children

Review
Clinical Approach to Pediatric Transverse Myelitis,
Neuromyelitis Optica Spectrum Disorder and Acute
Flaccid Myelitis
Cynthia Wang 1,2, * and Benjamin Greenberg 1,2
1 Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;
Benjamin.greenberg@utsouthwestern.edu
2 Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas,
TX 75390, USA
* Correspondence: cynthia.wang@utsouthwestern.edu




Received: 10 April 2019; Accepted: 7 May 2019; Published: 17 May 2019


Abstract: Pediatric transverse myelitis (TM) is an acquired, immune-mediated disorder that leads
to injury of the spinal cord and often manifests as weakness, numbness, bowel dysfunction, and/or
bladder dysfunction. Multiple etiologies for myelitis can result in a similar clinical presentation,
including idiopathic transverse myelitis (TM), multiple sclerosis (MS), neuromyeltis optica spectrum
disorder (NMOSD) associated with anti-aquaporin 4 antibodies, MOG antibody-associated disease,
and acute flaccid myelitis (AFM). Diagnosis relies on clinical recognition of the syndrome and
confirming inflammation through imaging and/or laboratory studies. Acute treatment is targeted
at decreasing immune-mediated injury, and chronic preventative therapy may be indicated if TM
is determined to be a manifestation of a relapsing disorder (i.e., NMOSD). Timely recognition and
treatment of acute transverse myelitis is essential, as it can be associated with significant morbidity
and long-term disability.

Keywords: transverse myelitis; neuromyelitis optica spectrum order; acute flaccid myelitis;
pediatric; review

1. Introduction
Pediatric transverse myelitis (TM) accounts for about 20% of the total number of cases of transverse
myelitis [1]. Transverse myelitis can result from multiple pathological mechanisms. Idiopathic
transverse myelitis refers to a single episode of TM, postulated to arise from post-infectious immune
activation. TM can also be a part of a relapsing inflammatory disorder, such as multiple sclerosis (MS)
or neuromyelitis optica spectrum disorder (NMOSD). Infections of the spinal cord cause direct tissue
injury, and in some cases, may trigger downstream immune mechanisms that lead to additional injury
(i.e., acute flaccid myelitis).

2. Demographic Features and Epidemiology

The incidence of acute transverse myelitis (ATM) in children under the age of 16 years is estimated
to be 2 per million children per year based on studies in the UK and Canada [2]. Within the pediatric
population, idiopathic myelitis has been more frequently reported in children under 5 and over
10 years of age [3]. There is a slight male predominance (1.1–1.6:1) in prepubertal individuals, while
female predominance is observed following puberty, particularly in cases in which TM represents a
manifestation of MS or NMOSD. No ethnic predisposition has been reported. A preceding illness is
noted in two-thirds of cases [4].

Children 2019, 6, 70; doi:10.3390/children6050070 www.mdpi.com/journal/children

Children 2019, 6, 70 2 of 6

3. Clinical Features
Clinical manifestations of TM may include pain, paresthesias, numbness, weakness (typically
paraplegia or quadriplegia), bowel dysfunction, and/or bladder dysfunction. During the acute setting,
muscle tone and deep tendon reflexes in affected extremities may be decreased, but typically increased
tone and hyperreflexia (secondary to corticospinal tract involvement) becomes apparent over time.
The time course from symptom onset to maximal severity can vary considerably depending on the
etiology and severity of disease, ranging from 4 hours to 21 days [5]. The diagnostic criteria established
by the Transverse Myelitis Consortium Working Group (TMCWG), which includes bilateral extremity
weakness and a clear sensory level, can be utilized in children with the caveat that younger children
may not reliably report a sensory level.

4. Diagnostic Approach
A diagnosis of transverse myelitis can be established with a consistent clinical history and
neurological exam, supported by radiographical and laboratory studies, and exclusion of alternate
etiologies. An acute to subacute time course is typical of transverse myelitis given its immune-mediated
mechanism. Hyperacute or chronic development of symptoms prompt consideration of alternative
etiologies, such as vascular and metabolic myelopathies, respectively. TM can be mistaken for
peripheral nervous system disorders, such as Guillain–Barré syndrome (GBS), as both can acutely
manifest as weakness and areflexia. However, a sensory level and urinary retention should raise
concern for spinal cord localization. Furthermore, a variant of TM, acute flaccid myelitis (AFM) can
mimic axonal GBS, but causes changes in the anterior horns of the spinal cord when magnetic resonance
imaging (MRI) imaging is obtained. Once there is clinical suspicion for myelopathy, it should be
treated as a medical emergency, as a compressive lesion must be ruled out. Cerebrospinal fluid (CSF)
studies are also used to evaluate for infectious myelitis, but should not delay initiation of empirical
intravenous corticosteroids if there is suspicion for an inflammatory myelopathy.

