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Reversible Dementia

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 CHAPTER
6

Reversible Dementia
INTRODUCTION

There are many potentially reversible causes of dementia, which may

respond to specific interventions if diagnosed in time. One out of five
cases of dementia may have a condition, which may respond to definite
treatment. Table 1 enlists few of the potentially reversible causes of
dementia. In a study of 1000 persons attending a memory disorder clinic,
19% had a potentially reversible cause of the cognitive impairment and
23% had a potentially reversible concomitant condition. The three most
common potentially reversible diagnoses in this series were depression
(pseudo-dementia), hydrocephalus, and alcohol dependence.1
In this chapter, the authors will discuss some important causes of
potentially reversible dementia with few relevant case discussions.

• Alcohol-related dementias
• Vitamin B12 deficiency
• Endocrine dysfunction: Thyroid, parathyroid, and adrenal dysfunction
• Metabolic disturbances: Uremic/dialysis, chronic hepatic
encephalopathy
• Infection: Neurosyphilis
• Drugs/substance abuse
• Anatomic abnormalities: NPH, secondary hydrocephalus

Manish Modi1*, Sudhir Sharma2

1
Assistant Professor, 2Assistant Professor
Department of Neurology, PGIMER, Chandigarh-160012, India

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 86 Differential Diagnosis of Dementia Syndromes

Table 1  Causes of Reversible Dementia

•  Alcoholism
•  Drug/medication intoxication
•  Vitamin deficiencies: B1, B6, B12
•  Endocrine disorders: Thyroid, parathyroid, adrenal hypo- or hyperfunction
•  Organ failure: Liver, kidney, pulmonary
•  Chronic infections: Neurosyphilis, PMLE, tuberculosis, fungal, protozoal
•  Chronic inflammation: Sarcoidosis, coeliac disease, Whipple’s disease
•  Surgical conditions: Sub-dural hematoma, normal-pressure hydrocephalus
(NPH), primary and metastatic brain tumors
•  Psychiatric disorders: Depression, schizophrenia, conversion disorder
•  Others: Vasculitis, acute intermittent porphyria; non-convulsive status

ALCOHOL-RELATED DEMENTIAS

Alcoholism can predispose to cognitive impairment by a variety of

mechanisms. Major alcohol-related conditions include alcoholic cognitive
impairment (alcoholic dementia), Wernicke-Korsakoffs syndrome
(WKS), and Marchiafava-Bignami disease (MBD).

Alcoholic Dementia

Heavy alcohol consumption is associated with cognitive impairment

distinct from the amnesia of Korsakoff ’s syndrome.2 Although light-to-
moderate alcohol consumption can lower the risk of dementia, heavy
alcohol consumption leads to brain injury. Heavy alcohol intake involves
ten or more years of at least 150 mL or 120 g of absolute alcohol per day.3
Alcoholic dementia is more apparent in elderly than in young subjects and
appears earlier and with less alcohol consumption in women than in men.

Leading Clinical Symptoms and Signs

Alcoholic dementia is a mild and minimally progressive frontal-executive
disorder. There is poor working memory, decreased verbal fluency,
circumstantiality, perseveration, impaired abstraction, and decreased
behavioral initiation.4

Diagnosis
On magnetic resonance imaging (MRI), particularly in older alcoholics,
there is ventricular enlargement and diffuse atrophy disproportionately

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 Chapter 6  |  Reversible Dementia 87

affecting prefrontal regions.4 The apparent cortical atrophy does not

predict intellectual impairment and is partially reversible with continued
abstinence, possibly by rehydration.5 Abstinence also results in a partial
reversal of neuropsychological deficits and white matter volume loss in
the frontal lobes. Functional imaging shows decreases in medial frontal-
cortical metabolism on a background of normal global activity with a loss
of region-to-region correlations.6

The Wernicke-Korsakoff Syndrome (Thiamine Deficiency)

Severe thiamine (vitamin B1) deficiency, a problem in chronic alcoholics

with poor nutritional intake, results in the abrupt onset of ophthalmoplegia,
ataxia, and delirium (Wernicke’s encephalopathy or WE) followed by
a prolonged amnestic disorder (Korsakoff’s syndrome). If thiamine is
administered in the acute stage of WE, ophthalmoplegia may reverse
within a few minutes or hours, and the other abnormalities may improve
gradually over the course of several days. Typically, the Korsakoff’s amnesia
becomes apparent as the WE resolves. Many alcoholics with repeated
subclinical episodes of thiamine deficiency, however, develop memory loss
and pathologically proven Korsakoff’s amnesia in the absence of acute WE.7

Leading Clinical Symptoms and Signs

Korsakoff ’s syndrome has specific features. The amnesia has an
anterograde component with inability to learn new material and a
retrograde component affecting the recall of information learned for
up to several years prior to onset of the syndrome. The recall of more
remote information is less impaired than is recently acquired knowledge.
In contrast, procedural (motor skill) memory is relatively preserved. In
addition to amnesia, there may be confabulation in the initial phase of
Korsakoff ’s syndrome, and a tendency to placidity, inertia, and deficits
in executive abilities.8 On neurologic examination, nystagmus, ataxia,
and peripheral neuropathy are common.

Diagnosis
MRI changes in the WKS occur in the diencephalic region. There is
shrinkage of the anterior diencephalon, atrophy of the mammillary
bodies, and enlargement of the third ventricle with areas of hypodensity

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 88 Differential Diagnosis of Dementia Syndromes

in its walls and around the sylvian aqueduct.9 On T2-weighted and fluid-
attenuated inversion recovery (FLAIR) MRI images, there are high signal
intensities bilaterally, and on diffusion-weighted images (DWIs), there
are reversible areas of high-signal intensity in the corresponding areas.9
These MRI changes occasionally occur in alcoholics without a history
of WKS, suggesting a subclinical form of this syndrome.10

Treatment
The treatment for WKS is thiamine administration. Adequate nutritional
supplementation and the thiamine enrichment of flour or other foods
can prevent its development. Once established, the memory deficit does
not immediately reverse with thiamine administration, but adequate
thiamine should prevent worsening or recurrence of the disorder. If
thiamine intake is subsequently maintained, some degree of spontaneous
recovery occurs in most Korsakoff ’s patients.

