Transcript Presentation - Neuropathology

Case Study
Steve Factor, M.D.
PGY-4 Neurology Resident (2014-2015)
Clinical History
26 year old female financial consultant with past medical
history of migraines presents to Neurology Clinic with
her boyfriend. He states that over the past few months
she has become excessively impulsive and become
prone to aggressive outbursts.
In addition, he recently found out that she has had
unprotected sex with three partners in as many weeks,
but seems unconcerned with her new behavior and how
it may affect him.
She and her boyfriend deny any evidence of delusions,
hallucinations.
Mental Status Examination
 Mild deficits in the rate of information processing,
attention, memory, cognitive flexibility, and problem
solving.
 In conversation, she is mildly restless with improperly
timed episodes of laughter, expansive affect, elevated
mood and prone to sudden change of topic.
 A&Ox3, little insight or judgment into her actions.
Neurologic Exam
 CN: 2-12 normal
 MOTOR: 5/5 strength in all extremities proximally and
distally, normal bulk but slightly increased tone in
bilateral lower extremities
 SENSORY: normal sensation in all modalities
 REFLEXES: 2+ in all extremities except 3+ bilateral
patellas. No clonus, downgoing toes.
 CEREBELLAR: normal FTN, HTS bilaterally
 GAIT: mildly spastic gait with good casual arm
swing
Differential Diagnosis?
Differential Diagnosis?
 Psychosis
 Bipolar Depression
 Schizophrenia
 Schizoaffective Disorder
 Excessive alcohol consumption
 Amphetamine/Cocaine use
Expert Differential Diagnosis
 Anti-NMDA receptor encephalitis
 HIV dementia
 Huntington’s Disease
 Creutzfeld-Jakob Disease
 Multiple Sclerosis
 Porphyria
 Frontal Temporal Lobe Dementia
Describe Imaging Findings
T2 Flair
T2 FLAIR
T1 +C
CT w/o contrast
GRE
T1
Imaging StudiesInterpretation
 Extensive symmetrical T2 hyperintensity in the
periventricular white matter that extends to the
subcallosal white matter with sparing of the subcortical
U-fibers.
 Frontal, temporal, and parietal lobes are involved with
frontal lobe predominance. Changes are confluent and
the splenium is also involved.
 There is no diffusion restriction.
 What is differential diagnosis after imaging?
 What additional testing would you recommend?
Other Studies
 Normal CBC, BMP, LFTs, coags
 Negative HIV test
 Normal Cortisol, ACTH levels
 EEG: normal awake and sleep
 LP:




OP 14; 1 WBC, 17 RBC, 29 Glucose, 40 Protein
No oligoclonal bands, normal IgG index
JC virus Ab negative
HSV/VZV pcr’s were negative
 What is new Differential Diagnosis?
Differential Diagnosis
 Multiple Sclerosis- Marburg type
 Multiple Sclerosis
 ADEM
 Metachromatic Leukodystrophy
 Adrenoleukodystrophy
 Pelizaeus-Merzbacher disease
Expert summary &
interpretation
 Young patient presented with poor insight into her own
behavioral disinhibition and dysexecutive cognitive
syndrome. Tone was increased in her legs and gait
was mildly spastic.
 MRI shows confluent bilateral periventricular white
matter changes, most prominent frontally
 LP shows no evidence of inflammation or elevated IgG
index
Expert summary &
interpretation
 Bilaterally symmetric T2 hyperintensity on MRI is highly
uncommon for ADEM or MS and its multiple variants.
Lack of IgG index elevation also helps rule out MS.
 Lack of ataxia, prominent psychiatric presentation, and
lack of U-fiber involvement helps rule out PelizaeusMerzbacher disease.
 Bilateral frontal white matter involvement on MRI, lack
of adrenal insufficiency helps rule out
Adrenoleukodystrophy (MRI findings of biventricular
hyperintensity in parieto-occipital regions).
Expert summary &
interpretation
 Psychiatric presentation with mild cognitive decline,
spasticity in lower extremities, and MRI with
biventricular confluent white matter lesions
predominantly in frontal regions most consistent with
diagnosis of Metachromatic Leukodystrophy, adult
form.