5. Diagnostic Workup

5.1. Magnetic Resonance Imaging (MRI)

Magnetic resonance imaging (MRI) of the spinal cord should be obtained to evaluate for
extrinsic and intrinsic causes of myelopathy. Transverse myelitis typically manifests as abnormal
T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities affecting one or more cord segments.
Shorter segment lesions are more suggestive of multiple sclerosis-related TM, while lesions longer than
three vertebral segments increase the probability of NMOSD and idiopathic TM. Children are more
likely to have longitudinally extensive myelitis regardless of etiology, thus making the length of the
lesion less diagnostically useful in this population. Enhancement can be present but is not necessary to
diagnose TM. Idiopathic transverse myelitis and NMOSD-associated myelitis often manifest as central
lesions that can encompass two-thirds or more of the cross section of the cord [6]. In contrast, acute
flaccid myelitis has predominantly gray matter involvement, and mixed patterns have been observed
in MOG-antibody associated myelitis [7,8].

5.2. Cerebrospinal Fluid (CSF)

Cerebrospinal fluid analysis should include evaluation of cell count and differential, protein, and
glucose analysis. The CSF is abnormal in about 50% of TM cases, often with lymphocytic pleocytosis,
elevated protein, but normal glucose. Children with myelitis tend to have a pleocytosis of greater
magnitude than adults, with a mean white blood cell count of 136/mm3 [1]. Evidence of intrathecal
antibody synthesis, as demonstrated by positive oligoclonal bands and increased Immunoglobulin
G (IgG) index, are suggestive of autoimmune myelitis. This pattern is observed most commonly
with multiple sclerosis, although other autoimmune as well as infectious etiologies can also produce
such findings. Aquaporin-4 antibody can be assessed in CSF, though the serum test is more sensitive.
Children 2019, 6, 70 3 of 6

Assessing for viral pathogens, such as enterovirus, West Nile virus, and other arboviruses associated
with myelitis, may be relevant depending on the time of year and geographical location. Of note,
serologic testing or viral isolation from non-central nervous system (CNS) sources is often necessary to
prove viral pathology in the setting of myelitis.

5.3. Serum
Serum laboratory testing for anti-AQP4 and MOG antibodies through cell-based assays should be
considered in any child with myelitis, as a positive result would be clinically significant in relation to
ongoing surveillance and management. Paraneoplastic myelitis is rare and sometimes associated with
amphiphysin and CRMP-5 antibodies in adults [9,10], but has not been reported in children. Anti-GFAP
syndromes have been described in pediatric patients and can manifest as meningoencephalomyelitis
with spinal cord lesions spanning greater than three vertebral segments. A distinguishing MRI brain
feature is a radial enhancement pattern [11]. Evaluation for metabolic myelopathies with testing of
vitamin B12, copper, and vitamin E should be considered in children at risk for gastrointestinal and
metabolic comorbidities. 25-Hydroxy vitamin D level is associated with a greater risk of acquiring MS
and having more active disease. It may be important in other autoimmune neurological disorders as
well and should be evaluated to guide dosing recommendations.
Infectious serologies for West Nile virus, varicella-zoster virus, herpes simplex virus, human T
lymphotropic virus, human immunodeficiency virus (HIV), and Zika virus are additional tests that
might be considered in the appropriate clinical context. Bacterial infections including mycoplasma,
Borrelia species, syphilis, and Listeria monocytogenes have also been reported in association
with myelitis.

5.4. Other Studies

Additional studies can be considered based on the patient’s history and examination. If there is
concern for sarcoidosis, computerized tomography (CT) of chest can help screen for granulomatous
lung disease, although this is rare in children. Paraneoplastic workup might involve CT chest, abdomen,
and pelvis, though these studies typically have very low yield in children. Electrophysiological and
other adjunctive tests, including visual evoked potentials, nerve conduction studies/electromyography
and optical coherence tomography to identify patterns of diffuse CNS inflammation, may be helpful if
the etiology of myelitis is uncertain.