Marchiafava-Bignami Disease

The hallmark of this syndrome is the presence of acute demyelination

of the corpus callosum. Primarily described in middle-aged Italian males
with excessive intake of red wine, it may occur in other nationalities, in
females, and rarely, in non-alcoholics.11

Leading Clinical Symptoms and Signs

Clinically, the disorder may start with stupor or coma. With recovery, the
patients may have seizures and dementia with complex attention deficits,
memory and language difficulty, personality changes, and, if tested, signs
of inter-hemispheric disconnection (e.g., left-hand anomia, apraxia,
agraphia).12 At autopsy, the primary lesion is demyelination continuing
to complete necrosis of the central portion of the corpus callosum. In
some cases, there is demyelination of the anterior and hippocampal
commissures, optic chiasm, and white matter of the cerebral hemispheres,
cerebellar peduncles, or regions of the central pons.

Diagnosis
Neuroimaging in (MBD) shows changes consistent with demyelination.
On MRI, there is moderate atrophy of posterior callosal regions and severe
atrophy of anterior callosal regions in the setting of generalized atrophy.

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 Chapter 6  |  Reversible Dementia 89

On T1-weighted images, there are areas of diminished signal intensity

with gadolinium enhancement in the corpus callosum.13 There may be
resolution or residual cystic lesions on follow-up. On [18F]-fluoro-2-
deoxy-D-glucose positron emission tomography (PET), there is reduced
whole brain metabolism that is most pronounced in frontal and parietal
lobes and thalami.14

CASE REPORT 1

Present History

A 45-year-old gentleman, chronic alcoholic, presented with five-day

history of speech disturbances and gait abnormality. Two days prior to
admission, he had generalized tonic clonic seizures and altered sensorium.
The patient had been consuming an average of 350 mL of country liquor
per day for the last 20 years.

Past History

There was no history of vaccination, prior fever or upper respiratory

infection, or GIT symptoms.

Examination
Examination revealed signs of malnutrition. There were no signs of
liver-cell failure. The patient was confused and disorientated. Signs of
meningeal irritation were absent. There was dysarthria having both
spastic and scanning components. His comprehension was intact. Fundus
and extraocular movements were normal. There was no nystagmus and
other cranial nerves were normal. Motor examination revealed normal
power in all limbs, with increased tone and brisk reflexes with extensor
plantar responses bilaterally. Gait was wide based and spastic. There was
no evidence of disconnection syndrome.

Investigations

MRI brain disclosed hyperintense lesions in the central portion of the

corpus callosum with sparing of upper and lower layers, subcortical white

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 90 Differential Diagnosis of Dementia Syndromes

matter, putamen on T2WI (Figure 1) and FLAIR. These lesions were

hypointense on T1WI, showed restriction on DWI, and did not show
contrast enhancement. Electroencephalography (EEG) showed diffuse
theta range slowing but no epileptiform discharges. Cerebrospinal fluid
(CSF) examination, hemoglobin, liver function tests, ammonia levels,
Vitamin B12, and ACE levels were normal. ANA and ANCA were negative.

Treatment

On the basis of the clinical history and imaging, a diagnosis of MBD

was made and high-dose vitamin B complex including 500 mg/day
Thiamine was administered daily intramuscularly for 14 days followed
by once weekly for one month. His sensorium, speech, and gait improved

Figure 1  MRI Brain (T2W Saggital Section) Disclosed Hyperintense

Lesions in the Central Portion of the Corpus Callosum.

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 Chapter 6  |  Reversible Dementia 91

gradually. After four months, the patient showed a complete recovery

with normal neurological examination. Repeat MRI brain showed
significant resolution of lesions with subtle high signal intensity in the
body of the corpus callosum.

VITAMIN B12 DEFICIENCY

There are several causes of B12 (cobalamin) deficiency. The most

common is autoimmune chronic atrophic gastritis with decreased intrinsic
factor necessary for B12 absorption (pernicious).15 Other causes include
malnutrition, malabsorption, and exposure to the anesthetic nitrous oxide.16

Leading Symptoms and Signs

The features of B12-deficiency dementia are psychomotor slowness,

confusion, memory defects, depression, and psychosis. There can be
associated peripheral neuropathy with superficial sensory impairment,
burning paresthesias, and early loss of ankle jerks. There can also be evidence
of a demyelinating myelopathy of the posterior and lateral columns (sub-acute
combined degeneration) with impaired vibratory sense, limb weakness,
spasticity, increased muscle stretch reflexes, and extensor plantar responses.
Hematologic features may include a megaloblastic anemia, oval
macrocytosis, poikilocytosis, leucopenia with hypersegmented poly-
morphonuclear leukocytes, and a thrombocytopenia. The neurologic
manifestations can occur in the absence of these hematologic features.17

Diagnosis

The diagnosis of B12 deficiency depends on low serum B12 levels

(<200 pg/mL), and the treatment depends on the administration of
B12.18 There may be symptoms of B12 deficiency with normal or
borderline levels (<350 pg/mL) in the elderly or in those with abnormal
plasma vitamin B12 binding antibodies.19 Further indications of B12
deficiency are serum methylmalonic acid and homocysteine levels,
which rise as markers of tissue B12 deficiency and decline in response to
therapy.20 In pernicious anemia, there are additional antiparietal cell and
anti-intrinsic factor antibodies as well as a positive Schilling test.

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 92 Differential Diagnosis of Dementia Syndromes

Treatment

Treatment consists of 1000 µg of vitamin B12 IM daily for 10 days,

weekly for a month, and monthly thereafter. Neurologic improvement
is usually evident within a few days of initiating therapy and is often
complete by one month, but permanent deficits may remain. Finally,
clinicians must be aware that administration of folic acid may reverse
the hematologic abnormalities of B12 deficiency while allowing the
neurologic changes to progress.

