilias or other risk
wall pathology, such as inflammation. Even if DWI does not show ischemia, factors are present.
MRA is indicated in children presenting with a transient deficit concerning for
transient ischemic attack who may have an underlying cerebral arteriopathy. ● When possible, MRI is the
optimal study for diagnosis
Head CT can rule out intracranial hemorrhage, but it is insensitive for early
of acute childhood arterial
acute ischemic stroke.51 Although CT angiogram of the head and neck can detect ischemic stroke.
arterial abnormalities, including stenosis and occlusion, it requires significant
09/2022
radiation and contrast, and it often does not add significantly to head MRA. Head
CT may be indicated in a child who cannot have an MRI (eg, a child with a
cardiac pacemaker).
Cerebral catheter angiography is the most sensitive method of luminal
imaging for cerebral arteriopathy, including stenosis and occlusion. It is invasive
and requires significant radiation as well as sedation; however, complications are
rare in the hands of experienced angiographers.52
Investigations
Investigations into the etiology of childhood stroke will be guided by past
medical history, clinical presentation, and neuroimaging, including
neurovascular imaging.
CARDIOLOGY EVALUATION. Transthoracic echocardiogram is indicated for
suspected cardiac thrombus or vegetation or to assess right-to-left shunt in a
child with or at risk for systemic venous thrombosis in whom the stroke
etiology is not clear. Rarely, abnormalities are seen on transesophageal
echocardiogram that were not detectable on transthoracic echocardiogram,
particularly vegetations and left atrial thrombi.53 ECG is indicated especially if
cardiac arrhythmia or heart failure is suspected. If cardiac arrhythmia is
suspected but not seen on routine ECG, Holter monitoring may be indicated.
LABORATORY STUDIES. Laboratory studies in acute childhood arterial ischemic
stroke will depend on suspected etiology, clinical concerns, and potential
treatment options. As risk factors for childhood arterial ischemic stroke
are often multiple, screening investigations for thrombophilia are usually
indicated (TABLE 7-2). Not all studies are indicated in all patients, and
the volume of blood required for assays should be considered, particularly
in infants.
Evaluation for the presence of cerebral arteriopathy is performed as described
in the previous section on diagnosis. CSF evaluation for inflammatory markers or
infection should be considered in children with arteriopathy of unknown
ISCHEMIC STROKE
etiology or suspected meningitis or encephalitis. If varicella-zoster

virus–associated arteriopathy is suspected, CSF examination is indicated for
diagnosis. Varicella vasculopathy is confirmed by the presence of varicella-zoster
virus DNA in the CSF or by the demonstration of intrathecal anti–varicella-zoster
virus antibody synthesis.54 CSF evaluation in primary CNS vasculitis may show
pleocytosis or elevated protein, although this is often absent, particularly in

large-medium vessel disease.47
Acute Care
The goals of acute care of childhood arterial ischemic stroke are to limit injury,
salvage the penumbra, prevent stroke extension, treat complications, and
prevent recurrent stroke. Children with acute stroke should be admitted to the
pediatric intensive care unit for a minimum of 48 hours for neurologic and
medical monitoring and aggressive management of complications. Urgent
neuroimaging should be obtained for any neurologic deterioration.
Rescuing the penumbra is the primary goal of acute care. The penumbra refers
to the area of brain surrounding the core infarct where cell death has not yet
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TABLE 7-2 Laboratory Investigations in Childhood Arterial Ischemic Stroke
Urgent
u Standard
⋄ Complete blood count

⋄ Prothrombin time/international normalized ratio (INR) a
⋄ Activated partial thromboplastin time

⋄Erythrocyte sedimentation rate
⋄C-reactive protein
⋄Electrolytes
⋄Antithrombin III activity
⋄Lupus anticoagulant
⋄Toxicology screen
u If clinically indicated
⋄Urine β-human chorionic gonadotropin

⋄Blood gas
⋄Hemoglobin S percentage
⋄Warfarin INR if on warfarin a
⋄Low-molecular-weight
heparin b
heparin activity/anti-Xa activity if on low-molecular-weight
⋄Fibrinogen
160 FEBRUARY 2018

occurred but will occur if delivery of blood is not restored. Maintaining optimal KEY POINT
cerebral perfusion pressure requires careful attention to blood pressure,
● The goals of acute care of
including maintenance of adequate blood volume. The head of the bed should be childhood arterial ischemic
kept flat, and adequate access for IV fluids should be established. Transient stroke are to limit injury,
hypertension, possibly representing a compensatory mechanism to maintain salvage the penumbra,
cerebral perfusion, is common following childhood arterial ischemic stroke, prevent stroke extension,
treat complications, and

and permissive hypertension is usually recommended. In the rare situation
prevent recurrent stroke.
where treatment of hypertension is necessary, blood pressure should be
lowered cautiously, with close monitoring for decline in neurologic status.
Adequate oxygenation is necessary; however, supplemental oxygen is not
routinely indicated unless hypoxemia is present, except in patients with stroke
associated with sickle cell anemia where supplemental oxygen may initially
be used.
To decrease metabolic demands on the brain, fever should be avoided and
aggressively treated; excess clothing and blankets should be removed, and
acetaminophen should be administered. A cooling blanket may be indicated
as well but should not be used in patients with sickle cell anemia because of
09/2022
Acute
u Standard
⋄Protein C activity a
⋄Protein S free antigen a
⋄Homocysteine
⋄ -dimer
D
⋄Antiphospholipid antibody panel

⋄Hemoglobin electrophoresis if not done as newborn

⋄Protein C activity, protein S activity, antithrombin III may need to be repeated outside the acute period
⋄CSF for varicella-zoster virus DNA by polymerase chain reaction and anti—varicella-zoster virus antibodies
Nonurgent
u Standard
⋄Factor V Leiden or activated protein C resistance

⋄Factor II (prothrombin mutation G20210A)
⋄Lipoprotein (a)
⋄Antinuclear antibodies
⋄Glycosylated hemoglobin
a
Can be affected by warfarin.
ISCHEMIC STROKE
the risk of vasoocclusive crisis. Clinical and electrographic seizures should

be treated, but no data support seizure prophylaxis with antiepileptic
medications. The child should have nothing by mouth in the event that
sedation is needed for procedures and pending clearance for safe swallowing
on swallowing evaluation.
Increased Intracranial Pressure

Based on extrapolation from experience with adult patients, urgent neurosurgical
consultation for possible decompressive hemicraniectomy should be sought for
malignant middle cerebral artery infarct.55 Suboccipital craniectomy should be
considered in the setting of neurologic deterioration due to edema associated
with cerebellar infarct. In adults with malignant infarcts, intracranial pressure
monitoring has not been shown to be useful and may delay surgical treatment.55
Reperfusion Therapies
IV recombinant tissue plasminogen activator (rtPA) is not approved by the US
Food and Drug Administration (FDA) for use in childhood arterial ischemic
stroke, and formal guidelines do not recommend its use outside a clinical trial.7,56
09/2022
However, it has been used in childhood acute ischemic stroke following published
consensus-based safety guidelines.19 Its use in childhood should follow a careful
informed consent discussion, including lack of rigorous safety and efficacy data in
childhood. Contraindications to IV rtPA for acute stroke in childhood should be
carefully reviewed, and IV rtPA should be used in the setting of a developed stroke
program able to provide postintervention monitoring.19 Although not FDA
approved for use in children, recent studies in adults have demonstrated the safety
and efficacy of mechanical thrombectomy.57 Mechanical embolectomy should
only be performed by a neurointerventional team with pediatric experience after
full discussion with the parents or guardian, including the lack of safety and
efficacy data for children and the potential for vascular injury and stroke.
Preventing Early Stroke Recurrence

Following arterial ischemic stroke, recurrence occurs in one-fifth of children, and
it can occur in the immediate poststroke period.14 Once the absence of intracranial
hemorrhage has been confirmed on neuroimaging, anticoagulation may be an
option to prevent stroke recurrence. Acute anticoagulation can be considered in
children while etiologic evaluation for acute stroke is under way, as the etiology
of childhood stroke is often due to cardiac or vessel-to-vessel embolus and
heparin may decrease the risk of recurrent embolic events. Anticoagulation is
recommended for children at high risk of recurrent ischemia, including those with
extracranial cervicocephalic arterial dissection, those at risk for cardiac embolism,
and selected children with hypercoagulable states.56,58 Anticoagulation is often
initiated with continuous IV heparin or unfractionated heparin. Risks of IV
heparin include new or increased bleeding and, rarely, heparin-induced
thrombocytopenia, a serious antibody-mediated complication of heparin.59
Contraindications to heparin include active major bleeding, significant blood on
neuroimaging, large hemispheric infarcts with midline shift or involving more
than one-third of the middle cerebral artery territory, history of heparin-induced
thrombocytopenia, platelet count of less than 50,000, and recent intracranial
hemorrhage. Anticoagulation is usually avoided in children with small vessel CNS
162 FEBRUARY 2018

vasculitis and moyamoya arteriopathy because of underlying risk of intracranial KEY POINTS
hemorrhage in these patients.
● To decrease metabolic
Unfractionated heparin has a short half-life and is rapidly reversed by demands on the brain, fever
protamine. If the child is stable and no immediate invasive procedures such should be avoided and
as lumbar puncture or diagnostic conventional angiography are planned, aggressively treated in
unfractionated heparin infusion can be transitioned to low-molecular-weight patients with childhood

arterial ischemic stroke;
heparin. Low-molecular-weight heparin is associated with a lower risk of excess clothing and blankets
hemorrhage and heparin-induced thrombocytopenia, but it has a more should be removed, and
prolonged half-life and is incompletely reversed by protamine. acetaminophen should
If an anticoagulant medication is not used, antiplatelet therapy with aspirin, be administered.
which inhibits platelet activity by irreversibly inhibiting cyclooxygenase-1, is
● The child with acute
recommended in the absence of contraindications.7,56 arterial ischemic stroke
TABLE 7-3
60
summarizes the recommendations for reperfusion strategies and should have nothing by
anticoagulation in early childhood arterial ischemic stroke. The American College mouth in the event that
of Chest Physicians guidelines contain a full review of the use of antithrombotic sedation is needed for
procedures and pending
therapies in childhood.7 clearance for safe
swallowing on swallowing
Outcome evaluation.
Following childhood arterial ischemic stroke, 6% to 10% of children die, some
09/2022
from the stroke itself and others from comorbid conditions, and more than 75% ● Following arterial
ischemic stroke, recurrence
will experience long-term neurologic deficits.12,13 Importantly, up to 20% of
occurs in one-fifth of
children will have another stroke.14 Risk factors for recurrent stroke include children, and it can occur in
cerebral arteriopathy, heart disease, sickle cell anemia, and elevated lipoprotein the immediate poststroke
(a).14,25,61,62 Stroke prevention precautions include avoidance of dehydration and period.
other thrombophilic states, avoidance of vasoconstricting medications,
maintenance of normal weight and blood pressure, and avoidance of activities
where head trauma or rapid head or neck movement are likely.
Early rehabilitation medicine consultation, including admission to a
rehabilitation service, will optimize outcome following childhood arterial
ischemic stroke. Neuropsychological evaluation to guide return to school is
important in the initial poststroke period, with full neuropsychological testing
indicated at approximately 6 months following stroke when the deficit is more
stable. Follow-up neuropsychological testing is often indicated, as educational
needs change and new challenges arise.
Childhood stroke is a significant psychosocial stressor for patients and
families. Early support from a coordinated care team, including social work, and
ongoing support after discharge, often including mental health counseling, is
important in optimizing outcome.
CEREBRAL VENOUS SINUS THROMBOSIS

Cerebral venous sinus thrombosis occurs when thrombosis is present in the major
venous sinuses draining the brain. Many patients with cerebral venous sinus
thrombosis will develop venous infarcts, which may herald their diagnosis, but
infarcts do not always occur. The incidence of cerebral venous sinus thrombosis in
children is approximately 0.4 per 100,000 per year,63 although with improved
neuroimaging, this number is likely an underestimate. Cerebral venous sinus
thrombosis can involve the dural sinuses (superior sagittal, transverse, or sigmoid
sinus), deep venous system (eg, internal cerebral veins), or superficial cortical
veins. In children, multiple venous sinuses are usually involved, with the
transverse sinus most commonly affected, followed by the sagittal sinus.64
ISCHEMIC STROKE
Presentation
Headache is the most common presenting symptom of cerebral venous sinus
thrombosis, although it is nonspecific and frequently seen in other childhood
illnesses. Other presenting symptoms include seizures, lethargy, cranial nerve
palsies, hemiparesis, and vomiting. Declining mental status is an ominous
presentation suggesting involvement of the deep venous system.

Etiology
In most children presenting with cerebral venous sinus thrombosis, underlying
risk factors can be identified and usually involve venous stasis, dehydration,
hypercoagulable states, and direct injury to the vessel from trauma or infection.65,66
Urgent underlying risk factors such as infection and hematologic malignancy are not
rare. Medication history, including history of exogenous estrogen use, should be
sought. Prothrombotic disorders are identified in approximately one-half of children
with cerebral venous sinus thrombosis and in more than one-half of children with
unprovoked cerebral venous sinus thrombosis (TABLE 7-4 and CASE 7-4).65,66
09/2022
TABLE 7-3 Acute Treatments in Childhood Arterial Ischemic Stroke
Treatment Current Recommendations

IV recombinant tissue IV rtPA is not approved by the US Food and Drug Administration (FDA) for use in childhood
plasminogen activator (rtPA) arterial ischemic stroke. The American College of Chest Physicians recommends that it be
used only as part of a research protocol.7 The American Heart Association guidelines are
similar but note lack of consensus for use in older adolescents.56 If IV rtPA is used, published
consensus-based guidelines including indications, contraindications, and monitoring exist.19
Mechanical embolectomy Published evidence-based guidelines supporting safety and efficacy for use in adults exist57;
however, safety and efficacy data are not available for children. Mechanical embolectomy
should only be considered by a neurointerventional team with pediatric experience.
Anticoagulation therapy Anticoagulation is recommended for children at high risk of recurrent stroke, including those
with extracranial cervicocephalic arterial dissection, those at risk for cardiac embolism
(excluding valvular endocarditis), and selected children with hypercoagulable states.7,56
Anticoagulation is usually initiated with IV heparin, which can be reversed if necessary. Heparin
is usually transitioned to low-molecular-weight heparin, which has less risk of bleeding and
heparin-induced thrombocytopenia (a potentially life-threatening antibody-mediated
complication of heparin), but low-molecular-weight heparin cannot be reversed rapidly.
Longer term, low-molecular-weight heparin or warfarin is used. Newer oral anticoagulants
have not been well studied in pediatric stroke.
Aspirin If anticoagulation is not indicated, antiplatelet therapy with aspirin at a dose of 1–5 mg/kg/d
is recommended for secondary stroke prevention.7,56 The higher dose of 3–5 mg/kg/day may
be used earlier following stroke. Aspirin is recommended for a minimum of 2 years7; however,
the optimal length of therapy is unknown. Some clinicians consider sickle cell anemia to be a
contraindication to aspirin therapy.56
Blood transfusion Exchange transfusion is recommended for stroke in the child with sickle cell anemia.7
Transfusion may be indicated in the child with severe anemia and stroke, particularly if
cerebral perfusion is at risk, such as in the setting of cerebral arteriopathy.
Antiviral therapy Acyclovir has been recommended for varicella-zoster virus vasculopathy with virologic
confirmation of active central nervous system varicella-zoster virus infection.54,60
IV = intravenous.
164 FEBRUARY 2018

Diagnosis KEY POINTS
Cerebral venous sinus thrombosis may be detectable on CT, especially if contrast
● Headache is the most
is used; however, the sensitivity is poor. Brain MRI, particularly contrast- common presenting
enhanced T1-weighted sequences, is the optimal study to diagnose cerebral symptom of cerebral venous
venous sinus thrombosis as well as associated venous congestion and venous sinus thrombosis, although it
stroke. Time-of-flight magnetic resonance venography (MRV) is usually performed, is nonspecific and
frequently seen in other
but gaps in flow in areas with slow or irregular flow may mimic cerebral venous sinus childhood illnesses.
thrombosis, so correlation with T1-weighted and T2-weighted images for
assessment of clot burden and venous sinus patency is necessary. Anatomic ● In most children
variations in dural venous sinus anatomy contribute to challenges in diagnosis of presenting with cerebral
venous sinus thrombosis,
cerebral venous sinus thrombosis, and careful review of imaging, comparison of
underlying risk factors can
imaging modalities, and repeat imaging may be necessary for accurate diagnosis. be identified and usually
involve venous stasis,
Investigations dehydration,
Initial laboratory studies include complete blood count, electrolytes, blood urea hypercoagulable states, and
direct injury to the vessel
nitrogen, creatinine, glucose, prothrombin time, activated partial from trauma or infection.
thromboplastin time, erythrocyte sedimentation rate, and antithrombin III
activity in preparation for diagnostic imaging and acute treatment, as well as a ● Brain MRI (particularly
pregnancy test in females of childbearing age. contrast-enhanced T1-
09/2022
weighted sequences) is the

optimal study to diagnose
Acute Care cerebral venous sinus
Children with acute symptomatic cerebral venous sinus thrombosis require thrombosis as well as
intensive care monitoring, as they are at risk of declining neurologic status and associated venous
congestion and venous
death, especially if the deep venous system is involved. Adequate hydration and
stroke.
treatment of infection are critical. Complications of cerebral venous sinus
thrombosis occur because of obstruction of venous outflow and ischemic and ● Children with acute
hemorrhagic venous infarcts. Large venous infarcts can result in increased symptomatic cerebral
intracranial pressure, and urgent treatment of elevated intracranial pressure venous sinus thrombosis
require intensive care
including decompressive craniectomy and resection of infarcted brain may be monitoring, as they are at
necessary to prevent herniation. In children with progressive severe cerebral risk of declining neurologic
venous sinus thrombosis, particularly those with declining neurologic status, status and death, especially
thrombolysis or thrombectomy (or surgical decompression) may be considered if the deep venous system is
involved.
if no improvement with anticoagulation is seen.7
Seizures are common in patients with cerebral venous sinus thrombosis,
particularly with cortical vein infarcts.66 Intracranial hypertension can also result
in headache, vision loss, and cranial neuropathies. If concerns occur about vision
loss due to intracranial hypertension, lumbar puncture to urgently drop
intracranial pressure may be necessary.
The American College of Chest Physicians and American Heart Association
(AHA) guidelines recommend anticoagulation for a minimum of 3 months,
initially with unfractionated heparin or low-molecular-weight heparin.7,56 If
intracranial hemorrhage is present, the AHA recommends anticoagulation and
the American College of Chest Physicians recommends either anticoagulation or
follow-up neuroimaging in 5 to 7 days and anticoagulation if the thrombus has
propagated.7,56 In a series of children with cerebral venous sinus thrombosis,
propagation of thrombus and worse clinical outcome was associated with lack of
anticoagulation in childhood cerebral venous sinus thrombosis.67 Five percent of
children had “major” intracranial hemorrhage associated with anticoagulation;
however, children with “significant intracranial hemorrhage” on presentation,
other contraindications, and those for whom the attending physician declined
ISCHEMIC STROKE
KEY POINT anticoagulation were not treated with anticoagulation in this study. The findings
are consistent with adult guidelines in which anticoagulation is recommended
● Death due to cerebral
venous sinus thrombosis is
regardless of the presence of intracranial hemorrhage.68
rare; however, neurologic
sequelae including Outcome
encephalopathy and
Death due to cerebral venous sinus thrombosis is rare; however, neurologic
seizures are common.

sequelae including encephalopathy and seizures are common.69 Vision loss can
occur because of the development of intracranial hypertension due to occlusion
of venous sinuses and can present early in the clinical course. Elevated intracranial
TABLE 7-4 Risk Factors Associated With Cerebral Venous Sinus Thrombosis
Inherited Thrombophilia
u Factor II (prothrombin mutation G20210A)

u Factor V Leiden
09/2022
u Protein C deficiency
u Protein S deficiency
u Antithrombin III deficiency

u Elevated homocysteine
Medications
u Asparaginase
u Exogenous estrogens (including estrogen-containing creams)

Infection
u Head and neck infection
⋄Sinusitis
⋄Otitis media
⋄Mastoiditis
⋄Oropharyngeal infection
u Primary varicella-zoster virus infection (chickenpox)
Autoimmune/Inflammatory Disorders
u Systemic lupus erythematosus
u Inflammatory bowel disease
Other Acute and Chronic Illness

u Dehydration
u Nephrotic syndrome
u Hematologic malignancy
u Sickle cell anemia

Trauma
u Head injury
166 FEBRUARY 2018

A 15-year-old boy presented with a 1-day history of severe headache; CASE 7-4
right upper extremity numbness and tingling and weakness; worsening
nausea and vomiting; and an episode of loss of consciousness and
collapse. He had a history of precursor B-cell acute lymphoblastic
leukemia and had received PEG-L-asparaginase 10 days prior to

presentation. His examination suggested left hemispheric dysfunction,

although this was complicated by polyneuropathy and general
deconditioning. His antithrombin III antigen level was low at 46%.
Time-of-flight magnetic resonance venography (MRV) showed a superior
sagittal sinus thrombosis involving a 7-cm to 8-cm segment of the superior
sagittal sinus (FIGURE 7-4A). Susceptibility-weighted imaging (SWI) showed
a hemorrhagic infarct in the left parietal region and venous congestion
most prominent in the left cerebral hemisphere (FIGURE 7-4B). He was
treated with enoxaparin with resolution of his thrombosis and neurologic
deficit.
09/2022
FIGURE 7-4
Imaging of the patient in CASE 7-4. A, Time-of-flight magnetic resonance venogram shows
a superior sagittal sinus thrombosis with absent flow (arrow) involving a 7-cm to 8-cm segment
of the superior sagittal sinus. B, Susceptibility-weighted imaging (SWI) shows a hemorrhagic
infarct in the left parietal region (arrow) and venous congestion, most prominent in the
left cerebral hemisphere.
This case exemplifies cerebral venous sinus thrombosis in the setting of COMMENT
malignancy and asparaginase chemotherapy. The full mechanism of
asparaginase-induced thrombophilia is unclear, but asparaginase induces
antithrombin III deficiency.
ISCHEMIC STROKE
pressure can persist even in cases where complete recanalization is seen

on neuroimaging.
Following cerebral venous sinus thrombosis, children are at an increased risk of
recurrent pathologic thrombosis, including in the acute setting, and preventative
precautions should be discussed. Recurrent cerebral venous sinus thrombosis was
reported in 6% of children who were followed for an average of 36 months

following initial cerebral venous sinus thrombosis. Recurrent cerebral venous

sinus thrombosis was more likely in patients with persistent occlusion following
cerebral venous sinus thrombosis, those with a heterozygous prothrombin
mutation G20210A, those not treated with anticoagulant therapy, and children in
whom the initial cerebral venous sinus thrombosis occurred after 2 years of age.70
CONCLUSION
Perinatal stroke, childhood arterial ischemic stroke, and childhood cerebral
venous sinus thrombosis are important causes of childhood morbidity. Strategies
to improve outcome include early recognition, prevention of early as well as
late recurrence, prevention and treatment of complications, and rehabilitation
09/2022
and psychosocial support.
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55 Wijdicks EF, Sheth KN, Carter BS, et al.
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170 FEBRUARY 2018

Epileptic REVIEW ARTICLE
Encephalopathies

C O NT I N U U M A U D I O
I NT E RV I E W A V A I L AB L E
O NL I N E
By Shaun A. Hussain, MD, MS
ABSTRACT
PURPOSE OF REVIEW: This
article reviews the manifestations and treatment
of the epileptic encephalopathies, which are a heterogeneous group of
disorders characterized by both seizures and neurocognitive impairment. CITE AS:
2018;24(1, CHILD NEUROLOGY):171–185.
RECENT FINDINGS: Next-generation (exome- and genome-based) sequencing
technologies are revolutionizing the identification of single-gene causes Address correspondence to
of epileptic encephalopathy but have only had a modest impact on Dr Shaun A. Hussain, University
of California Los Angeles,
patient-specific treatment decisions. The treatment of most forms of
Pediatric Neurology, 10833 Le
09/2022
epileptic encephalopathy remains a particularly challenging endeavor, Conte Ave, Room 22–474, Los
with therapeutic decisions chiefly driven by the electroclinical syndrome Angeles, CA 90095–1752,
shussain@mednet.ucla.edu.
classification. Most antiseizure drugs are ineffective in the treatment
of these disorders, and treatments that are effective often entail RELATIONSHIP DISCLOSURE:
significant risk and cost. Dr Hussain serves on the board
of directors of the Child
Neurology Foundation and
SUMMARY: The epileptic encephalopathies continue to pose a major receives personal compensation
challenge in diagnosis and treatment, with most patients experiencing for serving on the advisory
boards of INSYS Therapeutics
very poor outcomes, although a significant minority of patients respond to, Inc, Mallinckrodt
or are even cured by, specific therapies. Pharmaceuticals, and UCB, Inc;
for serving as a consultant for
Eisai Inc; and for serving on the
speaker’s bureau of and as a
consultant for Mallinckrodt
INTRODUCTION Pharmaceuticals. Dr Hussain has
received research/grant support
T
he term epileptic encephalopathy refers to a heterogeneous group from Eisai Inc, GW
of epileptic disorders in which epileptic activity itself (ictal or Pharmaceuticals, INSYS
Therapeutics Inc, Lundbeck, and
interictal) impairs cognitive and behavioral function above and UCB, Inc. Dr Hussain has served
beyond what is expected from the underlying pathology alone.1 It on the editorial board of the
is important to note that the precise mechanisms underlying epileptic Journal of Pediatric Epilepsy and
received compensation for
encephalopathy are unknown, but they likely reflect widespread neuronal service as an expert medical
network dysfunction.2 The prognosis of these disorders is generally quite poor, witness in cases relevant to
but a significant minority of cases can be ameliorated and even cured by prompt pediatric epilepsy.
diagnosis and successful treatment. Although some overlap among these UNLABELED USE OF
syndromes exists, the identification of a specific electroclinical syndrome is PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
critically important, as it guides treatment and informs prognosis. Although
Dr Hussain discusses the
many specific structural, genetic, and metabolic causes for epileptic unlabeled/investigational use of
encephalopathy have been described, the identification of a specific etiology clobazam, ezogabine, felbamate,
prednisolone, topiramate, and
often proves elusive, despite tremendous advances in neuroimaging and genetic zonisamide for the treatment of
diagnostics. Furthermore, even in cases in which a specific diagnosis can be epileptic encephalopathy and
ascertained, the evaluation may be quite time-consuming and must not delay infantile spasms.
treatment. For this reason, these syndromes are distinguished based on age of © 2018 American Academy
onset, seizure type(s), and characteristic EEG patterns. This article describes the of Neurology.
EPILEPTIC ENCEPHALOPATHIES
09/2022
FIGURE 8-1
Suppression burst. Interictal suppression burst is typical of both early infantile epileptic
encephalopathy and early myoclonic encephalopathy and is reminiscent of burst suppression
that accompanies pharmacologic- or injury-induced encephalopathy. In suppression burst,
the bursts tend to be high voltage and irregular, in contrast to the well-formed epileptiform
discharges more typically encountered with burst suppression. Suppressions between the
bursts tend to be very low amplitude (less than 10 mV).
cardinal features of key syndromes within the spectrum of epileptic

encephalopathy and discusses abbreviated guides to treatment.
EARLY INFANTILE EPILEPTIC ENCEPHALOPATHY

Early infantile epileptic encephalopathy, also known as Ohtahara syndrome, is
among the epileptic encephalopathy syndromes with neonatal onset, often
beginning by 2 weeks of age.3 The seizure type classically associated with this
syndrome is a tonic spasm. These episodes are highly variable but typically
manifest with a paroxysmal jerk (usually with a duration of more than
250 milliseconds) followed by sustained tonic extensor posturing of the upper
and/or lower extremities, which lasts several seconds. These spasms typically
emerge in clusters and may occur hundreds of times per day. The electrographic
signature of these seizures is similarly heterogeneous but usually manifests with a
burst of chaotic, generalized, high-amplitude, mixed-frequency activity (often
with superimposed spikes, polyspikes, or paroxysmal fast activity) followed by
generalized voltage attenuation and often with the subsequent appearance of
diffuse low-voltage fast activity.4
The interictal EEG in early infantile epileptic encephalopathy is characterized
by a suppression-burst pattern (FIGURE 8-1). This pattern is characterized
by bursts of high-amplitude spikes and polyspikes that alternate with periods of
electrographic suppression and is often indistinguishable from the
172 FEBRUARY 2018

aforementioned ictal pattern. As is typical of many forms of epileptic encephalopathy, KEY POINTS
an incredible variety of structural and metabolic etiologies are associated with
● The term epileptic
early infantile epileptic encephalopathy (TABLE 8-1). Among the more common encephalopathy refers to
structural etiologies are hemimegalencephaly and cortical dysplasia. Myriad disorders in which epileptic
metabolic causes include nonketotic hyperglycinemia, pyridoxine dependency, activity threatens cognition
and a variety of disorders implicating the mitochondrial respiratory chain. above and beyond what
would be expected from
Similarly, genetic associations with early infantile epileptic encephalopathy are pathology alone.
numerous, with a list of single-gene mutations that is likely to grow substantially
as modern approaches to exome and genome sequencing are implemented on a ● Early infantile epileptic
wider scale. The vast structural, metabolic, and genetic heterogeneity of this encephalopathy is
interictally characterized by
disorder highlights its age specificity and lack of etiologic specificity.
the suppression-burst
The treatment of early infantile epileptic encephalopathy is overall quite pattern.
challenging, with limited data indicating modest efficacy of a variety of
antiepileptic drugs, as well as the ketogenic diet. Accordingly, the prognosis of ● Genetic associations with
early infantile epileptic encephalopathy is generally poor, with most patients all forms of epileptic
encephalopathy are
suffering adverse neurocognitive outcomes, early death, and transition to other numerous, with a list of
forms of epileptic encephalopathy such as infantile spasms and Lennox-Gastaut single-gene mutations that is
syndrome. However, in a minority of patients for whom etiology-specific likely to grow substantially as
treatment is available and promptly administered (eg, hemispherectomy for modern approaches to
09/2022
exome and genome

hemimegalencephaly or pyridoxine for pyridoxine dependency), excellent sequencing are implemented
neurodevelopmental outcomes are possible. on a wider scale.
EARLY MYOCLONIC ENCEPHALOPATHY

