Case Discussion - Word finding difficulties x 2 years Jeffrey M. - - PowerPoint PPT Presentation

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Case Discussion

Jeffrey M. Gelfand, MD, MAS, FAAN

UCSF MS and Neuroinflammation Center

Recent Advances in Neurology - 2017

51 yo right-handed woman with

• 2 years of insidiously worsening right leg

heaviness/weakness, limping, cane within 1 year, painless

• Word finding difficulties x 2 years
• Urinary urgency x 2 years
• Subtle cognitive changes, esp slowness of

thinking, x 8 years

History - 2

• Carried diagnosis of “discoid lupus” (had

patchy hair loss).

• Received pulse glucocorticoids, Rituximab,
• ral steroids and hydroxychloroquine 1 year

prior for suspected “CNS Lupus”

• Insidiously worsened

Past Medical History

Hypertension Patchy hair loss several years prior, ?discoid lupus

Family History

Arthritis, SLE, migraine

Social History

Former smoker, no drug use, no relevant travel or exposure

PHYSICAL EXAM

BP 144/100; HR 60 regular. Thin, no scalp lesions, no facial rash, no active synovitis. Digits forward 6. Delayed recall 2/3. Noticeably cognitively slow overall. Saccadic intrusions to smooth pursuit. Mild R ptosis. Slowed FFM. Mild right hemiparesis (pyramidal). Hyperreflexic. Ataxic gait. Slow. 25 foot timed walk 18.5 seconds with a cane.

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• Bilateral supratentorial

FLAIR hyperintensities.

• Numerous foci of

reduced diffusion in the bifrontal periventricular and deep white matter

• No abnormal

enhancement

• MRA brain normal
• MRI Spine with mild DJD, no cord lesions

MRI 1 year after the above

DWI ADC

Diagnostics

LABS + ANA, + RNP, +Smith antibodies. PLT 138. SPEP with polyclonal gammopathy. Negative or normal: DS-DNA, Smith. SSA/SSB, RF, SCL-70, Jo-1, Histone, ESR, complements, CK, ACE, HIV, Lyme, TSH, TPO, UA. CSF Opening Pressure: 16 cm 0 WBC, 1 RBC, protein 33, glucose 59 (serum 81) IgG index 0.48; Matched bands in CSF and serum VDRL NR EMG-NCS: Mild right axonal peroneal neuropathy that does not explain her right leg weakness

A Diagnostic Test was Performed…

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• CSF1R mutation: Novel non-

conservative amino acid substitution L817Q in exon 19 in the CSF1R gene. All pathogenic mutations to date have been reported in this tyrosine kinase residue. Considered to be pathogenic and diagnostic.

Whole Exome Sequencing

CSF1R – Adult Onset Leukodystrophy with Spheroids and Pigmented Glia (ASLP)

• Syndrome described 1984; CSF1 receptor mutations recognized 2012;

Autosomal dominant

• Encompasses two pathological conditions: hereditary diffuse

leukoencephalopathy with neuroaxonal spheroids (HDLS) and familial pigmentary orthochromatic leukodystrophy (POLD).

• CSF1R primarily expressed on microglia, lesser on neurons – increasingly

viewed as a “microglial-opathy” + axon loss

• Median age of onset 42 (range 18-60 yrs in larger series). Relatively rapid

neurological progression (cognitive, motor, gait) to death (e.g. Guerreiro, JAMA

Neuro, 2013; Konno, Neurology, 2014)

• Allo-HSCT may slow progression, possibly by chimerism of wild type CSF1R

from monocytes – can HSCs can replace microglia when injured? (Eichler, et. al.

Brain 2016)

MRI 8 months later: Interval bifrontal diffusion restriction. Unchanged bilateral supratentorial white matter volume loss and thinning of the callosal body.

Referred for allo-HSCT

Clinical Pearls

• Leukoencephalopathy plus persistent foci of reduced diffusion can be a

helpful radiographic clue for CSF1R diagnosis.

• This condition, which may account for ~10% of adult onset

leukodystrophies, can be mistaken for MS or other vasculopathies

• Prompt use of whole exome sequencing to confirm a genetic cause of

adult-onset leukodystrophy can accelerate diagnosis, spare brain biopsy and allow for timely treatment

• Exome sequencing is a complex process in which every variant cannot

possibly be examined in detail -- missense mutations are most likely to be missed. Meticulous phenotyping can nominate specific genes (i.e. CSF1R) for closer scrutiny and increase diagnostic yield.