HYPOTHYROIDISM (MYXEDEMA)

Leading Symptoms and Signs

Diminished thyroid activity causes psychomotor retardation, apathy,

lethargy, depression, and, when profound, “myxedema madness” with
deficits in attention and memory, paranoia, and hallucinations. Other
neurologic manifestations are cranial nerve and peripheral neuropathies,
myopathy, ataxia, coma, and seizures. Non-neurologic manifestations of
myxedema include edema or effusions, weight gain, menorrhagia, cold
intolerance, coarse hair, thickened skin, and constipation.21

Diagnosis

Laboratory studies demonstrate low levels of serums thyroxine and

triiodothyronine, elevated levels of thyroid-stimulating hormone (TSH),
and background slowing with diminished amplitude on EEG. MRIs do
not show specific changes, but there is global hypoperfusion on SPECT
that entirely reverses after correction of hypothyroidism.22 The cognitive
changes, however, may persist after corrections.23 Hypothyroidism is
treated by administering exogenous thyroid preparations.

HYPERTHYROIDISM

Hyperthyroidism occurs most commonly in the second and third

decades of life and affects women more often than men. Non-neurologic
manifestations include weight loss, tremulousness, heat intolerance,

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 Chapter 6  |  Reversible Dementia 93

tachycardia, palpitations, exertional dyspnea, an enlarged thyroid gland,

and exopthalmos.

Leading Neurologic Symptoms and Signs

Potential neurologic manifestations include myopathy, peripheral

neuropathy, corticospinal tract disease, chorea, seizures, optic neuropathy,
and exophthalmic ophthalmoplegia.24 The dementia is associated with
anxiety, restlessness, irritability, emotional lability, distractibility, poor
attention, impaired memory, and difficulty with calculations. In the
elderly, thyrotoxicosis may present in masked (apathetic hypothyroidism)
form with lethargy, apathy, and psychomotor retardation.

Diagnosis

The diagnosis depends on identification of an elevated free-thyroxine

index and resin triiodothyronine uptake. Management includes attention
to the underlying cause of the thyrotoxicosis; some symptoms may be
controlled by Propranolol therapy.

HASHIMOTO’S ENCEPHALOPATHY

Leading Symptoms and Signs

This sub-acute dementia consists of confusion, frontotemporal deficits,
delusions, myoclonus, ataxia, and possible stroke-like episodes. There
are often complex partial seizures and myoclonic jerks. Hashimoto’s
encephalopathy typically affects patients when they are euthyroid.25

Diagnosis

There are marked elevations in antibodies against thyroglobulin or

thyroid peroxidase, or both.26 Anti-neuronal antibodies may be positive,
suggesting a shared antigen between the brain and the thyroid gland.
There are periodic discharges on EEG, and bilateral mesial temporal
atrophy with increased signal on T2-weighted MRI. SPECT demonstrates
global hypoperfusion.27

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 94 Differential Diagnosis of Dementia Syndromes

Management

Patients with HE often recover quickly if treated with corticosteroids.

CASE REPORT 2

Presenting Complaints
A 45-year-old male, presented with insidious onset progressive behavioral
abnormalities in the form of disinhibition, aggressiveness and impulsivity
of two-month duration, and short-term memory disturbances and
executive dysfunction for one month. He became dependent on his
family members for activities of daily living (ADLs). There was no history
of loss of consciousness, seizures, myoclonus and focal motor, or sensory
or autonomic disturbances. No relevant associated symptoms in the
form of fever, loss of weight, loss of appetite, or symptoms suggestive of
connective tissue disorders were noted in the history. He was an alcohol
consumer and a bidi smoker for 10 years.

Past History

No significant past or family history was obtained.

Examination

On examination, he was grossly disoriented in time place, and person

with a poor attention span. Hence, his detailed lobar assessment was
not possible. His fundus as well as cranial nerve examinations were
normal. However, he had pyramidal signs in the form of grade 1
spasticity (on Ashworth scale) of both upper and lower limbs as
well as hyper-reflexia and extensor plantar response bilaterally with
frontal release reflexes as well in the form of prominent snout and
pout reflex. No features of extrapyramidal dysfunction, cerebellar
dysfunction, or signs of meningeal irritation were noted. Rest of the
physical examination was normal. A provisional diagnosis of rapidly
progressive dementia was made and the patient was evaluated as per
standard protocol.

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 Chapter 6  |  Reversible Dementia 95

Investigations

His hemogram, biochemistry, renal, and hepatic parameters were within

normal limits. Serum Vit B12 levels were 879 pg/mL (N: 200–900 pg/
mL) and he was euthyroid. HIV ELISA was nonreactive as was S. VDRL,
HBsAg and Anti-HCV. A cerebrospinal fluid (CSF) evaluation was
carried out which revealed no cells with protein of 42 mg/dL and sugar
of 80 mg/dL (CBS: 120 mg/dL). His CSF analysis including VDRL was
negative. Surface 16 channel electroencephalogram revealed diffuse theta
range slowing without epileptiform discharges. Gad-contrast enhanced
MRI brain was normal. Contrast-enhanced computerized tomography
(CECT) scan of the chest and abdomen was normal. Autoimmune
profile was negative for ANA, anti-ds DNA, c-ANCA, and P-ANCA.
However, his anti-TPO antibodies were significantly elevated (> 600 IU/
mL, N < 60 IU/mL).

Treatment

Considering the possibility of HE, he was started on oral Prednisolone

60 mg once daily. Within a few days of initiation of steroids, he started
showing improvement in his cognitive status and by the end of one
month, he started recognizing his relatives and talking coherently with
normalization of electroencephalogram even though residual memory
disturbances persisted.

CUSHING’S DISEASE

Cushing’s disease results from long-term overproduction of

glucocorticoids by the adrenal medulla, usually due to pituitary
adenomas, or from iatrogenic administration of exogenous steroids. The
clinical manifestations are obesity, rounding of the face, thinning and
bruisability of the skin, striae formation, hirsutism, acne, oligomenorrhea,
limb weakness, osteoporosis, hypertension, and diabetes.

Leading Symptoms and Signs

Mental changes include depression, psychomotor retardation, irritability,

poor concentration and memory, psychosis, and disturbed sleep patterns.