Early myoclonic encephalopathy is frequently discussed in combination with
early infantile epileptic encephalopathy, and a debate exists as to whether these
syndromes are truly distinct entities. Like early infantile epileptic
encephalopathy, early myoclonic encephalopathy begins in the neonatal period.
The clinical presentation is most often heralded by fragmentary focal myoclonia
of the face or extremities, with seemingly random migration from one part of
the body to another.5 In short order, the syndrome’s ictal repertoire expands to
Key Clinical Features of Epileptic Encephalopathies TABLE 8-1
Subtype Age of Onset Etiology Interictal EEG Seizure Type(s)
Early infantile epileptic Neonatal Structural and genetic Suppression burst Tonic spasms
encephalopathy more than metabolic
Early myoclonic Neonatal Metabolic more than Suppression burst Myoclonic, focal seizures
encephalopathy structural and genetic
Epilepsy of infancy with Neonatal, Genetic, especially KCNT1 Nonspecific Focal seizures, status epilepticus
migrating focal seizures infancy
Infantile spasms 3 to 12 months Structural, genetic, Hypsarrhythmia Epileptic spasms
metabolic
Lennox-Gastaut 1 to 6 years Structural, genetic, Slow spike-wave Atypical absence, tonic, atonic,
syndrome metabolic myoclonic, epileptic spasms,
focal, generalized tonic-clonic
EEG = electroencephalogram.
highly pharmacoresistant multifocal seizures, which frequently exhibit

concomitant autonomic phenomena such as apnea.6 The interictal EEG is
characterized by a suppression-burst pattern nearly identical to that observed in
early infantile epileptic encephalopathy (FIGURE 8-1). A transition to
hypsarrhythmia, with evolution of infantile spasms, is not infrequent. In
comparison to early infantile epileptic encephalopathy, early myoclonic

encephalopathy is more frequently attributed to inborn errors of metabolism

such as the various aminoacidopathies, especially nonketotic hyperglycinemia,
and less often linked to structural abnormalities such as cortical dysplasia.7 The
prognosis of early myoclonic encephalopathy is quite poor, and, as in early
infantile epileptic encephalopathy, this reflects a paucity of effective treatments.
Anecdotal reports support the use of a variety of antiepileptic drugs (AEDs) as
well as nonpharmacologic approaches such as the ketogenic diet.
EPILEPSY OF INFANCY WITH MIGRATING FOCAL SEIZURES

Epilepsy of infancy with migrating focal seizures (previously known as
malignant migrating partial seizures of infancy) is the form of epileptic
encephalopathy in which the electroclinical signature was most recently
elucidated.8 The age of onset is typically within the first few months of life.
09/2022
Epilepsy of infancy with migrating focal seizures is characterized by focal

seizures with multiple topographic origins that migrate within and between
cerebral hemispheres, at times with each hemisphere exhibiting simultaneous
independent seizures.9 These seizures are typically quite prolonged, and they
often fulfill criteria for status epilepticus. The interictal EEG tends to be
nonspecifically abnormal, with prominent slowing, disorganization, and
multifocal independent epileptiform discharges, although not hypsarrhythmia.9
As in early infantile epileptic encephalopathy, only anecdotal reports suggest
limited success with a variety of AEDs, the ketogenic diet, and vagal
nerve stimulation.
Although most forms of epileptic encephalopathy exhibit highly diverse
genetic, metabolic, and structural etiologies, epilepsy of infancy with migrating
focal seizures appears to be somewhat more homogeneous. Most cases exhibit
normal or nonspecifically abnormal MRI features, and genetic characterization
appears to be more specific than other forms of epileptic encephalopathy.
Although individual cases of epilepsy of infancy with migrating focal seizures
have been linked to mutations in the SCN1A, SCN2A, PLCB1, TBC1D24, and
SLC25A22 genes, numerous subsequent reports with larger cohorts have now
implicated the KCNT110 gene, which codes for a voltage-gated potassium
channel subunit. KCNT1 mutations have thus emerged as the most frequent
cause of epilepsy of infancy with migrating focal seizures, and manipulation of
potassium currents is a prime target of emerging therapeutic approaches. At
present, given a lack of effective treatments, the prognosis of epilepsy of infancy
with migrating focal seizures is uniformly poor, with highly intractable seizures
and an unfortunately high incidence of early death.8
INFANTILE SPASMS
Infantile spasms were first described by Dr William J. West in a letter to the
editor of The Lancet in 1841,11 in which he described the syndrome’s key
manifestations in his own son. Infantile spasms usually begin later than early
infantile epileptic encephalopathy, early myoclonic encephalopathy, or epilepsy
174 FEBRUARY 2018

of infancy with migrating focal seizures, with onset most often between the ages KEY POINTS
of 3 and 12 months, although onset has been reported as late as childhood and
● Early myoclonic
even adulthood (in which case, it is more aptly termed epileptic spasms). The encephalopathy bears great
prognosis of infantile spasms is generally poor, with most children exhibiting resemblance to early
psychomotor retardation and intractable epilepsy. However, infantile spasms are infantile epileptic
a critical example of an epileptic encephalopathy in which prompt diagnosis and encephalopathy but is
more often caused by inborn
successful treatment can yield normal neurodevelopmental outcomes, at least in errors of metabolism.
cases where the underlying cause of infantile spasms does not threaten
development independent of seizures. Although infantile spasms have been ● The hallmark of epilepsy
associated with myriad structural, genetic, and metabolic entities, the exact of infancy with migrating
focal seizures is frequent,
pathogenesis of infantile spasms remains uncertain and probably depends on
long seizures with multifocal
etiology. In cases where an acquired cause of infantile spasms is identified (eg, origin and migration (as
hypoxic-ischemic encephalopathy, postnatal hemorrhage), the onset does not opposed to spread).
immediately follow the antecedent insult; instead, spasms begin several months
after acquired injury.12,13 As illustrated in CASE 8-1, this delay suggests a period of ● KCNT1 mutations have
emerged as the most
subclinical epileptogenesis and thus an opportunity to potentially prevent frequent cause of epilepsy
infantile spasms among infants at risk. Moreover, although many brain insults with migrating focal
carry some risk of infantile spasms, the majority of “at-risk” children do not seizures, and manipulation
actually develop infantile spasms. The precise genetic or environmental factors of potassium currents is a
09/2022
prime target of emerging

shared by at-risk children who actually manifest infantile spasms remain therapeutic approaches.
unknown. The discovery of such factors could potentially allow for identification
of patients at highest risk and justify the use of high-risk preventive therapies ● Prompt diagnosis of
(eg, adrenocorticotropic hormone [ACTH]). infantile spasms is a critical
prerequisite for successful
The seizures (spasms) that characterize infantile spasms are highly variable in
treatment.
appearance, but they typically occur in clusters and often commence upon
awakening. Spasms have generally been described as flexor (forced anterior ● The seizures (spasms)
flexion of the neck and axial musculature, often with concomitant elevation and that characterize infantile
extension of the bilateral upper extremities), extensor (forced extension of the spasms are highly variable in
appearance, but they
head and neck), or mixed flexor/extensor.15 Individual spasms generally last typically occur in clusters
between 0.5 and 1.0 seconds and repeat every 5 to 30 seconds in clusters of and often commence upon
approximately 2 to 20 minutes.16 Patients with focal structural etiologies of awakening.
infantile spasms often exhibit asymmetric spasms, typically with head
● Although often a
movement away from the pathologic hemisphere and more vigorous dramatic interictal
extension/elevation of the contralateral arm.17 Needless to say, many variations abnormality, hypsarrhythmia
on this theme exist. is often relatively subtle or
The interictal EEG background pattern of hypsarrhythmia (FIGURE 8-2), absent; the absence of
hypsarrhythmia neither
which manifests with extremely high-voltage chaotic waveforms and
excludes the diagnosis of
superimposed multifocal epileptiform discharges, is often, but not always, seen infantile spasms nor
for some portion of the time in which infantile spasms are present.18 warrants less aggressive
Mirroring the variability of ictal spasms, multiple atypical or modified variants treatment.
of hypsarrhythmia have been described.19 However, the identification and
classification of hypsarrhythmia can be quite difficult, especially in borderline
cases,20 and patients without hypsarrhythmia have been described.21
Although treatment strategies vary greatly, two principal pharmacologic
approaches predominate. The first is hormonal therapy, including ACTH
(biological and synthetic depot preparations) and a variety of corticosteroid
agents (eg, prednisolone, prednisone, methylprednisolone, hydrocortisone).
Although most practice parameters tend to favor high-dose short-duration
regimens of ACTH,15 debate continues regarding the ideal dose and duration
of therapy.22 Furthermore, whereas ACTH is clearly favored over relatively
CASE 8-1 A 12-month-old boy presented with developmental regression

experienced over the past month. He had stopped babbling, seemed less
interactive, and no longer reached toward his toys. His history was notable
for a ruptured arteriovenous malformation (arising from the anterior
division of the left middle cerebral artery) status post hematoma
evacuation and resection of the malformation at the age of 4 months. His

postoperative right hemiparesis had been improving. The boy’s parents

described recent clusters of head drops and concomitant upward eye
rolls, beginning at age 11 months. Each head drop lasted less than 1 second
and manifested with forceful anterior flexion of the neck as well as slight
elevation of the right arm. The clusters typically occurred daily upon first
morning awakening, with 15 to 25 head drops over 3 to 5 minutes.
A diagnosis of infantile spasms was confirmed by video-EEG. The
interictal record demonstrated abundant multifocal spikes (left more
than right) on an asymmetric, high-voltage (albeit less than 200 6V), and
disorganized background (higher voltage and more severe
disorganization was demonstrated over the left hemisphere). Each
head drop was accompanied by a symmetric and irregularly generalized
09/2022
spike or sharp wave, immediately followed by diffuse relative

attenuation for 1 to 2 seconds afterward. Brain MRI demonstrated the
evolution of previously characterized structural injury, with marked
gliosis and atrophy throughout the distribution of the left middle
cerebral artery, with ex vacuo dilation of the left lateral ventricle.
The boy did not respond to sequential courses of prednisolone
(20 mg 3 times a day, approximately 6 mg/kg/d) and adrenocorticotropic
hormone (ACTH) (44 IU 2 times a day, approximately 150 IU/m2/d). Six
days after commencing vigabatrin with rapid titration to 750 mg 2 times
a day (approximately 100 mg/kg/d), the seizures stopped, and the
patient seemed to “wake up.” Repeat video-EEG after 2 weeks of
vigabatrin therapy demonstrated absence of epileptic spasms with
continued hemispheric asymmetry but marked reduction (normalization)
in voltage and visualization of the anterior-posterior gradient (organization)
over the right hemisphere. The vigabatrin was tapered off after 6 months,
and after 6 years, the boy maintained seizure freedom, and he was
socially and academically age appropriate. He exhibited incoordination
and weakness of the right hand but no other motor deficits.
COMMENT This patient presented with developmental regression and substantial

encephalopathy out of proportion to his left hemispheric pathology
(ie, epileptic encephalopathy), which is typical of infantile spasms. The
aforementioned aggressive treatment regimen was warranted despite the
absence of hypsarrhythmia (traditional voltage criteria were not met). Had
vigabatrin proven inefficacious, left hemispherectomy would have been
the author’s next step in management. With contemporary available data,
simultaneous vigabatrin and hormonal therapy may have been considered,
rather than sequential courses of treatment.14
176 FEBRUARY 2018

09/2022
FIGURE 8-2
Hypsarrhythmia. Hypsarrhythmia is characterized by extraordinary high-voltage (nonepileptiform
slow waves with amplitude consistently more than 200 mV), abundant, multifocal or generalized
epileptiform discharges (which are often so frequent as to obscure the background EEG), and
disorganization (loss of the anterior-posterior voltage-frequency gradient in wakefulness).
Hypsarrhythmia is typical of infantile spasms, but not required for diagnosis.
lower-dose corticosteroid preparations,23 the presumed superiority of ACTH

has been challenged by several contemporary studies employing very high-dose
prednisolone.24,25 The exact mechanism of action of ACTH and corticosteroids in
the treatment of infantile spasms is unknown. Aside from the aforementioned
hormonal therapies, the main pharmacologic alternative is vigabatrin, an
irreversible inhibitor of g-aminobutyric acid (GABA) transaminase. Vigabatrin is
often used as a first-line treatment, especially outside the United States, although
it appears to be somewhat less effective than hormonal therapies,22 with a
possible exception being the treatment of infantile spasms associated with
tuberous sclerosis complex. Vigabatrin appears to be considerably more effective
in the treatment of infantile spasms associated with tuberous sclerosis complex in
comparison to infantile spasms associated with other etiologies,26 and a broad
consensus supports vigabatrin as the preferred initial therapy for treatment of
tuberous sclerosis complex–associated infantile spasms.15 Despite demonstrated
efficacy, the use of vigabatrin has been curtailed by fear of irreversible peripheral
vision loss as well as reversible and largely asymptomatic MRI signal changes
seen in the basal ganglia, thalami, brainstem tegmentum, and deep cerebellar
nuclei. However, the risk of vision loss—especially clinically meaningful
visual impairment—appears to be very low in infants,26 and the risk of
vigabatrin-associated MRI phenomena is reasonably low and dose-dependent.27
In addition to these pharmacologic approaches, resective surgery is commonly
undertaken among patients who are refractory to medical therapy and exhibit
focal structural etiologies such as cortical dysplasia.28 Limited data support the
use of the ketogenic diet29 or treatment with a variety of drugs,
including topiramate and zonisamide.
LENNOX-GASTAUT SYNDROME
Lennox-Gastaut syndrome is the most common form of epileptic encephalopathy,

in part because of inconsistent, nonspecific, and rather inclusive diagnostic

criteria. As in other forms of epileptic encephalopathy, reported etiologies
8are incredibly varied, perhaps more so than any other form of epileptic
encephalopathy, including a substantial minority of patients for whom a specific
cause is unknown despite extensive diagnostic queries.30 Most definitions of
Lennox-Gastaut syndrome require (1) multiple seizure types, (2) cognitive
impairment, and (3) the interictal EEG pattern termed slow spike wave (typically
1.0 Hz to 2.5 Hz, usually generalized and occasionally multifocal) (FIGURE 8-3).31
Among children with Lennox-Gastaut syndrome, the most commonly
reported seizures include atypical absence seizures, tonic seizures (often or
exclusively occurring during sleep), and drop seizures (classically referring to
atonic seizures but inclusive of tonic, myoclonic, or generalized tonic-clonic
seizures in some classification schemes). Age of onset is usually later than the
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forms of epileptic encephalopathy described above and typically occurs between

the ages of 1 and 6 years.31 Although Lennox-Gastaut syndrome may arise in an
otherwise healthy child, Lennox-Gastaut syndrome often begins as an evolution
from infantile spasms or other forms of epileptic encephalopathy and reflects a
significant degree of shared pathogenesis among these disorders.
FIGURE 8-3
Slow spike wave. Generalized slow (1 Hz to 2.5 Hz) spike wave is typically encountered
as an interictal phenomenon accompanying Lennox-Gastaut syndrome, especially in sleep.
It is also observed as an ictal electrographic pattern during atypical absence seizures.
178 FEBRUARY 2018

The developmental prognosis of Lennox-Gastaut syndrome is quite poor KEY POINTS
and, based on the majority of definitions requiring cognitive impairment as a
● The age of onset of
diagnostic criterion, is essentially a foregone conclusion.32 The principal goals of Lennox-Gastaut syndrome is
treatment are seizure control and, to a much more limited extent, improvement usually later than other
of cognition. Among the seizure types that define Lennox-Gastaut syndrome, forms of epileptic
drop seizures often prove most difficult to control, and they impart encephalopathy and
typically occurs between
disproportionately large morbidity given the potential for traumatic injury to the the ages of 1 and 6 years.
face, jaw, teeth, and brain. As such, the elimination of drop seizures is a critical
goal in management. Although complete seizure freedom is rarely achieved in ● Drop seizures are a
the management of Lennox-Gastaut syndrome, substantial improvement in common manifestation of
Lennox-Gastaut syndrome
seizure burden is frequently accomplished with a variety of AEDs. Efficacy has
and pose disproportionate
been demonstrated with topiramate,33 valproic acid,34 felbamate,35 lamotrigine,36 harm given the potential for
benzodiazepines (especially clonazepam37), and rufinamide.38 Of particular note physical injury.
is the specific effectiveness of clobazam and rufinamide to combat drop seizures.
In addition to AEDs, considerable support exists for adjunct therapies including ● Reports of seemingly
miraculous success
the ketogenic diet, focal surgical resection when appropriate, corpus accompanying the use of
callosotomy, and vagal nerve stimulation, with the latter two particularly useful cannabidiol-enriched
for atonic seizures. Among investigational therapies in clinical trials for cannabis extracts for
Lennox-Gastaut syndrome, considerable excitement and debate is focused on treatment of seizures in
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Lennox-Gastaut syndrome
cannabidiol, including both pure pharmaceutical preparations and have been balanced by
cannabidiol-enriched cannabis extracts (“medical marijuana”).39 Reports of concerns of reporting bias
seemingly miraculous success accompanying the use of cannabidiol-enriched and the possibility that the
cannabis extracts40 have been balanced by concerns of reporting bias41 and the perception of favorable
efficacy is confounded by
possibility that favorable efficacy—even in clinical trials—is confounded by drug interaction with
drug interaction with clobazam.42 The results of ongoing clinical trials are clobazam.
highly anticipated.
● Landau-Kleffner
LANDAU-KLEFFNER SYNDROME AND THE SYNDROME OF CONTINUOUS syndrome and the syndrome
of continuous spike and
SPIKE AND WAVE IN SLOW SLEEP wave in sleep exhibit similar
Landau-Kleffner syndrome and the syndrome of continuous spike and wave in EEG patterns but clearly
slow sleep (CSWS) are often discussed together based on similar nocturnal distinct phenotypes.
interictal electrographic features, but the associated clinical phenotypes are
● Electrical status
completely distinct (TABLE 8-2). Typically, a child with Landau-Kleffner epilepticus in slow sleep is
syndrome presents at school age with rapidly progressive linguistic deterioration frequently missed on routine
(specifically, acquired auditory agnosia) with preservation of other cognitive EEGs, as activation of
domains.43 A history of self-limited or easily controlled seizures is common, but epileptiform discharges
occurs most often in
some children presenting with Landau-Kleffner syndrome have no history of slow-wave sleep.
epilepsy whatsoever.44 In stark contrast, children and adolescents with CSWS
typically have long-standing and severe epilepsy as well as global neurocognitive
impairment.45 In fact, most cases of CSWS are identified coincidentally during
the evaluation of sleep/overnight EEG in patients with highly intractable
epilepsy. The awake EEG in patients with Landau-Kleffner syndrome tends to be
either normal or minimally abnormal, with occasional epileptiform discharges
and perhaps mild background slowing. In contrast, the awake EEG in patients
with CSWS tends to be markedly abnormal, with severe background slowing and
frequent multifocal epileptiform discharges. The key electrographic signature of
both Landau-Kleffner syndrome and CSWS is a dramatic activation of interictal
discharges in sleep, especially slow-wave sleep. The occasional to frequent
discharges seen in wakefulness are activated in sleep and consume the background
EEG. This interictal pattern was thus termed electrical status epilepticus in slow sleep
(ESES), and in its original description was defined as a spike-wave burden of

at least 85%, meaning that greater than 85% of the EEG during slow-wave sleep is
occupied by epileptiform discharges (FIGURE 8-4).46
Practically speaking, a spike-wave index can be defined by sampling
slow-wave sleep and calculating the percentage of 1-second epochs that contain
an epileptiform discharge. Needless to say, several challenges arise in the

implementation of this quantification approach.45–47 Although it is clear that

these dramatically activated EEG patterns are a potential marker of severe
linguistic or global neurocognitive dysfunction, it has not been established that
an increasing spike-wave index is associated with increased cognitive
impairment. Furthermore, contemporary descriptions of ESES suggest that
spike-wave indexes smaller than 85% may be clinically significant.48
The treatment of ESES is largely guided by small cohort studies, but several
treatment strategies are noteworthy.49–51 In the case of Landau-Kleffner
syndrome, dramatic language deterioration can be followed by equally dramatic
recovery of language with accompanying normalization of the sleep EEG.
The two mainstays of therapy are benzodiazepines (especially diazepam49 or
clobazam50) and high-dose corticosteroids.51 As illustrated in CASE 8-2, the
author favors an oral diazepam challenge (1 mg/kg at bedtime, maximum
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dose 20 mg), administered with continuous EEG monitoring as well as

cardiorespiratory telemetry.52 The author has observed several patients with
substantial clinical and electrographic recovery after even a single dose, although
treatment failures and relapses certainly can occur.53 The author typically
continues relatively high-dose diazepam (approximately 0.25 mg/kg/d to
0.5 mg/kg/d) for several weeks or even months, depending on extended clinical
and electroencephalographic response. The most widely acknowledged therapy
for ESES is prednisone, with typical dosage in the range of 1 mg/kg/d to
TABLE 8-2 Characteristics of Syndromes Associated With Electrical Status Epilepticus

in Slow Sleep
Age of Comorbid Presenting

Syndrome Onset Etiology Epilepsy Features Response to Treatment Prognosis
Landau-Kleffner 5 to Unknown Mild, focal/ Acquired auditory Favorable clinical and Favorable
syndrome 12 years multifocal agnosia electrographic response
seizures (ie, resolution of electrical
status epilepticus in slow
sleep)
Syndrome of After Genetic/ Severe, Usually identified Poor clinical response Clinical response not
continuous 1 year structural/ highly in setting of severe and variable electrographic well established and
spike and wave metabolic variable epilepsy/cognitive response variable electrographic
in slow sleep impairment response
Autistic 1 to Unknown Highly Autistic regression Poor Unknown

regression with 2 years variable
epileptiform
EEG
EEG = electroencephalogram.
180 FEBRUARY 2018

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FIGURE 8-4
Electrical status epilepticus in slow sleep. Electrical status epilepticus in slow sleep is the interictal
EEG pattern associated with multiple clinical syndromes, including Landau-Kleffner syndrome,
the syndrome of continuous spike and wave in slow sleep, and autistic regression with epileptiform
EEG. The key feature is sleep activation (ie, nearly continuous epileptiform discharges during sleep)
in contrast to occasional or rare epileptiform discharges observed during wakefulness. In this
sample, the spike-wave index is 93%, as 14 of 15 seconds contain a spike. Discharges may be
focal, generalized, or both and are often bicentral or bitemporal in topographic distribution.
2 mg/kg/d.51 The author tends to favor prednisone, for patients who fail
benzodiazepine therapy, as the risks and side effect burden of long-term
corticosteroid therapy are substantial.
In contrast to other forms of epileptic encephalopathy, the prognosis of
Landau-Kleffner syndrome is generally favorable, as reflected in the brisk
clinical and electrographic recovery that usually accompanies treatment.
Unfortunately, although children with CSWS often exhibit modest or even
dramatic electrographic improvement (diminished spike-wave index),
substantial neurocognitive improvement has not been reported widely. It
may be that the neurocognitive impairment accompanying CSWS is too
long-standing and hard wired to be remedied by presently available
treatments.54 In addition, the spectrum of syndromes associated with ESES
includes not only Landau-Kleffner syndrome and CSWS but also a related
syndrome in which cognitive impairment is dominated by autistic features
(autistic regression with epileptiform EEG)45 as well as rare cases of rolandic
epilepsy, in which the burden of seizures and nocturnal spike wave is
especially high (malignant rolandic epilepsy).55 Whereas patients with
malignant rolandic epilepsy, similar to Landau-Kleffner syndrome, tend to
respond favorably to the aforementioned treatments, children with autistic
regression with epileptiform EEG unfortunately exhibit an unsatisfying
response to therapy reminiscent of CSWS. Finally, it should be noted that
CASE 8-2 A 9-year-old girl presented for a second opinion with a 3-year history of
occasional focal seizures and a 2-year history of insidious cognitive
deterioration with school failure, requiring a transition to a special-needs
classroom and social withdrawal. Prior to the onset of seizures, the
patient had been a precocious and socially adept student who enjoyed
school and excelled in all academic disciplines. At the onset of seizures,

which were brief left temporal-onset focal seizures with alteration of

consciousness and without secondary generalization occurring
exclusively during the day, a routine EEG in wakefulness and drowsiness
demonstrated occasional left centrotemporal spikes. MRI of the brain
was normal. After institution of treatment with levetiracetam and, later,
clobazam, her seizures were controlled, but cognitive deterioration
continued to progress. Once freedom from seizures was achieved, the
child’s parents had been told nothing could be done.
Upon seeking this second opinion 2 years later, an overnight EEG
demonstrated a pattern similar to FIGURE 8-4. Occasional left
centrotemporal spikes in wakefulness were dramatically activated in
sleep with a spike-wave index of greater than 90%, satisfying criteria for
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electrical status epilepticus in slow sleep (ESES). A diazepam challenge

and titration of clobazam did not improve symptoms of encephalopathy
and did not impact the burden of spikes on repeat EEG. A subsequent
course of corticosteroids (prednisone 20 mg 2 times a day, approximately
1 mg/kg/d) accompanied near resolution of interictal spikes, and her parents
reported modest improvement in verbal comprehension and speech
fluency. Friends and teachers not familiar with the recent diagnostic
revelations and treatment did not identify a substantial change in cognition
or behavior. Although the burden of spikes remained much improved on
EEG, the patient did not make any substantive improvement with sequential
courses of other antiepileptic drugs and IV immunoglobulin (IVIg).
COMMENT This patient’s presentation is reminiscent of Landau-Kleffner syndrome,

although with a somewhat higher burden of seizures and with a relatively
slow cognitive decline. This contrasts with the typically precipitous acquired
auditory agnosia of Landau-Kleffner syndrome. Although linguistic dysfunction
was apparent, her neuropsychological performance implicated broader
dysfunction. The social dysfunction may either be a direct feature of the
epileptic encephalopathy or it may reflect anxiety and depression, which
accompanied academic decline and disintegration of her social life. This
case is an illustration of lost opportunity. It is possible that a clinical
response (neuropsychological functioning) would have been meaningful
had ESES been discovered at the onset of cognitive decline and been
followed immediately by appropriate treatment. As in this case, ESES is
frequently missed on routine outpatient EEGs, as activation of epileptiform
discharges occurs most often in slow-wave sleep.
182 FEBRUARY 2018

there are rare reports of ESES accompanying focal structural lesions such as KEY POINT
cortical dysplasia or tumor, which have responded quite favorably to
● Although uncommon in
surgical resection.56 epileptic encephalopathy,
meaningful response, or
even a cure, requires prompt
CONCLUSION diagnosis and treatment.

Epileptic encephalopathy encompasses a very broad range of disorders with

diverse etiology, highly variable age of onset, and heterogeneous response to
therapy. Although prognosis is generally poor, even dismal, for children with the
earliest onset of epileptic encephalopathy, important exceptions occur. Across all
forms of epileptic encephalopathy, any chance of meaningful improvement, with
respect to both seizures and neurocognitive outcomes, critically depends upon
prompt electroclinical diagnosis followed by expeditious and appropriate
therapy. Epileptic encephalopathy remains a challenging focal point of ongoing
clinical, translational, and basic research. A tremendous need exists for salient
animal models to facilitate the identification of novel treatments. Until such
therapies are available, the clinical identification and appropriate application of
existing therapies remains an essential first step.
09/2022
ACKNOWLEDGMENT
This work was supported by the Elsie and Isaac Fogelman Endowment and the
Milken Family Foundation.
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09/2022
REVIEW ARTICLE

Epilepsy Syndromes in
I NT E R V I E W A V AI L A B L E Childhood
ONLINE
By Phillip L. Pearl, MD, FAAN
ABSTRACT
PURPOSE OF REVIEW: Epilepsy syndromes are an important clinical construct in
pediatric epilepsy, as they encompass recognizable patterns seen in
patients with epilepsies, whether of the more benign variety or associated
with encephalopathy.
RECENT FINDINGS: Syndromes may be organized by age of onset: neonatal,

infantile, childhood, or adolescent. The assignment of a syndrome has
specific implications for diagnosis, management, and prognostication. The
09/2022
2010 revised classification of the epilepsies by the International League

Against Epilepsy preserved the syndrome approach, while progress in
genetics continues to advance our understanding of the pathophysiology
and overlap of the epilepsy syndromes.
SUMMARY: Given that mutations of the same gene may cause both
encephalopathic and relatively benign epilepsies, an understanding of the
CITE AS:
pediatric epilepsy syndromes remains vital to patient care.
2018;24(1, CHILD NEUROLOGY):186–209.
INTRODUCTION
T
Dr Phillip L. Pearl, Department of he lexicon (and thus conceptualization) of seizures and epilepsy has
Neurology, Boston Children’s undergone considerable revision since 2010,1 with new taxonomies
Hospital, 300 Longwood Ave,
Boston, MA 02115, Phillip. for seizure types, epilepsy etiology, and syndromes. The relatively
Pearl@childrens.harvard.edu. recent broad classifications of epilepsy as idiopathic, symptomatic, or
cryptogenic have been replaced by the concepts of genetic, structural,
Dr Pearl receives research/grant metabolic, infectious, immune, and unknown. Advances in neuroimaging and
support from the National neurogenetics have transformed our ability to assign an etiologic category to a
Institutes of Health/National
Institute of Neurological
given patient’s epilepsy. Of special importance in pediatric epilepsy is the
Disorders and Stroke (R01 NS grouping of electroclinical clusters that are recognized as epilepsy syndromes. The
82286) and the Succinic epilepsy syndromes continue to represent a vital approach to understanding the
Semialdehyde Dehydrogenase
Deficiency Association and
diagnosis, etiology, pathophysiology, prognosis, treatability, and comorbidities
publishing royalties from Demos of large groups of patients, even if their elucidation with ongoing discoveries will
Medical Publishing and naturally lead to revisions of the syndromes over time. The pediatric epilepsy
UpToDate, Inc. Dr Pearl has
provided occasional medicolegal syndromes are now organized primarily by the age of presentation (TABLE 9-12).
testimony on pediatric neurology. This article discusses the clinical aspects of the pediatric epilepsy syndromes. For
more information on epileptic encephalopathies, refer to the article “Epileptic
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL Encephalopathies” by Shaun A. Hussain, MD, MS,3 in this issue of Continuum.
USE DISCLOSURE:
Dr Pearl reports no disclosure. NEONATAL ONSET
© 2018 American Academy The electroclinical syndromes of the neonate are relatively dichotomous, with
of Neurology. some being essentially benign (eg, benign neonatal seizures and benign familial
186 FEBRUARY 2018

neonatal seizures) and some highly encephalopathic (eg, early infantile epileptic KEY POINTS
encephalopathy and early myoclonic encephalopathy). Yet common genetic
● The previous
loci exist between these groups, and it remains challenging to identify the clinical classification of the
outcome based on genotype alone. Hence, use of the epilepsy syndrome nosology epilepsies as idiopathic,
persists, while advances continue in gene identification and the functional symptomatic, and
consequences of mutations and variants that are expected to lead to increased cryptogenic has been
replaced by the terms
understanding and parcellation of these disorders. genetic, structural-metabolic,

and unknown; these terms
Benign Neonatal Seizures have overlap with the
Formerly called fifth-day fits or benign idiopathic neonatal convulsions, the previous terms but are not
identical.
syndrome of benign neonatal seizures describes a self-limited disorder presenting
with seizures within the first week of life following an uneventful gestational ● The electroclinical
and perinatal course. The great majority of the seizures occur between days 4 and clusters known as epilepsy
6, hence the term, fifth-day fits. Patients are otherwise asymptomatic, with syndromes continue to
represent a clinically useful
normal neurologic status between events, and the family history is negative for
approach to evaluating,
early-life seizures. The symptomatology is typically unifocal clonic and rarely managing, and counseling
focal tonic, and the events tend to dissipate after 2 days. Treatment tends to be patients and families with
initiated for acute seizure management and does not have to be continued for pediatric epilepsy, even if
long once the diagnosis is established and other conditions, including hypoglycemia, their elucidation with
09/2022
ongoing discoveries will

sepsis, and meningitis, are excluded. While the EEG background may be normal naturally lead to revisions
or nonspecific, an ictal pattern called theta pointu alternant has been described: a of the syndromes over time.
nonreactive, discontinuous focal, theta frequency rhythm with intermixed sharp
waves that may shift between hemispheres and persist days to weeks following ● Benign familial neonatal
epilepsy was among the
cessation of clinical seizures.4 The overall outcome is considered to be favorable, first epilepsy syndromes for
although long-term studies are lacking. which the causative genes
were identified, although
Benign Familial Neonatal Epilepsy the range of phenotypes
now associated with
Benign familial neonatal epilepsy has the historical distinction of being among the
KCNQ2 mutations has
first epilepsy syndromes for which the causative genes were identified, although broadened to include
the range of phenotypes now associated with mutations of the KCNQ2 gene has severe epileptic
broadened to include severe epileptic encephalopathies with multiple encephalopathies, thus
representing the
comorbidities, thus representing the complexity of genotype-phenotype correlation.
complexity of
In contrast to benign idiopathic neonatal seizures, seizure onset tends to be genotype-phenotype
somewhat earlier (ie, between days 2 and 3) in an otherwise healthy full-term correlation.
neonate. Onset has rarely been described as late as 2 to 3 months. Seizure
symptomatology may include hypertonia, apnea, facial movements, and clonus, ● Early-onset epileptic
encephalopathies include
but myoclonus, spasms, or generalized tonic-clonic seizures may also occur. The early myoclonic
episodes are of brief duration but may cluster and be very frequent. Seizure encephalopathy, with a
remission is expected by 6 months of age, although an approximately 10% burst-suppression EEG
incidence of later epilepsy exists.5 pattern that becomes
prominent during sleep,
Transmission is by autosomal dominant inheritance, with a high degree and early infantile epileptic
(approximately 85%) of penetrance associated with mutations in the potassium encephalopathy (Ohtahara
channels KCNQ2 (on chromosome 20q) and KCNQ3 (on chromosome 8q). Recent syndrome), with a
advances in genetic testing have shown that KCNQ2 and, rarely, KCNQ3 combination of tonic
seizures, burst-suppression
mutations are associated with at least a transient reduction in potassium ion
EEG pattern throughout
current amplitude, although more severe phenotypes, with both loss and gain of wakefulness and sleep, and
function, have been associated with the same genes.6 The diagnosis of benign more often an association
familial neonatal epilepsy is established with a normal neurologic examination, with a structural brain
anomaly.
positive family history of neonatal seizures, and clinical course consistent with the
syndrome. Confirmation with genetic testing is also available but is not necessary.
EPILEPSY SYNDROMES
Early-onset Epileptic Encephalopathies

