Neurology Case of the Week
HASSANAIN TOMA, MD
NEUROLOGY PGY-4
M A R C H 2 9 TH, 2 0 1 3
Chief Complaint
Difficulty balancing when
walking.
HPI
- Acute unsteady in gait tendency to fall – x6 weeks.
- Difficulty with puzzles and going up/down stairs.
- Progressively worsened over past 2 weeks .
- Deny- mental status change, posturing, eye
deviation, impairment of responsiveness, irritability,
nausea, vomiting.
PAST MEDICAL/ SURGICAL/
BIRTH HISTORY:
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born full term by vaginal delivery.
Uncomplicated pregnancy, labor
and delivery.
received routine newborn care
and then went home with mother.
Adverse Reactions/Allergies:

FAMILY HISTORY:

GROWTH/DEVELOPMENT:

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Was normal and appropriate for
the age
Word sentences, uses about 50
words

Deny neurologic or
neurodevelopmental issues.
SOCIAL HISTORY:
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MEDICATIONS:
Milk Products(Rashes)

ibuprofen PRN
Lives at home with 24 yo
mother (healthy) & and
maternal grandparents
Father is 21 yo, healthy
Goes to daycare 3 days a week
as mother is still in college
IMMUNIZATIONS:

Up to date
Physical Exam
General: Awake, alert, appears of stated age,
active boy.
Head/Neck: normocephalic. No neck masses.
Eyes: PERRL. Conjunctiva clear. Fundi benign.
ENT: TM's pearly and nonbulging bilaterally. No
erythema or exudate of oropharynx. Dry lips.
Chest: CTAB, no wheezing.
CV: RRR, no murmurs, rubs, or gallops.
Abdomen: abdomen is soft. Non distended.
+BS
Lymph: No cervical LAD.
Skin: No rashes seen on visible skin.
Mental State: Awake, alert, oriented to self.
Cooperative and follows simple commands.
Speech: clear, non-dysarthric.
CN II: PERRL, visual fields full to confrontation.
CN III, IV, VI:EMOI, no nystagmus.
CN V: sensation intact. Strong jaw clench.
CN VII: Symmetrical facial movement.
CN VIII: grossly intact.
CN IX & X: Gag present, uvula midline.
CN XI: strong shoulder shrug.
CN XII: tongue midline.
Motor: Symmetrical strength, appropriate for
age U/E. Weakness b/l LE with decreased
tone. Helps with arm when getting up from
supine.
Sensory: intact to light touch, pin prick.
Reflexes: 2 b/l UE, 3 b/l LE. 2 beats clonus b/l.
downgoing toes.
Coordination: Mild ataxia b/l
Gait: wide-based, unsteady, ataxic pattern.
Labs
HEMATOLOGY
WBC
HGB
HCT
Platelet
Normal diff
12.3
12.1
35.5%
294
SED rate
8
CHEMISTRY
Sodium
Potassium
Chloride
Carbon Dioxide
Anion Gap
Calcium
Glucose
BUN
Creatinine
141
4.2
104
24
13
10.4
91
9
0.23
Protein Total
Albumin
Bilirubin, Total
Bilirubin, Direct
Bilirubin, Indirect
AST
ALT
7.4
4.8
0.7
0.0
0.6
41
29
Alk Phos
215
What??
Where??
Vegetative, Autonomic, Endocrine Disorders
Convulsion/grand mal seizure
Post-ictal status
Hydrocephalus Syndrome
Reference to Organ System
Ataxia, cerebellar, acute
Cerebellar disorder
Cerebellar syndrome, acquired
Heirarchical Major Groups
Brain stem disorders
Drugs
Anticonvulsants Administration/Toxicity
Benzodiazepines Administration/Toxicity
Drug reaction/Side effect
Tricyclic antidepressant Administration/Toxicity