6. Acute Treatment
Acute management of transverse myelitis has been informed primarily by case series and expert
opinion, as no randomized controlled trials have been done in this population. The American Academy
of Neurology (AAN) guidelines states that corticosteroids only have class IV evidence to support their
use, though in practice, they are often first-line treatments and have low risk for potential harm even
in cases of transverse myelitis mimics. Typically, corticosteroids are given as 30 mg/kg (up to 1000 mg)
of intravenous methylprednisolone daily for 3–5 days. Other preparations of corticosteroids, such as
dexamethasone or oral administration of high-dose prednisone or prednisolone, may also be used.
With severe cases of myelitis or symptoms refractory to IV corticosteroids, therapeutic plasma
exchange (PLEX) has been a very effective acute treatment for acute transverse myelitis, particularly in
conditions in which a pathogenic antibody is felt to be central to the disease process. Plasma exchange
has been shown to be effective in idiopathic transverse myelitis, neuromyelitis optica, and MOG
antibody associated disease. Studies of plasma exchange in children have demonstrated that it is a safe
and effective treatment [12]. The typical treatment regimen involves 1.1–1.5 plasma volume changes
every other day for 5–7 sessions.
Other frequently used acute therapies include intravenous immunoglobulin (IVIG), which can
also be given concurrently or following IV corticosteroids. Certain forms of myelitis, particularly
Children 2019, 6, 70 4 of 6

those related to systemic inflammatory and connective tissue disorders, such as systemic lupus
erythematosus, may respond preferentially to treatments such as cyclophosphamide [13].

7. Forms of Acute Myelitis

Idiopathic transverse myelitis is often diagnosed when no specific etiology is found following an
appropriate and comprehensive workup. In many cases, there is a history of a preceding respiratory or
gastrointestinal illness. These forms of TM are often monophasic, but can cause significant morbidity.
With improvements in molecular testing techniques, some of these conditions are now known to
represent forms of neuromyelitis optica spectrum disorder, MOG antibody associated disease, and
multiple sclerosis. In one study of adults previously diagnosed with idiopathic TM, an alternative and
specific myelopathy diagnosis was made in 69.9% of 226 referred patients, which was led by vascular
myelopathy and clinically isolated syndrome/multiple sclerosis [14].

7.1. Neuromyelitis Optica Spectrum Disorders (NMOSD)

Neuromyelitis optica spectrum disorder (NMOSD)-related myelitis is classically described to
be longitudinally extensive, involving three or more vertebral segments. It is frequently associated
with optic neuritis and typically involves severe attacks without disease progression between relapses.
The discovery of its antigenic target, aquaporin-4, and improvements in cell-based assays have
broadened our understanding of the spectrum of neuromyelitis optica. Shorter NMOSD lesions
have been reported [15] and brainstem, diencephalon, and brain involvement have also been
increasingly recognized. Younger children tend to have longitudinally extensive myelitis, such
as with MOG-antibody associated myelitis and idiopathic TM, so this characteristic of anti-AQP4
antibody-mediated NMOSD is less specific in the pediatric population. Natural history studies have
demonstrated that if untreated, NMOSD leads to high morbidity and mortality, with over 50% of
patients with relapsing neuromyelitis optica becoming blind in one or both eyes or requiring ambulatory
help within 5 years of disease onset [16]. Thus, all patients with acute transverse myelitis should be
tested for anti-AQP4 antibodies.
Therapeutic plasma exchange for severe presentations and/or incomplete recovery following
corticosteroids is recommended, as it often improves motor and vision outcomes [17]. Chronic
immunosuppression should be initiated after the first attack in individuals positive for AQP-4
and a compatible clinical history, as poor recovery from exacerbations greatly contributes to
disease-associated disability.

7.2. Acute Flaccid Myelitis (AFM)

Acute flaccid myelitis (AFM) has been an increasingly recognized syndrome in children. In this
condition, typically children or young adults present with rapidly progressive, often asymmetric,
flaccid weakness. Over 90% of affected individuals have a mild viral respiratory illness or fever before
the onset of neurological symptoms [18]. Areflexia or hyporeflexia is present in the most severely
affected limbs, though reflexes can be normal or brisk below the level of spinal cord injury. Sensation
and bowel and bladder function can be relatively spared. Radiographically, AFM corresponds to
hyperintense T2 signal in the central gray matter of the spinal cord, particularly the anterior horns.
The clinical and radiological phenotype of AFM is similar to poliomyelitis. Although the cause of
acute flaccid myelitis (AFM) is still unproven, a temporal and geographical correlation with enterovirus
infections has led to this being the most favored etiology. The most frequently associated virus has
been the enterovirus D68, being detected in respiratory specimens, but CSF testing is almost always
negative for enterovirus when tested with PCR. Enterovirus A71 has been implicated in other cohorts
of AFM patients [19]. The Center for Disease Control and Prevention (CDC)’s case classification for
AFM requires an MRI showing spinal cord lesion largely restricted to gray matter and spanning one or
more spinal segments in a clinically compatible case. The majority of established cases have occurred in
the fall seasons of 2014 (120 cases), 2016 (149 cases), and 2018 (223 cases). Prospective epidemiological
Children 2019, 6, 70 5 of 6