The early-onset epileptic encephalopathies are syndromically separated into early
infantile epileptic encephalopathy (Ohtahara syndrome) and early myoclonic
encephalopathy, both of which typically begin in the neonatal period.
In 1976, Ohtahara first described the syndrome of tonic seizures associated
with burst suppression on EEG with onset in the first 10 days of life, although
both in utero onset and onset later in early infancy are described. The separation
of early infantile epileptic encephalopathy and early myoclonic encephalopathy
TABLE 9-1 Pediatric Epilepsy Syndromes by Age of Onseta
Neonatal Onset
u Benign (idiopathic) neonatal seizures (fifth-day fits)
u Benign familial neonatal epilepsy
u Early infantile epileptic encephalopathy (Ohtahara syndrome)

09/2022
u Early myoclonic encephalopathy

Infantile Onset
u Myoclonic epilepsy in infancy (benign Dravet variant)
u Benign epilepsy of infancy
u Benign familial infantile epilepsy

u Epilepsy of infancy with migrating focal seizures
u Hemiconvulsion-hemiplegia-epilepsy syndrome
u West syndrome (infantile spasms, hypsarrhythmia; to be distinguished from benign

myoclonus of early infancy, which is not an epilepsy)
u Severe myoclonic epilepsy of infancy (classic Dravet syndrome)
u Myoclonic encephalopathies in nonprogressive disorders
Childhood
u Genetic epilepsy with febrile seizures plus (can begin in infancy)
u Panayiotopoulos syndrome (early-onset childhood occipital epilepsy)
u Myoclonic-atonic (formerly astatic) epilepsy (Doose syndrome)

u Benign epilepsy with centrotemporal spikes (benign rolandic epilepsy)
u Late-onset childhood occipital epilepsy (Gastaut type)
u Epilepsy with myoclonic absences (Tassinari syndrome)
u Lennox-Gastaut syndrome
u Epileptic encephalopathy with continuous spike and wave in slow sleep
u Acquired epileptic aphasia (Landau-Kleffner syndrome)
188 FEBRUARY 2018

rests on clinical criteria. Whereas myoclonic seizures can occur in either,
the predominant seizure type in early infantile epileptic encephalopathy
is tonic versus myoclonic in early myoclonic encephalopathy. Both are
associated with discontinuity on EEG, although the burst suppression in early
myoclonic encephalopathy is more evident during sleep, as opposed to a
persistent burst-suppression pattern during both the awake and sleep states in
Ohtahara syndrome.7 Either can progress to West syndrome with infantile

spasms or Lennox-Gastaut syndrome, which is associated with predominantly
u Childhood absence epilepsy (pyknolepsy)
u Generalized epilepsy with eyelid myoclonia (Jeavons syndrome)b

09/2022
Adolescence to Adult Onset
u Juvenile absence epilepsy

u Juvenile myoclonic epilepsy
u Epilepsy with generalized tonic-clonic seizures alone
u Progressive myoclonus epilepsies
u Mesial temporal lobe epilepsy with hippocampal sclerosis

u Autosomal dominant focal epilepsy with auditory features
u Autosomal dominant nocturnal frontal lobe epilepsy
Syndromes With Less Specific Age Relationship
u Familial focal epilepsy with variable foci (childhood to adult)
u Reflex epilepsies
a
Modified with permission from Berg AT, et al, Epilepsia.2 © 2010 International League Against Epilepsy.
b
Not listed as a syndrome by the International League Against Epilepsy but instead recognized under
absence seizures with special features.
EPILEPSY SYNDROMES
tonic seizures, slow spike-wave discharges and intermittent runs of

multiple spikes or fast activity on EEG, and profound neurodevelopmental
impairment. Early infantile epileptic encephalopathy is more likely associated
with structural malformations as opposed to metabolic disorders (eg, glycine
encephalopathy, pyridoxine/pyridoxal 50 -phosphate dependency, biotinidase
deficiency, Leigh syndrome) in early myoclonic encephalopathy, but

crossover exists.
A list of early infantile epileptic encephalopathy genes has now been
delineated: early infantile epileptic encephalopathy 1 is associated with ARX (in
particular, associated with lissencephaly); early infantile epileptic encephalopathy
2 is associated with CDKL5; early infantile epileptic encephalopathy 3 is associated
with SLC25A22; early infantile epileptic encephalopathy 4 is associated with
STXBP1; early infantile epileptic encephalopathy 7 is associated with KCNQ2
(refer to the previous discussion on benign familial neonatal epilepsy); and early
infantile epileptic encephalopathy 11 is associated with SCN2A, thus adding to
the list of sodium channelopathies associated with epileptic encephalopathies
(later-onset entities include SCN1A, associated with Dravet syndrome, as well as
genetic epilepsy with febrile seizures plus [GEFS+], and SCN8A).
09/2022
INFANTILE ONSET
Epilepsy syndromes of infantile onset range from benign and self-limited to
severe with significant encephalopathy. Indeed, the term Dravet syndrome has
been used to refer to both benign and severe myoclonic epilepsies of infancy,
although the common current usage of this eponymous term refers to the
syndrome of severe myoclonic epilepsy of infancy.
Benign Myoclonic Epilepsy in Infancy

Benign myoclonic epilepsy in infancy, sometimes called myoclonic epilepsy in
infancy and attributed to Charlotte Dravet, should not be confused with classic
Dravet syndrome, previously called severe myoclonic epilepsy of infancy, which
is associated with SCN1A mutations (see description later in this article). Benign
myoclonic epilepsy in infancy presents in otherwise healthy infants between
4 months and 3 years of age with myoclonic seizures that tend to be triggered by
sensory stimuli, whether tactile, auditory, or photic; it is thus suggestive of a
form of reflex epilepsy. The episodes may be very subtle, especially at onset, with
brief head nods or eye rolling, but eventually increase in frequency and involve
altered responsiveness and sometimes falls. A family history of generalized
epilepsy or febrile seizures is present in up to one-third of affected patients. EEG
usually shows 3 Hz to 4 Hz generalized spike- or polyspike-and-wave activity
concomitant with the myoclonia and sometimes a photoparoxysmal response.
Generalized tonic-clonic seizures may be seen later in childhood or even early
adolescence, but otherwise the long-term outlook is good, although cognitive and
behavioral impairments have been described.8,9
Benign Epilepsy of Infancy/Benign Familial Infantile Epilepsy

The syndromes benign epilepsy of infancy and benign familial infantile epilepsy
have overlapping features, including symptomatology associated with infantile
seizures: staring, decreased responsiveness, cessation of activity, eye deviation,
and head turning. Apnea, cyanosis, automatisms, and multifocal seizures can
occur, as can clusters of seizures and evolution to generalized convulsive seizures.
190 FEBRUARY 2018

The patients are initially otherwise neurodevelopmentally normal, although KEY POINTS
later development of other paroxysmal symptoms, including paroxysmal
● Benign myoclonic
kinesigenic dyskinesia, episodic ataxia, familial hemiplegic migraine, or a epilepsy of infancy includes
combination, can occur. Mutations in PRRT2, demonstrating autosomal myoclonic seizures in
dominant inheritance with variable penetrance, appears among the most otherwise developmentally
common etiologies in familial cases. healthy infants and

typically has a reflex
This epilepsy is pharmacoresponsive, particularly to medications commonly component.

used for focal-onset seizures. Prognosis is excellent for ultimate seizure remission
and normal neurologic outcome, other than the development of movement ● Benign familial infantile
disorders in some cases. epilepsy is often associated
with PRRT2 mutations,
medication
Epilepsy of Infancy With Migrating Focal Seizures responsiveness, and a good
Epilepsy of infancy with migrating focal seizures is a rare but severe epilepsy with outcome, although also
onset following the neonatal period but before 6 months of age with multifocal associated with other
paroxysmal disorders such
seizures that have a “ping-pong” or migratory quality.10 An enigmatic disorder
as paroxysmal kinesigenic
with a nearly uniformly poor prognosis, its cause has, until recently, been dyskinesia and familial
considered unknown. Several genetic associations have been made, including hemiplegic migraine.
sodium channels SCN1A and SCN2A; PLCB1, associated with phospholipase
metabolism; and potassium channelopathies, including KCNT1 and SLC12A5. For ● Hemiconvulsion-
09/2022
hemiplegia-epilepsy
more information, refer to the article “Epileptic Encephalopathies” by Shaun A. syndrome may present as
Hussain, MD, MS,3 in this issue of Continuum. prolonged unilateral
convulsions during a febrile
Hemiconvulsion-Hemiplegia-Epilepsy Syndrome illness, followed by
hemiparesis, progressive
Hemiconvulsion-hemiplegia-epilepsy syndrome is a relatively uncommon pediatric cerebral hemiatrophy, and
epilepsy syndrome but is important to recognize. It may have onset in infancy or epilepsy that may become
childhood, usually occurring before 4 years of age and manifesting as prolonged intractable over time.
unilateral convulsive seizures (ie, super-refractory status epilepticus [longer than
24 hours]) in the context of a febrile illness, followed by hemiparesis, progressive
cerebral hemiatrophy, and epilepsy that may become intractable over time. The
incidence appears to be decreasing, attributed to improved emergency treatment
of status epilepticus and a decrease in febrile status epilepticus because of
increased rates of childhood vaccination against common infectious illnesses.
Some patients will have a latency period with evident seizure control but months
to years after onset develop pharmacoresistant focal-onset seizures.
Several groups of patients may develop this syndrome. One group is children
with preexisting structural abnormalities who develop superimposed acute-onset
prolonged hemiconvulsions with subsequent hemiparesis. Other cases have
instead had underlying coagulation disorders or genetic mutations, including
SCN1A and CACNA1A mutations. Typically, fever and a mild illness, often an
upper respiratory tract infection, underlie the presentation, suggesting a
contributory element of inflammation as well as hyperthermia.11
EEG findings may be bilateral acutely, both ictally and interictally, although
predominant over the involved hemisphere; over time, background activity
improves over the contralateral hemisphere. In the chronic stage, ictal EEGs may
be poorly localizing but usually lateralize to the involved side. Acute imaging
reveals edema of the involved hemisphere with abnormal signal of subcortical
white matter and cortex but in a nonvascular distribution. Diffusion-weighted
signal is also notably increased in the ipsilateral basal ganglia, thalamus, and
internal capsule. This is followed by progressive hemiatrophy, with imaging
findings that may be reminiscent of Rasmussen syndrome. The distinction
EPILEPSY SYNDROMES
between these two entities is based on clinical grounds. Hippocampal sclerosis

may be evident in patients with hemiconvulsion-hemiplegia-epilepsy syndrome.
Differentiation from febrile infection–related epilepsy syndrome (FIRES) may
be challenging, although the lateralized aspect of hemiconvulsion-hemiplegia-
epilepsy syndrome is noteworthy and in FIRES, the acute phase of refractory
seizures or status epilepticus tends to be associated with cognitive deficits (often

severe) and highly pharmacoresistant epilepsy. In contrast, in hemiconvulsion-

hemiplegia-epilepsy syndrome, it is more typical to see a seizure-free period in
the range of months to years, although unprovoked seizures may then ensue.
The prognosis in hemiconvulsion-hemiplegia-epilepsy syndrome is variable,
from resolution of hemiplegia and good intellectual outcome to pharmacoresistant
epilepsy and permanent hemiparesis. Epilepsy surgery, including lobar or multilobar
resection and hemispherectomy, may be required to obtain seizure control.
West Syndrome
West syndrome is the most common epilepsy syndrome in infancy, occurring in
an estimated 4 per 10,000 live births and characterized by the triad of epileptic
spasms, hypsarrhythmia on EEG, and neurodevelopmental arrest or regression.12
Traditionally categorized as cryptogenic or symptomatic, a diverse range of
09/2022
etiologies exists, and an underlying cause can be identified in approximately half

of cases following clinical evaluation and MRI, with additional causes diagnosed
in at least half of the remaining cases by additional investigations, especially
genetic studies. Some genetic disorders have a strong association with infantile
spasms (eg, tuberous sclerosis complex and Down syndrome) as do mutations in
an increasing number of genes, including CDKL5, ARX, FOXG1, GRIN1,
GRIN2A, MAGI2, MEF2C, SLC25A22, SPTAN1, and STXBP1.
The EEG pattern of the “chaotic rhythm,” hypsarrhythmia was described in
the 1950s by Frederic and Erna Gibbs as a continuously abnormal pattern of
very-high-amplitude (often up to 500 μV) with asynchronous slow waves and
multifocal spikes and polyspikes. This was later expanded by Kellaway and others
into modified forms, recognizing pseudonormalization upon arousal and in rapid
eye movement (REM) sleep as well as variants such as increased interhemispheric
synchronization, hemihypsarrhythmia, and hypsarrhythmia characterized by
predominantly slow waves, discontinuous records, and focal abnormalities. Later
investigators derived scoring systems to assess the severity of hypsarrhythmia and
suggested that lower voltages qualify for a designation of modified hypsarrhythmia.
A key point is that hypsarrhythmia is the interictal background, while the actual
spasm has an ictal signature that also has multiple forms, usually manifested as a
high-voltage transient, either a diffuse slow or sharp wave, followed by an
electrodecremental response with superimposed low-amplitude fast activity.
Evidence-based treatment of infantile spasms includes adrenocorticotropic
hormone (ACTH), prednisolone, or the g-aminobutyric (GABA)-transaminase
inhibitor vigabatrin, the latter showing particular efficacy in children with
tuberous sclerosis complex.13,14 A high risk exists that patients will develop
cognitive impairment, autism spectrum disorder, and chronic epilepsy, including
Lennox-Gastaut syndrome.
Severe Myoclonic Epilepsy of Infancy (Dravet Syndrome)

The syndrome of severe myoclonic epilepsy of infancy, eponymically
associated with Charlotte Dravet’s early descriptions, became a headliner
192 FEBRUARY 2018

given the discovery of an association with SCN1A mutations, now recognized in KEY POINTS
at least 80% of patients and the cause of the majority of cases previously
● West syndrome
attributed to pertussis vaccine encephalopathy. Patients with severe myoclonic comprises the triad of
epilepsy of infancy are very sensitive to elevated temperature, both fever and infantile spasms,
ambient temperatures, and often initially experience hemiconvulsive febrile hypsarhythmia on EEG, and
seizures and go on to have recurrent febrile and afebrile myoclonic, focal, and neurodevelopmental arrest
or regression.
generalized (atypical absence and convulsive) seizures. The hemiconvulsive

aspect alternates sides, which is characteristic of the syndrome. Reflex seizures ● Dravet syndrome, or
may occur, whether in response to fever, immersion in hot water, intense severe myoclonic epilepsy
physical activity, visual patterns, or photosensitivity. In contrast to of infancy, is caused by
heterozygous mutations of
Lennox-Gastaut syndrome, tonic seizures are unusual. Severe myoclonic
the sodium channel SCN1A
epilepsy of infancy is typically a medically intractable epilepsy that leads to in at least 80% of affected
cognitive decline and motor deficits, including development of a crouch gait patients.
by the time of adolescence. A recognized association exists with status epilepticus
as well as sudden unexpected death in epilepsy (SUDEP). Treatment options ● Patients with Dravet
syndrome frequently
for severe myoclonic epilepsy of infancy include valproate, clobazam, and present in infancy with
stiripentol (not approved by the US Food and Drug Administration [FDA]) as prolonged hemiclonic
well as the ketogenic diet. A role may exist for cannabidiol,15 although its seizures and are sensitive to
reported efficacy could be related to a drug-drug interaction, leading to higher elevated temperatures.
09/2022
clobazam blood levels. Sodium channel blockers typically exacerbate the seizures ● Sodium channel blockers
in severe myoclonic epilepsy of infancy, as opposed to epilepsy syndromes should be avoided in Dravet
caused by SCN2A and SCN8A mutations, which are treatable with sodium syndrome, although they
channel blockers. are effective in SCN2A- and
SCN8A-related epilepsies.
Myoclonic Encephalopathies in Nonprogressive Disorders ● Myoclonic epilepsies in

Myoclonic encephalopathies in nonprogressive disorders are a group of nonprogressive disorders
syndromes having the common features of myoclonic seizures presenting may be medically
between 1 month and 6 years of age in children with neurodevelopmental refractory and associated
with developmental
impairment and pharmacoresistant epilepsy. This is seen most commonly in decline (as seen in genetic
association with genetic etiologies such as Angelman, Rett, Prader-Willi, or etiologies such as
Wolf-Hirschhorn (4p-) syndromes. Other causes can be categorized as Angelman, Rett,
underlying malformations of cortical development (eg, polymicrogyria), Prader-Willi, or
Wolf-Hirschhorn [4p-]
remote injury (eg, prenatal or perinatal hypoxic-ischemic encephalopathy), syndromes), underlying
or unknown etiology. Seizures can be very frequent, and status epilepticus malformations of cortical
is not uncommon. EEGs may show virtually continuous slow and superimposed developmental (eg,
spike activity so that it can be difficult to distinguish baseline from epileptic polymicrogyria), or remote
injury (eg, prenatal or
activity, especially in Angelman syndrome. While development is abnormal perinatal hypoxic-ischemic
at baseline, progressive decline may occur upon the onset of the epilepsy, encephalopathy).
sometimes with superimposed movement disorders felt to represent
extrapyramidal dysfunction.
CHILDHOOD ONSET
The epilepsy syndromes with childhood onset range from relatively common and
more benign disorders (including focal-onset seizure types as in benign rolandic
epilepsy and the early- and late-onset forms of benign occipital epilepsy and
generalized-onset forms such as childhood absence epilepsy) to epileptic
encephalopathies ranging from Lennox-Gastaut syndrome to epileptic
encephalopathy with continuous spike and wave in slow sleep (CSWS). These
are relatively common in the practice of most neurologists, especially
pediatric neurologists.
EPILEPSY SYNDROMES
Genetic Epilepsy With Febrile Seizures Plus

GEFS+ is a familial electroclinical syndrome that can have onset in infancy or
childhood and, like Dravet syndrome, is associated in at least some cases with
mutations of the SCN1A gene encoding for a voltage-gated sodium channel
subunit. The first word in the syndrome name was originally generalized but
was later changed to genetic, since both generalized and focal seizures may occur.
At least two family members should be affected to establish the diagnosis

clinically. A range of phenotypes is described, from simple febrile seizures to
mixed febrile and afebrile seizures that may be prolonged, focal, or occur in
clusters. In addition, in some families GEFS+ may overlap with Dravet and Doose
(myoclonic-astatic epilepsy) syndromes,16,17 and the clinical distinction between
these epileptic encephalopathies and GEFS+ may be challenging. Hippocampal
sclerosis can occur as well, consistent with its association with a history of
prolonged febrile seizures.
The onset of GEFS+ is usually between 6 months and 6 years of age, and boys
and girls are affected equally. The children typically develop normally, and
exceptions to this may represent overlap with other channelopathies as
mentioned. Inheritance is autosomal dominant with incomplete penetrance.
Gene mutations are identified in a minority of affected families and are usually of
09/2022
the missense type. In addition to SCN1A, mutations of the SCN1B channel and
the GABA-A receptor gene GABRG2 have been identified in affected families.
While truncation mutations are more likely associated with more severe
phenotypes, genotype alone does not allow distinction between GEFS+ and
Dravet syndrome. Thus, GEFS+ is increasingly recognized as a spectrum
disorder with a syndromic diagnosis made on clinical, not genetic, grounds.
Recognition, however, may be helpful to guide treatment, as sodium channel
blockers such as phenytoin, carbamazepine, oxcarbazepine, and lamotrigine
may be deleterious in this otherwise pharmacoresponsive epilepsy that typically
remits by adolescence.
Panayiotopoulos Syndrome (Early-Onset Childhood Occipital Epilepsy)

Of the benign childhood occipital epilepsies, the most common form is the
early-onset type also known as Panayiotopoulos syndrome, or early-onset
childhood occipital epilepsy. Syndrome onset is usually between 3 and
6 years of age, although a wide range, from 1 to as late as 14 years, has been
described. The most prominent feature is an autonomic component, and the
classic scenario is a seizure with recurrent vomiting with onset during sleep.
The events can be prolonged (ie, at least 5 minutes and sometimes even hours)
and feature nausea, vomiting, and eye deviation with preserved consciousness.
Other autonomic symptoms include bowel or bladder incontinence, pallor,
pupillary changes, and syncope. The events may secondarily generalize
into convulsions.
The EEG detects spikes that can be shifting and multifocal, with the occipital
regions involved in about half of recordings. There may not be close correlation
between the timing of electrographic ictal discharges and clinical symptoms. The
etiology is unknown, and positive family histories are lacking in these patients.
The episodes tend to be infrequent, and intermittent benzodiazepine use is a
viable alternative to prophylactic antiseizure medicines. Long-term remission
typically occurs within 2 years after onset, although there is a crossover with
benign epilepsy with centrotemporal spikes (BECTS).
194 FEBRUARY 2018

Myoclonic-Atonic Epilepsy (Doose Syndrome) KEY POINTS
Initially reported as centrencephalic myoclonic-astatic petit mal, myoclonic-atonic
● Genetic epilepsy with
epilepsy was formerly known as myoclonic-astatic epilepsy of Doose and is now febrile seizures plus is often
termed myoclonic-atonic epilepsy because of the characteristic initial myoclonic associated with SCN1A
component followed by a fall.18 mutations and may overlap
The myoclonus manifests as large-amplitude symmetric jerks of the with Dravet (severe myoclonic
epilepsy of infancy) and
arms, legs, neck, and shoulders that may result in a head drop and upper limb Doose (myoclonic-astatic
flexion or abduction. This is followed by loss of muscle tone and a fall. epilepsy) syndromes in the
Besides myoclonic-atonic events, other seizure types occur, including same families.
absence, tonic-clonic, and tonic as well as myoclonic or nonconvulsive status
● Panayiotopoulos
epilepticus. The syndrome presents between 18 months and 5 years of age,
syndrome (early-onset
with a peak at age 3 years. childhood occipital
The EEG demonstrates recurrent paroxysms of generalized spike or polyspike epilepsy) has a relatively
and wave, typically without clinical correlate and with a satisfactory background, young age of onset (3 to
6 years), prominent
although parasagittal theta frequency slowing is characteristic as well. A
autonomic symptoms
photoparoxysmal response may be present. Myoclonic events are associated with (especially prolonged
bursts of 2 Hz to 4 Hz epileptiform activity. Nonconvulsive status epilepticus vomiting), and long-term
may occur, resembling an epileptic encephalopathy. remission.
As with the absence epilepsy syndromes, a genetic etiology is suspected, and
09/2022
● Myoclonic-atonic
the family history is often positive for epilepsy. The phenotype has been epilepsy, or Doose
associated with the GEFS+ syndrome (discussed earlier in this article) and syndrome, has been
mutations in SCN1A, SCN1B, GABRG2, and SLC6A1, a GABA-transporter gene. associated with a number
Standard antiseizure drug therapy consists of valproic acid, ethosuximide, or of genes, including
mutations of sodium
benzodiazepines, and topiramate, lamotrigine, rufinamide, and levetiracetam channels and the
may also show benefit. The ketogenic diet and its variants (eg, modified Atkins g-aminobutyric acid-A
diet) have been particularly helpful in some patients. The role of the vagus nerve receptor, and may be
stimulator or corpus callosotomy is unclear, but protective measures (such as particularly responsive to
the ketogenic diet.
wearing a helmet) may be needed because of the atonic falls. Fortunately,
long-term remission occurs in the majority of patients, although the remainder
tend to develop intractable epilepsy with intellectual impairment.
Benign Epilepsy With Centrotemporal Spikes (Benign Rolandic Epilepsy)

BECTS is a common pediatric epilepsy syndrome, accounting for nearly 25% of
the childhood epilepsies and serving as the prime example of a nonlesional focal
epilepsy with an excellent outcome. The usual age of onset is 4 to 11 years, with a
peak at age 7 to 8 and male predominance. The timing of seizures is usually
shortly after sleep onset or just before awakening, although about one-fourth of
patients may have seizures only during the awake state.19
Seizures tend to be infrequent, and up to 20% of patients will have only a
single seizure. The symptomatology, when elicitable from a history of an event in
wakefulness or upon arousal, tends to begin with paresthesia on one side of the
tongue or mouth, followed by dysarthria or gagging-type noises, jerking of the
ipsilateral face, and excessive drooling (CASE 9-1). Secondary generalization may
occur. Duration is typically brief, in the range of seconds to minutes, but status
epilepticus as well as a postictal Todd paresis may occur.
The EEG background is normal but punctuated by high-voltage sharp or blunt
spike discharges involving either centrotemporal region (ie, rolandic spikes)
with potentiation during the drowsy and non-REM sleep states (FIGURE 9-1). A
classic finding is the tangential electrical dipole with anterior positivity and
centrotemporal negativity. Similar spikes can be seen on the EEG of up to 0.7% of
EPILEPSY SYNDROMES
KEY POINTS children with no history of epilepsy, so identification of centrotemporal spikes

must be interpreted according to the clinical context.20
● Benign epilepsy with
centrotemporal spikes Cognition is in the normal range, although a range of deficits have been
(benign rolandic epilepsy) described on neuropsychological testing of language, visuospatial skills, verbal
accounts for nearly 25% of and nonverbal memory, and executive function skills. Whether the presence of
the childhood epilepsies, the interictal spike discharges and their frequency has a deleterious impact on
has a peak age of onset of 7
to 8 years, and has

learning and memory remains a topic of research. Studies have suggested
anticipated long-term impairment in fine motor skills, but the affected domains of neuropsychological
remission by 14 to 16 years function, if any, remain unknown.21
of age. The etiology is suspected to be genetic, and the “benign” designation refers
not only to the outcome but also to the lack of a corresponding anatomic lesion.
● The late-onset form of
benign childhood occipital Inheritance appears to be complex, likely multifactorial, including noninherited
epilepsy (Gastaut type) is or epigenetic factors. Some genes have been implicated, including the glutamate
associated with occipital receptor GRIN2A as well as RBFOX1, RBFOX3, and DEPDC5.
spike-wave discharges that
Pharmaceutical treatment is generally reserved for patients with very frequent
are activated by eye
closure and attenuate upon events or daytime events interfering with functioning, or if secondary
eye opening. No structural generalization occurs. This is generally a pharmacoresponsive epilepsy, and
pathology is associated traditional antiseizure medicines used include carbamazepine, oxcarbazepine,
with this form of epilepsy, levetiracetam, lamotrigine, and valproate, among others. Long-term remission is
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and long-term remission is

anticipated in about half of almost universally attained by the age of 14 to 16 years.
patients.
Late-onset Childhood Occipital Epilepsy (Gastaut Type)
● Lennox-Gastaut
Late-onset childhood occipital epilepsy, eponymically known as Gastaut type,
syndrome is composed of
the combination of mixed tends to have onset in later childhood, with a peak between 8 and 11 years. The
generalized seizures that symptomatology is more classically occipital than that of Panayiotopoulos
are predominantly tonic, syndrome, as the symptoms tend to be visual hallucinations, eye deviation, eye
slow spike-and-wave flutters, transient vision loss, and ocular pain. Postictal headache is a common
discharges (1.5 Hz to 2.5 Hz)
on EEG, and cognitive and prominent symptom. Secondary generalization with loss of consciousness
impairment, often with and convulsive activity may occur. The EEG has a classic appearance of bilateral
regression. occipital spike-and-wave discharges precipitated by eye closure and attenuated
CASE 9-1 A 7-year-old boy awoke making guttural sounds, and his parents found that
one side of his mouth and face were twitching with progression to the
ipsilateral hand. He remained awake and aware but could not speak, although
afterward he explained that he first felt some tingling of his tongue and mouth
when he awoke. He had been up very late playing video games the night
before. He had an otherwise normal neurologic history and examination. EEG
showed independent bilateral biphasic and triphasic centrotemporal broad
spike discharges, which were most active in drowsiness.
COMMENT This constellation of clinical and EEG findings allows for an accurate diagnosis
of benign epilepsy with centrotemporal spikes, or benign rolandic epilepsy.
Reassurance can be provided that this is an epilepsy syndrome without a
corresponding lesion on imaging, and long-term remission is anticipated by
14 to 16 years of age. Restricted focal seizures such as described in this case
would not typically require antiseizure medication.
196 FEBRUARY 2018

FIGURE 9-1
Benign epilepsy with centrotemporal spikes (benign rolandic epilepsy). EEG of a 6-year-old
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boy shows right centrotemporal blunt discharges with anterior positivity and more posterior
negativity, consistent with a tangential electrical dipole. Sensitivity 20 mV/mm, high-frequency
filter 70 Hz, low-frequency filter 1 Hz.
by eye opening. The latter is sometimes called the fixation off phenomenon
because visual fixation will abort the spike-wave discharges. Occipital spikes that
do not show this phenomenon raise suspicion for a symptomatic occipital
epilepsy, such as with the presence of an anatomic lesion, as opposed to
late-onset childhood occipital epilepsy.
As with Panayiotopoulos syndrome (early-onset childhood occipital epilepsy),
the etiology is unknown, and family histories are rarely positive for relatives with
this form of epilepsy. In contrast with Panayiotopoulos syndrome, the seizures
tend to be more frequent, and medications typically used for focal-onset seizures
are at least partly effective in producing seizure control. At least half of patients
experience long-term remission.
Epilepsy With Myoclonic Absences (Tassinari Syndrome)