Metachromatic
Leukodystrophy
Metachromatic
Leukodystrophy
LFB
Metachromatic
Leukodystrophy
LFB
Metachromatic
Leukodystrophy
Cresyl Violet
Metachromatic
Leukodystrophy
LFB / Cresyl Violet
(Dentate Nucleus)
Metachromatic
Leukodystrophy
Cresyl Violet
Peripheral Nerve
Metachromatic
Leukodystrophy
Cresyl Violet Renal
Tubules
Tay-Sachs (GM2 gangliosidosis)
 H&E
 LFB / PAS
 PAS
 Toluidine Blue
Leukodystrophies for
dummies
 What is a “Leukodystrophy”?
 Leuko- white, dystrophy- degenerating
 Unlike disorders such as MS or GBS where
there is loss of previously normal myelin,
leukodystrophies present with hypomyelination
or dysmyelination
Leukodystrophies for
dummies- Diagnosis
 How does Leukodystrophy generally present?
 Childhood-onset leukodystrophy
 Presents after normal development; cognitive decline, some
personality changes, loss of motor skills
 Adult-onset leukodystrophy
 Often presents with slowly worsening cognitive skills and
psychiatric abnormalities (often mistaken at first for primary
psychiatric disease), lower limb spasticity, sometimes bulbar
palsy
Leukodystrophies for
dummies
 Types of Leukodystrophy of Adulthood:
 Adult cerebral X-linked and female heterozygote
Adrenoleukodystrophy, Adrenomyeloneuropathy, Alexander
disease, Leukodystrophy with neuroaxonal spheroids,
Vanishing white matter disease, Metachromatic
leukodystrophy
 Differential Diagnosis
 Infiltrative tumors (gliomas, CNS lymphoma), Toxic
leukoencephalophy (chemo, radiation, drugs of abuse),
Metabolic leukoencephalopathy (anoxia, CO poisoning),
CNS inflammation (MS, ADEM), Infestion (HIV
encephalopathy, PML, encephalitis), Vasculopathy
(CADASIL)
Leukodystrophies- Diagnosis of Adult-onset forms
 Metachromatic Leukodystrophy- Autosomal Recessive
 Defect in lysosomal enzyme Arylsulfatase A leads to accumulation of
sulfatide in lipid membranes
 Diagnostic tests:
 Arylsylfatase A presence in leukocytes
 Urinary excretion of sulfatides
 Adrenoleukodystrophy –X-linked recessive
 Defect in ABCD1 (adenosine 5’-triphosphate-binding cassette transporter)
which maps to Xq28; codes for peroxisomal membrane protein.
 Diagnostic test: serum very long chain fatty acids
 Alexander Disease- De novo mutations in majority
 GFAP gene mutation (GFAP= glial fibrillary acid protein)
 Pathophysiology possibly related to toxic GFAP aggregates
 Vanishing White Matter Disease- AR, penetrance age
dependent
 Mutation in eIF2B possibly causes an abnormal unfolded protein response
Leukodystrophies for dummiesDiagnosis by MR Imaging
Recommended workup for
Metachromatic Leukodystrophy
 CHILDHOOD/JUVENILE FORM:
 Gait disturbances ataxia, spastic quadriplegia, optic atrophy,
peripheral neuropathy decerebrate posturing
 ADULT FORM:
 Presents in 20s-30s, sometimes as late as 70’s. Often with psychiatric
changes dementia, spastic paraparesis, incontinence.
 Workup shows:
 MRI shows diffuse white matter changes (Anterior>Posterior) with U-fiber
sparing
 High urinary excretion of sulfatides
 Low arylsulfatase A in leukocytes
 *Little role for traditional neuropathology*
 Treatments
 Bone marrow transplant or hematopoietic stem cell transplant
 Ineffective in symptomatic patients
REFERENCES
 Costello, Daniel J; Eichler, April F; Eichler, Florian S.
“Leukodystrophies: Classification, Diagnosis, and
Treatment”. The Neurologist 15 (2009): 319-328. Print.