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 96 Differential Diagnosis of Dementia Syndromes

Diagnosis

Laboratory tests that confirm the diagnosis include elevated serum

cortisol levels, increased urinary excretion of 17-hydroxycorticosteroids,
and failure to suppress serum cortisol levels following administration
of dexamethasone. Hippocampus and frontal lobe functions may be
particularly disrupted in CD.28 When serum cortisol levels return to
normal, the mental status alterations resolve.

ADDISON’S DISEASE

Too little cortisol can result in a dementia syndrome.

Leading Symptoms and Signs

The principal features are weakness, apathy, irritability, depression,

suspiciousness, agitation, and memory impairment along with anorexia,
weight loss, hypotension, and hyperpigmentation of the skin.28

Diagnosis

Typical abnormalities on laboratory studies include hyponatremia,

hyperkalemia, low levels of 24-hour urinary steroids, and failure of the
adrenal to respond to adrenocorticotropic hormone. Addison’s disease
may also accompany adrenoleukodystrophy. Treatment of the adrenal
insufficiency normalizes mental status in most cases.

UREMIC ENCEPHALOPATHY AND DIALYSIS

DISEQUILIBRIUM SYNDROME (DDS)

Leading Symptoms
The clinical manifestations of uremic encephalopathy (UE) include
fluctuating level of consciousness, disorientation, impaired attention,
sleep inversion, headache, and seizures.

Leading Clinical Signs

Asterixis and myoclonus.

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 Chapter 6  |  Reversible Dementia 97

Management

Dialysis and renal transplant.

Clinical Relevance of the Disorder

UE is reversible with appropriate renal replacement therapy. UE may
accompany either acute or chronic renal disease. Pathophysiology of UE
includes accumulation of metabolites, hormonal disturbances, changes
in intermediary metabolism, and changes in concentration of excitatory
and inhibitory neurotransmitters.29
Clinical features of UE include fluctuating level of consciousness,
disorientation, impaired attention, altered sleep pattern, headache,
asterixis, myoclonus, and seizures. The differential diagnosis of UE,
peculiar to renal disease patients include electrolyte derangements, WE
due to thiamine deficiency, dialysis disequilibrium caused by cerebral
edema due to rapid removal of osmotically active solutes (urea), and
hypertensive/posterior reversible encephalopathy syndrome due to
uncontrolled blood pressure/autoregulation failure.
Electrolyte disturbances, such as hypercalcemia, hypophosphatemia,
hyponatremia, and hypermagnesemia, can produce cognitive dysfunction
and encephalopathy as the major clinical manifestation. Correction
of the underlying metabolic abnormality typically leads to resolution
of symptoms. Compromised nutritional status and accelerated loss of
thiamine in patients on dialysis increases risk of thiamine deficiency.
The full clinical triad of ophthalmoplegia, ataxia, and confusion is rarely
present, so a high index of suspicion and treatment with thiamine can
result in a good outcome.
Dialysis disequilibrium syndrome (DDS) is occurrence of
neurological signs and symptoms, attributed to cerebral edema, during
or following shortly after intermittent hemodialysis. Early findings
include headache, nausea, disorientation, restlessness, blurred vision,
and asterixis. More severely affected patients progress to confusion,
seizures, coma, and even death. Many milder signs and symptoms
associated with dialysis such as muscle cramps, anorexia, and dizziness
developing near the end of a dialysis treatment are also part of this
syndrome. It is usually associated with high solute removal such as urea

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 98 Differential Diagnosis of Dementia Syndromes

during hemodialysis. Prevention is the mainstay of therapy in DDS,

particularly in new dialysis patients who are at highest risk. The initial
dialyses should be gentle, but repeated frequently. The aim is a gradual
reduction in blood urea nitrogen.29

Conclusion

Encephalopathy in renal failure has many mechanisms. Most of these are

reversible and appropriate treatment results in good outcome.

CHRONIC HEPATIC ENCEPHALOPATHY

Leading Symptoms

Hepatic encephalopathy (HE) develops slowly in cirrhotic patients,

starting with altered sleep patterns and eventually progressing through
asterixis to stupor and coma.

Leading Clinical Signs

Apart from signs of chronic liver failure, patients with HE show

asterixis and depending on the stage of HE show extrapyramidal signs
predominantly hypokinesia, rigidity, and tremor. Patients may show
hyper-reflexia and plantar extensor reflexes in addition to extrapyramidal
signs in stage III HE.

Management

It includes management of precipitating factors and strategies to lower

ammonia levels including administering certain sugar molecules (e.g.,
lactulose) or antibiotics (e.g., Meomycin, Metronidazole) to reduce the
production of ammonia in the gastrointestinal tract.

Clinical Relevance of the Disorder

A striking feature of HE is the reversibility of symptoms, which in the

case of a precipitant-induced coma, can fully improve if appropriately

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 Chapter 6  |  Reversible Dementia 99

managed. HE can be defined as a potentially reversible disturbance in

central nervous system (CNS) function secondary to hepatic insufficiency
or portal-systemic shunting.30 The onset of neuropsychiatric symptoms is
often insidious, starting with changes of personality and alterations in sleep
patterns. Shortened attention span and lack of muscular coordination
including asterixis (or “flapping tremor”) follow, progressing eventually
through lethargy to stupor and coma. Motor signs including rigidity and
ataxia are not uncommon.

Diagnosis

Clinical history and physical examination are the most valuable tools to
make the diagnosis. A history of chronic liver disease or the presence of
altered liver function tests in a patient with the described symptoms and
signs strongly suggests HE. However, the diagnosis of HE is a diagnosis
of exclusion. There are no diagnostic liver function test abnormalities;
although an elevated serum ammonia level in the appropriate clinical
setting is highly suggestive of the diagnosis. Examination of the
cerebrospinal fluid (CSF) is unremarkable, and computed tomography
of the brain shows no characteristic abnormalities until late in stage IV
when cerebral edema may supervene. The MRI studies of the brain of
cirrhotic patients typically display a characteristic pallidal hyperintensity
in T1-weighted images (Figure 2).31 EEG may show a characteristic
(but nonspecific) symmetric, high-voltage, triphasic slow-wave (2 to
5 per second) pattern on the electroencephalogram. Other diagnostic
possibilities to exclude are intracranial occupying lesions, cerebrovascular
events, infectious diseases, or other metabolic disorders. Asterixis can also
be seen in patients with uremia, hypercapnia, phenytoin intoxication,
or hypomagnesemia. Detailed physical examination, searching for signs
of cirrhosis and determination of plasma ammonia or performance of
specific neurophysiological or neuroimaging techniques may be useful to
make a positive diagnosis.