Epilepsy with myoclonic absences is characterized by very prominent rhythmic
myoclonic or clonic activity during absence seizures. Onset peaks at 7 years of age,
with a range of 1 to 12 years, and males predominate (as opposed to in childhood
absence epilepsy, discussed later in this article). Additional generalized tonic-clonic
seizures and cognitive impairment tend to be associated with this syndrome.
The EEG is similar to the generalized 3 Hz spike-and-wave discharges of
typical absence seizures, yet with myoclonia occurring coincident with the
spikes. It is not unusual for the family history to be positive for epilepsy and for
cognitive impairment to be present. While the medications used are similar to
those for childhood absence epilepsy and generalized epilepsy with eyelid
myoclonus, these seizures tend to be pharmacoresistant.
Lennox-Gastaut Syndrome
Lennox-Gastaut syndrome is defined as a constellation of multiple generalized
seizure types, with tonic being predominant; EEG background of slow (less than
EPILEPSY SYNDROMES
KEY POINTS 3 Hz) spike-and-wave discharges, plus paroxysmal fast activity during sleep; and
cognitive impairment, usually with regression. Onset is usually by the age of
● Continuous spike and
wave in slow sleep is an 8 years, with a peak incidence at 3 to 5 years. Lennox-Gastaut syndrome has a
electroclinical syndrome male predominance, and the syndrome may be preceded by West syndrome.
with an epileptic While many cases have no discernable etiology, others are associated with
encephalopathy structural lesions, (eg, focal cortical dysplasia, subcortical band heterotopia,
characterized by mixed
generalized seizures, perisylvian polymicrogyria) as well as phakomatoses (eg, tuberous sclerosis

cognitive deterioration, and complex, hypomelanosis of Ito), meningitis or encephalitis, hypoxic-ischemic
the EEG pattern of encephalopathy, and genetic epilepsies. For further information about this
electrical status epilepticus syndrome and its diagnosis and treatment, refer to the article “Epileptic
in slow sleep. While the
terms continuous spike and
wave in slow sleep and
electrical status epilepticus Epileptic Encephalopathy With Continuous Spike and Wave in Slow Sleep
in slow sleep are CSWS is an electroclinical syndrome with an epileptic encephalopathy
sometimes used
interchangeably, some
characterized by mixed generalized seizures, cognitive deterioration, and the
authors prefer to use the EEG pattern of electrical status epilepticus in slow sleep (ESES). The terms CSWS
former for the epilepsy and and ESES are sometimes used interchangeably, although ESES is considered, at
the latter for the EEG least by some, to represent an EEG pattern as opposed to a clinical syndrome.
pattern.
Seizures tend to begin between 3 and 5 years of age, although the ESES pattern may
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● Acquired epileptic not be present, and thus diagnosis not established, until several years later. The
aphasia (Landau-Kleffner traditional definition of ESES relies on spike-wave activity occupying 85% of
syndrome) is an acquired slow-wave sleep, usually manifested by slow (1.5 Hz to 2.5 Hz) spike-wave
epileptic aphasia discharges having a diffuse distribution. Varying approaches to detecting this
characterized classically by
an auditory agnosia and involvement exist (eg, visual overview, measuring how many seconds are
electrical status epilepticus impacted and counting numbers of spikes to produce a spike index). Some
in slow sleep on EEG. investigators suggest reducing this relatively high percentage to approximately
50% to allow detection of more individuals who may benefit from a diagnosis and
therapy. Etiologies range from cryptogenic to structural brain abnormalities
(eg, cortical dysplasia or polymicrogyria) to long-standing thalamic lesions.
Treatment is usually attempted to improve the EEG, whether with valproate,
levetiracetam, benzodiazepines, corticosteroids, or other antiseizure medicines.
Epilepsy surgery may be indicated if the patient has a resectable lesion. Seizures
typically remit by adolescence, but neurocognitive sequelae persist.
Acquired Epileptic Aphasia (Landau-Kleffner Syndrome)

Acquired epileptic aphasia, or Landau-Kleffner syndrome, originally emphasized
an acquired auditory agnosia as a presenting symptom, ie, loss of understanding
of previously familiar words or sounds. It has a 2:1 male predominance, and
age of onset is typically 3 to 7 years, with a range between 2 and 14 years. The
syndrome is characterized by the loss of previously acquired language skills, as
opposed to loss of perhaps a few words seen somewhat commonly in children of
younger ages presenting with autism spectrum disorder, although the distinction
can be difficult. The language regression can be rapid or prolonged, and
associated attention and behavior problems and irritability are common. Various
seizure types, both generalized and focal, are expected, albeit infrequent, and
the EEG may be represented by ESES, although predilection for the perisylvian
and posterior temporal regions is typical.
The etiology is unknown, although recent data have implicated mutations of the
N-methyl-D-aspartate (NMDA) receptor subunit gene GRIN2A.22 As with CSWS,
seizure control may be attained, typically with valproate or benzodiazepines and
198 FEBRUARY 2018

possibly steroids or IV immunoglobulin (IVIg). Early therapeutic intervention
may be related to improved outcomes based on anecdotal reports and small series,
although controlled prospective studies are lacking.23
Childhood Absence Epilepsy (Pyknolepsy)

Childhood absence epilepsy, also known as pyknolepsy from the Greek root
pykno for crowded or dense given the very frequent occurrence of these spells, is
the prototype of the common pediatric epilepsy syndromes. This syndrome
comprises approximately 15% of the childhood-onset epilepsies, has a typical age
of onset between 4 and 10 years with a peak between 5 and 7 years, and affects
girls more frequently than boys.24 Earlier onset (before age 4) raises concern
regarding underlying glucose transporter type 1 deficiency, and later onset (after
age 11) is unusual.
The syndrome of childhood absence epilepsy is characterized clinically by
the typical absence seizure, meaning abrupt impairment of consciousness, often
with associated behavioral arrest, staring, eye fluttering, or automatisms
associated with generalized 3 Hz to 4 Hz spike-and-wave discharges with an
otherwise normal background on EEG (FIGURE 9-2). The duration is usually
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about 10 seconds, although longer episodes may occur. Hyperventilation at the

bedside is especially valuable in diagnosis and, to some extent, for follow-up for
medication effectiveness, although concordance with the more accurate
hyperventilation procedure during an EEG is not perfect. In contrast, atypical
absence seizures are associated with less abrupt onset and offset, slower
spike-wave paroxysms, and an abnormal interictal EEG background.
The classic EEG signature of typical absence seizures in childhood absence
epilepsy is the generalized bilaterally synchronous and symmetric regular 3 Hz
FIGURE 9-2
EEG of an 8-year-old girl with childhood absence epilepsy. Note that she was unaware of the
three words recited during the 6-second paroxysm. Sensitivity 30 mV/mm, high-frequency
EPILEPSY SYNDROMES
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FIGURE 9-3
EEG of a 10-year-old girl with childhood absence epilepsy. Note that the paroxysm has
features of anterior voltage predominance, incompletely abrupt onset, and variability in
spike-wave frequency at onset and offset. These features are not unusual in typical absence
seizures. The remainder of the background is normal. Sensitivity 50 mV/mm, high-frequency
spike-and-wave paroxysms of abrupt onset and offset. In reality, the discharges tend
to be frontal dominant as opposed to truly generalized; often show a frequency
range, especially at onset, of 3 Hz to 4.5 Hz; and tend to slow down to 2 Hz to 2.5 Hz
by the end of a discharge (FIGURE 9-3). In addition, it is not unusual for one
hemisphere to show onset a few milliseconds before the other, and fragmentary
spike or polyspike discharges that may be confined to one region, especially
bifrontal discharges, are commonly seen in non-REM sleep. It is not unusual to see
brief runs of spike-wave discharges without clear clinical accompaniment, and
clinicians may use a 3-second cutoff to distinguish such a run as an ictal event. While
the interictal background is normal in childhood absence epilepsy, it is not unusual
to see prominent runs of occipital intermittent rhythmic delta activity.
The pathophysiology of typical absence syndromes has been at the cornerstone
of understanding generalized spike-wave discharges, especially in terms of
the evolving understanding of thalamocortical electrical circuitry and the
still-unsettled fundamental question of whether primary generalized seizures even
exist as a truly generalized event. The early centrencephalic theory emphasized the
pacemaker role of the midline thalamus, which evolved over the past 50 years to a
thalamic clock theory, emphasizing the nucleus reticularis of the thalamus as the
principal generator driving the cortical rhythms. This has more recently been
modified to a corticothalamic theory incorporating oscillations in the thalamus
interacting reciprocally with the cortex. The corticothalamic circuit includes
cortical glutamatergic neurons projecting from cortical layer VI to the nucleus
200 FEBRUARY 2018

reticularis thalamus, thalamic relay neurons with excitatory projections to cortical KEY POINT
pyramidal neurons, and nucleus reticularis thalamus neurons that have inhibitory
● Childhood absence
GABA-ergic projections with recurrent connections internally and with the epilepsy is associated with
thalamic relay neurons (but no direct connection to cortical neurons). seizure freedom and
Nucleus reticularis thalamus neurons have the capacity for oscillatory firing long-term remission in up to
(ie, rhythmic bursts that are involved in sleep spindle formation) and for 75% of patients, with
positive prognostic factors
continuous single-spike firing (ie, tonic firing during wakefulness). The cellular being normal
events behind the nucleus reticularis thalamus shift between oscillatory and tonic neurodevelopmental
firing modes are mediated by spikes present in thalamocortical and nucleus status, absence of
reticularis thalamus neurons mediated through low-threshold transient calcium generalized tonic-clonic
seizures, and negative
channels known as T channels. Upon depolarization, these channels allow brief family history of epilepsy.
calcium inflow before becoming inactivated; deinactivation requires relatively Yet a serious risk of
lengthy hyperpolarization mediated by GABA-B receptors. Thus, abnormal accidents and increased
oscillatory rhythms may be caused by abnormalities of the T channels or enhanced comorbidities, including
learning and attentional
GABA-B activity. This is consistent with the observation that medications that
disabilities, exists.
suppress T channels, eg, ethosuximide and valproate, are effective antiabsence
drugs, and medications that increase GABA-B activity (eg, vigabatrin) exacerbate
absence seizure activity. In contrast, GABA-A agonists (eg, benzodiazepines)
that preferentially enhance GABA-ergic activity in nucleus reticularis thalamus
09/2022
neurons can suppress absence seizures.

The hereditary aspect of absence seizures was recognized long ago and
emphasized in the historic twin studies by William Lennox, eponymically
famous for the Lennox-Gastaut syndrome that features atypical absences.25 As
discussed earlier, genes thus far associated with the phenotype of typical
childhood absence epilepsy include the voltage-gated calcium channel gene
CACNA1A as well as GABA-A receptor genes GABRG2 and GABRG3. Overall,
however, the precise mode of inheritance and genes involved in this relatively
common childhood epilepsy remain largely unidentified.26
The optimal antiseizure medicines for use in absence epilepsy have long been
recognized as ethosuximide and valproic acid, with some role for clonazepam
and possibly lamotrigine. A double-blind randomized controlled trial studied
the effectiveness of ethosuximide, valproic acid, and lamotrigine as initial
monotherapy and reported superior efficacy in ethosuximide (53%) and valproic
acid (58%) versus lamotrigine (29%, P<.001).27 Given that attentional
dysfunction was less problematic in the group treated with ethosuximide than in
the group treated with valproic acid (33% versus 49%, P=.03), ethosuximide
remains the usual first-line therapy for absence seizures, although this therapy
failed in a considerable proportion of patients (47%) because of either seizures or
adverse effects, rendering treatment problematic in some patients.
By the same token, the outcome is often good, with seizure freedom reported
in 57% to 74% of patients.28,29 Yet generalized tonic-clonic seizures can occur,
especially in patients who do not respond to initial ethosuximide monotherapy
and in those patients who do not experience long-term remission. Accidental
injuries are well reported during absence seizures30 as are comorbidities
including inattention, learning disabilities involving verbal and visuospatial
skills, depression, anxiety, low self-esteem, and social isolation.
Generalized Epilepsy With Eyelid Myoclonia (Jeavons Syndrome)

Eyelid myoclonia with absences is a syndrome recognizable to clinicians although
not included in the latest International League Against Epilepsy (ILAE)
EPILEPSY SYNDROMES
classification. The episodes are brief absences (usually less than 10 seconds) with
prominent eye blinking and upward eye deviation, often triggered by eye
closure. Similar episodes can occur in a number of epilepsies, so the term Jeavons
syndrome is used if it appears to be an isolated epilepsy without other neurologic
manifestations. The syndrome represents a blending of features of absence and
myoclonic epilepsy.
The ictal EEG pattern reveals diffuse 3 Hz to 6 Hz polyspike-and-wave

complexes; these may be precipitated by eye closure (FIGURE 9-4). Occasional
preceding occipital bursts have been reported as well. A generalized
photoparoxysmal response can also be seen on EEG, and it can sometimes be
ameliorated using blue-colored or polarized lenses, which can provide a
mitigation strategy as the symptoms may be pharmacoresistant.
Medications usually tried are those used for primary generalized seizures (eg,
valproic acid, ethosuximide, and benzodiazepines). The prognosis is variable, as
the eyelid myoclonia can be frequent, generalized tonic-clonic seizures may
occur, and long-term remission is not the rule.
ADOLESCENT ONSET
The epilepsy syndromes of adolescent onset include the more commonly known
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generalized epilepsies, such as juvenile absence and juvenile myoclonic epilepsy,

as well as the progressive myoclonus epilepsies, which have a complex
phenotype frequently including a degenerative course. In addition, focal-onset
epilepsy syndromes may appear in this period, including mesial temporal lobe
epilepsy with hippocampal sclerosis, autosomal dominant focal epilepsy with
auditory features, and autosomal dominant nocturnal frontal lobe epilepsy.
FIGURE 9-4
EEG of an 11-year-old boy with Jeavons syndrome shows generalized spike-and-wave discharges
following eye closure. Sensitivity 30 mV/mm, high-frequency filter 70 Hz, low-frequency filter 1 Hz.
202 FEBRUARY 2018

Juvenile Absence Epilepsy KEY POINT
Juvenile absence epilepsy is an absence syndrome having later onset than childhood
● Juvenile myoclonic
absence epilepsy and without the typical clustering. The age of onset for juvenile epilepsy has a mixed
absence epilepsy peaks at 15 years, with a range of 10 to 19 years. Seizures tend to be prognosis, with seizure
more sporadic but somewhat longer than in childhood absence, and automatisms, freedom expected but
speech arrest, and loss of awareness are frequently seen. The EEG demonstrates long-term remission not
anticipated.
paroxysms of generalized 3 Hz to 4 Hz spike- or polyspike-and-wave activity. As

with juvenile myoclonic epilepsy, triggers include sleep deprivation, alcohol, and
hyperventilation. Myoclonic and generalized tonic-clonic seizures may occur but are
less prominent than in juvenile myoclonic epilepsy.
As with the other generalized genetic epilepsies, the absence seizures in
juvenile absence epilepsy respond to ethosuximide, whereas agents with a
broader spectrum of efficacy (eg, valproate or lamotrigine) are useful if
additional seizure types occur. Juvenile absence epilepsy is typically a
pharmacoresponsive syndrome, although medications that can exacerbate
absence seizures should be avoided (including phenytoin, carbamazepine,
gabapentin, pregabalin, and vigabatrin). Valproate is often efficacious but can
have problematic adverse effects, such as hepatopathy, pancreatitis, and
thrombocytopenia. It is also associated with a risk of congenital malformations
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and early childhood cognitive effects if administered to women during the first
trimester of pregnancy. While patients with juvenile absence epilepsy tend to
achieve seizure control, a lifelong requirement for medication is expected.
Juvenile Myoclonic Epilepsy

Juvenile myoclonic epilepsy was initially known as impulsive petit mal of Janz.
It is relatively common, comprising 5% to 10% of all epilepsies. Onset is usually
between 12 and 18 years of age. The most constant clinical feature is myoclonic
seizures predominantly involving the upper extremities, especially upon
awakening. The vast majority of patients will additionally develop generalized
tonic-clonic seizures, and at least one-third will experience absence seizures.
The EEG background is preserved but features abrupt paroxysmal generalized
4 Hz to 6 Hz spike- or polyspike-and-slow-wave activity, sometimes described as
having an inverted W configuration (FIGURE 9-5). The discharges are potentiated
by sleep and, in particular, sleep deprivation. Other triggers may be arousal,
alcohol use, menses, and photic stimulation (FIGURE 9-6). Myoclonic seizures
tend to be accompanied by rapid polyspikes in the range of 10 Hz to 16 Hz or fast
spike-and-wave activity (faster than 3 Hz). Generalized tonic-clonic seizures
may follow escalation of the myoclonic seizures or occur independently.
In terms of etiology, the genetics are suspected to be complex, analogous to
childhood absence epilepsy. There may be a positive family history of epilepsy in
a proband, but this is variable. Linkage studies in families have implied a role for
mutations of the GABRA1 gene of the GABA-A receptor as well as genes
encoding for voltage-gated potassium channels, chloride channels, and other
genes; considerable heterogeneity exists.
The prognosis of juvenile myoclonic epilepsy is mixed: seizure freedom is
achievable, but remission is not expected. Valproate is efficacious for the range of
seizures seen in juvenile myoclonic epilepsy but should be avoided in women of
child-bearing age because of its adverse effect profile, including teratogenicity
and polycystic ovary syndrome. It is well suited for males and has the advantage
of treating comorbidities such as migraine or bipolar disease. An especially high
EPILEPSY SYNDROMES
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FIGURE 9-5
Juvenile myoclonic epilepsy. EEG of a 16-year-old boy shows paroxysms of 4 Hz to
6 Hz generalized spike-and-wave discharges. Sensitivity 20 mV/mm, high-frequency filter
70 Hz, low-frequency filter 1 Hz.
FIGURE 9-6
EEG of a 16-year-old boy with juvenile myoclonic epilepsy shows photoparoxysmal response
at an intermittent photic stimulation rate of 12 Hz. Sensitivity 30 mV/mm, high-frequency
204 FEBRUARY 2018

rate of psychiatric comorbidity appears to exist in juvenile myoclonic epilepsy, KEY POINTS
especially involving mood and anxiety disorders.31 Levetiracetam or lamotrigine
● Epilepsy with
may be effective for the seizures of juvenile myoclonic epilepsy. Myoclonic generalized tonic-clonic
seizures tend to be worsened by carbamazepine, oxcarbazepine, phenytoin, seizures alone has onset in
gabapentin, and vigabatrin; thus, these agents are avoided. The vast majority of adolescence or young
patients (80% or more) will relapse if taken off antiseizure medicines.32 It adulthood and is associated
with generalized 3 Hz to
appears that the presence of generalized tonic-clonic seizures or EEG worsening 4 Hz spike-and-slow-wave
during or following medication withdrawal are prognostic factors for a higher paroxysms on EEG and
risk of seizure recurrence.33 Lifestyle factors, such as medication compliance, pharmacoresponsiveness
avoidance of alcohol and illicit drugs, and avoidance of sleep deprivation and but a lifelong predisposition
to seizures.
flashing lights, represent cardinal advice of prime importance for patients with
juvenile myoclonic epilepsy. ● Progressive myoclonus
epilepsies (eg,
Epilepsy With Generalized Tonic-Clonic Seizures Alone Unverricht-Lundborg
disease, Lafora body
The syndrome of generalized tonic-clonic seizures alone is within the purview
disease, myoclonic
of adolescent syndromes given a typical age of onset of 16 years, with a range epilepsy with ragged red
between 6 and 28 years. The designation generalized tonic-clonic seizures upon fibers, and neuronal ceroid
awakening fits into this classification and could be considered a subtype of this lipofuscinosis) manifest by
syndrome. The seizures tend to occur within 1 to 2 hours of awakening and myoclonus (cortical and
09/2022
subcortical), cognitive
sometimes upon falling sleep. regression, and generalized
As with the other genetic generalized epilepsies, the EEG shows 3 Hz to 4 Hz spike or polyspike and
generalized spike-and-slow-wave paroxysms. Again, the common triggers are wave on EEG with a
sleep deprivation, photic stimulation, stress, and alcohol. Absence episodes can be photoparoxysmal
response.
documented, although they are not the predominant seizure type. The syndrome
is pharmacoresponsive, but a lifelong predisposition to seizures is expected.
Progressive Myoclonus Epilepsies

Progressive myoclonus epilepsies are a constellation of disorders manifesting
as myoclonus (cortical and subcortical) along with cognitive regression,
usually with onset during adolescence. Generalized tonic-clonic seizures can
also occur. It can be challenging to distinguish this constellation of symptoms
from juvenile myoclonic epilepsy, especially at disease onset, although
associated ataxia often exists in progressive myoclonus epilepsies. The most
common underlying causes are Unverricht-Lundborg disease (the so-called
Baltic myoclonus disease), Lafora body disease, myoclonic epilepsy with
ragged red fibers (MERRF), and neuronal ceroid lipofuscinosis. The most
frequently encountered EEG pattern is that of generalized spike- or
polyspike-and-wave and a photoparoxysmal response.
Unverricht-Lundborg disease is an autosomal recessive disease caused by
dodecamer repeat expansions or point mutations in the cystatin B gene. In
contrast to the other progressive myoclonus epilepsies, neuronal inclusions are
not present. The age of onset is between 6 and 16 years and the EEG shows
progression, including slower background along with epileptiform activity, as
the disease unfolds.
Lafora body disease, also autosomal recessive, is characterized by
polyglucosan intracellular neuronal inclusions that are positive using
histologic periodic acid-Schiff staining. Patients develop myoclonic and
generalized tonic-clonic seizures, myoclonus, vision loss, cerebellar ataxia,
and dementia. The associated gene NHLRC1 encodes for laforin, a
tyrosine phosphatase.
EPILEPSY SYNDROMES
MERRF is a mitochondrial disorder leading to myoclonus, generalized seizures,

encephalopathy, ataxia, vision and hearing loss, neuropathy, and myopathy.
Muscle biopsy reveals so-called ragged red fibers on Gomori trichrome staining.
The inheritance is matrilineal and onset is in the second decade of life.
Neuronal ceroid lipofuscinoses are a heterogeneous group of lysosomal
storage diseases with various forms of neuronal inclusions (curvilinear,

fingerprint, and granular deposits) depending upon the subtype. They are
classified as type 1 (CLN1) through type 10 (CLN10), and range from infantile to
adolescent and adult onset. These, too, are progressive disorders with dementia,
vision loss, pyramidal and extrapyramidal dysfunction, and seizures. Genetic
testing facilitates their diagnosis, and the associated seizures are pharmacoresistant,
rendering patient management largely a matter of supportive and ultimately
hospice care.
Mesial Temporal Lobe Epilepsy With Hippocampal Sclerosis

Mesial temporal lobe epilepsy with hippocampal sclerosis was identified in the
revised 2010 classification system by the ILAE as a stand-alone epilepsy
syndrome. This is justifiable based on its relatively high prevalence, consistency
of symptomatology, and frequent amenability to surgical intervention. Onset
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may be in early childhood but is frequently in adolescence or early adulthood.

Hippocampal sclerosis is a pathologic finding of atrophy and gliosis of the
hippocampus as well as the amygdala, parahippocampal gyrus, and entorhinal
cortex. MRI, especially high-resolution coronal T2-weighted or fluid-attenuated
inversion recovery (FLAIR) sequences, is very sensitive for detection. Mesial
temporal sclerosis may be unilateral or bilateral and is especially associated with a
history of prior febrile status epilepticus.
Mesial temporal seizures are often preceded by autonomic or abdominal
auras, such as déjà vu or jamais vu, fear, rising epigastric sensations, or
experiencing bad odors or tastes. Typical seizure symptomatology includes
behavioral arrest with a vacant stare and impaired responsiveness with a
duration of about 30 to 60 seconds. Automatisms accompany these events, such
as lip smacking, swallowing, chewing, or picking or fidgety movements.
Automatisms of the hand ipsilateral to the seizure focus may occur, especially
when there is dystonic posturing of the upper extremity contralateral to the
temporal lobe focus. The presence of “ictal speech,” meaning the patient has the
ability to speak during the seizure, lateralizes the seizure focus to the
nondominant (usually right) cerebral hemisphere. Postictal nose wiping is done
by the hand ipsilateral to the focus. The symptomatology is similar to that of
adults, although younger children may not have all these features. Postictal
deficits may represent the effects of seizure propagation as opposed to the seizure
onset. Amnesia for the event is typical.
Interictal EEG may show intermittent focal and even rhythmic temporal
slowing as well as anterior temporal spike or sharp discharges. The typical ictus
on scalp EEG reveals a nearly monomorphic rhythmic discharge in the 5 Hz to
9 Hz theta to alpha frequency range, maximally present at the anterior
temporal region.
Mesial temporal sclerosis is relatively unlikely to respond to antiseizure
medicines, as opposed to approximately two-thirds of patients with other types
of focal seizures, who have successful seizure control on medical therapy. Failure
to respond to two appropriate trials of antiseizure medicines is now defined as
206 FEBRUARY 2018

medical intractability and indicates candidacy for epilepsy surgery evaluation,
especially because seizure freedom is achievable in up to 90% of selected patients
undergoing temporal lobectomy.34
Autosomal Dominant Partial/Focal Epilepsy With Auditory Features

Autosomal dominant partial/focal epilepsy with auditory features, also referred

to as familial lateral temporal lobe epilepsy, often presents in the adolescent

years and has been linked to mutations of a nonchannel gene known as LGI1
(leucine-rich, glioma-inactivated 1) in about half of affected families.35 The
symptomatology is simple auditory hallucinations, such as buzzing, clicking, or
ringing sounds. When unilateral or when significantly lateralized, the
localization is the contralateral temporal lobe. Accompanying symptoms may be
more complex auditory symptoms, such as ringing, singing, whistling,
humming, or talking sounds, as well as visual, autonomic, psychic, or olfactory
phenomena. Impairment of consciousness or secondary generalization to
convulsive episodes is rare. EEG is most likely to show intermittent midtemporal
slowing or rare interictal temporal or temporooccipital discharges, and brain
imaging is unrevealing. This syndrome tends to be pharmacoresponsive.
09/2022
Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

Autosomal dominant nocturnal frontal lobe epilepsy has peak onset in early
adolescence but with a range from age 1 year to early adulthood. The
symptomatology is typical of frontal lobe hypermotor seizures, with brief and
often complex phenomena occurring in clusters during sleep. Distinguishing
these seizures from parasomnias can be challenging. Manifestations include
kicking, bicycling, or flailing movements involving the lower or upper
extremities. Vocalizations may be prominent and signal the appearance of panic
attacks. Brain imaging is normal as a rule, and interictal EEG is often normal as
well, rendering diagnosis dependent on overnight video-EEG recordings to
capture stereotypical behavior that may be associated with ictal activity,
although the latter may be obscure on scalp recordings. This autosomal dominant
syndrome has been linked to genes of the neuronal nicotinic acetylcholine
receptor (CHRNA4, CHRNA2, CHRNB2) and, more recently, the KCNT1
potassium channel.36 While nighttime dosing of antiseizure medications that are
usually effective for focal-onset seizures (eg, oxcarbazepine, lamotrigine) is a
practical management strategy, about one-third of patients are treated with
polypharmacy and remain refractory to medications.37
SYNDROMES WITH LESS-SPECIFIC AGE RELATIONSHIP

The syndromes of familial focal epilepsy with variable foci and reflex epilepsies
have a wide range of onset, from childhood to early adulthood.
Familial Focal Epilepsy With Variable Foci

Familial focal epilepsy with variable foci is an autosomal dominant syndrome
with a wide range of onset, from childhood to early adulthood, although typically
seizures begin in childhood or early adolescence. In contrast with autosomal
dominant nocturnal frontal lobe epilepsy, daytime seizures are characteristic.
Seizures are often manifested by an initial, albeit nonspecific, aura, followed by
motoric activity as well as automatisms and sometimes secondary generalization.
Members of an affected family often have differing seizure symptomatology,
EPILEPSY SYNDROMES
KEY POINT although for an individual patient, the seizures tend to be stereotypical. Patients
may have associated focal cortical dysplasia. More recently, mutations of the
● Reflex epilepsies are
characterized by seizures mechanistic target of rapamycin (mTOR) pathway inhibitor gene DEPDC5
exclusively or have been associated with this syndrome as well as the other autosomal
predominantly triggered by dominant focal epilepsy syndromes discussed, autosomal dominant nocturnal
a variety of stimuli, most frontal lobe epilepsy and autosomal dominant partial/focal epilepsy with
commonly of visual,
auditory, or tactile auditory features.38

phenomena.
Reflex Epilepsies
A variety of triggers can induce seizures, which is remarkable given that seizures
are often distinguished from other behaviors by their spontaneous onset. The
syndromes characterized by predominantly or exclusively triggered seizures are
known as the reflex epilepsies. The most common provoking stimuli are light and
sound as well as tactile stimulation, although a variety of phenomena have been
reported to induce seizures, including reading, eating, hair brushing, or hearing a
particular piece of music. These syndromes may be lesional but more often are
associated with autosomal dominant transmission with incomplete penetrance.39
09/2022
CONCLUSION
The electroclinical syndromes of childhood include a range of epilepsies, from
generalized seizures to focal-onset and mixed-onset seizures and from benign
to severe phenotypes. Yet these clusters of clinical phenomenology are
recognizable and greatly augment the practice of pediatric epilepsy.
Categorization based on age of onset is a rational approach to these entities.
Appropriate syndromic recognition and diagnosis allow for a considerably
more accurate and personalized approach to evaluation, treatment, and
prognostication to better plan for the management of the child’s seizures as
well as neurodevelopmental outcome.
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REVIEW ARTICLE