Antihistamine Administration/Toxicity/effect
Benzodiazepine toxicity/overdose
Tricyclic overdose
Carbamazepine (Tegretol/Carbatrol) adm
Phenytoin (Dilantin) Administration/Toxicity
Poisoning (Specific Agent)
Poisoning
Solvent/inhalation/Huffing propane etc
Glue sniffing/ingestion
Gasoline poisoning
Trauma Causes
Concussion
Head trauma
Arteriosclerotic, Vascular, Venous Disorders
Cerebellar hemorrhage/hematoma
Infectious Disorders (Specific Agent)
Viral acute illness/Viremia
Labyrinthitis, viral
Meningitis Bacterial
Post infectious cerebellitis
Infected organ, Abscesses
Brain abscess
Brain stem encephalitis
Neoplastic Disorders
Brain tumor
Neuroblastoma, CNS
Opsoclonic-myoclonic/paraneoplastic syn
Allergic, Collagen, Auto-Immune Disorders
Acute Postinfectious Cerebellitis
Multiple Sclerosis
Deficiency Disorders
Vitamin E deficiency
Congenital, Developmental Disorders
Cerebral AV malformation
Arteriovenous malformations
Hydrocephalus, obstructive
Hydrocephalus, communicating
Hydrocephalus
Hereditary, Familial, Genetic Disorders
Ataxia-telangiectasia
Myoclonic encephalopathy/childhood
Cerebellar ataxia, congenital/hered.
Friedreich's Ataxia
MRI – T1
MRI – T2
MRI – T2
MRI – T2
MRI - FLAIR
MRI – FLAIR
MRI - SWI (Susceptibility)
MRI – T1 w Contrast
MRI – T1 w CONTRASTv
MRI – T1 w CONTRASTv
MRI- Differential Diagnosis
Category A: severely deficient myelination
predominant finding:
• Pelizaeus-Merzbacher disease
• Salla disease
• Cockayne syndrome type II
• Tay syndrome
• Alpers disease
• Menkes syndrome
• infantile neuronal ceroid lipofuscinosis
• Sandhoff disease
Category B: global cerebral white matter
involvement.
• “infantile onset vacuolating leukoencephalopathy
• “CACH” (childhood cerebellar ataxia and central
hypomyelination)
• “the disease of the vanishing white matter”
Category C: extensive cerebral white matter
abnormalities
• fronto-occipital gradient and relative sparing of the
occipital lobes
• Alexander disease
Category D: that of patients showing predominantly
periventricular white matter abnormalities
• Autosomal dominant leukoencephalopathy
• metachromatic leukodystrophy
• Krabbe disease
• X-linked adrenoleukodystrophy
Category E: isolated multifocal white matter
abnormalities with a predominantly lobar location
and relative sparing of arcuate fibers and
periventricular white matter
• acute disseminating encephalomyelitis
• multiple sclerosis
• congenital cytomegalovirus infection
Category F: white matter changes in a predominantly
subcortical location. preferentially involve the
arcuate fibers
• such as l-2-hydroxyglutaric aciduria
• Kearns-Sayre syndrome
Category G: white matter disorders in a
predominantly posterior fossa location.
• Refsum disease
• cerebrotendinous xanthomatosis
• adrenomyeloneuropathy
MRI- Differential Diagnosis
Labs
 Arylsulfatase A activity
59.6 nmol/hr/mg
 EIF Gene Sequence:
 Sequence analysis of the coding region of the EIF2B5 gene
identified a heterozygous disease-associated
missense mutation in exon 2, p.Thr91Ala (c.271A>G),
 missense mutation in exon 7, p.Arg339Pro (c.1016G>C)