studies are needed to establish a causal relationship between AFM and specific enterovirus subtypes
and determine what makes certain individuals more susceptible to developing AFM.
Presently, the CDC states that there are currently no targeted therapies/interventions with enough
evidence to endorse or discourage their use for the treatment or management of AFM, including
corticosteroids, IVIG, and therapeutic exchange. Other treatments that have been proposed include
fluoxetine, antiviral medications, interferon, and other immunosuppressive medications, but these are
not recommended by the CDC.

8. Prognosis/Long-Term Management
Although many children have substantial recoveries from transverse myelitis, as high as 40% have
residual deficits that interfere with activities of daily living and impact quality of life [1]. Improvement
in spinal cord function is typically most apparent in the first three months following the onset of
symptoms, but can continue over many years with appropriate rehabilitation. Motor recovery from
AFM is slower and less complete compared to immune-mediated myelitis. In the 2014 Colorado cohort,
the majority of children exhibited persistent motor deficits at 1 year [20].
Recurrence of TM is very unlikely in children with myelitis due to an identifiable viral etiology
and no child with AFM has been reported to have subsequent myelitis events.
For children determined to have myelitis secondary to autoimmune condition, chronic
immunomodulatory therapy should be considered. Since NMOSD has a well characterized relapsing
disease course, identification of AQP4 antibodies and a clinical attack meeting Wingerchuk diagnostic
criteria for NMOSD should prompt initiation of immunosuppression.
Presently, rituximab, mycophenolate mofetil, azathioprine, and daily corticosteroids are the most
frequently utilized treatments based on expert opinion and retrospective studies. Several therapies of
differing mechanisms have completed phase III clinical trials in adults with NMOSD.

9. Summary/Future Directions
Our understanding of pediatric TM has grown significantly with the discoveries of
antibody-mediated forms of myelitis and the identification of new potential infectious etiologies.
Despite differences in pathobiology, the clinical presentation of myelitis shares many features. Effective
management of myelitis requires recognition of the syndrome, initiating empirical treatment, and using
imaging and laboratory studies to establish a cause and guide medical decision-making. Research
aimed at further elucidating the molecular mechanisms and antigenic targets of different forms of
myelitis is needed to improve treatments and long-term outcomes for children with myelitis.

Author Contributions: C.W. contributed to writing—original draft preparation, B.G. contributed to

writing—review and editing.
Conflicts of Interest: Greenberg has received grant support from the NIH, PCORI, NMSS, Guthy Jackson
Charitable Foundation for NMO, Genentech, Chugai, Medimmune and Medday. He has received consulting fees
from Alexion and Novartis. He serves on the advisory board for the Transverse Myelitis Association. Wang’s
fellowship was supported by the Transverse Myelitis Association.

References
1. Pidcock, F.S.; Krishnan, C.; Crawford, T.O.; Salorio, C.F.; Trovato, M.; Kerr, D.A. Acute transverse myelitis in
childhood: center-based analysis of 47 cases. Neurology 2007, 68, 1474–1480. [CrossRef] [PubMed]
2. Absoud, M.; Greenberg, B.M.; Lim, M.; Lotze, T.; Thomas, T.; Deiva, K. Pediatric transverse myelitis.
Neurology 2016, 87, S46–S52. [CrossRef] [PubMed]
3. Abboud, H.; Petrak, A.; Mealy, M.; Sasidharan, S.; Siddique, L.; Levy, M. Treatment of acute relapses in
neuromyelitis optica: Steroids alone versus steroids plus plasma exchange. Mult. Scler. 2016, 22, 185–192.
[CrossRef] [PubMed]
Children 2019, 6, 70 6 of 6