Evaluation and
Management of the
ONLINE
Child With Autism

Spectrum Disorder
By Nicole Baumer, MD, MEd; Sarah J. Spence, MD, PhD
CITE AS:
248–275.
ABSTRACT
Address correspondence to PURPOSE OF REVIEW:Autism spectrum disorder is a neurodevelopmental
Dr Sarah J. Spence, Boston
Children’s Hospital, Department
disorder defined by deficits in social communication and the presence
of Neurology, Fegan 11, 300 of restricted and repetitive behaviors and interests. This article provides
09/2022
Longwood Ave, Boston, MA the tools to diagnose and manage patients with autism spectrum
02115, sarah.spence@childrens.
harvard.edu. disorder.
RELATIONSHIP DISCLOSURE: RECENT FINDINGS: Autism spectrum disorder is a heterogeneous condition with
Dr Baumer has received
personal compensation for
varying presentations, multiple etiologies, and a number of comorbidities
speaking engagements from the that impact the course and management of the disorder. This article
Massachusetts Down Syndrome defines the core features of social communication deficits, including
Congress and St. Luke’s
Hospital, New Bedford,
problems with social reciprocity, decreased nonverbal communication,
Massachusetts, and has and difficulties in developing and maintaining relationships. The second
provided expert legal testimony domain of repetitive behaviors and restricted interests, which includes
on cases regarding Down
syndrome. Dr Spence has the presence of stereotyped behaviors or speech, insistence on sameness
received personal and behavioral rigidity, intense or out of the ordinary interests, and
compensation for speaking
unusual responses to sensory stimulation, is also delineated. Comorbidities
engagements from Cold Spring
Harbor Laboratory, the Kennedy commonly seen with autism spectrum disorder include medical,
Krieger Institute, and Westwood neurologic, and psychiatric conditions. Despite intense research efforts,
Lodge psychiatric hospital and
receives research/grant
the etiology of autism spectrum disorder remains unknown in most
support from the National cases, but it is clear that a strong genetic component exists that
Institute of Mental Health interacts with various environmental risk factors. Current research is
(5R01MH100186–02).
identifying overlapping neurobiological pathways that are involved in
UNLABELED USE OF pathogenesis. Treatment involves intensive behavioral therapy and
educational programming along with traditional ancillary services,
USE DISCLOSURE:
Drs Baumer and Spence discuss such as speech/language, occupational, and physical therapies.
the unlabeled/investigational Psychopharmacologic treatments are also used to target certain symptoms
use of several classes of
psychoactive medications,
and comorbid conditions.
including atypical neuroleptics,
alpha agonists, selective SUMMARY: Neurologists can play an important role in diagnosing autism
serotonin reuptake inhibitors, spectrum disorder according to clinical criteria through a comprehensive
stimulants, mood stabilizers,
and melatonin, for the
evaluation that includes a thorough medical and developmental history,
treatment of autism spectrum behavioral and play observations, and a review of standardized cognitive
disorder. and language evaluations. Neurologists are also responsible for investigating
© 2018 American Academy etiologies, recommending and advocating for appropriate behavioral and
of Neurology. educational interventions, and identifying and often managing comorbidities.
248 FEBRUARY 2018

KEY POINTS
INTRODUCTION
A
utism spectrum disorder is a complex heterogeneous ● What is now termed
neurodevelopmental disorder characterized by deficits in social autism spectrum disorder
was historically made up of
communication and social reciprocity in addition to repetitive
multiple distinct disorders
behaviors and restricted interests. Language and cognitive
(ie, autistic disorder,

impairment may co-occur. Onset of symptoms is in early pervasive developmental
childhood, and the disorder is usually thought to be lifelong. First described in disorder–not otherwise
1943 by Leo Kanner, autism was thought to be a rare disorder for many years. specified, and Asperger
disorder). In the Diagnostic
However, in the past 2 to 3 decades, the estimated prevalence has increased and Statistical Manual of
steadily and dramatically. This is thought to be due to a number of factors, Mental Disorders, Fifth
including the broadening of the diagnostic criteria, some diagnostic substitution, Edition (DSM-5), all of
and increased recognition and knowledge of the disorder. Additionally, there these are combined into
one, termed autism
may be other reasons that are currently unknown and the target of much speculation. spectrum disorder.
The most recent estimate from the Centers for Disease Control and Prevention
(CDC) is that 1 in 68 children has a diagnosis of autism spectrum disorder.1 Given ● Current diagnostic
the 4:1 male to female ratio, that represents an incidence of 1 in 42 boys and 1 in criteria for autism spectrum
disorder focus on two
189 girls.1 The clear male preponderance has not yet been fully explained but
domains of function:
likely reflects genetic and hormonal factors. Despite intense research efforts, the deficits in social
exact pathophysiology remains largely unknown but is believed to involve a
09/2022
communication and the

complex interplay between genetics and environmental factors. presence of restricted
interests and repetitive
What is now termed autism spectrum disorder was historically made up of
behaviors.
multiple distinct disorders (ie, autistic disorder, pervasive developmental
disorder–not otherwise specified, and Asperger disorder).2 In the Diagnostic
and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), all of these
disorders are combined into one, termed autism spectrum disorder.3
Neurologists are often called on to diagnose autism spectrum disorder. This article
reviews the clinical features and diagnostic criteria of autism spectrum disorder
according to the DSM-5 and gives a framework for how to approach the diagnostic
process, identify comorbidities, investigate etiologies, and manage the disorder.
DIAGNOSTIC CRITERIA
Current diagnostic criteria focus on two domains of function: deficits in social
communication and the presence of restricted interests and repetitive behaviors
(FIGURE 12-1).
Because behavioral profiles change with development and specific symptoms
may come and go over time, DSM-5 allows for a history of symptoms, even if
not currently manifested, to meet criteria for diagnosis. The diagnosis can be
made by showing these behaviors were present by history as long as the current
profile is consistent with autism spectrum disorder and functional impairment
that is considered clinically significant is ongoing.
Symptoms must be present in the early developmental period, and it is important
to consider whether the impairing symptoms are best explained by autism
spectrum disorder or another condition, such as global developmental delay or
cognitive impairment/intellectual disability. In autism spectrum disorder,
impairment in social and communication skills and behaviors must be out of
proportion to what is expected for the individual’s developmental functioning.
Deficits in Social Communication and Social Interaction

Social communication encompasses a number of skills. DSM-5 requires that
deficits be present in all three of the following areas: social-emotional reciprocity,
AUTISM SPECTRUM DISORDER
FIGURE 12-1
Autism spectrum disorder core symptom domains according to the Diagnostic and
09/2022
Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).
nonverbal communication, and social relationships.3 These are true deficits that
represent a deviation from the expected developmental trajectory, irrespective of
the level of developmental function.
SOCIAL-EMOTIONAL RECIPROCITY. Abnormalities in social reciprocity involve

the quantity and quality of social interest and engagement, including social
initiation, response and engagement in basic social exchange, reciprocal/
back-and-forth communication, sharing of emotions, and appropriate response
to environmental stimuli. This subdomain represents the very building blocks of
social interaction (initiation, response, and turn taking).
The earliest symptoms can manifest as a lack of a reciprocal social smile,
lack of response to the child’s name being called, decreased engagement in
interactive baby games like peekaboo or pat-a-cake, and problems imitating
the actions of others. Children also struggle with social orienting, show little
awareness or interest in others, have difficulty sharing interests and enjoyment
with others, or have trouble with social overtures. Some children may
demonstrate social interest but lack the social skills to initiate and join in play,
take turns, follow rules, and play cooperatively. They may be socially immature
and have difficulty respecting appropriate social boundaries or perceiving subtle
social cues. They may also struggle with communicating their emotions or
understanding the emotions of others. Children with good expressive speech
often will not use it to functionally communicate in a social manner such as to
express ideas, ask questions, engage in back-and-forth conversation, volunteer
information, or comment on the environment.
NONVERBAL COMMUNICATION. Deficits in nonverbal communication encompass

problems in expressing and understanding various behaviors (such as eye contact,
tone of voice, body language, facial expressions, gestures, and bringing/
sharing/showing of interests and activities) and the ability to integrate verbal and
250 FEBRUARY 2018

nonverbal communication. Children with autism spectrum disorder do not
typically compensate for difficulty in verbal communication with nonverbal
strategies (as seen in those with developmental language disorder), demonstrating
a more significant and specifically social communication deficit. They have
difficulty initiating and responding to joint attention (ie, the shared focus on an
object or an event, so that both parties are paying attention to the same thing).
SOCIAL RELATIONSHIPS. Children with autism spectrum disorder have deficits

in a wide range of behaviors required for building and maintaining successful
social relationships, especially with same-age peers. This subdomain can be
conceptualized as difficulties with behaviors needed for higher-order social
interaction. Young children with autism spectrum disorder may show little
interest in other children or may be avoidant of any interaction, instead engaging
in solitary or parallel play. Many children have difficulty varying or adapting
their behavior to different social situations and have difficulty understanding
different points of view or taking another’s perspective, referred to as a deficit in
theory of mind.4 Verbal children often only converse about topics of personal
interest and are not aware when someone is not interested (eg, lecturing like a
“little professor”). Language can be overly literal, and children may not
09/2022
understand idioms or sarcasm, making it difficult to discern joking from teasing

or real bullying. Many children with autism spectrum disorder do not have
understanding or insight into friendships or other social relationships.
DEFICITS IN SOCIAL AND COMMUNICATIONS SKILLS IN OTHER CONDITIONS. Difficulties

with social and communication skills can also be seen in children with other
medical and neurodevelopmental disabilities, including hearing loss, specific
language impairment, global developmental delay, attention deficit hyperactivity
disorder (ADHD), social anxiety, and psychosocial deprivation (TABLE 12-1).
Repetitive Behavior and Restricted Interests

This domain includes a number of aberrant behaviors in four different areas,
including repetitive behaviors or stereotypies, rigid or inflexible behavior, unusual
or restricted interests, and differences in sensory reactivity (a new category in
DSM-5).3 DSM-5 requires behaviors to be present in two of the four areas.
STEREOTYPIC MOVEMENTS, REPETITIVE OBJECT USE, OR VOCALIZATIONS/VERBALIZATIONS.

Motor stereotypies include finger movements, body posturing, rocking, spinning,
hand/arm flapping, full-body tensing, toe walking, or repetitive jumping. Unusual
and repetitive use of objects can be seen in nonfunctional play, repetitive play
(eg, flipping light switches, opening/closing doors), or unusual use of toys rather
than playing with them as intended (eg, lining up toys, spinning the wheels on
cars). Stereotypies can also be vocal, with repetitive sounds or verbal echolalia.
Echolalia can be the immediate echoing of what was said around the child or
delayed echoing, with scripting/reciting lines from books or videos.
INFLEXIBILITY, THE NEED FOR SAMENESS, ROUTINES, OR RITUALS. Resistance to change

can be demonstrated by needing to take the same route to a given destination,
eating the exact same foods or having food presented in the same way, or
always having to finish what is started. Cognitive inflexibility is shown by
black-and-white/rigid thinking, repetitive questioning, overly strict adherence
to rules, and behavioral or verbal rituals. A hallmark of children with autism
spectrum disorder is that minor changes to routine, transitions, or unexpected

events often elicit excessive tantrums or major changes in affect.
OVERLY INTENSE OR UNUSUAL INTERESTS. Interests can involve topics that are
seemingly abnormal in focus (eg, a 5-year-old knowing everything about
elevators, air conditioners, or the weather) or perseverative or excessive in

intensity (eg, age-appropriate interest in cars/trains or letters/numbers but at
an unusual level of detail and to the exclusion of other topics or activities).

Children may show an unusual attachment to objects (eg, needing to carry
something with them at all times) or show an atypical or intense interest in
small parts of things or how things work.
OVERREACTIVITY OR UNDERREACTIVITY TO SENSORY STIMULATION OR UNUSUAL

SENSORY BEHAVIORS. The sensory symptoms may involve any of the senses (eg,
auditory, visual, tactile, or olfactory). They can be seen in unusual sensory
interests (eg, overfascination with water play), adverse responses to seemingly
innocuous sounds (eg, the vacuum cleaner) or things touching the skin (eg,
clothing tags), a high pain tolerance, or excessive mouthing or smelling of
objects. Individuals may show fascination with lights or spinning objects.
09/2022
Children may demonstrate unusual visual behaviors, such as peering out of the
TABLE 12-1 Differential Diagnostic Considerations in Autism Spectrum Disorder
Differential Diagnosis of Language Delay

u Developmental language disorder/specific language impairment
u Constitutional language delay (“late talker”)
u Hearing loss
u Global developmental delay/intellectual disability

u Psychosocial deprivation
Differential Diagnosis of Social Impairment
u Social anxiety
u Generalized anxiety disorder

u Shy temperament
u Learning disabilities
u Attention deficit hyperactivity disorder
u Social communication disordera

Differential Diagnosis of Stereotypic, Repetitive, or Rigid Behaviors
u Intellectual impairment
u Obsessive-compulsive disorder
u Stereotypic movement disorder

u Complex tics/Tourette syndrome
a
A new diagnosis in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [DSM-5]
characterized by significant pragmatic language impairment without accompanying restricted interests
and repetitive behaviors.
252 FEBRUARY 2018

corners of their eyes, viewing objects from unusual angles, or holding objects KEY POINT
very close to their eyes. Some children engage in behaviors such as crashing into ● Given the single
things, pushing their bodies into small spaces, or being calmed by tight hugs, diagnostic label in DSM-5,
which may represent proprioceptive sensory seeking behaviors. specifiers were added to
better characterize the
STEREOTYPIC AND REPETITIVE BEHAVIORS IN OTHER CONDITIONS. Stereotypic and particular profile of any
one patient with autism
repetitive behaviors can also be seen in children with intellectual impairment,

spectrum disorder. It is
obsessive-compulsive disorder, stereotypic movement disorder, and complex important for clinicians to
tics/Tourette syndrome. indicate whether
associated cognitive
Specifiers impairment or language
Given the single diagnostic label in DSM-5, specifiers were added to better disorder exists.
characterize the particular profile of any one patient. It is important for clinicians
to indicate whether associated cognitive impairment or language disorder exists
(CASE 12-1). These disorders not only impact the presentation of autism
A 2-year-old boy was brought by his parents for evaluation of speech CASE 12-1
delay. He had no spoken language but did have some unusual and
09/2022
repetitive vocalizations, which were not directed to communicate with

others. He did not use gestures or point to indicate what he wanted. He
had no way of telling his parents what he wanted; he just cried and his
parents had to “figure it out.” He did not respond when his name was
called, nor did he follow commands. His parents did not think he listened
to them or understood them. On further questioning, his parents also
reported that he seemed “in his own world” all the time. He did not
approach them or other children, nor did he respond when others
approached him. They also reported almost continuous repetitive
behaviors, including hand flapping, toe walking, and flicking a string.
He did not play with toys in a typical way; instead he just lined them up.
He had major temper tantrums whenever his routine was disrupted. He
would only drink out of one sippy cup and once required an emergency
department visit for IV hydration when they lost the cup and he refused to
drink. He would not allow anyone to touch his head or cut his fingernails.
He would only wear sweatpants. He put his hands over his ears and
became very distressed with loud noises, such as the flushing of a toilet or
the hand dryer in a public bathroom. His hearing test was normal. The
reports from early intervention suggested global developmental delay
with a developmental quotient of 40 overall but relatively spared
motor function.
This case illustrates a classic case of autism spectrum disorder with both COMMENT
language and cognitive impairment. Symptoms are present in both
domains and all subdomains and are present in the early developmental
period. This child is very young and presents with global developmental
delay, but his social communication deficits are even greater than what
would be expected for his cognitive level, with no response to social
overtures, no social smiling, and no attempts to communicate.
spectrum disorder, they are also important for recommendations about therapy
and management. Many co-occurring conditions are seen in individuals with
autism spectrum disorder, so additional specifiers should be used when
applicable. The specifier of whether a known medical, genetic, or environmental
condition is present is used for medical comorbid conditions such as epilepsy,
sleep disturbances, or metabolic disorders. It should also be used for known

neurogenetic syndromes or for abnormal genetic findings from chromosomal

microarray or gene panels that are thought to be pathogenic. Specifying a
co-occurring neurodevelopmental or neurobehavioral disorder is important for
acknowledgement of co-occurring psychiatric conditions such as anxiety or ADHD.
Severity Ratings
Historically (based on the Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition [DSM-IV]),2 pervasive developmental disorder–not otherwise
specified and Asperger disorder were used as a proxy for those with milder
impairment, and autistic disorder was used for those with more severe impairment.
The merging of these three diagnoses into a single diagnosis of autism spectrum
disorder created the need to delineate severity. However, severity of different
symptoms in the two domains is not always the same. Therefore, in the current
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diagnostic profile, severity should be assigned for each domain separately:
u Level I: needs support

u Level II: needs substantial support
u Level III: needs very substantial support
DSM-5 offers examples of behaviors that help assign the severity ratings.
COMORBID MEDICAL CONDITIONS

Several conditions that can co-occur with autism spectrum disorder are
particularly relevant for neurologists. Defining these comorbidities guides
proper management.
Intellectual Disability
Intellectual disability has always been defined as having an IQ score that is
greater than two standard deviations below the mean (ie, less than 70) and
showing functional impairment. Previous epidemiologic studies had reported
that the majority of individuals with autism spectrum disorder had intellectual
disability.5 However, recent surveys now show that intellectual disability occurs
in approximately 50% or less of individuals with autism spectrum disorder but is
more common among females.1
Epilepsy
Large population-based studies suggest that approximately 20% of individuals
with autism spectrum disorder will develop epilepsy in their lifetime and will
likely need to see a neurologist for management. Therefore, neurology practices
may see a higher percentage of individuals with autism spectrum disorder and
epilepsy. Risk factors include syndromic autism,6,7 intellectual disability, and
female sex.8 All seizure types can occur, and the age of onset appears to have a
bimodal distribution, with peaks in early childhood and adolescence/early
adulthood. It should be noted that children with very-early-onset seizures
254 FEBRUARY 2018

(eg, infantile spasms) have an increased risk of autism spectrum disorder. KEY POINTS
Autism spectrum disorder is also more prevalent in individuals with epilepsy
● Large population-based
than in the general population9,10; although this sometimes goes unrecognized.11
studies suggest that
Treatment of epilepsy in a patient with autism spectrum disorder is similar to approximately 20% of
general treatment principles, but careful consideration should be taken to
individuals with autism

minimize behavioral side effects when choosing seizure medications.12 spectrum disorder will
develop epilepsy in their

lifetime. Risk factors
Sleep Disorders include syndromic autism,
Sleep disturbance, namely insomnia, is a very common symptom in individuals intellectual disability, and
with autism spectrum disorder, and it greatly impacts quality of life for the child female sex. All seizure types
and family. Poor sleep has been associated with behavioral problems in autism can occur, and the age of
spectrum disorder.13 Sleep problems can involve difficulty with sleep onset, onset appears to have a
bimodal distribution, with
interrupted sleep, overnight and early morning awakenings, or overall decreased peaks in early childhood or
sleep time.14 Some of the issues may be related to poor sleep hygiene, with a lack adolescence/early
of consistent bedtime routine, behavioral dysregulation leading to conflict at adulthood.
night, inability to recognize or learn the environmental cues of it being time to
● Previously, behavioral
settle down, or inability to sleep independently. Therefore, counseling on good
issues were only attributed
behavioral techniques is important before treatment with medication.15 to the autism spectrum
disorder itself; however,
09/2022
Abnormal Motor Profiles it is now recognized that

In addition to motor stereotypies and tics, children with autism spectrum comorbid psychiatric
disorder may also have a history of delayed fine and gross motor milestones, poor conditions occur in children
with autism spectrum
coordination, motor planning difficulties, or even gait abnormalities.16,17 Toe disorder, and DSM-5
walking is a common stereotypy, but it is not usually related to lower extremity explicitly allows the
spasticity. Ancillary physical and occupational therapy is often needed. diagnosis of co-occurring
psychiatric conditions as
a specifier.
Metabolic Disorders
In rare cases, individuals with metabolic disorders may present with an autism
spectrum disorder phenotype. These are especially important to recognize, as
they may represent treatable conditions. Disorders such as succinic semialdehyde
dehydrogenase deficiency (SAADH), disorders of creatine transport, and
mitochondrial disorders have been associated with autism spectrum disorder.18
Gastrointestinal Disorders
A variety of gastrointestinal disorders have been reported to be more prevalent in
patients with autism spectrum disorder, including gastroesophageal reflux
disease, constipation, and diarrhea. Initially this comorbidity was made
(in)famous by the putative tie between “autistic enterocolitis” and the
measles-mumps-rubella vaccine. While this theory was discredited with a
number of studies in the past decade, the real gastrointestinal problems in
patients should not be overlooked.19 Often gastrointestinal symptoms can be
tied to unusual feeding behavior with very restricted food intake. In some
cases, the child may even present with failure to thrive or severe obesity
secondary to the restricted intake pattern. In these situations, behavioral
feeding therapy can be very beneficial.
COMORBID PSYCHIATRIC/BEHAVIORAL DISORDERS

Behavioral challenges are very common in individuals with autism spectrum
disorder and may be reflective of a co-occurring neurodevelopmental or
psychiatric disorder. Previously, behavioral issues were only attributed to the
autism spectrum disorder itself; however, it is now recognized that comorbid
psychiatric conditions occur in children with autism spectrum disorder, and

DSM-5 explicity allows the diagnosis of co-occurring psychiatric conditions
as a specifier. Recent reports suggest that psychiatric conditions are more
commonly reported in young children and adults with autism spectrum
disorder compared to controls.20 Unfortunately, the reported rates of different
psychiatric disorders are quite variable. This is likely because of a number of

factors, including changing definitions and diagnostic criteria for both autism
spectrum disorder and other psychiatric disorders over time, overlap of certain
symptoms (eg, obsessions seen in obsessive-compulsive disorder [OCD] and
restricted/fixated interests seen in autism spectrum disorder), small and clinically
referred samples, difficulty in determining psychiatric symptoms in individuals
with intellectual disability and language disorders, and the previous prohibition in
the DSM on making a diagnosis of certain psychiatric disorders in a patient with
autism spectrum disorder. Co-occurring behavioral or psychiatric disorders can
add significantly to functional impairment and therefore should represent
treatment targets.
Attention Deficit Hyperactivity Disorder

A high degree of symptom overlap exists between ADHD and autism spectrum
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disorder. Reported rates of ADHD comorbidity range from 30% to 90%. Many
young children with autism spectrum disorder present with symptoms of
hyperactivity and impulsivity. Safety concerns such as bolting (suddenly
running away from caregivers) or wandering are particularly problematic.
Additionally, older children may appear to have inattention when in fact they
may be hyperfocused on their own special interest. Learning problems, cognitive
difficulty, and social challenges can also complicate the clinical picture. Careful,
thorough evaluation is required to distinguish those with ADHD, autism
spectrum disorder, or both autism spectrum disorder and ADHD and determine
the most appropriate treatments.
Anxiety
Generalized anxiety disorder, social anxiety, separation anxiety, specific phobias,
and OCD have all been reported at higher rates in autism spectrum disorder than
in the general population. A meta-analysis showed that nearly 40% of those with
autism spectrum disorder also had at least one type of anxiety disorder.21 It may be
difficult to distinguish the obsessive thoughts in OCD from preoccupations and
fixations in autism spectrum disorder, and some overlap exists. However, it should
be noted that in autism spectrum disorder, the thoughts do not usually lead to
distress; in fact, they are thought to be pleasurable.22
Mood Disorders
Both depression and bipolar disorder can occur in individuals with autism
spectrum disorder, although the reported rates of comorbidity are variable,
ranging from 0% to 50%.22 Depression is especially common in adolescents who
have enough social awareness to realize that they are different and have difficulty
establishing and maintaining friendships and romantic relationships.
Psychosis and Schizophrenia

Originally, childhood autism was thought to be a form of schizophrenia, but,
over time, it was recognized that the two are separate disorders. Still, some
256 FEBRUARY 2018

overlap exists with the negative symptoms of schizophrenia and the social
communication impairments of autism spectrum disorder. Rates of diagnosis of
psychosis and schizophrenia are reported to be quite low in those with autism
spectrum disorder, ranging from 0% to 6%.22 This may be, in part, because of the
difficulty in determining the symptoms in an individual with autism spectrum
disorder and comorbid language and intellectual disability. Clinically,

hallucinations are uncommon, but the clinician must be careful when inquiring
about symptoms, as overly literal interpretation of language may be misleading.
For example, a patient with autism spectrum disorder may respond “yes”
when asked “Do you ever hear voices when no one else is there?” but could be
referring to someone talking on an electronic device or the telephone.
Catatonia
Catatonia is a relatively rare occurrence in individuals with autism spectrum
disorder but is increasingly being recognized. It was included as a specifier in
DSM-5 and should be considered in individuals who experience a change in
mental status and significant regression in skills with prominent motor
symptoms, especially later in childhood or adolescence.
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PROPOSED ETIOLOGIES
Despite years of inquiry and tremendous research efforts, the etiology of most
cases of autism spectrum disorder remains unknown. As a heterogeneous,
behaviorally defined disorder, it is clear that there will not be just one unifying
cause. For this reason, some prominent researchers have referred to autism
spectrum disorder as the autisms,23 with the recognition that there are multiple
etiologies. Clearly, a strong genetic component exists in autism spectrum
disorder, but many other factors have been implicated, such as the role of the
environment, immunologic dysregulation, metabolic disturbance, and various
mechanisms of early brain injury (eg, teratogenicity, prematurity,
developmental or acquired structural brain lesions). Given that social behavior
and communication are some of the highest-order functions of the human brain,
it is perhaps not surprising that many ways exist in which these aspects of
development may get onto the wrong track. Recent research points to many
different, yet often overlapping, neurobiological pathways involved in the
pathogenesis of autism spectrum disorder.
Much of the research into etiology has focused on genetics, perhaps because
autism spectrum disorder is one of the most heritable of all neuropsychiatric
disorders. Twin and family studies suggest the heritability estimate to be about
50% (ranging from 26% to 93%). Monozygotic twins have a much higher
concordance rate than dizygotic twins and siblings, and other relatives are at
higher risk than the general population. Sibling recurrence risk is approximately
20%, and it increases as the number of affected children in the family rises.24
Various genetic mechanisms could be involved in the pathophysiology of autism
spectrum disorder. The common variant hypothesis suggests that many different
and commonly found inherited gene variants each contribute only a small amount
to the phenotype but combine in such a way as to cause autism spectrum disorder.
Many rare variants have also been identified. These pathologic mutations or variants
are known to be causally related to the phenotype. These are often de novo in the
individual with autism spectrum disorder. Autism spectrum disorder has long been
associated with certain neurogenetic syndromes (eg, tuberous sclerosis complex and
fragile X syndrome); however, more and more monogenic forms of autism

spectrum disorder are being discovered as detection methods for genetic variations
have improved over time. Karyotyping was only able to detect large aberrations,
such as the isodicentric chromosome 15q duplications. Chromosomal microarray
detects far smaller copy number variations with microdeletion and duplication
syndromes (eg, 16p11 deletion/duplication or 22q13 deletion/duplication), and now

whole-exome and whole-genome sequencing allow for detection of changes at the

individual gene level. Currently, over 800 genes have been associated with autism
spectrum disorder, available on the Simons Foundation Autism Research Initiative
(SFARI) gene list.25 Large-scale sample collection and genotyping have been done,
and more efforts are under way to try to untangle the exact genetic architecture
of autism spectrum disorder. Recent efforts have focused on the overlapping
neuronal pathways to which these genes contribute, including cellular signaling
pathways that are responsible for synaptic function and synaptogenesis, cell
adhesion molecules involved in circuit development (connectivity), and chromatin
remodeling proteins involved in regulation of gene expression.26–28
Anatomically, theories have been proposed about aberrant circuitry or an
overall disconnection syndrome, which have been supported by structural
and functional imaging studies.29,30 Physiologically, it is postulated that the
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mechanism could be an excitatory/inhibitory imbalance in the brain.31 Interest

in the immune system has also been ongoing, with one of the most robust
animal models of autism spectrum disorder resulting from maternal inflammation
during pregnancy.32 Environmental factors present both prenatally and
postnatally are also being actively investigated (eg, prematurity, teratogens,
prenatal and postnatal toxicologic exposures).33 Finally, recently research has
been focused on the gene by environment interaction and
epigenetic mechanisms.34,35
EXISTING PRACTICE GUIDELINES/PARAMETERS

Several sets of guidelines have been published by various professional
organizations for screening, evaluation, and management of autism spectrum
disorder.36–42 Some are older and do not reflect the DSM-5 diagnostic criteria.
While some differences exist, all parameters recommend multidisciplinary
evaluation, medical evaluation, and genetic testing. It should be noted that in
2016, a controversy arose over screening for autism spectrum disorder when the
US Preventive Services Task Force stated that not enough data existed to endorse
universal screening for children with autism.43 In 2016, the American Association
of Pediatrics reiterated recommendations for developmental surveillance and
specific autism spectrum disorder screening at ages 18 and 24 months and for all
children who fail routine developmental surveillance.44
CLINICAL OFFICE EVALUATION

To make a diagnosis of autism spectrum disorder, clinicians should obtain a
detailed history, including specific queries about diagnostic criteria as well as a
physical examination and targeted behavioral observations.
General History
The medical history should include birth history, age of parents at birth (older
paternal age being a risk factor for autism spectrum disorder), perinatal risk
factors, and pregnancy or delivery complications, such as maternal diabetes
258 FEBRUARY 2018

mellitus or infection during pregnancy, prematurity, low birth weight, and KEY POINT
potential prenatal exposures. Clinicians should assess for a history of frequent
● The evaluation for autism
ear infections, hearing loss, and major illnesses or injuries (head injury). The
spectrum disorder involves
general medical history should also include an assessment of medical issues, three primary components:
particularly those commonly seen in children with autism spectrum disorder (eg,
a detailed developmental
feeding and gastrointestinal concerns, sleep disturbance, and seizures/epilepsy), and behavioral history from
primary caregivers, direct

and assessment for pica/lead exposure. Behavioral phenotypes or co-occurring
clinical observations,
medical conditions may also provide clues as to an underlying genetic or and review of data and
metabolic condition. A history of frequent illnesses, vomiting, growth problems, impressions from other child
or regression may be suggestive of a metabolic disorder. Queries should be care providers or teachers,
made about medications and use of vitamins, complementary and alternative especially with regard to
peer interactions and
therapies, dietary treatments or elimination of dietary items, and allergies/ behaviors. It is important
intolerances (food and medication). to include a detailed and
A detailed family history should be obtained, including a history of disorders thorough assessment of
such as epilepsy and seizures, genetic/metabolic and autoimmune disorders, early and previous
developmental functioning
speech delay or language problems, intellectual disability or learning difficulties, to assess for past behaviors
or ADHD/attentional problems. A family history of psychiatric illness, such as consistent with autism
schizophrenia, mood disorders, or anxiety, should be assessed, and the family spectrum disorder.
should be asked about possible consanguinity.
09/2022
Social history should include a history of trauma, neglect, or psychosocial

deprivation. Developmental and educational services, including total number of
hours and types of services and therapies and/or educational programming,
should be noted.
General Developmental History

Because autism spectrum disorder often co-occurs with cognitive and language
impairments and because DSM-5 requires assessment of these specifiers, a
detailed history of development and current functioning should be obtained.
It should be noted that up to 30% of children with autism spectrum disorder
experience a regression in skills in the early developmental period. Parental
report of developmental history can be corroborated by review of developmental
milestones in the medical record.
LANGUAGE. A history of the child’s early expressive language and social

communication skills should be obtained, including age of onset of babbling,
single words, phrased speech, and sentences as well as a history of language
regression. Current modes of communication should be documented, such as use
of signs, picture systems, or technology systems. Evaluation should specifically
assess skills in receptive language (understanding of yes/no, following of
instructions/commands), expressive language (vocabulary, length of utterances),
and pragmatic language (greetings, requests, commenting, conversations).
Specific tools can be used to assess language skills (refer to TABLE 12-245–61).
OVERALL DEVELOPMENTAL/COGNITIVE FUNCTIONING. Because the social and

behavioral impairments must be more than what is expected of the child’s
developmental stage, the clinician must have information about the patient’s
cognitive skills. This can be done by reviewing previous cognitive testing and
developmental assessments or by obtaining this as part of the comprehensive
diagnostic evaluation. A review of the child’s adaptive skills should include
feeding, sleep, dressing, and toileting. In children with autism spectrum disorder,
the adaptive skills may be lower than would be expected for the cognitive level.
Specific tools can be used to aid in the assessment of cognitive and adaptive
skills (refer to the section that follows and TABLE 12-2).
Specific Autism Evaluation