This result is consistent with a diagnosis of
Leukoencephalopathy with Vanishing White Matter in this
individual.
Vanishing White Matter
Disease
NO, IT’S NOT MAGIC!
What do we know?
Vanishing White Matter (VWM) disease has also been known as:
• Childhood ataxia with central nervous system hypomyelination
• Leukoencephalopathy with vanishing white matter
• Cree leukoencephalopathy
-
autosomal recessive neurological disease.
chronic and progressive white matter disorder,
exacerbated by infection or head trauma.
The disease belongs to a family of conditions called the leukodystrophies.
The cause of the disease are mutations in any of the 5 genes encoding subunits of
the translation initiation factor EIF-2B:
- EIF2B1, EIF2B2, EIF2B3, EIF2B4, or EIF2B5.
It was not recognized as a clinical syndrome until the 1990s.
atypical diffuse sclerosis- 1962
 1st description in 1962, by Eicke et al.
 36 yo F initially presented at 31 yr with gait difficulties
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and secondary amenorrhoea.
The clinical disease course was chronic progressive with
episodes of rapid deterioration after minor physical
trauma.
At autopsy, a diffuse, cystic destruction of the cerebral
white matter was found.
Around the cystic areas, a dense “network” of
oligodendrocytes was seen.
Only mild fibrillary astrocytosis and scant sudanophilic
lipids were present.
The diagnosis was “atypical diffuse sclerosis”.
Epidemiology
 incidence and prevalence ?
Perhaps one of the more common leukodystrophies.
 Among patients with a leukodystrophy of unknown etiology
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40% met clinical criteria for VWM,
23% met MRI criteria
At the time of these studies, genes were not defined.
 Unaffected Cree adults population:

1/10 adults were heterozygous for a G584A mutation on the EIF2B5 gene
 suggesting a high carrier rate in select populations
 Prevalence is only limited by the physician’s ability to identify the disease. As of
2006, more than 200 people have been identified with VWM, many of whom
were originally diagnosed with an unclassified leukodystrophy.
Clinical Presentation
 Febrile illness, minor head trauma, or severe fright often leads to sudden
neurologic deterioration
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prominent ataxia and spasticity, optic atrophy and seizures can occur.
Loss of motor functions, irritability, vomiting, coma, and even fever.
coma, with incomplete recovery .
 Intellectual functioning is usually relatively spared.
 There are now five clinical subtypes:
1. Antenatal- 3rd trimester with decreased fetal movements & oligohydramnios.
2. Infantile- 1st yr of life - severe type
3. Early childhood- 1-5 yrs of age- most common variant,
4. Late childhood/juvenile- 1 - 5 yrs of age.
5. Adult- over 15 yrs - same as childhood and juvenile but spasticity > ataxia
Genetics
 5 genes that encode subunits of the eukaryotic translation initiation
factor eIF2B.
 The eIF2B protein complex is composed of 5 different subunits
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eIF2Balpha, eIF2Bbeta, eIF2Bgamma, eIF2Bdelta, and eIF2Bepsilon.
The genes are named EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5
located on chromosomes 12q24.3, 14q24, 1p34.1, 2p23.3, and 3q27, respectively.
 Genotype-phenotype correlations
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Phenotypic heterogeneity among members of the same family and among individuals
with the same mutation
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phenotype is influenced by the environment and other genetic factors?
However, certain genotype-phenotype correlations have been described, as illustrated by the
following examples
Pathogenesis
 initiation factors needed for translation of mRNA to polypeptides.
 The eIF2B protein complex

initiation of protein synthesis and the cellular response to stress by
activating the initiation factor eIF2.
 During periods of stress- trauma, heat, and infection.
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causes the misfolding of proteins.
decreased activity of eIF2B disrupts the cellular response to stress.
glial cells have a selective vulnerability to decreased eIF2B activity.
Investigations
Blood tests:
 Various abnormal findings
 Elevation of serum aminotransferases and lactic dehydrogenase indicates
liver dysfunction
 Elevation of creatine kinase, urea nitrogen and amylase indicates
concomitant involvement of the muscles, kidneys and pancreas
respectively.
Genetic Testing
 Genetic testing — Approximately 90% of individuals diagnosed by clinical and MRI
criteria have mutations in one of the five causative. More than 120 mutations of
EIF2B genes have been reported. Mutations in the EIF2B5 gene account for more
than one-half of cases .
 Genetic testing may be particularly important to establish the diagnosis of VWM in
patients with neonatal or early infantile-onset variants, as brain MRI features in
early-onset disease may be atypical and are unlikely to meet MRI criteria for VWM.
Labs
 Laboratory testing — Routine laboratory tests are generally normal in patients
with VWM. Standard cerebrospinal fluid (CSF) analysis is likewise normal.
 A reduced CSF asialotransferrin/total transferrin ratio <8%