Treatment

Management of HE consists of general supportive measures, treatment

of precipitating factor, and strategies to lower blood ammonia levels.

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 100 Differential Diagnosis of Dementia Syndromes

Figure 2  Axial T1 Image Shows Bilateral Symmetrical Hyperintensity

in the Region of Globus Pallidi in a Patient with Altered Sensorium
and Chronic Liver Disease Suggestive of HE.

Protein should be excluded from the diet, and constipation should be

avoided. Ammonia absorption can be decreased by the administration
of lactulose; a non-absorbable disaccharide that acts as an osmotic
laxative may also diminish ammonia production. Intestinal ammonia
production by bacteria can also be decreased by oral administration
of an antibiotic such as Neomycin or Metronidazole. Other strategies
intended to increase the conversion of ammonia into harmless
molecules outside the brain include agents like L-ornithine L-aspartate,
which helps to incorporate ammonia into the amino acid glutamine
in the skeletal muscle. Flumazenil, a short-acting benzodiazepine
antagonist, may have a role in management of HE precipitated by use
of benzodiazepines.

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 Chapter 6  |  Reversible Dementia 101

Conclusion

HE is a potentially reversible disturbance in CNS function and in the

setting of acute precipitating factor may be fully reversible.

NEUROSYPHILIS
Neurosyphilis spans all the stages of disseminated disease. CNS
invasion occurs during the first few weeks or months of infection and
CSF abnormalities are detected in as many as 40% of the patients
during secondary stage. Syphilis characterizes the most chronic form of
meningitis and pathological changes are sequalae to the chronicity of
meningeal reaction. Meningeal, meningovascular, and parenchymatous
syndromes are perhaps best viewed as a continuum of the disease rather
than as discrete disorders. All these disease processes are different clinical
expressions of the same fundamental pathological events, especially
meningeal invasion, obliterative endarteritis, and parenchymal invasion.

GENERAL PARESIS

This encephalitic form reflects widespread parenchymal damage and

typically presents as progressive dementia beginning 15–20 years after
original infection.32,33 The disease manifestation can be remembered by
the mnemonic PARESIS

P:  Personality
A:  Affect
R:  Reflexes (hyperactive)
E:  Eye (Argyll Robertson pupils)
S:  Sensorium (illusions, delusions, hallucinations)
I:  Intellect (decrease in recent memory, orientation, calculation,
insight)
S:  Speech

Laboratory Findings: CSF

The diagnosis of neurosyphilis is based on clinical evidence and is

supported by CSF abnormalities, particularly CSF pleocytosis and reactive

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 102 Differential Diagnosis of Dementia Syndromes

CSF VDRL tests. The CSF pleocytosis in neurosyphilis is lymphocytic

and is generally mild. Mild elevations of CSF protein concentration
ranging from 45 to 200 mg/dL, are also common, with higher values
in early neurosyphilis compared to late neurosyphilis. The CSF VDRL
is considered to be the gold standard for diagnosis of neurosyphilis. The
accepted sensitivity of CSF VDRL ranges from 30–70% though it is
considered to be very specific. False positive results may be seen when
CSF is visibly blood tinged. Thus, a reactive CSF VDRL establishes the
diagnosis of neurosyphilis, but a non-reactive test does not exclude the
diagnosis. In contrast to CSF VDRL test, CSF treponemal antibody tests
such as CSF fluorescent treponemal antibody absorption test are sensitive
but not specific for the diagnosis of neurosyphilis. Thus, a non-reactive
CSF treponemal antibody may exclude the diagnosis of neurosyphilis but
a reactive test does not establish the diagnosis.32

Treatment

The Center for Disease Control (CDC) recommends high-dose

intravenous Penicillin G as first-line therapy for neurosyphilis and
intramuscular procaine penicillin with oral Probenecid as an alternative
in adults, but not children. Other alternative therapies include Ceftriaxone,
Erythromycin, Doxycycline, etc. The success of neurosyphilis therapy
is judged by resolution or stabilization of clinical abnormalities and by
resolution of CSF abnormalities. CDC guidelines state that CSF WBC
count should decline at six months and all CSF abnormalities should
resolve by two years after treatment. Careful follow up after neurosyphilis
therapy is mandatory for all patients. CSF should be reexamined three
months after therapy. If CSF WBC count is normal and the CSF VDRL
is non-reactive at three months, no further LP is required. For those
with persistent CSF abnormalities at three months after therapy, CSF
should be reexamined at six months after therapy and every six months
thereafter until CSF WBC and CSF VDRL reactivity normalize. Failure
of the CSF WBC count to decrease six months after therapy or failure of
CSF VDRL to decline four fold 1 year after therapy is an indication for
retreatment. Serum VDRL or RPR should be obtained at three, six and
twelve months after therapy and every three to six months thereafter until
they are nonreactive. Failure of serum RPR or VDRL to decline fourfold

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 Chapter 6  |  Reversible Dementia 103

(or to non-reactive if initial titer is < 1:2) at one year after therapy is an
indication for retreatment. 32,33

CASE REPORT 3

Present History

A 42-year-old man presented with one year history of

• Prominent personality and psychiatric manifestations

• Progressive cognitive decline over a period of one year
• Extrapyramidal features and myoclonus for six months
• Focal seizures with secondary generalization for four months

Changes in Personality and Psychotic Symptoms

Irritability, lack of concern for family and friends, delusions of grandeur,

visual and auditory hallucinations.

Cognitive Decline

Noticed for four months in the form of forgetfulness for recent events,
loss of spatial orientation, and disinhibition; dependent for all ADLs
for three months.

Extrapyramidal Symptoms

Started six months into the illness in the form of bradykinesia, rigidity,
generalized tremor, and hypophonic speech.