The evaluation for autism spectrum disorder involves three primary components:
a detailed developmental and behavioral history from primary caregivers, direct

clinical observations, and review of data and impressions from other child care
TABLE 12-2 Assessments for Evaluation of Development/Cognition, Adaptive Skills,

Speech and Language, Behavior
Developmental Testing: For very young children or those with significant cognitive impairment,
these tests can be used and will yield a developmental quotient rather than a formal IQ score
u Bayley Scales of Infant and Toddler Development (BSID)45
u Mullen Scales of Early Learning (MSEL)46

09/2022
Cognitive Testing (IQ): These assessments are often done in the school setting or by outside
providers and should be reviewed by the neurologist
u Stanford-Binet Intelligence Scales (SB)47
u Wechsler Preschool and Primary Scales of Intelligence (WPPSI)48

u Wechsler Intelligence Scale for Children (WISC)49
u Differential Abilities Scale (DAS)50,a
u Leiter International Performance Scale-Revised (Leiter-R)51,a
Adaptive Skills
u The Vineland Adaptive Behavior Scales (VABS)52
u The Adaptive Behavior Assessment System (ABAS)53
u Scales of Independent Behavior-Revised (SIB-R)54

Speech and Language Tests
u Peabody Picture Vocabulary Test (PPVT)55
u Receptive-Expressive Emergent Language Test (REEL)56
u Clinical Evaluation of Language Fundamentals-preschool version, school-age version (CELF)57

u Test of Pragmatic Language (TOPL)58
Behavioral Scales: These scales are not autism spectrum disorder symptom specific, but they
can be helpful in identifying comorbid behavioral or psychiatric symptoms and disorders,
which can aid in treatment planning
u Achenbach Child Behavior Checklist (CBCL)59
u Aberrant Behavior Checklist (ABC) (for children with developmental delays)60

u Developmental Behavior Checklist (DBC)61 (for children with intellectual disabilities;
gives comparison score for children with same level of intellectual disability)
IQ = intelligence quotient.
a
Especially helpful for minimally verbal/nonverbal children.
260 FEBRUARY 2018

providers or teachers, especially with regard to peer interactions and behaviors. KEY POINT
As the DSM-5 diagnostic criteria allow for a history of symptoms, even if not
● The Centers for Disease
currently manifested, it is important to include a detailed and thorough
Control and Prevention’s
assessment of early and previous developmental functioning to assess for past Act Early Campaign website
behaviors consistent with autism spectrum disorder.
has resources on
Autism spectrum disorder is a heterogeneous condition, and many symptoms developmental milestones,
including checklists for

and signs within each DSM-5 diagnostic subdomain can be manifestations
typical social and
of relevant deficits. Detailed questions should be tailored to the child’s communication milestones
developmental, cognitive, and language level. TABLE 12-3 contains examples from 2 months to 5 years of
of questions to query specific impairments for each diagnostic subdomain in age, photo/video libraries
DSM-5, if a standardized tool is not being used. These questions were created of developmental
milestones, and an autism
by expert clinicians and are used by providers in the authors’ clinic during an office case training curriculum for
assessment. These questions cover content similar to that assessed in standardized health care professionals.
autism assessment tools. Standardized diagnostic tools (TABLE 12-462–68) can be
used to assess for autism spectrum disorder symptoms but are not required.
DEFICITS IN SOCIAL COMMUNICATION. Assessment of social communication

deficits includes querying for delay or absence of typical developmental
milestones as well for the presence of unusual behaviors. For example, typically,
09/2022
babies develop a social smile by 2 to 3 months of age; respond consistently to

their name by 6 months; enjoy interactive baby games by 6 to 12 months; use
and copy gestures, including pointing, by 12 months; demonstrate a range of
emotions by 18 months; engage in simple pretend play by 18 months and more
complex make-believe by 3 years; demonstrate verbal turn taking between 12
and 24 months; and play cooperatively at 4 years of age.69 Atypical social
communication behaviors may include social isolation and avoidance, using an
adult’s hand as a tool to get needs met, or atypical prosody.
The CDC Act Early Campaign website has resources on developmental
milestones, including checklists for typical social and communication milestones
from 2 months to 5 years of age, photo/video libraries of developmental milestones,
and an autism case training curriculum for health care professionals.69
SOCIAL RECIPROCITY. Assess early social engagement and interactions as an infant
or toddler, participation in reciprocal social interactions, social orienting, sharing
of enjoyment and interests, social interest, and initiation. Older children may
be socially immature and have difficulty perceiving social cues and conventions.
When assessing social-emotional reciprocity, consider language level and
whether language is used for social communication. Some children may be
nonverbal, or they may use signs or pictures to communicate needs.
NONVERBAL COMMUNICATION. The clinician should determine how the child

makes his or her needs known using nonverbal strategies as well as whether the
child can accurately interpret or understand nonverbal cues. It is important to be
aware that caregivers may be exquisitely able to anticipate the child’s needs and
wants, compensating for the deficits in verbal and nonverbal communication.
Therefore, they may not always recognize and report these challenges.
SOCIAL RELATIONSHIPS. Difficulty with peer relationships is a core feature

of children with autism spectrum disorder, but it can be difficult to assess,
particularly in young children who may have limited exposure to same-aged peers.
It is helpful to inquire about how the child behaves on the playground or
TABLE 12-3 Clinical Questions to Query DSM-5 Diagnostic Criteria for Autism Spectrum
Disorder
Social Reciprocity
u Age at which child developed social smile?

u Responds to name being called?

u Enjoyment of interactive baby games like peekaboo or pat-a-cake?
u Imitation of other’s actions?
u Soothed by physical contact or cuddling?
u Awareness of or interest in others?
u During play, checks in with others, allows others to join in play, prefers to play alone, or actively
resists when others attempt to join in play?
u Initiates social interaction or demonstrates social interest?
u Able to take turns during play, follow rules, play cooperatively?
u Engages only in physical or roughhouse play?
u In the more verbal child:
⋄ Use of language to make requests?

09/2022
⋄ Offers information or comments?

⋄ Shares ideas, interests, emotions, or enjoyment?
⋄ Able to converse socially?
⋄ Use of turn-taking in conversation?
⋄ Able to discuss a variety of topics (not just preferred topics), stay on topic, or respond
appropriately to questions?
Nonverbal Communication
u Responds to or initiates joint attention (eg, looks to a point or points to direct attention)?
u Abnormal reliance on physically directing others to communicate needs (eg, using an adult’s
hand as a tool, moving people’s hands toward something or away from them, or leading or
guiding others to gain access to items)?
u Accurately interprets facial expressions, gestures, and nonliteral language?
u A typical prosody (eg, singsong or robotic or announcer voice), imitation of original inflection
of speaker, eg, like an announcement)?
u Uses common gestures, such as waving, clapping, nodding, or giving high fives?
u Integrates verbal and nonverbal strategies (eg, naturally combines eye gaze, natural
gestures, spoken language)?
Social Relationships
u Atypical reaction to peers (eg, avoidant, running away when approached, watchful but not
making overtures)?
u Engages in interactive/shared imaginative play?
u Preference for play with younger or older children or adults rather than same-aged peers?
u Has play dates?
262 FEBRUARY 2018

u Has a best friend?

u Is invited to birthday parties of classmates?

u Varies behavior in different social contexts, such as with familiar versus unfamiliar people or in
outside versus inside settings?
u Understands friendships?
u Understands others’ perspectives?

u Understands jokes or sarcasm?
u Distinguishes friendly teasing from meanness?

u Navigates social conflicts with friends or in romantic relationships?
u Makes inappropriate comments (eg, about another’s appearance) and does not understand
these may be hurtful?
u Perceives subtle social cues, such as someone not being interested in play or a hearing about
a particular topic, lecturing like a “little professor”?
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Stereotypic Movements, Repetitive Object Use, or Vocalizations/Verbalizations

u Motor stereotypies (eg, jumping up and down, rocking, hand flapping, finger wiggling or
posturing, spinning objects or self, toe walking, pacing)?
u Unusual or repetitive play (eg, flipping lights on/off, flushing toilets, lining up toys, spinning
or focusing on car wheels or spinning objects)?
u Vocal or verbal stereotypies (eg, repetitive sounds, immediate or delayed echolalia/scripted
speech)?
u Use of rote or overlearned language, use of statements out of context or without social intent?
u Idiosyncratic language, pronoun reversal, or use of neologisms?
Inflexibility; the Need for Sameness, Routines, or Rituals
u Follows specific rituals (eg, needing to get dressed in exactly the same way every morning,
needing the same sippy cup or place at the table, overly elaborate bedtime routines)?
u Insists on eating the same foods every day (eg, extreme food selectivity) or wearing same
clothes every day (eg, only gray T-shirts)?
u Does not tolerate changes in routine?
u Difficulty with transitioning from one activity to another?
u Strict adherence to rules or black-and-white thinking?
u Needs to finish something once it is started?
u Compulsive fixing, arranging objects, or cleaning?
Overly Intense or Unusual Interests
u Extreme attachment to particular objects, excluding typical transitional object (eg, needing
to hold a stick or a toy car in each hand)?
u Overly interested in letters and numbers at a very young age?
u Excessive interests in age-appropriate topics (eg, extensive knowledge about superheroes,
dinosaurs, or certain video games but not being able to talk about or play with anything else)?
u Unusual interests that would not be expected for age (eg, weather, maps, transportation
schedules)?
u Excessively in-depth knowledge of topics such as history, science, trivia (to the exclusion of
other interests)?
Overreactivity or Underreactivity to Auditory, Visual, or Tactile Stimulation or Unusual
Sensory Behaviors
u Intolerance of certain sounds (eg, vacuum, blender, hand dryer in bathrooms), crowds,
being touched?
u Refuses to wear certain clothing fabrics or is bothered by the tags in the back of the shirt,
clothing seams?
u Extreme difficulty with things touching their heads (eg, wearing hats or getting haircuts) or with
cutting fingernails and toenails?
u Restricted eating that is based on certain food textures or oral aversion?
u Looks at things from unusual angles or peers out of the corner of the eyes?
09/2022
u Mouths, licks, or smells nonfood objects?

u Rubs objects against their skin?
u Proprioceptive sensory-seeking behavior (eg, craving deep pressure or being calmed by strong
hugs or having body parts squeezed)?
DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.
TABLE 12-4 Autism-Specific Assessmentsa
Autism Spectrum Disorder Diagnostic Toolsb
u Autism Diagnostic Observation Schedule Second Edition (ADOS-2)62
⋄ Semistructured standardized assessment of communication, social interaction, and

play for children suspected to have social and communication challenges along the
autism spectrum continuum
⋄ Several modules chosen based on language skills

⋄ During the assessment, the examiner pulls for social bids and makes note of specific
repetitive or atypical behaviors; developed for research purposes, but may be used
in clinical care as well
u Autism Diagnostic Interview-Revised (ADI-R)63
⋄ Companion tool to the ADOS; lengthy standardized interview querying all aspects of
the child’s development and current functioning
Screening Tools, Tools Used to Support Autism Spectrum Disorder Diagnosis
u Social Communication Questionnaire (SCQ)64
⋄ Parent questionnaire based on items from the ADI-R with 40 yes/no items; screening tool
264 FEBRUARY 2018

at the park. Children with autism spectrum disorder have particular difficulty with
higher-order social or relational skills, such as empathy and the ability to
appropriately adjust behaviors in different social contexts. Some children are
highly reliant on others for direct communication or to provide the scaffolding for
social interaction, and therefore they only succeed in highly supported social
environments. Some children may show affection and social engagement with
certain close family members and siblings, but they exhibit an overall atypical
pattern of relating to people. Social skill deficits may become more prominent in
late elementary school age or middle school, when social relationships become more
complex and nuanced and children typically take more ownership of their social
plans. Of note, excessive focus on unique interests and ideas and rigid behavior
(CASE 12-2) may impair friendships for children with autism spectrum disorder, or
they may be particularly drawn to others with similarly focused interests.
REPETITIVE BEHAVIOR AND RESTRICTED INTERESTS. Assessment of this domain

requires querying the presence of abnormal or unusual behaviors that are atypical
for age and developmental level. It is important to consider the severity and degree
to which behaviors impair functioning when evaluating these symptoms.
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STEREOTYPIC MOVEMENTS, REPETITIVE OBJECT USE, OR VOCALIZATIONS/

VERBALIZATIONS. When assessing for the presence of repetitive motor patterns,
note that many typically developing children flap their hands or jump up and
down when excited; this should be distinguished from a persistent and repetitive
pattern of hand flapping as seen in autism spectrum disorder. Children with
intellectual disability can also have stereotypies. Fidgeting and tics can
u Social Responsiveness Scale Second Edition (SRS-2)65
⋄ Caregiver report measure (parent or teacher) that contains subscales in social awareness,
social cognition, social communication, social motivation, and autistic mannerisms
u Childhood Autism Rating Scale 2 (CARS-2)66
⋄ Clinician-administered tool that scores observed and historical behavior;

a parent-completed rating scale is also available to aid in the assessment
u Gilliam Autism Rating Scale-3 (GARS-3)67
⋄Can be used by teachers, parents, and clinicians in individuals ages 3–22
⋄ Items are grouped into four subtests that examine stereotyped behaviors,
communication, social interaction, and developmental disturbances
u Developmental Play Scale68
⋄ Qualitative measure of a child’s play skills, including presymbolic play and symbolic play
a
Note that many of these assessments are copyrighted and only available for purchase through testing companies.
b
These tools can be used across ages. Specific training for administrator is required.
sometimes be seen in other neurodevelopmental disabilities and should be

distinguished from stereotypies when coding symptoms. Echolalia can be normal
in early language development but does not usually persist.
INFLEXIBILITY; THE NEED FOR SAMENESS, ROUTINES, OR RITUALS. Cognitive rigidity,

inflexibility, and ritualistic behavior should be queried. Some children may be

quite self-directed, following their own personal agenda. Attempts to guide the
child’s activities or conversation may be met with refusals or excessive distress.

Often, families need to make extreme accommodations and adhere to strict
routines to prevent meltdowns and tantrums.
CASE 12-2 A 16-year-old boy presented with school problems and anxiety. His
parents reported that he was very bright, but he still had trouble
completing his work at school. He got into frequent conflicts with
teachers because he did not think he needed to show his work. He also
interpreted language extremely literally. For example, he got into trouble
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at school for leaning on a desk. When the teacher told him sitting on
the desk was not allowed, he explained that he was not sitting, he
was leaning, which was “completely different.” He was interested in
friendships at school, but his peers did not want to spend time with him
because play always had to be his way, and he was very inflexible. He
even made up his own rules for his video games. He also had “no filter”
and frequently made inappropriate overtures. He was bullied at school.
He had fluent speech but had an unusual high-pitched prosodic tone. He
was also described as a kid who “lectures at you” rather than having a
conversation with you. He had intense and unique interests in maps and
weather and had memorized the Paris Metro system, although he had
never been to Paris. He talked about these a lot and did not realize when
someone else was not interested. His early developmental history was
notable for early speaking and reading and difficulty interacting with
other kids his age but interacting well with adults and older children. He
had some motor stereotypies but now only performed them in private.
Previous cognitive testing showed strengths in verbal skills (verbal IQ of
140) and relative weakness in nonverbal skills (nonverbal IQ of 110.)
COMMENT This case illustrates an adolescent with autism spectrum disorder and no
language or cognitive impairment (in fact, note the discrepancy in verbal
compared to nonverbal IQ, which is not uncommon in autism spectrum
disorder). Despite fluent speech, he still has significant social
communication deficits (difficulty with back-and-forth conversation, very
literal language, social interest but poor skills). He also showed some
stereotypies in the past but recognizes this is not typical behavior, so now
only does them in private. He has rigid behavior and very intense interests.
In the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
(DSM-IV), he would have been diagnosed with Asperger disorder.
266 FEBRUARY 2018

OVERLY INTENSE OR UNUSUAL INTERESTS. Assess for preoccupations or unusual KEY POINTS
attachments and for interests that seem overly intense (such that it is the only
● Behavioral observations
thing the child will talk about or play with, to the exclusion of new or different
must be made throughout
activities) or for interests in topics that would not otherwise be age appropriate. the entirety of the clinic
visit. Observations begin in

OVERREACTIVITY OR UNDERREACTIVITY TO AUDITORY, VISUAL, OR TACTILE the waiting room with
STIMULATION OR UNUSUAL SENSORY BEHAVIORS. Assess for both sensory aversions observation of the child
and sensory-seeking behavior in all sensory domains. with other children and
assessment of greetings
and transition to the
Behavioral/Play Observations/Direct Assessment examination room; passive
Behavioral observations must be made throughout the entirety of the visit. observations continue
Observations begin in the waiting room with observation of the child with throughout the visit
other children and assessment of greetings and transition to the examination while obtaining the
developmental history with
room; passive observations continue throughout the visit while obtaining
caregivers and through
the developmental history with caregivers and through assessment during assessment during
evaluator-directed play and interactions with the child. Specific behaviors the evaluator-directed play
evaluator can directly observe include quality of the interaction with caregivers and and interactions with
the child.
medical staff (lack of response to name, lack of emotional reciprocity, difficulty
initiating or responding to joint attention, poor social referencing, disengagement), ● Observations must be
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quality of play (repetitive or stereotyped, or lack of imaginative interactive play), considered in the context
nonverbal communicative behaviors (poor eye contact, lack of pointing, paucity of of the overall developmental
history and corroborative
gestures and facial expressions), quality and content of verbal language (repetitive
information and within the
or unusual vocalizations, echolalic or scripted speech, abnormal prosody, lack context of the social and
of back and forth conversation, engagement in monologues about preferred cultural convention for the
interests), presence of rigid or maladaptive behaviors (intolerance to transition, child’s age group and
reduced frustration tolerance, aggression or self-injurious behavior), and sensory- cultural/ethnic status.
seeking or avoidant behaviors (unusual inspection of toys, oversensitivity to tactile
portions of the examination, licking/mouthing objects).
It is often helpful for the evaluator to point out to parents any pertinent
observations during the evaluation. For example, “I’m noticing ___. Does this
occur in other settings?” Again, as the direct observations and assessment only
reflect a brief snapshot and do not occur in the child’s natural environment, it is
important to determine whether observations in the office setting are consistent
with those reported in other settings. Observations must be considered in the
context of the overall developmental history and corroborative information and
within the context of the social and cultural convention for the child’s age group
and cultural/ethnic status.
A wide variety of presentations of the deficits and the presence of abnormal
behaviors can be observed in the office setting in children with autism spectrum
disorder. Many of these behaviors are listed in various autism spectrum
disorder–specific questionnaires and observational scales (TABLE 12-4).
Physical Examination
Because of the association of autism spectrum disorder with neurogenetic
syndromes, the general physical examination should include assessment for
dysmorphic features (eg, large prominent ears as in fragile X syndrome or facial
features indicative of genetic or metabolic syndromes), growth parameters
(height, weight, and head circumference [macrocephaly greater than 98% is
present in 20% of patients with autism spectrum disorder70]); and skin
examination, including Wood’s lamp, to assess for neurocutaneous stigmata
such as hypopigmented spots or ash leaf spots as in tuberous sclerosis complex
(CASE 12-3) or hyperpigmented spots as in neurofibromatosis.36,37,41 Neurologic

examination should focus on the patient’s level of activity, attention, cranial
nerves, muscle tone assessing for severe hypotonia, motor coordination/planning,
reflexes, and gait (toe walking).
Standardized Tools, Rating Scales, and Assessments

By DSM-5 diagnostic criteria, no standardized tools are required for diagnosing

autism spectrum disorder. However, a number of tools, such as standardized
questionnaires and rating scales, parent interviews, and direct assessments
(including autism spectrum disorder–specific tools), can help clarify the
diagnostic profile (TABLE 12-4).
An accurate diagnosis of autism spectrum disorder does require standardized
assessments of cognition, adaptive function, and speech and language skills to
help clinicians distinguish global delays from deficits limited or targeted to
language and social communication skills.36,37,41 Children with autism spectrum
disorder may have global delays, but they will have more extreme deficits in
socialization and communication. Formal cognitive and language assessments
are also needed to determine specifiers required in the DSM-5 and should be
considered when assigning the diagnosis. In some cases, an occupational therapy
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assessment for sensory issues is helpful. An understanding of the child’s specific
CASE 12-3 A 3-year-old girl with autism spectrum disorder with cognitive and language
impairment was referred by her pediatrician for neurologic evaluation.
Her past medical history revealed that she was born in a poorly resourced
country and had early-onset seizures and developmental delay. Her
mother had a hard time describing the seizure symptomatology the
patient experienced as an infant, and, unfortunately, no records were
available. She had been on medication but was taken off after 6 months,
and the seizures did not return. However, she had recently developed
some new spells with behavioral arrest and unresponsiveness. Physical
examination revealed macrocephaly and hypopigmented lesions seen on
the trunk on Wood’s lamp examination. Given the diagnoses of autism
spectrum disorder, global developmental delay, seizures, and the
examination findings, tuberous sclerosis complex was suspected.
An EEG showed multifocal spikes and one electroclinical seizure, and a
brain MRI revealed tubers and subependymal nodules. Therefore, the
autism spectrum disorder diagnostic specifiers were amended to include
an association with tuberous sclerosis complex and epilepsy.
Recommendations included starting anticonvulsant treatment; medical
surveillance for tuberous sclerosis complex–associated conditions;
genetic counseling; and intensive speech, educational, and behavioral
interventions for autism spectrum disorder.
COMMENT This case exemplifies the importance of a careful physical examination,

which, in this case, pointed to a distinct etiology. It also illustrates how to
use the specifiers in the diagnosis.
268 FEBRUARY 2018

areas of strengths and weaknesses in these developmental domains is also KEY POINTS
important for tailored treatment planning.
● By DSM-5 diagnostic
criteria, no standardized
Evaluation of Etiology tools are required for
Ruling out treatable conditions is important in all children. Formal audiologic diagnosing autism spectrum
evaluation should be completed in all children with language delay and diagnosis disorder. However, a
number of tools, such as
(or suspicion) of autism spectrum disorder.36,37,41 Lead testing should be done for standardized
all children with developmental delays and those still in an oromotor stage of questionnaires and rating
development or with pica.36,37 scales, parent interviews,
The neurologist has an important role in identifying possible neurogenetic or and direct assessments
(including autism spectrum
metabolic syndromes in individuals diagnosed with autism spectrum disorder
disorder–specific tools),
and should be aware of phenotypes that may be suggestive of specific syndromes. can help clarify the
Neurogenetic syndromes and disorders occur in about 10% to 20% of children diagnostic profile.
with autism spectrum disorder.24 For example, children with fragile X syndrome,
● An accurate diagnosis of
tuberous sclerosis complex, 15q duplication syndrome, neurofibromatosis,
autism spectrum disorder
Angelman syndrome, Prader-Willi syndrome, Down syndrome, and Williams requires standardized
syndrome have higher rates of autism than in the general population.37 assessments of cognition,
Chromosomal microarray is recommended for all individuals with autism adaptive skills, and speech
and language skills to help
spectrum disorder.37,40,42 Fragile X testing is commonly performed, although
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clinicians distinguish global

it is important to note that conflicting recommendations exist regarding delays from deficits limited
whether fragile X analysis should be offered to all patients with autism or targeted to language and
spectrum disorder, only boys, or only those with autism spectrum disorder and social communication skills.
cognitive impairment. ● Formal audiologic
The yield of genetic testing is higher in those who have syndromic features, evaluation should be
dysmorphology, or intellectual disability.40 Additional etiologic testing, completed in all children
including gene mutation analyses, should be considered for children if concerns with language delay and
diagnosis (or suspicion) of
exist for a specific neurogenetic or metabolic syndrome or if the child has a autism spectrum disorder.
history of developmental regression. The American College of Medical Genetics
and Genomics guidelines include estimates of diagnostic yield that can be ● Lead testing should be
done for all children with
discussed with families. Genetic counseling should be offered to all families.40 developmental delays and
Further etiologic testing, including metabolic testing, EEG, and neuroimaging/ those still in an oromotor
brain MRI, are not recommended as standard care but should be considered for some stage of development or
children based on individual phenotypic features.36,37,40,41 EEG should be considered with pica.
if concern exists for clinical or subclinical seizures or in the setting of regression to ● The neurologist has an
assess for possible Landau-Kleffner syndrome/acquired epileptic aphasia. For important role in identifying
more information on Landau-Kleffner syndrome, refer to the article “Epileptic possible neurogenetic or
metabolic syndromes in
individuals diagnosed with
Neuroimaging is indicated in the setting of microcephaly, hypertonia, focal autism spectrum disorder
examination, or concern for tuberous sclerosis complex or a neurodegenerative and should be aware of
condition. Toe walking in the absence of evidence of spasticity/upper motor phenotypes that may be
neuron signs is likely behavioral and does not require neuroimaging. suggestive of specific
syndromes.
Metabolic/mitochondrial testing; general screening for immunologic
deficiencies; evaluation for toxins, heavy metals, food allergies, and celiac
antibodies; and thyroid tests can be considered in those with appropriate
phenotypes but are not recommended routinely.36
Differential Diagnosis
Social and communication difficulties and repetitive behaviors are seen in other
medical and neurodevelopmental disorders. The evaluator must determine
whether impairing symptoms are best explained by autism spectrum disorder or
another condition (TABLE 12-1). It should be noted that multiple conditions

can co-occur in the same child.
Applying Specifiers
The medical history, formalized assessments, ancillary testing, record review,
and direct observation can be used to determine if a child has cognitive and
language impairment and any comorbid medical or neurodevelopmental
disorders that should be assigned as specifiers. While some of these symptoms

may not be specific to autism spectrum disorder, they are important to document
because they can represent significant morbidity in the patient and can be targets
for specific interventions.
GENERAL MANAGEMENT OF AUTISM SPECTRUM DISORDER

When a child is diagnosed with autism spectrum disorder, adequate time
should be made available to answer questions, guide the family toward
treatment and service options, and make appropriate referrals. All families
should be offered information and support and should be provided
with accessible materials. Multiple resources are available, including those
available online from various government resources (eg, the CDC and the
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National Institutes of Health [NIH]) and private foundations and groups (eg,
Autism Speaks, Autism Society of America, American Academy of Pediatrics).
Families should also be referred and given information about local autism support
centers, which are available in most states.
The written evaluation report is often used by families to advocate for
services, therapies, and educational programs. Therefore, it should provide
specific documentation of the diagnostic evaluation findings and evidence-based
recommendations for treatment. Recommendations should be detailed and
tailored to the child’s individual developmental needs.
Behavioral and educational therapies are the mainstay of treatment for
autism spectrum disorder.38,41,72 Children younger than 3 years of age should be
assessed by the early intervention team, and an individualized family service
plan (IFSP) should be developed. They should be referred for both general
developmental and autism-intensive services. Children older than age 3 years
should be referred to their local public school for a school evaluation to
determine special education eligibility (often referred to as a team or core
evaluation). Most children with autism spectrum disorder will be deemed
eligible for services through an individualized education program (IEP) through
Individuals With Disabilities Education Act (IDEA). Some children may receive
accommodations under a 504 plan through the Rehabilitation Act of 1973.
Home-based services may also be accessed through the IFSP, IEP, or private or
public health insurance. Many states now have laws mandating private insurance
to pay for autism spectrum disorder–related behavioral therapies. Recently, the
Centers for Medicare & Medicaid Services mandated public insurance coverage
for autism spectrum disorder services as well.
The National Research Council Recommendations for Educating Children
With Autism include at least 25 hours of total service time, maximal
individualized instruction with a low student to teacher ratio, and parent/family
involvement. These recommendations are available for free download from
the National Academies Press (nap.edu/catalog/10017/educating-children-with-
autism) and can be referenced when advocating for appropriate services.72
270 FEBRUARY 2018

Behavioral Therapy KEY POINTS
Research has consistently shown that early intensive behavioral interventions
● The yield of genetic
can help young children with autism spectrum disorder gain skills and improve testing for autism spectrum
long-term outcomes.72–74 Applied behavior analysis (ABA) is currently disorder is higher in those
considered the gold-standard treatment for autism spectrum disorder. ABA is a who have syndromic
methodology based on learning theory principles that teaches skills and decreases features, dysmorphology,
or presence of intellectual
maladaptive behaviors through repetition and reinforcement. It can be used to disability. Additional
improve communication, socialization, adaptive behaviors, and cognition.72,75 etiologic testing, including
ABA can be delivered in an outpatient clinical setting, in the home, or in school. gene mutation analyses,
Several kinds of behavioral therapies are available, including discrete trial should be considered for
children if concerns exist
training (traditional ABA) and ABA-based hybrids such as the Early Start Denver for a specific neurogenetic
Model (ESDM)73 and pivotal response treatment (PRT).76 Naturalistic or metabolic syndrome or if
approaches are also available, such as Floortime.77 Some of these models the child has a history of
incorporate parents as interventionists. Play-based and social-pragmatic developmental regression.
behavioral interventions are also used to target core autism deficits of social
● The evaluator must
engagement, emotional thinking, and social skills. Treatment and Education of determine whether social
Autistic and Related Communication Handicapped Children (TEACCH) is a and communication
structured teaching method that is especially useful for visual learners.78 difficulties and repetitive
behaviors are best explained
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by autism spectrum
Allied Services and Therapies
disorder or another medical
Speech and language therapy and a total communication approach involving
or neurodevelopmental
the use of gestures and signs (American Sign Language), picture exchange disorder.
communication systems (PECS), communication boards, visual supports, and
assistive technology and devices may be used to support functional communication. ● Behavioral and
Occupational therapy can be helpful for addressing adaptive skill needs, sensory educational therapies are
the mainstay of treatment
needs, and fine motor/visuomotor support. While not a lot of research-based for autism spectrum
evidence exists to support most sensory integration techniques, some techniques disorder.
and tools may be helpful for some children, such as the use of brushing, weighted
vests, and sensory toys. The development of social skills can also be facilitated ● The National Research
Council Recommendations
by using social skills groups. Some school programs have “lunch bunch” groups, for Educating Children With
and social skills groups are also available in the community. Autism include at least
25 hours of total service
Counseling time, maximal individualized
In those with average intelligence and typical language skills, counseling instruction with a low
methodologies can be successfully employed for core symptoms of rigidity and teacher to student ratio, and
parent/family involvement.
inflexibility as well as comorbid psychiatric disorders (eg, depression, anxiety)
and behavioral dysregulation. While the use of psychotherapy is obviously limited ● Applied behavior
for individuals with language and cognitive impairment, cognitive-behavioral analysis, a methodology
therapy (CBT) techniques have been modified for use with the autism spectrum based on learning theory
principles that teaches
disorder population with good outcomes.79
skills and decreases
maladaptive behaviors
Pharmacologic Therapies through repetition and
Currently, no medications are US Food and Drug Administration (FDA) reinforcement, is currently
approved for the treatment of the core symptoms of autism spectrum disorder; considered the gold-
this is an area of unmet need and active research. However, up to two-thirds of standard treatment for
autism spectrum disorder.
children with autism spectrum disorder use psychoactive medications to treat
impairing symptoms associated with autism spectrum disorder,80,81 and
medication use increases with age.82
Co-occurring behavioral or psychiatric disorders are common in autism
spectrum disorder, such as ADHD (with lack of safety awareness), anxiety,
aggression/irritability, and self-injurious behavior. Medications used in other
KEY POINTS psychiatric disorders can be effective in individuals with autism spectrum
disorder as well. The only two medications that are FDA approved for use in this
● Currently, no
medications are US Food
population are risperidone and aripiprazole, both atypical antipsychotics and
and Drug Administration approved specifically for treating irritability and aggression in children with
autism spectrum disorder. Other medications are used to treat commonly occurring
approved for the treatment

of the core symptoms of symptoms, such as anxiety or OCD (selective serotonin reuptake inhibitors
autism spectrum disorder;