4. Thomas, T.; Branson, H.M.; Verhey, L.H.; Shroff, M.; Stephens, D.; Magalhaes, S.; Banwell, B. The demographic,
clinical, and magnetic resonance imaging (MRI) features of transverse myelitis in children. J. Child Neurol.
2012, 27, 11–21. [CrossRef] [PubMed]
5. Transverse Myelitis Consortium Working Group. Proposed diagnostic criteria and nosology of acute
transverse myelitis. Neurology 2002, 59, 499–505. [CrossRef] [PubMed]
6. Goh, C.; Desmond, P.M.; Phal, P.M. MRI in transverse myelitis. J. Magn. Reson. Imaging 2014, 40, 1267–1279.
[CrossRef] [PubMed]
7. Wang, C.; Narayan, R.; Greenberg, B. Anti-myelin oligodendrocyte glycoprotein antibody associated with
gray matter predominant transverse myelitis mimicking acute flaccid myelitis: A presentation of two cases.
Pediatr. Neurol. 2018, 86, 42–45. [CrossRef]
8. Dubey, D.; Pittock, S.J.; Krecke, K.N.; Morris, P.P.; Sechi, E.; Zalewski, N.L.; Weinshenker, B.G.; Shosha, E.;
Lucchinetti, C.F.; Fryer, J.P.; et al. Clinical, radiologic, and prognostic features of myelitis associated with
myelin oligodendrocyte glycoprotein autoantibody. JAMA Neurol. 2018. [CrossRef] [PubMed]
9. Virani, S.; Tan, M.; Abraham, J. Transverse myelitis: Amphiphysin autoimmunity paraneoplastic syndrome
in a woman with breast cancer. Clin. Adv. Hematol. Oncol. 2009, 7, 180–182. [PubMed]
10. Keegan, B.M.; Pittock, S.J.; Lennon, V.A. Autoimmune myelopathy associated with collapsin
response-mediator protein-5 immunoglobulin G. Ann. Neurol. 2008, 63, 531–534. [CrossRef] [PubMed]
11. Flanagan, E.P.; Hinson, S.R.; Lennon, V.A.; Fang, B.; Aksamit, A.J.; Morris, P.P.; Basal, E.; Honorat, J.A.;
Alfugham, N.B.; Linnoila, J.J.; et al. Glial fibrillary acidic protein immunoglobulin G as biomarker of
autoimmune astrocytopathy: Analysis of 102 patients. Ann. Neurol. 2017, 81, 298–309. [CrossRef] [PubMed]
12. Noland, D.K.; Greenberg, B.M. Safety and efficacy of plasma exchange in pediatric transverse myelitis.
Neurol. Clin. Pract. 2018, 8, 327–330. [CrossRef] [PubMed]
13. Barile, L.; Lavalle, C. Transverse myelitis in systemic lupus erythematosus—The effect of IV pulse
methylprednisolone and cyclophosphamide. J. Rheumatol. 1992, 19, 370–372. [PubMed]
14. Zalewski, N.L.; Flanagan, E.P.; Keegan, B.M. Evaluation of idiopathic transverse myelitis revealing specific
myelopathy diagnoses. Neurology 2018, 90, e96–e102. [CrossRef] [PubMed]
15. Flanagan, E.P.; Weinshenker, B.G.; Krecke, K.N.; Lennon, V.A.; Lucchinetti, C.F.; McKeon, A.;
Wingerchuk, D.M.; Shuster, E.A.; Jiao, Y.; Horta, E.S.; et al. Short myelitis lesions in aquaporin-4-IgG-positive
neuromyelitis optica spectrum disorders. JAMA Neurol. 2015, 72, 81–87. [CrossRef] [PubMed]
16. Wingerchuk, D.M.; Lennon, V.A.; Lucchinetti, C.F.; Pittock, S.J.; Weinshenker, B.G. The spectrum of
neuromyelitis optica. Lancet Neurol. 2007, 6, 805–815. [CrossRef]
17. Trebst, C.; Jarius, S.; Berthele, A.; Paul, F.; Schippling, S.; Wildemann, B.; Borisow, N.; Kleiter, I.; Aktas, O.;
Kümpfel, T.; et al. Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the
Neuromyelitis Optica Study Group (NEMOS). J. Neurol. 2014, 261, 1–16. [CrossRef] [PubMed]
18. Centers for Disease Control and Prevention. AFM Investigation 2019. Available online: https://www.cdc.
gov/acute-flaccid-myelitis/afm-surveillance.html (accessed on 15 May 2019).
19. Fernandez-Garcia, M.D.; Kebe, O.; Fall, A.D.; Dia, H.; Diop, O.M.; Delpeyroux, F.; Ndiaye, K. Enterovirus
A71 genogroups C and E in children with acute flaccid paralysis, West Africa. Emerg. Infect. Dis. 2016, 22,
753–755. [CrossRef] [PubMed]
20. Martin, J.A.; Messacar, K.; Yang, M.L.; Maloney, J.A.; Lindwall, J.; Carry, T.; Kenyon, P.; Sillau, S.H.; Oleszek, J.;
Tyler, K.L.; et al. Outcomes of Colorado children with acute flaccid myelitis at 1 year. Neurology 2017, 89,
129–137. [CrossRef] [PubMed]

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).