Myoclonus
Started six months into the illness. The myoclonic jerks were generalized,
distal, asynchronous, and precipitated by spontaneous movements.

Seizures

Patient gave history of two episodes of left-focal seizures with secondary

generalization, four months prior to presentation.

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 104 Differential Diagnosis of Dementia Syndromes

Past History

In retrospect, a history of genital ulcerations 10 years prior was obtained.

Examination
Patient was bed ridden, incontinent for urine and stools. He had an
expressionless face and presence of primitive reflexes in the form of positive
palmomental, snout, glabellar tap, and grasp reflex. He had hypophonic and
dysarthric incoherent speech. Neurological examination also revealed mild
left-facial paresis and left hemiparesis with generalized hyper-reflexia. In
addition, there were extrapyramidal signs in the form of bilateral cogwheel
rigidity. However, there was no evidence of Argyll Robertson pupil.

Investigations

His hemogram and blood biochemistry was normal; HIV serology was
negative; blood VDRL was reactive (1:64 dil); and TPHA was positive
(1:80 dil).
CSF examination revealed 40 cells/cmm, all lymphocytes; proteins:
102 mg%; sugar: 75 mg% (CBS:102 mg%); VDRL: reactive(1:4 dil);
cryptococcal antigen was negative and cultures were sterile.
EEG showed diffuse slowing suggestive of an encephalopathy.
MRI brain showed diffuse cerebral atrophy with prominent extra-axial
CSF spaces and dilated supratentorial ventricular system; nonspecific
T2/FLAIR hyperintensities seen in bilateral periventricular white matter
(Figure 3); meningeal thickening and enhancement on contrast images
suggestive of pachymeningitis.

Course and Management

The patient was treated with crystalline Penicillin 4 MU every 4

hourly for 14 days and agitated behavior controlled with Olanzapine
and Clonazepam. After receiving antibiotics, the myoclonus subsided;
patient became ambulant, continent for bowel and bladder. At present,
patient is fully independent in ADLs although he still has impaired recall
of recent memory and a spastic speech.

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 Chapter 6  |  Reversible Dementia 105

Figure 3  MRI Brain (Axial T2 Image) Shows Diffuse Cerebral

Atrophy with Ex-vacuo Dilation of Ventricles and Non-specific
White Matter Changes.

DRUG-INDUCED COGNITIVE DYSFUNCTION

Drugs are the most common cause of reversible cognitive dysfunction.

Drugs exert effect on cognition through their metabolic effects,
alteration in immunologic factors, and through interference of
synaptic transmission.34 In addition, substance abuse can result in
cognitive dysfunction not only during intoxication but also during
withdrawal. The risk of cognitive impairment proportionately
increases as the number of drugs used by an individual increases.
Specific populations are more susceptible to the cognitive impairing
effects of substances, especially those of older age, those with human
immunodeficiency virus (HIV), alcoholism or brain damage. There
are few data regarding which medications produce a greater frequency

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 106 Differential Diagnosis of Dementia Syndromes

of memory impairment. One study found opioids to be the leading

medications associated with delirium in hospitalized patients,
then benzodiazepines, anticholinergic agents, nonsteroidal anti­
inflammatory agents (NSAIDs) and alcohol or sedative withdrawal.35
In outpatients, adverse effects on cognition were most common with
benzodiazepines, antipsychotic drugs, Cimetidine, Methyldopa,
Aspirin, insulin, Pethidine (Meperidine), Amoxapine, Amantadine,
Propranolol, Hydrochlorothiazide, and Reserpine.36

Anticholinergic Drugs

Medicines with anticholinergic properties are the common cause of

drug-induced cognitive decline. The higher the serum anticholinergic
activity, the greater is the risk of cognitive impairment. Patients exposed
to anticholinergics can develop confusion and memory impairment.
More severe anticholinergic toxicity results in hallucinations, delirium,
and agitation. The elderly are more sensitive to anticholinergic effects.
Several commonly used psychotropics have anticholinergic properties,
specifically antidepressants, antipsychotics, and antiparkinsonian agents.
Other drugs with anticholinergic properties include histamine blockers
like cimetidine, ranitidine, famotidine, etc., and direct cholinergic
antagonists like scopolamine.

Anticonvulsants

All anticonvulsants are capable of producing some degree of cognitive

dysfunction presenting as psychosis, confusion, or memory loss.
These more significant cases of cognitive dysfunction associated
with anticonvulsant therapy have been reported with Primidone and
Phenobarbital. The newer antiepileptic agents such as Topiramate and
Levetiracetam are also implicated in causing cognitive dysfunction
and psychosis respectively.

Antiparkinsonian Drugs

Apart from anticholinergic agents, which are particularly likely to cause

cognitive dysfunction, all dopaminergic agents can cause delirium

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 Chapter 6  |  Reversible Dementia 107

and psychosis including Levodopa, Pramipexole, and Ropinirole.

Amantadine is also associated with confusion.

Hypnotics/Sedatives

All sedatives have the potential to produce cognitive impairment.

Benzodiazepines are one of the medications most frequently contributing
to delirium. Benzodiazepines are often associated with the development of
confusion and anterograde memory loss. The elderly are more susceptible.

Anti-hypertensives

Among anti-hypertensives, delirium has been more pronounced with

Guanabenz, Clonidine, and Methyldopa. Beta blockers have moderate
potential to cause delirium. Diuretics, angiotensin converting enzyme
inhibitors, and calcium channel blockers are considered low risk to cause
delirium.
Apart from these, there is a whole range of drugs capable of causing
cognitive dysfunction like antibiotics, NSAIDS, steroids, immunosupressants,
and chemotherapeutic agents.

Conclusion

In a patient with a new or sudden onset of cognitive impairment, both

disease and drug-related causes should be considered. If a drug-related
cause is suspected, that agent should be withdrawn and patient observed
for reversal of dementia. Recognition of drug-induced dementia is
particularly important as omission of offending agent can often reverse
the cognitive decline.

Hydrocephalus

The term hydrocephalus is derived from the Greek words “hydro”

meaning water and “cephalus” meaning head. As the name implies, it is
a condition in which the primary characteristic is excessive accumulation
of fluid in the brain. Hydrocephalus may be congenital or acquired.
Hydrocephalus may also be communicating or non-communicating.