[SSRIs]); ADHD symptoms of impulsivity, hyperactivity, and inattention (alpha
however, risperidone and
aripiprazole are approved agonists, stimulants); sleep dysfunction (melatonin or sedatives); and mood
specifically for treating the disorders (SSRIs, atypical neuroleptics, and mood stabilizers). Children with
symptoms of irritability and autism spectrum disorder tend to experience more side effects from medications;
aggression in children.
therefore, medication dosing trials should “start low and go slow.” For
● Co-occurring behavioral medications commonly used, published doses may be used, although the
or psychiatric disorders are starting dose is often lower than published dosing recommendations.
common in autism spectrum
disorder. Medications used Complementary and Alternative Medicine
in other psychiatric
disorders can be effective in
Treatments such as dietary modifications, vitamins and supplements, acupuncture,
individuals with autism chiropractic, chelation, hyperbaric oxygen, and immunologic agents are widely
spectrum disorder as well. used by families in children with autism spectrum disorder. To date, inadequate
scientific peer-reviewed research exists to support these treatments.83 Treating
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● Children with autism

clinicians should inquire about the use of these treatments and provide guidance
spectrum disorder tend to
experience more side regarding potential side effects or harm. Even if not thought to be harmful, many
effects from medications; complementary and alternative medicine treatments can be costly. Families
therefore, medication should be provided with information about the lack of controlled data available,
dosing trials should “start but this should be done in a nonjudgmental manner, and resources and information
low and go slow.”
should be provided to families about how to evaluate and monitor alternative
treatments. Families should be advised that complementary and alternative
medicine treatments should not replace proven behavioral treatments.
CONCLUSION
Autism spectrum disorder is a complex heterogeneous disorder, with
symptoms of social communication deficits and restricted/repetitive
behaviors that are present early in development and are usually lifelong. The
impairments significantly impact the child’s ability to function both at home
and in the community. Because of the neurodevelopmental nature of the
disorder, neurologists are often called upon to make the diagnosis and perform
an etiologic evaluation. Neurologists may also primarily manage neurologic
comorbidities and may serve as a medical home for overall care of the patient
with autism spectrum disorder. To aid in this task, this article has reviewed
core symptoms, comorbidities, and proposed etiologies and provided an
approach to the office visit with questions for the diagnostic evaluation,
recommendations for workup, and a summary of treatment approaches.
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REVIEW ARTICLE

Transition From Pediatric
to Adult Neurologic Care
ONLINE
By Ann H. Tilton, MD, FAAN; Claudio Melo de Gusmao, MD

S U P P L E M E N T AL D I G I T A L
CONTENT (SDC)
A VA I L A B L E O N L I N E
ABSTRACT
PURPOSE OF REVIEW: With advances in medical care, the number of youths
surviving with medically complex conditions has been steadily increasing.
Inadequate transition planning and execution can lead to gaps in care,
unexpected emergency department visits, and an increase in health care
costs and patient/caregiver anxiety. Many barriers that prevent adequate
transition have been identified, including insufficient time or staff to
provide transition services, inadequate reimbursement, resistance from
patients and caregivers, and a dearth of accepting adult providers.
09/2022
RECENT FINDINGS: Transitionis distinct from transfer of care. Transition is a

planned multistage process, while transfer refers to a point in time
where responsibility of care shifts from one provider to another. Key
CITE AS: differences exist between the pediatric and adult models of care. A
CONTINUUM (MINNEAP MINN) successful transition should empower the patient to understand and take
276–287.
responsibility in managing his or her condition; foster independent
functioning to the extent that is possible; integrate educational, legal, and
Address correspondence to community resources in the care plan; and identify appropriate adult
Dr Ann Tilton, Children’s Hospital health care providers at the time of transfer. Different models have been
of New Orleans, 200 Henry Clay
Ave, Ste 3314, New Orleans, LA proposed to streamline the transition process, with improvement in
70118, atilto@lsuhsc.edu. patients' knowledge of their condition, self-efficacy, and confidence.
Dr Tilton serves on the board of SUMMARY: Neurologists have a key role in supporting their patients in the
directors of the American transition to adulthood. This article reviews basic tenets and provides
Academy of Neurology, on the tools to assist in navigating the complex transition process. These tenets
editorial boards of the Journal of
Child Neurology and Neurology, are intended to improve quality of care and decrease clinician burden and
and as a consultant for Ipsen remain an active area of research.
Biopharmaceuticals, Inc. Dr Tilton
has received personal
compensation for speaking
engagements, and
research/grant support from INTRODUCTION
A
Ipsen Biopharmaceuticals, Inc, ttaining biological adulthood is an expected part of life. Advances in
and receives patent royalties
through her institution for medical science in the past few decades have allowed an increasing
botulinum toxin in the prevention number of children with medically complex conditions to survive
and treatment of acne. Dr de and experience this milestone. In the United States, it is currently
Gusmao reports no disclosure.
estimated that about 18% of the population aged 12 to 18 years has
UNLABELED USE OF special health care needs, nearly double the prevalence in younger children
PRODUCTS/INVESTIGATIONAL USE
DISCLOSURE:
between 0 and 5 years of age.1 Children’s hospitals are caring for an increasing
Drs Tilton and de Gusmao number of patients outside of the traditional pediatric age range, and neurologic
report no disclosure. conditions are particularly common reasons for adult visits to pediatric
© 2018 American Academy emergency departments.2 In aggregate, patients older than 18 years of age cost
of Neurology. pediatric hospitals about $627 million per year.3 Every year, about 750,000
276 FEBRUARY 2018

youths require transfer from pediatric to adult care; unfortunately, KEY POINTS
less than 40% meet nationally defined transition core outcomes.1,4 In 2011, the
● Every year, about
American Academy of Pediatrics endorsed a guideline for assisting 750,000 youths require
practitioners in transitioning patients, but its impact is still largely minimal in transfer from pediatric to
neurologic practices.5 adult care; unfortunately,
In addition to physical limitations, neurologic conditions may impart less than 40% meet
nationally defined
cognitive issues that preclude complete independence at a time when educational transition core outcomes.
and social service supports come to an end with no similar services available for
adults. Furthermore, in many pediatric-onset neurologic conditions, such as ● In many pediatric-onset
epilepsy, the burden of disability may be present even if patients are in clinical neurologic conditions, such
as epilepsy, the burden of
remission. About two-thirds of all patients with pediatric-onset epilepsy may disability may be present
become seizure-free in adulthood, but up to 80% of these patients will have even if patients are in
ongoing cognitive, behavioral, or psychiatric problems associated with poor clinical remission.
social outcomes.6,7
● The distinction between
Transition to adult care can be defined as the planned movement of
child-centered and
adolescents and young adults with chronic physical and medical conditions from adult-centered care is
a child-centered to an adult-oriented health care system.8 The distinction important.
between child-centered and adult-centered care is important, as differences exist
between these models of care. Pediatric neurology has been described as ● Adult medicine carries an
09/2022
expectation that knowledge

comprehensive and family oriented, whereas adult neurology is disease-centered and management of
and focused on the individual.9,10 Adult medicine carries an expectation that disorders should be
knowledge and management of disorders should be assigned to the patient, but assigned to the patient,
these skills are not necessarily fostered during pediatric care. but these skills are not
necessarily fostered during
The transition process for neurologic patients may be particularly challenging. pediatric care.
Patients and families may struggle to come to terms with reduced expectations
for adult independence and may express anger or grief at the nature of ● Transition should be
limitations imposed by the medical condition and at assuming responsibility for viewed distinctly from
transfer of care. Transition
their medical care.11 A successful transition should aim to achieve several goals:
is a planned multistage
(1) to prepare the youth to understand his or her chronic illness and take process, while transfer
responsibility for its management (to the extent that the patient’s cognitive refers to a point in time
capacity allows), (2) to empower patients and caregivers to allow them to where responsibility of care
function as independently as possible in adult-oriented medicine, (3) to identify shifts from one provider to
another.
the appropriate adult health care providers for transfer, and (4) to communicate
effectively with accepting providers.11,12 Key components of transition planning
are as follows:
u Prepare the youth to understand his or her chronic illness and take responsibility for
its management (to the extent that the patient’s cognitive capacity allows)
u Empower patients and caregivers to allow them to function as independently as

possible in adult-oriented medicine
u Identify the appropriate adult health care providers for transfer; even if an appropriately
trained adult neurologist counterpart is not immediately available for transfer,
transition planning should still apply
u Communicate effectively with accepting providers
Transition should be seen more broadly than as simply transfer of care.

Transition is a planned multistage process, while transfer refers to a point in time
where responsibility of care shifts from one provider to another. Transfer of care
TRANSITION TO ADULT NEUROLOGIC CARE
KEY POINTS is one of several desired goals of a successful transition. Notably, in some
neurologic subspecialties, an adult neurologist counterpart may not be readily
● Inadequate, unplanned,
or incomplete transition may identifiable (eg, neurometabolic disorders, neurodevelopmental or neurogenetic
cause significant morbidity. disorders). In these situations, a patient may be determined to be better served
Often, entry to the adult by the expertise of a particular provider through adulthood, and transfer does not
care system for neurologic occur. Nevertheless, transition planning is still applicable in these cases; patients
patients occurs at a time of
crisis and with significant should be gradually prepared for the adult model of care and will require
gaps in care. Even in patients coordination and assistance to transfer to adult care in other domains (eg,
with complex chronic primary care, other non-neurologic subspecialties).
conditions, this interval can Transfer does not mark the end of transition; young patients entering adult
be longer than 1 year, with
potential for lapses in care
care often require specific attention as they continue to adapt to the adult model
and increased high-acuity of care. Pediatric providers may still consult with adult colleagues in particularly
emergency department complex cases.11 Inadequate, unplanned, or incomplete transition may cause
visits. significant morbidity. Often, entry to the adult care system for neurologic
patients occurs at a time of crisis and with significant gaps in care.13,14 Even in
● Transition is best viewed
as not only being composed patients with complex chronic conditions, this interval can be longer than 1 year,
of philosophical tenets but with potential for lapses in care and increased high-acuity emergency
also of well-defined steps department visits.15,16 The increase in costs and health care utilization has been
that provide the details
described in several neurologic conditions, including epilepsy, cerebral palsy,
09/2022
necessary for implementation.

spina bifida, muscular dystrophy, intellectual disabilities, and other
● It is best that the youth neurodevelopmental disabilities.3,17–19
and caregivers have a clear Many barriers have been identified that preclude a successful transition in a
expectation that a transition variety of pediatric-onset neurologic disorders: having the time, support staff,
into the adult health care
system will be scheduled.
and appropriate reimbursement for transition planning; hesitancy and resistance
from patients and caregivers to conclude a long-standing relationship; finding
● The initial discussion of knowledgeable and accepting providers at the time of transfer; poor communication;
transition with patient and and a gamut of legal, financial, and institutional hurdles.11,20–23 Meanwhile, patients
caregivers should raise
continue to risk morbidity and mortality as these barriers preclude safe transition.
awareness of upcoming
changes in the care model Different models have been proposed to streamline the transition process, but
through adolescence, heterogeneity exists in outcomes assessments and a limited number of studies
including private sessions have been conducted on which to base the choice of the most appropriate
between the youth and
framework. Organized transition programs have demonstrated improvement in
health care provider, the
expectation of knowledge patients' knowledge of their condition, self-efficacy, and confidence, but small
of the neurologic condition, sample sizes and short follow-up times preclude more generalizable
the gradual increase in conclusions.24 In the face of the relative dearth of data regarding this vexing
responsibility for managing problem in neurology, the Child Neurology Foundation convened a diverse
health care needs (to the
extent possible), and the multidisciplinary group in 2014 to develop eight specific principles to be
differing health care needs considered in the approach to the transition of the pediatric patient to adult
of adults. services, based on current evidence where available and expert opinion where it
was lacking.11 This multidisciplinary task force was composed of pediatricians;
adult and child neurologists; and nurse, allied health provider, patient, parent,
and advocacy group members. The group shared the common belief that
transition is best viewed as not only being composed of philosophical tenets but
also of well-defined steps that provide the details necessary for implementation.
Within the common tenets are references to a toolbox of letters and forms that
are available from the Child Neurology Foundation.25 This toolbox is included to
help accomplish the goal of a systematic approach to transition. The tools are
specifically adapted to meet the needs of patients with neurologic disorders and
are based on and modified from Got Transition/Center for Health Care
Transition Improvement, which is a cooperative agreement between the
278 FEBRUARY 2018

Maternal and Child Health Bureau and The National Alliance to Advance
Adolescent Health.26 To be concise, the eight principles are condensed here into
seven “tenets.” The last principle emphasizes adequate documentation and
communication between adult and pediatric providers, and this need is
highlighted throughout this article.
COMMON TENETS FOR TRANSITION

The child neurology team discusses with the youth and caregiver(s) the
expectation of the future transition to the adult health care system. This
discussion should be initiated early, ideally no later than the youth’s 13th birthday
(FIGURE 13-1 and SDC 13-127; links.lww.com/CONT/A236).
It is best that the patient and caregivers have a clear expectation that a
transition into the adult health care system will be scheduled. The initial
discussion is not meant to be extensive, but rather to introduce the concepts of
transition and transfer. Ideally, it raises awareness of upcoming changes in the
care model through adolescence, including private sessions between the patient
and health care provider, the expectation of knowledge of the neurologic
condition, the gradual increase in responsibility for managing health care needs
(to the extent possible), and the differing health care needs of adults. The age or
09/2022
age range at which the actual transfer may occur is defined by the medical
practice and is preferably consistently applied or, at the very least, applied with
well-defined exceptions. The main goal of this discussion is to assure the family
of a systematic transition. Some practices provide written notification as well as
brochures and readily accessible Web-based information summarizing a formal
transition policy that outlines goals and expectations.
An early discussion allows for transparency in the process and sufficient time
for the neurology team to meet several goals that are expected in the adult model
of care. This includes ensuring the adolescent understands and assumes
responsibility for his or her medical condition and medications and, when
necessary, assessing the adolescent’s ability to make independent decisions.
FIGURE 13-1
Core elements of transition planning and timeline.
KEY POINTS Advance preparation may also allay the natural anxiety incurred with the
expectation of changing physicians. Finally, it allows time to prepare patients for
● A regular review of the
patient’s self-management the philosophical differences in the level of expected independence between the
skills is important so that pediatric and adult health care systems. These can be unanticipated and very
gaps in the patient’s distressing if the patient and family are not equipped, especially for a child or
knowledge base can be young adult with special needs. Ensuring that part of the visit is spent meeting
identified and remedied
before transition. privately with the adolescent can help prepare caregivers and patients as they get
older. Thus, expectations should be clarified early and supported over time.
● Individuals with The child neurology team ensures that an assessment of the youth’s
intellectual disabilities should self-management skills begins soon after the expectation of transition is discussed
not be excluded from the
self-management
with the youth and continues on an annual basis. These assessments should be
assessment process, as documented in the patient’s medical record and communicated to other health
many may be able to care providers (FIGURE 13-1, SDC 13-228; links.lww.com/CONT/A237 and
SDC 13-3 ; links.lww.com/CONT/A238).
develop limited 29
self-management skills. In
As patients mature, their self-care abilities and level of independence evolve.
particular, individuals with
mild intellectual disability A regular review of the youth’s self-management skills is important so that gaps
may be able to exert some in the patient’s knowledge base can be identified and remedied (CASE 13-1). The
decision-making capacity caregiver’s knowledge of the patient’s disorder and medical needs should be
and often can become
assessed and any disparities addressed. If self-management is not possible, it is
09/2022
responsible for knowing

their diagnosis, taking critical to identify this lack of capacity for long-term planning. Individuals with
medication independently, intellectual disabilities should not be excluded from this process, as many may be
and participating in their able to develop limited self-management skills. In particular, individuals with
own care. mild intellectual disability may be able to exert some decision-making capacity
and often can become responsible for knowing their diagnosis, taking medication
independently, and participating in their own care.31,32
A variety of tools are available to assist with self-management, according to
the practice and conditions being treated. The Useful Websites section at the end
of this article lists some helpful resources for self-management. The
self-management assessments should be documented in the patient’s medical
record and shared with others who provide care.
The child neurology team engages the youth and his or her caregiver(s) in
phased transition planning, patient education, and transfer readiness at least
annually at scheduled visits, beginning at 13 years of age (FIGURE 13-1).
Youths and their caregivers should be involved as active participants in their
transition plans. Optimally, the plan is phased in and the evaluation of transfer
readiness occurs separately from acute clinical care to allow for adequate time and
clear expectations. The level of engagement may vary according to sociocultural
issues and the patient’s cognitive ability. Nevertheless, as previously stated,
individuals with intellectual disabilities should still be engaged to develop
self-management skills to the extent possible as limited by their cognitive abilities.14
In this planning, several items are ideally addressed: evaluation of the youth’s
current medical condition, including ongoing and long-term medical issues;
medications and knowledge of the potential side effects; genetic counseling, with
education on recurrence risk, puberty, and sexuality; and adolescent and young
adult issues such as alcohol, driving, and substance abuse. Basic elements of good
clinical care, such as overall wellness (including emotional and psychological
health), can also be included in these visits.
By the time the youth is 14 years of age, the child neurology team initiates
discussion with the caregivers regarding the youth’s expected legal competency
(whether a need for legal guardianship and power of attorney exists). If the
280 FEBRUARY 2018

A 12-year-old boy with Duchenne muscular dystrophy who was CASE 13-1
wheelchair dependent and had mild cardiomyopathy learned about
transition to adult health care in a regularly scheduled visit. In subsequent
visits, he was encouraged to become more independent in managing his
health and spent some time in private consultation. Starting at age 13, he
filled out the Transition Readiness Assessment Questionnaire (TRAQ)30
each year, and areas were marked for learning and improvement. He
downloaded a smartphone app to remind him to take his prednisone and
started to attend his regular physical therapy at the local rehabilitation
center independently using adaptive transportation services. Ongoing
clinic visits assessed his understanding of his health condition, gene
defect, and prognosis. Although he had borderline intellectual disability,
he fully understood the implications of his condition and was expected to
remain with decision-making capacity. His preferences played an
increasing role in the advance directive that was kept on file. The local
rehabilitation center recommended adaptive environmental controls aimed
at maximizing increasing independence while reducing caregiver burden.
When the patient was 16 years of age, the child neurologist invited a
09/2022
psychologist and occupational therapist to consult on plans for further

education and vocational planning. The patient was interested in developing
computer games and began to contribute to an online blog for youth with
muscular dystrophy. When he reached 17, the team started searching for
an adult practice. The state had no adult muscular dystrophy program,
but an accepting neuromuscular specialist was identified at a tertiary
academic medical center. A cardiologist in the same center agreed to
assume his care, and his pediatrician identified an accepting adult internist.
The patient was provided with a list of these professionals and told that
it would be his responsibility to make appointments and arrange
transportation. The clinic social worker offered contact information for the
Department of Disability Services, independent living resources,
vocational rehabilitation services, and support groups.
At the time of transfer, the clinic staff sent a transfer packet, including
the transition care plan and a medical summary, to the adult providers. The
contact information of the pediatric muscular dystrophy clinic was made
available for support as needed.
This case illustrates the multiple steps for transition of care from pediatric COMMENT
to adult care in a progressive neurologic condition with preserved
decision-making capacity. The availability of a multidisciplinary team and
ancillary resources such as transition tools greatly reduces the burden on
the clinician in transition planning.
KEY POINTS youth’s expected legal competency is unclear, an assessment of that capacity
should be made annually.
● Some patients with
cognitive limitations will A major concern in clinical care of neurologic patients is that individuals
require legal guardianship, with significant neurologic disabilities often enter the age of majority without
and starting the discussion having their legal competency addressed. Some youths with cognitive
by the age of 14 allows limitations will require legal guardianship (full or limited [eg, to medical
adequate planning before
the patient’s 18th birthday

decisions or financial conservatorship]) and starting the discussion by the age
(the age of majority in most of 14 allows adequate planning before the youth’s 18th birthday (the age of
states). majority in most states).
Therefore, if competency is unclear as majority approaches, a formal
● In the United States, if
evaluation is often required (CASE 13-2). Formal psychological and
no process has determined
otherwise, competency is neuropsychological assessments can offer detailed testing and needed insight and
automatically assumed at allow for reevaluation if the determination is unclear. Notably, establishing
majority, regardless of the competency or lack thereof is a matter of judicial decision. Nevertheless, some
degree of the individual’s
state courts require a clinical team report to assist them in making such
disability. This directly
impacts the young adult and determinations. This report often consists of evaluations performed by a
those providing care, as physician, psychologist, and social worker within a certain period of time, so
legally removing competency advance planning is key. In the United States, if no process has determined
is a lengthy and potentially otherwise, competency is automatically assumed at majority, regardless of the
09/2022
expensive process.
degree of the individual’s disability. This directly impacts the young adult and
● Some state courts require those providing care, as legally removing competency is a lengthy and potentially
a clinical team report to expensive process.
assist them in making Emphasis should always be placed on supporting the youth’s decision-making
decisions establishing
competency or lack thereof.
ability and supporting interventions that can maximize that ability. Caregivers
This report often consists of benefit from support and education during this difficult process as well. Social
evaluations performed by a workers, child life specialists, and other community-based support services may
physician, psychologist, and be helpful throughout the guardianship process.
social worker within a
A transition plan meeting the comprehensive needs of the youth is developed
certain period of time, so
advance planning is key. in collaboration with the youth, caregiver(s), other health care providers, school
personnel, vocational professionals, community services providers, and legal
services (as needed). The plan addresses health care finance and legal concerns;
primary care; other specialty care; and education about employment, housing,
and community services. The child neurology team reviews and ensures the
adequacy of the transition plan annually (FIGURE 13-1, SDC 13-4,33; links.lww.com/
CONT/A239 and SDC 13-534; links.lww.com/CONT/A240).
The transition team includes the child neurology care team and other
providers pivotal in the patient’s care, thus offering the ability to address the
comprehensive needs of patients with complex medical conditions. Optimally,
multiple parties collaborate and contribute. At its core, the team includes the
youth and the caregivers, the primary care physician and ancillary staff at the
medical home, subspecialists, and any other pertinent health care providers. The
neurologist is best qualified to systematically review the neurologic issues and
concerns and contribute to the neurologic component of the annual plan. It is
well recognized that the educational system, school personnel, vocational
professionals, legal professionals, community service providers, and others can
all contribute valuable insights. The contributions from each area vary as needs
evolve and may change over time.
The child neurology team is responsible for developing and verifying the
neurologic component of the transition plan of care and should update it
annually (SDC 13-5; links.lww.com/CONT/A240).
282 FEBRUARY 2018

A transition of care discussion began for a 13-year-old girl with tuberous CASE 13-2
sclerosis complex who had intractable epilepsy, autism spectrum
disorder, intellectual disability, and renal angiomyolipomas. A neurologist,
nephrologist, and psychiatrist were directly involved in her care. She
attended a special education school program and was able to follow

simple commands and communicate with a few words but was dependent
on assistance in several activities of daily living. The neurologist and the

patient’s mother decided that transfer of care would occur when she was
between 19 and 22 years of age, after guardianship was established. The
child neurologist encouraged the mother to initiate similar discussions with
the patient’s other specialists.
Over the next several years, transition issues were reviewed by a
member of the child neurology team during scheduled visits. Given the
patient’s severe intellectual disability, she was not expected to become
independent. By age 16, based on her individualized educational program
(IEP), it was determined that she would remain in school until age 21. The child
neurology team provided contact information for community resources, the
Tuberous Sclerosis Alliance, and a parent-to-parent support group as
09/2022
the family learned about adult daycare, school/vocational resources, and

disability services.
When the patient was 17 years of age, the neurology team informed the
mother of the steps required to meet state-specific regulations to attain
guardianship and a trust fund for Social Security benefits. A medical
summary and emergency care plan were completed by the family in
conjunction with the child neurologist. Members of the neurology team
contacted the patient’s other providers requesting an update to their
portions of the summary.
Shortly before the patient turned 18, the search began for an accepting
adult neurologist. Her mother contacted the Department of Disability
Services to explore vocational programs. In preparation for a court hearing
regarding guardianship, the child neurologist completed state-specific
forms in conjunction with a licensed social worker and the school
psychologist. A court hearing named the mother the legal guardian. By the
next office visit, an accepting adult epileptologist had been identified.
The mother’s knowledge about tuberous sclerosis complex, medications,
and seizure care were reviewed. A copy of the transfer packet was provided
to the family, and another was sent to the accepting adult clinician. After this
last visit, a member of the child neurologist’s team confirmed an
appointment was made and attended in the accepting practice.
This case illustrates the complex steps in transitioning a patient with a COMMENT
neurologic disorder and cognitive disability. It also underscores the
participation of the child neurology team as the care coordinator of a
team that includes multiple professionals, such as nurses, social workers,
the school, and parent organizations.
The neurologic component of the transition plan should include the following:
u A specific summary of health care issues
u A summary of the patient’s goals and preferences for adult service requirements
u The planned timing of the transfer to an adult provider of neurologic care (established in
accordance with the practice policy and in collaboration with the patient and caregiver)
u Any necessary additional testing or assessments to be completed before transfer
u A current assessment of the patient’s understanding of his or her neurologic diagnosis

and management
u Emergency plans and the patient’s advance care plan status (eg, medical power of
attorney, living will, do not resuscitate order)
u For those with profound cognitive disability, plans for establishing guardianship
The child neurology team, in collaboration with the youth and caregiver(s),
identifies an appropriate adult provider or providers for the neurologic condition(s)
before the anticipated time of transfer. The child neurology team coordinates the
transfer using a transfer packet (FIGURE 13-1; SDC 13-4, links.lww.com/CONT/A239;
09/2022
SDC 13-5, links.lww.com/CONT/A240; SDC 13-6, links.lww.com/CONT/A241;

35
SDC 13-7, links.lww.com/CONT/A242; and SDC 13-8, links.lww.com/CONT/A243).

36 37
The child neurology team is essential in identifying and collaborating with an

adult neurologist or other appropriate medical caregivers as the plans are made to
transfer the patient to adult services. The new accepting provider should be
established before the patient’s 18th birthday or at a time the child neurologist’s
practice defines as their time of transfer.
With an adult provider identified, information can be delivered before the
patient’s initial visit. A major tool in this transfer is the transfer packet, which
should include the transition care plan and a medical summary with relevant
medical information, such as imaging studies, electrophysiologic test results,
recent laboratory studies, and other pertinent data. If the plan has been
developed and maintained over time, it will provide indispensable assistance in
the road to transition. Both the child neurology provider and the new provider
will have information that will improve communication and deliver the details of
the patient’s medical information, medical care can be continued without
interruption, and the burden on the new physician will be substantially lessened.
The time of transfer is fraught with a great deal of anxiety, and identifying an
adult provider in advance may allow for an initial visit and an opportunity to ask
questions and discuss the transition to minimize distress.38 If possible, an
introductory meeting may be accomplished by either the adult provider visiting
the current practice or the patient having a less formal visit with the new
provider. While optimal, this is often difficult or unrealistic with typical practice
demands. Interest is growing in virtual visits in which the patient and family are
able to meet the new physician by Web-based video conferencing. In addition to
preliminary visits with the adult provider, successful transfer models described
in the literature include transition coordinators, joint pediatric-adult transition
clinics, and the use of nurse-led or social worker–led programs.9,22,39–43
Coordination of care with the medical home and adult primary care providers,
especially dual-trained medicine-pediatric physicians, can also serve as valuable
resources during the transfer process.
284 FEBRUARY 2018

The transition time frame is unquestionably best established before an acute KEY POINT
need exists. A follow-up visit or phone call by the child neurology provider ● The child neurology team
following the first visit with the new provider is reassuring to the family and is essential in identifying
demonstrates that this is indeed a transition among colleagues and an appropriate and collaborating with an
step in the maturing of the patient. adult neurologist or other
appropriate medical
Following the transition and transfer process of the pediatric patient to an
caregivers as the plans are
adult provider, integration of the patient into the new practice is necessary. This made to transfer the patient
integration is the incorporation of the new patient for ongoing care. A systematic to adult services.
model for integration is available and provides a corresponding framework for
the adult provider. This is especially helpful when integrating a youth with special ● A major tool in the
transfer to an adult health
health care needs. The gottransition.org website provides excellent resources, care provider is the transfer
including a policy of clinic expectations and orientation to adult practice.26 The packet, which should
transfer packet documents provide readiness information, the patient’s and include the transition care
family’s health concerns, and overall goals. The medical summary and emergency plan and a medical summary
with relevant medical
plan become an important ongoing document that should be updated regularly. information, such as imaging
Fortunately, there are readily available resources not only for the pediatric care studies, electrophysiologic
team but also for the adult care provider and team. The physician or other test results, recent
caregiver accepting a young adult with complex health care needs may never laboratory studies, and
other pertinent data.
have cared for a patient with a similar disorder. An open line of communication
09/2022
between the referring and accepting care teams offers immeasurable support. ● Child neurologists and
child neurology teams have
a key role in supporting their
patients in their transition to
CONCLUSION adulthood.
It is the authors’ belief that child neurologists and child neurology teams have a key
role in supporting their patients in their transition to adulthood. Pediatric neurologists
are particularly well poised to implement and engage in active transition planning
for their patients. Adult neurologists will likely encounter increasing numbers of
pediatric-onset neurologic disease in their practices. Some may feel insufficiently
trained in the management of particular conditions or perceive these patients to
be particularly challenging. Avoiding “cold” handoffs and fostering ongoing
communication and discussion with pediatric providers is key. It is hoped that this
article has provided tools to streamline the process and decrease the burden on the
medical team. Active advocacy is needed to minimize barriers (such as time constraints
and finding accepting providers) by instating reimbursement for transition services
and increased adult training opportunities in pediatric-onset neurologic diseases.
Ultimately, data are insufficient to determine the best model; however,
compelling evidence exists that lack of planning leads to undesired outcomes.
Research targeted at defining optimal transition outcomes and evaluating
different models quantitatively and qualitatively will shed further light on the
care of transitioning patients and improve quality and satisfaction with care.
USEFUL WEBSITES
CHILD NEUROLOGY FOUNDATION GOT TRANSITION
The Child Neurology Foundation website is a The Got Transition website is dedicated to improving
repository of resources and tools for health care transition from pediatric to adult health care for
providers and patients/caregivers to assist in the all patients. It originated from a cooperative
transition of neurologic patients. agreement between the Maternal and Child Health
childneurologyfoundation.org/transitions Bureau and The National Alliance to Advance
Adolescent Health and serves as a clearinghouse
for current transition information, tools, and resources.
gottransition.org
TRANSITION READINESS ASSESSMENT QUESTIONNAIRE MUSCULAR DYSTROPHY ASSOCIATION YOUNG

The East Tennessee State University Department of ADULT PROGRAMS
Pediatrics website provides the Transition The Muscular Dystrophy Association website
Readiness Assessment Questionnaire in provides resources to assist young adults with
downloadable PDF, Word, and Excel formats. neuromuscular disease in planning for education,
etsu.edu/com/pediatrics/traq/ employment, and personal care/independent
living.
mda.org/young-adults
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REVIEW ARTICLE

Neurologic Complications
I NT E R V I E W A V AI L A B L E in the Pediatric Intensive
ONLINE
Care Unit
By Mark S. Wainwright, MD, PhD
ABSTRACT
PURPOSE OF REVIEW: All critical care is directed at maintaining brain health,
but recognizing neurologic complications of critical illness in children
is difficult, and limited data exist to guide practice. This article discusses
an approach to the recognition and management of seizures, stroke,
and cardiac arrest as complications of other critical illnesses in the
pediatric intensive care unit.
09/2022
RECENT FINDINGS:Convulsive and nonconvulsive seizures occur frequently

in children after cardiac arrest or traumatic brain injury and during
extracorporeal membrane oxygenation. Seizures may add to neurologic
morbidity, and continuous EEG monitoring is needed for up to 24 hours
for detection. Hypothermia has not been shown to improve outcome
after cardiac arrest in children, but targeted temperature management
with controlled normothermia and prevention of fever is a mainstay
of neuroprotection.
SUMMARY: Much of brain-directed pediatric critical care is empiric.

