Case Study

1. Case Study Steve Factor, M.D. PGY-4 Neurology Resident (2014-2015)

2. 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.

3. 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.

4. 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

5. Differential Diagnosis?

6. Differential Diagnosis? • Psychosis • Bipolar Depression • Schizophrenia • Schizoaffective Disorder • Excessive alcohol consumption • Amphetamine/Cocaine use

7. Expert Differential Diagnosis • Anti-NMDA receptor encephalitis • HIV dementia • Huntington’s Disease • Creutzfeld-Jakob Disease • Multiple Sclerosis • Porphyria • Frontal Temporal Lobe Dementia

8. Describe Imaging Findings T2 Flair CT w/o contrast T2 FLAIR T1 +C GRE T1

9. Imaging Studies- Interpretation • 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?

10. 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?

11. Differential Diagnosis • Multiple Sclerosis- Marburg type • Multiple Sclerosis • ADEM • Metachromatic Leukodystrophy • Adrenoleukodystrophy • Pelizaeus-Merzbacher disease

12. 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

13. 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 Pelizaeus-Merzbacher 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).

14. 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.

15. Metachromatic Leukodystrophy

16. Metachromatic Leukodystrophy LFB

17. Metachromatic Leukodystrophy LFB

18. Metachromatic Leukodystrophy Cresyl Violet

19. Metachromatic Leukodystrophy LFB / Cresyl Violet (Dentate Nucleus)

20. Metachromatic Leukodystrophy Cresyl Violet Peripheral Nerve

21. Metachromatic Leukodystrophy Cresyl Violet Renal Tubules

22. Tay-Sachs (GM2 gangliosidosis) • H&E • LFB / PAS • PAS • Toluidine Blue

23. 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

24. 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

25. 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)

26. 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

27. Leukodystrophies for dummies- Diagnosis by MR Imaging

28. 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

29. REFERENCES • Costello, Daniel J; Eichler, April F; Eichler, Florian S. “Leukodystrophies: Classification, Diagnosis, and Treatment”. The Neurologist 15 (2009): 319-328. Print.