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 108 Differential Diagnosis of Dementia Syndromes

Communicating hydrocephalus occurs when the flow of CSF is

blocked after it exits the ventricles. This form is called communicating
because the CSF can still flow between the ventricles, which remain
open.1 Non-communicating hydrocephalus—also called “obstructive”
hydrocephalus—occurs when the flow of CSF is blocked along one or
more of the narrow passages connecting the ventricles. There are two
other forms of hydrocephalus which do not fit exactly into the categories
mentioned above and primarily affect adults: hydrocephalus ex-vacuo
and normal pressure hydrocephalus. Hydrocephalus ex-vacuo occurs
when stroke or traumatic injury cause damage to the brain and actually
the, brain tissue may actually shrinks in these cases.1

Leading Symptoms

Symptoms of hydrocephalus may include headache followed by

vomiting, nausea, blurred or double vision, problems with balance, poor
coordination, gait disturbance, urinary incontinence, slowing or loss of
developmental progress, lethargy, drowsiness, irritability, or other changes
in personality or cognition including memory loss.1, 37

Leading Clinical Signs

Clinical signs of hydrocephalus in adults may include altered mental

status, papilledema (swelling of the optic disk which is part of the optic
nerve), lateral rectus palsy, truncal and limb ataxia and spasticity.

Management

Hydrocephalus is most often treated by surgically inserting a shunt

system. This system diverts the flow of CSF from the CNS to another
area of the body where it can be absorbed as part of the normal circulatory
process.1, 38,39

Clinical Relevance of the Disorder

It is one of the reversible causes of dementia where surgical intervention

can be very gratifying.

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 Chapter 6  |  Reversible Dementia 109

CASE REPORT 4

Present History

A 62-year-old lady presented with headache, slowness in ADLs and

progressive memory disturbances of eight-month duration. For last six
months, she also had gait disturbance with slowness in ADLs and urinary
incontinence

Past Medical History/Surgical History

Patient had no past history of any medical or surgical illness. She was
non-hypertensive and non-diabetic. No past history of tuberculosis.

Physical Examination

Her general physical examination was normal. Systemic examination was

unremarkable. She had impairment of higher mental functions with mini-
mental score examination (MMSE) of 10/30. Cognitive domains severely
affected were executive function, recent memory, visuospatial skills, and
calculation. Cranial nerves were normal and fundus examination did
not show any papilledema. Motor examination revealed increased tone
in all four limbs with cogwheel rigidity. Power was normal and deep-
tendon reflexes were brisk. Plantar reflex was flexor bilaterally and
sensory examination was normal. She had short, shuffling gait. Various
differential diagnoses considered included chronic meningitis, chronic
subdural hemorrhage, intracranial space occupying lesion like frontal
lobe glioma/meningioma, NPH, and degenerative subcortical dementias.

Investigations

The hemogram was normal and biochemical parameters were within

normal limits. She underwent MRI of brain, which showed that there was
obstructive hydrocephalus with dilatation of lateral ventricles and third
ventricle. Fourth ventricle was not dilated and cause of hydrocephalus
was cyst in third ventricle. In addition, multiple variable-sized solitary
and conglomerate cystic lesions were seen in the right sylvian fissure, basal
cisterns, sulcal spaces, and third ventricle which were hypointense on

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 110 Differential Diagnosis of Dementia Syndromes

T1-weighted and fluid-attenuated inversion recovery (FLAIR) sequences

and hyperintense on T2-weighted sequences (Figure 4). No scolex was
seen within the cysts. The anterior part of right lateral ventricle was
pushed medially by conglomerate cystic lesions in right sylvian fissure
but there was no midline shift. Contrast-enhanced images showed patchy
enhancement of cyst walls and septae There was no perilesional edema or
any evidence of arachnoiditis. Diagnosis of racemose neurocysticercosis
(NCC) was kept. NCC serology (ELISA for IgG antibodies) in serum
and CSF was positive with titers of 1:1600 and 1:80 respectively.

Therapy and Course of the Disease, Complications

Patient underwent ventriculoperitoneal shunting. Post shunting, she had

significant improvement in her cognitive status with MMSE improving
to 22/30 at the time of discharge six days post shunting. Her gait also
improved and she became continent. She was discharged on oral steroids.
Cysticidal therapy was withheld due to concerns regarding provoking
acute brain inflammation and ependymitis from the death of cysts.

Figure 4  MRI Brain (Axial FLAIR) Showing Hydrocephalus and

Racemose NCC in Right Sylvian Fissure.

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 Chapter 6  |  Reversible Dementia 111

Followup

At three months, patient was doing well with MMSE score of 27/30 and
no gait or urinary disturbances.

Conclusion

Hydrocephalus is one of the potentially reversible causes of dementia and

should be ruled out with brain neuroimaging in all dementia patients.

NORMAL-PRESSURE HYDROCEPHALUS

Leading Symptoms

It is associated with a classic triad of dementia, gait disturbance, and

urinary incontinence.

Leading Clinical Signs

Gait disturbances are typically the first signs of NPH. They have been
variously described as apraxic, bradykinetic, glue-footed, magnetic,
parkinsonian and shuffling. The cognitive deficits of NPH are
characterized by psychomotor slowing, memory impairment, and
impaired executive function with preserved cortical tests such as naming.

Management

The treatment for NPH is surgical diversion of CSF. This is accomplished

by implanting a shunt to drain CSF from either the intracranial
ventricular system or the lumbar subarachnoid space to a distal site, such
as the peritoneal or pleural cavity or the venous system, where the CSF
can be re absorbed.

Clinical Relevance of the Disorder

Treatment with shunting procedures can improve the clinical symptoms

of gait disturbance, memory deficit, and bladder incontinence in patients
with NPH.