Recognition of neurologic complications of critical illness requires
CITE AS: multidisciplinary care, serial neurologic examinations, and an
appreciation for the multiple risk factors for neurologic injury present
288–299. in most patients in the pediatric intensive care unit. Through attention
to the fundamentals of neuroprotection, including maintaining or
Address correspondence to restoring cerebral perfusion matched to the metabolic needs of the
Dr Mark S. Wainwright, Division of
Neurology, Seattle Children's brain, combined with anticipatory planning, these complications can be
Hospital, 4300 Sand Point Way prevented or the neurologic injury mitigated.
NE, Seattle, WA 98105, Mark.
Wainwright@seattlechildrens.org.
Dr Wainwright serves as a
consultant for and on the clinical INTRODUCTION
T
advisory board of
he lack of data from randomized controlled clinical trials to guide
SAGE Therapeutics.
management of children with acute brain injuries or neurologic
UNLABELED USE OF complications of critical illness occurs in striking contrast with the
USE DISCLOSURE:
data available to neonatologists, adult neurointensivists, or adult
Dr Wainwright reports stroke neurologists. Early recognition of changes in the neurologic
no disclosure. examination is essential for brain-directed critical care for children. Therefore,
© 2018 American Academy neurologic management of the patient in the pediatric or cardiac intensive care
of Neurology. unit (ICU) requires an interdisciplinary team involving neurologists, intensivists,
288 FEBRUARY 2018

neurosurgeons, and allied disciplines, including physical medicine and KEY POINTS
rehabilitation and psychiatry.1,2 Management should include anticipation of
● Neurologic management
specific changes in the patient’s examination, an understanding of the cellular of the patient in the
mechanisms of injury causing that change, and a predefined intervention to pediatric or cardiac
address that mechanism.3 This article discusses the approach to diagnosis and intensive care unit (ICU)
management of common neurologic complications in the pediatric ICU, requires an interdisciplinary

team involving neurologists,

including seizures, stroke, cardiac arrest, weakness, and sympathetic hyperarousal,
intensivists, neurosurgeons,
as well as in two high-risk populations: children with acute liver failure and those and allied disciplines,
supported with extracorporeal membrane oxygenation (ECMO). including physical medicine
and rehabilitation and
GENERAL PRINCIPLES OF NEUROPROTECTION psychiatry.
All critical care is directed at maintaining brain health. In general, this means
● Neuroprotection aims to
maintaining or restoring cerebral perfusion matched to the metabolic needs of match cerebral perfusion
the brain, whether this involves management of complications such as stroke, with the metabolic
intracranial hemorrhage, cerebral edema, or refractory status epilepticus. The requirements of the injured
approaches needed to achieve this balance depend on the mechanism of the brain.
neurologic insult. ● Electrographic seizures
and electrographic status
SEIZURES IN THE INTENSIVE CARE UNIT epilepticus have been
09/2022
Seizure management, or evaluation for suspected seizures or nonconvulsive associated with increased
seizures, is the most frequent reason for a request for neurologic evaluation in the risk for neurologic morbidity
ICU. Since many patients in the pediatric ICU or cardiac ICU have a risk factor after neurologic insults.
for central nervous system (CNS) injury, the threshold for obtaining continuous ● Electrographic seizures
EEG monitoring to characterize spells or to detect nonconvulsive seizures should may cause secondary injury
be low. In the past decade, the burden posed by nonconvulsive seizures in and worsen outcome in
critically ill children has increasingly been recognized, seen in approximately critical illness.
30% of patients undergoing continuous EEG monitoring.4
Association of Seizures With Outcome

The rationale for the use of continuous EEG to detect nonconvulsive seizures is
based on the hypothesis that seizures are a secondary insult and that treatment of
these seizures will improve outcome. In a study of 259 pediatric ICU and cardiac
ICU patients with a range of neurologic insults who underwent continuous EEG
monitoring, seizure burden was defined as the maximum percentage of any
given hour occupied by electrographic seizures.5 The maximum total seizure
burden was much greater in patients with neurologic decline than in patients
without such alterations and was associated with greater risk for neurologic
decline for every 1% increase in maximum hourly seizure burden. In a study of
300 children with an acute neurologic disorder (137 of whom were
neurodevelopmentally normal) who underwent clinically indicated continuous
EEG in the pediatric ICU, electrographic seizures and electrographic status
epilepticus were associated with worse adaptive behavior after discharge than in
children without seizures.6 These studies suggest that seizures in critically ill
children are associated with greater neurologic injury and may worsen outcome.
This plausible hypothesis has not been tested in a prospective study.7
At-risk Populations in the Intensive Care Unit

Specific populations of children in the ICU who are at increased risk for
nonconvulsive seizures have been identified. Nonconvulsive seizures were
detected in approximately one-third of children with prior in-hospital convulsive
seizures, structural brain injuries, or previous interictal EEG abnormalities.8 In
NEUROLOGIC COMPLICATIONS IN PEDIATRIC ICU
KEY POINTS children supported by ECMO, nonconvulsive seizures were detected in 23%,9
and in neonates after cardiac surgery with cardiac bypass, nonconvulsive
● Continuous EEG
monitoring for nonconvulsive
seizures were detected in 8%.10 Nonconvulsive seizures occurred in 36% to 46%
seizures should be obtained of children with acute encephalopathy.5,11 Nonconvulsive seizures are now also
for at least 12 to 24 hours increasingly recognized after acute CNS insults, particularly traumatic brain
in children with persistent injury and cardiac arrest. A prospective study of 87 children with mild to severe
altered mental status
following generalized
traumatic brain injury identified early posttraumatic seizures in 43%, among
convulsive status epilepticus which 16% were solely electrographic.12 Acute seizures (both clinical and
or other clinically evident nonconvulsive) occurred in 48% of 73 children following spontaneous
seizures and after intracerebral hemorrhage (ICH).13 After resolution of convulsive status
supratentorial brain injury
epilepticus in 98 children, electrographic-only seizures were detected in 34%.14
with altered mental status.
Electrographic seizures and status epilepticus are particularly common after
● Many children in the abusive head trauma, typically without a clinical correlate.15
intensive care unit have risk
factors for ischemic or Criteria for Continuous Electroencephalographic Monitoring
hemorrhagic stroke. Since continuous EEG is a limited resource, some means of selecting patients for
monitoring must be identified. Criteria for selection of patients for continuous
EEG monitoring in the ICU have been proposed,16,17 including persistent altered
mental status following generalized convulsive status epilepticus or other
09/2022
clinically evident seizures and after supratentorial brain injury with altered
mental status. Routine EEG recording fails to detect nonconvulsive seizures in
approximately 50% of patients who are critically ill in which nonconvulsive
seizures were subsequently detected with continuous EEG monitoring.18
Accordingly, the recommendations for the use of continuous EEG in the ICU
include initiating monitoring as soon as possible and continuing for at least
12 to 24 hours.
Evaluation and Management

Management of seizures in the ICU follows the typical approach of one or
two doses of a benzodiazepine for emergent initial therapy. This is followed by
a second anticonvulsant such as fosphenytoin, phenobarbital, or levetiracetam.
A 2014 review of a protocol for management of refractory status epilepticus
is representative of this approach.19 In the ICU, other important considerations
apply. First, in children who are critically ill, seizures may be the first sign of
arterial or venous stroke, intracranial hemorrhage, electrolyte disturbances,
CNS infection, or adverse drug reaction. Importantly, in parallel with the
initiation of or increase in anticonvulsant therapy, appropriate diagnostic
studies (imaging, chemistries, drug levels, cultures) and appropriate empiric
therapy should begin immediately. Second, treatment should be escalated
quickly as seizures may be adding a second insult to a primary neurologic
injury. Finally, these patients require meticulous management of temperature,
blood pressure, and ventilation, all factors that regulate cerebral metabolic
demand and perfusion and may also contribute to secondary neurologic injury.
An example of this approach used at the author’s institution is shown
in FIGURE 14-1.
STROKE IN THE INTENSIVE CARE UNIT

Cardiac disease, infection, and cerebral arteriopathy are three of the most
common risk factors for arterial ischemic stroke in children.20 These risk factors
apply to most of the children in a pediatric or cardiac ICU. Therefore, arterial or
venous ischemic strokes and ICH must be considered in the differential for a
290 FEBRUARY 2018

09/2022
FIGURE 14-1
Approach to the management of refractory status epilepticus in infants and children.
EEG = electroencephalogram; IV = intravenous; MAP = mean arterial blood pressure;
Pco2 = partial pressure of carbon dioxide.
change in the neurologic examination or as the inciting event for seizures in

the ICU (CASE 14-1). A high index of suspicion for stroke and rapid access to
neuroimaging are essential components of ICU management. The majority of
spontaneous hemorrhagic strokes in children are associated with vascular
malformations, but they can also occur with transformation of an ischemic
stroke, venous thrombosis, or from bleeding into an intracranial tumor.22

Acute Management
Guidelines for management of stroke in children are available, but no
recommendations exist with Level I evidence.23 Short-term anticoagulation
may be considered for pediatric arterial ischemic stroke pending
determination of the cause of the stroke. This is in contrast with the
recommended practice in adults, for whom urgent anticoagulation is not
recommended.24 Anticoagulation may be considered for proven cardiac
thrombus or extracranial arterial dissection.23 At present, recombinant tissue
plasminogen activator (rtPA) is not recommended as standard care for arterial
ischemic stroke in children. However, it has been used following published
09/2022
CASE 14-1 A previously healthy 4-year-old girl presented to the emergency

department with abdominal pain, headache, and clonic movements of
the right arm. On initial examination 20 minutes after seizure onset, she
was unresponsive to voice, her eyes were deviated to the right, and she
had clonic movements of the right arm and leg. Her vital signs were
normal. She was treated with 0.1 mg/kg IV lorazepam followed 5 minutes
later by fosphenytoin at a loading dose of 20 mg phenytoin equivalents
(PE) per kilogram. Her abnormal movements stopped within 10 minutes of
administration of fosphenytoin. She was intubated for airway protection.
Head CT without contrast was normal. The first set of laboratory results
showed normal electrolytes, a white blood cell count of 23,000/μL,
hemoglobin of 7.7 g/dL, and platelet count of 1082 103/μL. Two hours
later, she was still not responsive. Based on the persistent decrease in
responsiveness after clinically resolved seizures, continuous EEG
monitoring was obtained and showed electrographic seizures with a
focus in the left temporal region. To identify the mechanism, an emergent
MRI with contrast was obtained and showed a thrombus in the left
transverse and sigmoid sinuses. The patient was treated with hydration.
Milk-induced anemia, resulting from excess milk intake leading to
iron-deficiency anemia, was identified as the primary risk factor for
cerebral venous sinus thrombosis.21 Anticoagulation was considered,
but the neurologic examination improved with hydration, and repeat
imaging 3 days later showed no progression of the thrombus.
COMMENT This case illustrates the importance of considering nonconvulsive seizures

in patients in the intensive care unit and the need to identify the factors
causing seizures in order to initiate timely focused therapy.
292 FEBRUARY 2018

consensus-based safety guidelines. For more information on the treatment of KEY POINT
ischemic stroke in children, refer to the article “Evaluation and Acute
● Empiric neuroprotective
Management of Ischemic Stroke in Infants and Children” by Catherine measures for suspected
Amlie-Lefond, MD,25 in this issue of Continuum. ischemic stroke may
In the ICU, management of arterial or venous ischemic stroke aims to include positioning the
minimize secondary injury through aggressive prevention of fever, maintenance head of the bed flat,
increasing IV fluid rate,

of euglycemia and normotension, and prevention of hypoxia. These
reducing antihypertensive
recommendations for children are based on limited pediatric data. In practice, dosing, allowing blood
these protective measures may include positioning the head of the bed flat, pressure at the upper limit
increasing IV fluid rate, reducing antihypertensive dosing, allowing blood of normal for age, and
targeted temperature
pressure at the upper limit of normal for age, and targeted temperature
management, with a goal
management, with a goal temperature lower than 37°C (98.6°F). These temperature lower than
measures augment cerebral blood flow, support cerebral perfusion, and limit 37°C (98.6°F).
excess cerebral metabolic demand. Importantly, all these measures can be
undertaken before an ischemic stroke is confirmed or ruled out by
neuroimaging, and they should be initiated as soon as a stroke is considered in
the differential diagnosis. An approach to the acute management of stroke in
children has been published.26 The fundamental principles of neuroprotection
in stroke include restoring cerebral blood flow, either through increasing
09/2022
volume or pressure (giving fluids or pressors); enhancing flow (antiplatelet

therapy or anticoagulation); and removing the thrombus while controlling
metabolic demand (meticulous temperature management and treatment
of seizures).
Hemorrhagic strokes may present with seizures or acute neurologic
deficits. Again, the key to management is early recognition. ICH is more
likely than arterial ischemic stroke to result in hydrocephalus, cerebral
edema, and increased intracranial pressure. Acute management includes
elevation of the head of the bed to optimize CSF drainage, hyperosmolar
treatment, and prevention of fever. Seizures are common with ICH and may
be electrographic only.13 Prophylactic treatment with an anticonvulsant may
be considered in children with elevated intracranial pressure given the
increased risk for acute seizures.13 Blood pressure should be maintained
within the normal range for age, but no specific blood pressure range has
been associated with a good outcome. Rather, it is essential to identify a target
blood pressure range and agree on the steps to maintain pressure in that
range. These steps may be accomplished while considering the need for
evacuation of the clot.
Imaging Studies and Diagnostic Evaluations

Imaging studies should begin with CT or MRI to first establish the diagnosis of
stroke to identify the presence of hemorrhage and to delineate the extent of
infarct. The author’s practice is to use limited MRI with diffusion-weighted and
gradient recalled echo (GRE) sequences to confirm the presence of ischemia
or hemorrhage.27 Cerebral venous sinus thrombosis may present with subtle
signs, including seizures and subarachnoid hemorrhage or ICH. An
echocardiogram is indicated in the evaluation of new stroke to detect a cardiac
source of emboli, abnormal cardiac anatomy, or intracardiac shunt and should
include bubble contrast. For most children, because of the thin chest wall and
good acoustic windows, a transthoracic study is sufficient to confirm the
presence or absence of each of these pathologies.28 Transthoracic studies
also permit performance of the Valsalva maneuver and cough during the
procedure to enhance detection of right-to-left shunting. The transesophageal
procedure should be reserved for patients for whom the transthoracic study
was inconclusive; the risks of sedation and temporary loss of the neurologic
examination should be weighed in determining the timing of the study. Initial
laboratory studies should, at a minimum, include measures of coagulation

and platelet count, with the remainder of the studies determined by the risk
factors specific to that patient.
Anticipatory Management
Brain-directed critical care requires a multidisciplinary team and a consensus
on best practices for the detection and management of brain insults. The
implementation of these practices is best achieved through joint rounds with
critical care, neurology, and neurosurgery services.1 Serial neurologic
examinations and close communication between these three services with
established goals for temperature, blood pressure, glucose, bed position, and
oxygen and PCO2 are essential for the care of children with stroke in the ICU.
Criteria for escalation in therapy, including thrombolysis and decompressive
hemicraniectomy, should be discussed early in the hospital course and revised
09/2022
at least daily based on the neurologic examination. This approach enables

timely recognition of stroke progression and a rapid coordinated escalation
of care with additional therapeutic interventions.
IN-HOSPITAL AND OUT-OF-HOSPITAL CARDIAC ARREST

Cardiac arrest in children is most often due to progressive tissue hypoxia and
acidosis resulting from respiratory failure and circulatory shock. Approximately
39% of children survive after in-hospital cardiac arrest.29,30 At present, no
pharmacologic therapies are known that target the cellular mechanisms of
neurologic injury after cardiac arrest. The Therapeutic Hypothermia After
Pediatric Cardiac Arrest (THAPCA) trial first compared outcomes in children
with out-of-hospital cardiac arrest who were randomly assigned either to
controlled normothermia (36.8°C [98.2°F]) or a moderate therapeutic
hypothermia (33.0°C [91.4°F]) treatment protocol.31 Therapeutic hypothermia
did not confer any significant benefit for good neurologic outcome (20% in
hypothermia versus 12% in normothermia) or survival (38% in hypothermia
versus 29% in normothermia) at 1 year. The in-hospital arm of the study
comprised 329 patients and also found no benefit in survival or functional
outcome at 1 year.32 Accordingly, the focus of neuroprotection following acute
resuscitation for in- or out-of-hospital cardiac arrest should be on rigorous
targeted temperature management with a goal of 36.8°C (98.2°F), maintenance
of normoxia, normocarbia, support for blood pressure in a normal range for
age, and normal electrolytes.33 The author’s practice is to maintain temperature
at 35.5°C (95.9°F) for 48 to 72 hours following cardiac arrest and to use
transcranial Doppler (TCD) measurement of cerebral blood flow to adjust
blood pressure goals and head-of-bed position to maintain cerebral perfusion.
Specifically, the patient is treated with the head of bed flat for the first 24 hours
to maintain cerebral perfusion, unless imaging or clinical signs of cerebral
edema with increased intracranial pressure exist. In this case, the head of the
bed is elevated to 30 degrees. Serial TCDs are obtained daily for at least 3 days.
If the TCDs show normal velocities for age (less than 2 standard deviations from
294 FEBRUARY 2018

age-dependent normal values over the next 48 hours), the head of the bed is KEY POINTS
elevated to 30 degrees to offset the development of cerebral edema
● Early recognition of
during reperfusion. stroke, meticulous control
Notably, a new American Academy of Neurology practice guideline for adults of blood pressure and
based on a review of 50 years of published studies recommends the use of temperature, and
hospital-initiated therapeutic hypothermia (32°C [89.6°F] to 34°C [93.2°F] for anticipatory planning are
the key steps for

24 hours) for comatose adults following out-of-hospital cardiac arrest and an
neuroprotection in patients
initial cardiac rhythm of pulseless ventricular tachycardia or ventricular in the intensive care unit.
fibrillation.34 Targeted temperature management (36°C [96.8°F] for 24 hours
with rewarming to 37°C [98.6°F] over 8 hours and maintained at less than 37.5°C ● Unlike adults, cardiac
[99.5°F] for 72 hours) is also effective in patients who are comatose with an initial arrest in children is most
often due to progressive
cardiac rhythm of either ventricular tachycardia or ventricular fibrillation, tissue hypoxia and acidosis
asystole, or pulseless electrical activity. For pediatrics, these recommendations resulting from respiratory
underscore the critical importance of targeted temperature management within a failure and circulatory shock.
narrow range of normothermia to ensure optimal neurologic recovery following
● While hypothermia has
cardiac arrest. not been shown to improve
outcome after cardiac
EXTRACORPOREAL MEMBRANE OXYGENATION AND NEUROLOGIC arrest in children, targeted
INJURY temperature management
09/2022
to maintain temperature of
ECMO provides cardiorespiratory support and serves as a rescue therapy for 36.8°C (98.2°F) for at least
critically ill children. Neurologic complications, including intracranial 48 hours should be
hemorrhage, stroke, and brain death, have been reported with ECMO.35 Among considered standard care.
682 patients younger than 18 years of age who underwent ECMO to aid in
● Nonconvulsive seizures
cardiopulmonary resuscitation, an acute neurologic injury (stroke, intracerebral
are common during
hemorrhage, or brain death) occurred in 22%. Among these 147 patients, the extracorporeal membrane
mortality rate was 89%.36 The risk for neurologic injury was highest in children oxygenation, and continuous
with heart disease or who were severely acidotic (pH less than 6.87) before EEG may be considered a
starting ECMO. A study of 2977 patients undergoing carotid artery cannulation standard practice.
for venoarterial ECMO identified neurologic injury, including seizures, stroke, or
hemorrhage, in 611 patients (21%).37 Neonates comprised most of the patients
cannulated via the neck vessels (61%) and had the greatest burden of neurologic
injury, but no association was shown between age risk for neurologic injury,
which was present across all age groups.
Surveillance for Neurologic Injury During Extracorporeal

Membrane Oxygenation
The need for sedation and neuromuscular blockade during ECMO impedes the
use of a neurologic examination to detect new acute neurologic injury. A
retrospective study of 19 children treated with ECMO who underwent
continuous EEG monitoring reported seizures in four patients (21%), and they
were exclusively nonconvulsive in three.9 Interictal discharges were associated
with seizures, and 24 hours of monitoring were required to detect all seizures.
Other approaches to the detection of neurologic injury during ECMO include
near-infrared spectroscopy38 and TCD measurement of cerebral blood flow
velocity.39 None of these approaches have been evaluated in prospective studies.
While these noninvasive approaches have promise for detection of vascular
CNS injuries, pediatric studies have not shown a reliable association with EEG
or TCD abnormalities, and further study is needed.9,39 At present, the use of
continuous EEG for the detection of seizures during the first 24 hours of ECMO
is reasonable.
KEY POINTS ACUTE LIVER FAILURE

Neurologic morbidity is the primary determinant of outcome in pediatric
● Young age and fever are
risk factors for neurologic
acute liver failure.40 Young age, fever, and presentation with seizures are
deterioration in children risk factors for neurologic deterioration with acute liver failure.41 Hepatic
with acute liver failure. encephalopathy is graded on a continuum from no or minimal evidence of
neurologic dysfunction (stages 0 to 2) to stupor (stage 3) and coma (stage 4).

● Intensive care unit–acquired
Stage 1 is characterized by subtle changes in affect (anxiety or euphoria) and

weakness occurs in children
but the precise impact on shortened attention span. In stage 2, the patient may be disinhibited, have a
morbidity is uncertain disruption of the sleep-wake cycle, or be less active. The clinical assessment
because there is no of stage 1 and stage 2 hepatic encephalopathy in infants and children with
consensus on the criteria for
subtle impairments of higher cognitive function depends on the experience
diagnosis in children.
and skill of the examiner. The objective of the neurologist in the care of these
● Before beginning patients is to detect early signs of neurologic deterioration and cerebral edema
treatment for sympathetic (CASE 14-2). Changes in the EEG background may be an early sign of hepatic
hyperarousal, other encephalopathy in children.42 The optimal duration of such monitoring has
treatable medical conditions
should be investigated.
not been studied. The author’s practice is to obtain continuous EEG
monitoring on admission to the ICU for a minimum of 1 to 2 hours for all
patients with acute liver failure, independent of the presence of clinical signs
of hepatic encephalopathy. If the EEG is abnormal, EEG monitoring is
09/2022
continued for 24 hours. Thereafter, the frequency of monitoring depends on

the progression of any EEG abnormalities. Management is aimed at limiting
neurologic injury until the patient has a recovery of liver function or receives a
liver transplant. An approach to neuroprotection in acute liver failure has been
published.42 The key principles involve the prevention of fever, aggressive
treatment of infection, and the early use of continuous renal replacement
therapy or hemodialysis for treatment of rising ammonia not responsive to
lactulose. Hyperosmolar therapy or therapeutic hypothermia may be
considered for the patient who progresses to stage 3 hepatic encephalopathy,
although a randomized trial of therapeutic hypothermia in adults with acute
liver failure showed no survival benefit.43
INTENSIVE CARE UNIT–ACQUIRED WEAKNESS

ICU-acquired weakness is a significant cause of morbidity in critically ill
adults. For children, no consensus exists on the criteria for ICU-acquired
weakness. Among 830 children admitted to an ICU, 1.7% had generalized
weakness, which persisted for up to 1 year.44 A study using International
Classification of Diseases (ICD) codes to identify ICU-acquired weakness using
the Virtual Pediatric Intensive Care Unit’s database reported an incidence
of 0.02%.45 In adults, the risk factors for ICU-acquired weakness include
difficulty in weaning from the ventilator, severe sepsis, and prolonged
mechanical ventilation. Until a standardized approach to confirming the
diagnosis in children is established, the incidence and impact of this disorder
on morbidity following critical illness in children cannot be determined.
SYMPATHETIC HYPERAROUSAL
Autonomic dysfunction is common after acquired brain injury and has
been called autonomic, diencephalic, or sympathetic storms. The current
nomenclature is paroxysmal sympathetic hyperactivity, which is characterized
by episodic changes in vital signs, including hyperthermia, tachycardia,
hypertension, or tachypnea. Paroxysmal sympathetic hyperactivity occurs
296 FEBRUARY 2018

in approximately 15% of children following acute brain injury, particularly
traumatic brain injury or cardiac arrest.46 The most important first step is
to evaluate for other treatable medical problems that can trigger increased
sympathetic tone in brain-injured patients, including dystonia storm,
urinary retention, ileus or constipation, hip or other dislocation or fractures,
gastroesophageal reflux, corneal abrasion, dental issues, or infection. Once

these conditions have been ruled out, the author of this article begins
treatment with gabapentin, followed by a scheduled benzodiazepine, then
clonidine or propranolol.47 No prospective studies have shown that any one
therapy is better than another.
A previously healthy 3-year-old boy presented with 1 week of vomiting CASE 14-2
and 2 days of jaundice. His physical examination showed an enlarged
liver. He was irritable but could be soothed by his mother, and this was
considered appropriate, as he had not slept well in 2 days. On neurologic
examination, he was able to follow commands and had fluent speech.
Routine EEG was normal. International normalized ratio (INR) was 1.6,
09/2022
ammonia 75 μmol/L, aspartate aminotransferase (AST) 1200 IU/L, and

alanine aminotransferase (ALT) 900 IU/L. He was treated with medical
management for acute liver failure. The next day he developed a fever
and antibiotics were started. On the morning of the second hospital day,
his INR increased to 4.5, he was more irritable, and his responses to
commands were slow. EEG showed new generalized slowing. He was
transferred to the pediatric intensive care unit for targeted temperature
management using an external cooling device. The case was discussed
with nephrology (in case plasma exchange or continuous renal
replacement therapy was needed) and with neurosurgery (for placement
of an intracranial pressure monitor). A noncontrast head CT was obtained
and showed no evidence of cerebral edema or increased intracranial
pressure. Over the next 12 hours, he progressed to stupor with extensor
posturing. During this progression, continuous renal replacement therapy
and hyperosmolar therapy with 3% normal saline were initiated. An
intracranial pressure monitor could not be safely placed because of the
coagulopathy. To prevent shivering while he was maintained at low
normothermia (35.5°C [95.9°F]), the patient was pharmacologically
paralyzed. EEG was used for surveillance for nonconvulsive seizures and
transcranial Doppler was obtained daily to monitor cerebral perfusion
and detect increased intracranial pressure. After 2 days of medical
management, liver synthetic function began to recover and
neuroprotective measures were relaxed.
This case illustrates the need for serial neurologic examinations in the COMMENT
intensive care unit and anticipatory planning for neurologic deterioration
at the earliest sign of new neurologic findings. Early treatment with targeted
temperature management to prevent fever, even if this means loss of the
neurologic examination, in this high-risk patient population is essential.
CONCLUSION
Recognition of neurologic complications of critical illness requires serial
neurologic examinations and an appreciation for the multiple risk factors for
neurologic injury present in most patients in the pediatric or cardiac ICU.
Through attention to the fundamentals of neuroprotection, including
maintaining cerebral perfusion and regulating cerebral metabolic demand,

combined with multidisciplinary care and anticipatory planning, these

complications can be prevented or the neurologic injury mitigated.
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REVIEW ARTICLE

A clinical risk score using risk factors for poor recovery

RELATIONSHIP DISCLOSURE: INTRODUCTION

300 FEBRUARY 2018

traumatic brain injury.

8 or less is classified as a severe TBI, a score of 9 to 12 is classified as a moderate

unless the clinician suspects an intracranial hemorrhage. Several clinical decision

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recovery processes of injured youth.

injury and concussion are

● Early involvement with a

Return to Learn and Return to Play

return, similar to return-to-play. To implement any protocol, it is critical to

the recommendations. Athletic trainers, however, may not be familiar with

TABLE 15-1 Graduated Return-to-School Strategya

Stage Aim Activity Goal of Each Step

3 Return to school part-time Gradual introduction of schoolwork; Increase academic activities

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dizziness, sleep problems) and psychogenic disturbances (eg, irritability,

Role of Exercise in Recovery From Persistent Postconcussion Symptoms

Graduated Return-to-Sport Strategya,b TABLE 15-2

Stage Aim Activity Goal of Each Step

3 Sport-specific exercise Running or skating drills; no head impact Add movement

activity even while some symptoms remain is growing.40 Individualized

retrospective review of children who had experienced sport-related concussion,

THE INFLUENCE OF PREINJURY LEARNING DIFFICULTIES ON RECOVERY

CASE 15-1 A 9-year-old boy with a history of untreated attention deficit

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therapies targeting premorbid learning difficulties should be implemented or

cognitive distortions. This includes all-or-nothing thinking, overgeneralization,

REPEAT INJURY, SECOND-IMPACT SYNDROME, AND CHRONIC

psychological, and cognitive difficulties influence outcome, especially in persistent

postconcussion syndrome. Prolonged periods of rest and social isolation

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AMERICAN ACADEMY OF NEUROLOGY, SPORT AMERICAN ACADEMY OF PEDIATRICS STATE ADVOCACY

19 National Conference of State Legislatures. Traumatic Accessed December 4, 2017.

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14(4):360–372. doi:10.1097/00001199–199908000–00005. jcen.24.3.270.982.

59 Fidan E, Lewis J, Kline AE, et al. Repetitive mild traumatic

By Clara D. M. van Karnebeek, MD, PhD

developmental disorder is characterized by limitations in both intellectual

228 FEBRUARY 2018

of age or older.3–5 allows for proper genetic

into account family

A more extensive history revealed an uncomplicated pregnancy and

An online application was reviewed and showed that, aside from a

COMMENT This case illustrates the importance of an etiologic diagnosis, defined as

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developmental delay (and

EVALUATION OF INTELLECTUAL DEVELOPMENTAL DISORDER

Step 1: Confirmation of Intellectual Developmental Disorder

available.1 Recognition of developmental plateauing or regression is absolutely

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disturbances, and systemic abnormalities. A clinical history with a ● A complete medical

system (CNS) injury or malformation? neurophysiology, single-gene

CHROMOSOMAL MICROARRAY AS A FIRST-TIER TEST. Chromosomal microarray has

polymorphism arrays, and fluorescence in situ hybridization (FISH) testing for

syndrome). Pioneering microarray studies in intellectual developmental disorder

CASE 11-2 An 8-year-old boy was seen by a developmental pediatrician for

234 FEBRUARY 2018