sensitivity & specificity of 100 and 94 percent, respectively, for the identification of patients with
eIF2B mutations.
 Because the test is inexpensive and rapid (<48 hours), the investigators
suggested that determination of asialotransferrin/transferrin ratio could be
used to screen cases with a suspected diagnosis of VWM prior to genetic
mutation analysis, which can take weeks to months before results are available.
However, the data set included no patients with neonatal or infantile onset, and
further confirmation is needed to determine if the test is useful in these
subgroups.
 Currently, determination of the asialotransferrin/transferrin ratio by two-
dimensional gel electrophoresis is available only on a research basis.
MRI- Dx Criteria
hyposignal on T1-weighted
sequences imaging (A, D)
hypersignal on T2 (B, E, G
FLAIR sequences imaging (C, F, H,
I),
infantile (C; arrow)
childhood (F; arrow)
juvenile/adult onset form these
areas are restricted to the frontal
white matter on FLAIR sequences
(H; arrow).
Pathology
 A coronal section of the left cerebral hemisphere
shows the rarefaction of the white matter with
microcystic changes in the periventricular area. The
U-fibers, corpus callosum, and internal capsule are
relatively spared (anti-MBP stain).
 At autopsy, gross sections of the brain demonstrate
extensive cystic, gelatinous, or cavitary degeneration
involving the periventricular and immediate
subcortical white matter, with partial sparing of the
U-fibers. Symmetric brainstem lesions within the
central tegmental tracts may be present.
 Microscopically, the white matter demonstrates
marked rarefaction, severe loss of myelin with spongy
degeneration, vacuolation, astrocytic gliosis, and
macrophage proliferation in some areas. Myelin loss
is seen in the retrobulbar optic nerve in some patients
Treatment
 Prognosis is often grave
 There is no cure or specific treatment for VWM.
 Avoidance of stressful situations is crucial to the management,
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contact sports should be avoided.
Since infection and fever can have deleterious effects, antibiotics and antipyretics should be used liberally
vaccinations, such as the influenza vaccine, should be kept up-to-date.
 Physical therapy, rehabilitation, and antispasmodic medications can be used to
improve the gait and tone.
 Antiepileptic drugs are used in patients with epilepsy.
 Melatonin has been shown to provide cytoprotective traits to glial cells exposed
to stressors such as excitotoxicity and oxidative stress.
OUR PATIENT- 4 month f/u
 NEUROLOGIC EXAM:
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MOTOR: slightly increased tone in his legs greater than his arms.
REFLEXES: 3 throughout , upgoing toes b/l, sustained ankle clonus b/l.
COORDINATION: subtle ataxia noted on reaching for objects.
MOBILITY: dramatically regressed in his ability to walk since his initial diagnosis
nonambulatory, significant truncal ataxia on sitting. He can still crawl and stand with help
 followed by Rehabilitation for tone management and equipment needs
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He does have AFOs in place and does have a walker which they are preparing to start using
They are doing daily stretches on him and he is getting PT and OT once every other week
 Mother avoids head trauma, and infections, fever
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Goes to daycare 3 days a week, on prophylactic amoxicillin daily.
 genetic counseling given – mother not interested.
References
1.
Fogli A, Wong K, Eymard-Pierre E, et al. Cree leukoencephalopathy and CACH/VWM
disease are allelic at the EIF2B5 locus. Ann Neurol 2002; 52:506.
2.
Eicke WJ. Polycystische umwandlung des marklagers mit progredientem verlauf.
Atypische diffuse sklerose? Arch Psychiat Nervenkr 1962; 203:599.
3.
van der Knaap MS, Pronk JC, Scheper GC. Vanishing white matter disease. Lancet
Neurol 2006; 5:413.
4.
Black DN, Booth F, Watters GV, et al. Leukoencephalopathy among native Indian
infants in northern Quebec and Manitoba. Ann Neurol 1988; 24:490.
5.
Upto date
6.
Emedicine