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 112 Differential Diagnosis of Dementia Syndromes

NPH is a progressive disorder that results in gait ataxia, cognitive

loss, and/or urinary incontinence, accompanied by imaging evidence of
ventriculomegaly.37 NPH is characterized by hydrocephalus with normal
CSF pressure on lumbar puncture and the absence of papilledema. It
was first brought to attention by Hakim and Adams in 1965.38 NPH
can be primary or secondary. When it occurs secondarily to other disease
processes, including subarachnoid hemorrhage, traumatic brain injury,
cerebral infarction, and meningitis, this syndrome is referred to as
secondary NPH. NPH in patients without known precipitants is termed
primary or idiopathic NPH.

Clinical Features

NPH is characterized clinically by the triad of gait disturbance, dementia

and urinary incontinence. Symptoms typically develop insidiously, and
generally occur between the sixth and eighth decades of life.39

Gait
Gait disturbances are typically the first signs of NPH. They are
characterized by a slow, wide-based gait, short shuffling steps, and
difficulty in turning and tandem walking. Patients often present with a
history of falls. Notably, there is no significant motor weakness.

Dementia
The cognitive deficits are typically of the subcortical type, characterized
by inattention, psychomotor retardation, and difficulty with executive
function. Apraxia, agnosia, and aphasia are rare in NPH.

Urinary Incontinence
Urinary incontinence is the third primary symptom of NPH. In early
stages of NPH, urinary frequency and urgency are present. With disease
progression, urinary and even fecal incontinence can be observed.
Urodynamic testing demonstrates bladder hyperactivity.

Diagnosis
All three components of the classic triad of gait, cognitive, and sphincteric
disturbance need not be present to establish the diagnosis of NPH.

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 Chapter 6  |  Reversible Dementia 113

The full diagnosis of NPH requires evidence from the patient’s clinical
history, physical examination, and neuroimaging.

Neuroimaging
Although no findings on imaging studies of the brain are sufficient on
their own to diagnose NPH, ventricular enlargement is necessary to
establish the diagnosis of NPH for patients with appropriate symptoms.
A frontal horn ratio (Evans’ index), defined as the maximal frontal horn
ventricular width divided by the transverse inner diameter of the skull,
signifies ventriculomegaly if it is 0.3 or greater.40
Other radiographic findings associated with NPH include the
following: periventricular hyperintensities; increased CSF flow velocity
in the aqueduct; thinning and elevation of the corpus callosum on sagittal
images; and no visible evidence of obstruction to CSF flow. Several other
brain-imaging techniques have been investigated in patients with NPH,
including single-photon emission CT, PET, nuclear cisternography,
and CSF flow velocity. The diagnostic value of these tests has not been
established, and, at present, these examinations are not part of the routine
work-up of patients with suspected NPH.

Differential Diagnosis

Differential diagnosis of NPH includes vascular dementia including

subcortical ischemic encephalopathy or Binswanger’s disease, Parkinson’s
disease with dementia, parkinsonian syndromes (Lewy body dementia,
corticobasal ganglionic degeneration, progressive supranuclear palsy, and
multiple-system atrophy), frontotemporal dementia, cervical spondylosis,
and peripheral neuropathy.

Prognostic Tests

These tests include a CSF tap test, external CSF drainage via spinal
drainage, and CSF outflow resistance determination. The CSF tap test,
also called a large-volume lumbar puncture, involves the withdrawal of
40–50 mL of CSF by means of lumbar puncture with symptoms assessed
during the first 24 h after the procedure. Symptomatic improvement after
CSF removal increases the likelihood of a favorable response to shunt

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 114 Differential Diagnosis of Dementia Syndromes

placement (positive predictive value 73–100%).41 The relatively low

sensitivity of the high-volume LP, estimated at 26–61%, makes it less
reliable to exclude a diagnosis of NPH.42 Assessing clinical response to
prolonged CSF drainage via a spinal catheter has a combination of high
sensitivity (50–100%), specificity (60–100%) and positive predictive
value (80–100%). Measurement of CSF outflow resistance via an infusion
test with lumbar catheter in place has a higher sensitivity at 57–100%.37,39

Treatment

The treatment for NPH is surgical diversion of CSF. This is accomplished

by implanting a shunt to drain CSF from either the intracranial
ventricular system or the lumbar subarachnoid space to a distal site, such
as the peritoneal or pleural cavity or the venous system, where the CSF
can be re-absorbed.

Outcome

Patients whose symptoms of gait disturbance, dementia, and/or urinary

incontinence have been of two years or less in duration tend to be more
responsive to surgical treatment than patients with more advanced or
longstanding manifestations of the clinical triad of NPH. Although all
symptoms can resolve following shunt surgery, gait is the most likely to
improve. NPH should be recognized as a potentially treatable cause of
gait disturbance and cognitive decline.

CELIAC SPRUE (Celiac Disease, Gluten-Sensitive

Enteropathy)
Celiac sprue is a relapsing-remitting inflammatory disease of the small
bowel that often results in malabsorption and improves with removal of
gluten from the diet. About 10% of patients have a range of neurologic
manifestations that may occur without gastrointestinal symptoms.43

Leading Clinical Symptoms and Signs

First, celiac sprue can result in cerebellar ataxia and cerebellar atrophy on
MRI, often with cortical (action- and stimulus-sensitive) myoclonus.43

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 Chapter 6  |  Reversible Dementia 115

Second, celiac sprue can result in seizures, often with bilateral

occipital calcifications.44 Third, celiac sprue can result in a progressive
leukoencephalopathy.45 These patients may also present with an insidious
dementia with cerebral atrophy, frontal- or posterior-focal encephalitides,
brainstem involvement or myelopathy, isolated cerebral vasculitis, progressive
multifocal leukoencephalopathy, and internuclear ophthalmoplegia.44,45

Diagnosis

The gold standard for diagnosis remains small intestinal biopsy with
characteristic findings, combined with a favorable response to a
gluten-free diet. Diagnostic antibodies (IgG, IgA) include antigliadin,
antiendomysial, antireticulin, antijejunal, and, most recently, anti-tissue
transglutaminase antibodies.43,44

Treatment

Treatment involves removal of all substances containing wheat, rye, and

barley, but not oats. In some patients, the neurologic manifestations
develop or progress despite resolution of intestinal symptoms and
pathology on a gluten-free diet.45 Refractory patients may respond to
corticosteroids and immunosuppressants.

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