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2/15/2019 1

RAIN Conference 2019 Difficult Diagnoses

Maulik Shah, MD, MHS UCSF Neurohospitalist Division February 15, 2019

Disclosures

• No relevant disclosures to this talk
• I am the CME quiz editor for JAMA Neurology
• I am on the board for Neurohospitalist

Rapidly progressive sensory deficits

• 57 year old man with mandibular squamous cell

carcinoma and small cell lung cancer with known CNS metastatic disease presented to hospital with progressive sensory disturbance and ataxia

• Started on ipilimumab and nivolumab

(checkpoint inhibitor therapy) two months prior to presentation

• Started with numbness in left hand, then to left

leg, then right leg, and then right hand

– Clumsiness, gait disturbance and recurrent falls – Progressed over weeks

Case, continued

• Neurologic Examination
• Normal mental status, withdrawn affect
• Mild dysarthria, end-gaze nystagmus
• Left > right clumsy finger taps without clear focal

weakness, but diffuse cachexia

• Left and right dysmetria, arms worse than legs
• Markedly absent proprioception in fingers and

wrists, in feet to level of knees

• Deep tendon reflexes absent in arms and legs

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Question #1

Which of the following has been reported as a neurologic complication of checkpoint inhibitor cancer therapy?

• A. Acute demyelinating polyneuropathy
• B. Cerebellitis
• C. Limbic encephalitis
• D. Myasthenia gravis
• E. All of the above have been reported in

the literature

A c u t e d e m y e l i n a t i n g p

• l

. . . C e r e b e l l i t i s L i m b i c e n c e p h a l i t i s M y a s t h e n i a g r a v i s A l l

• f

t h e a b

• v

e h a v e b e . .

3% 2% 88% 3% 3%

Checkpoint Inhibitor Neurotoxicity

• Immune-mediated cancer therapy, the use of

which has greatly expanded over last few years

• Inhibit down-regulatory signals directed toward T

cells via targets such as cytotoxic T-lymphocyte- associated antigen 4 (CTLA4) and programmed cell death-1 (PD-1)  leads to upregulation of cytotoxic T-cell activity and tumor death

• Used for melanoma, small cell lung cancer, renal

cell carcinoma, and increasingly for other treatment refractory neoplasms including primary CNS malignancy

Checkpoint Inhibitor Neurotoxicity, continued

• Adverse events have included tissue/organ-specific

autoimmune-based disease

– Colitis and thyroiditis

• Neurologic complications range from 2-5% in various

case series

– Rate >10% in some series of combination therapy – Often seen despite favorable response in terms of primary malignancy

• Pathophysiology unclear

– Shared antigen on healthy tissue and cancer cells – Activation of underlying autoimmune disease – “Unmasking” of paraneoplastic syndrome

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Checkpoint Inhibitor Neurotoxicity, continued

• Peripheral nervous system complications

– Demyelinating polyneuropathy / AIDP – Myositis including necrotizing myositis – Myasthenia gravis – Vasculitis  peripheral nerve disease

• Central nervous system complications

– Aseptic meningitis – Encephalitis, NMDA-receptor limbic encephalitis – Cerebellitis – Myelitis, necrotizing myelopathy

• Exacerbation of other inflammatory conditions

– Radiation toxicity

Case, continued Labs and Work-up

• Serum labs notable for SIADH
• EMG/NCS: Non-length-dependent, generalized

sensory neuropathy versus neuronopathy with multifocal involvement of motor nerves and nerve roots and mild demyelinating findings

• CSF with WBC 30 (95% lymphocytes), glucose 48,

and protein 184

• MRI Brain and systemic imaging showing

improvement in burden of metastatic disease

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Question #2

Which of the following etiologies is of primary concern given results of diagnostic testing and MRI spine imaging?

• A. Viral myelitis
• B. Autoimmune / paraneoplastic myelitis
• C. Metastatic disease with intramedullary

involvement

• D. Compressive spondylotic myelopathy
• E. Metabolic myelopathy

V i r a l m y e l i t i s A u t

• i

m m u n e / p a r a n e

• p

. . . M e t a s t a t i c d i s e a s e w i t h i . . . C

• m

p r e s s i v e s p

• n

d y l

• t

i . . . M e t a b

• l

i c m y e l

• p

a t h y

0% 72% 16% 7% 5%

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Question #3

Which of the following MR imaging pattern of findings would be most suggestive of a paraneoplastic cause of myelitis?

A. “Owl’s eye” appearance and hyperintensity of anterior spinal cord B. Nodular leptomeningeal and exiting nerve root enhancement C. Short segment peripherally based asymmetric homogenously enhancing single lesion D. Longitudinally extensive tract-specific symmetric T2 hyperintensity and contrast enhancement on T1

“Owl’s eye” appearance ... Nodular leptomeningeal... Short segment peripheral.. Longitudinally extensive ...

1% 85% 4% 10%

Case, continued

• CSF testing returned positive for CRMP-5-IgG

antibody

• Treated with high-dose IV steroids followed by
• ral taper
• Given lack of improvement, plasmapheresis was

initiated and patient completed five exchanges

• Deficits stabilized but did not improve
• No further treatments given goals of care and

patient desire to return home

CRMP-5 Autoimmune Myelitis

• Collapsing response-mediator protein 5

– Intracellular antigen

• Associated with variety of neurologic

presentations including

– Peripheral neuropathy – Retinopathy, optic neuropathy – Chorea, cerebellar ataxia – Myelitis

• Associated most commonly with small cell lung

cancer

– Renal cell carcinoma, thymoma, seminoma, others

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Paraneoplastic Myelitis

• In one case series, most patients had

longitudinally extensive myelitis with symmetric enhancement that was tract-specific or gray matter restricted

• CSF was inflammatory with pleocytosis, unique
• ligoclonal bands
• Anti-amphiphysin antibody most common,

CRMP-5 second

• Onset could occur months prior to neoplasm

discovery

• Poor prognosis for recovery even with cancer

therapy

Checkpoint Inhibitor Neurotoxicity Treatment

• Guidelines suggest that treatment is based on severity
• f neurologic symptoms
• Discontinuation of immune therapy
• High dose steroids followed by oral taper
• Adjunct based on disease and severity

– IVIg or plasmapheresis

• Goal may be stabilization of deficits

– In one case series, 30% of patients had minimal or no significant improvement

• Role of steroid-sparing agent

– Rituximab, cyclophosphamide, azathioprine

Multiple Sclerosis Neuromyelitis optica ADEM SLE MOG Sjogren’s Sarcoid Vasculitis HSV CMV EBV VZV HIV WNV (AHC) HTLV (not always inflammatory) Enterovirus 68, 71 Fungal: cocci, histo Tuberculosis Mycoplasma Lyme Syphilis Lymphoma Intramedullary tumors:

• Ependymoma
• Astrocytoma
• Hemangioblastoma

Paraneoplastic

• CRMP-5
• Amphiphysin
• GFAP

Vascular (Ischemic) Dural AV fistula Vitamin B12 deficiency Nitrous Oxide toxicity Vitamin E deficiency Copper deficiency Adrenoleukodystrophy / Adrenomyeloneuropathy HIV vacuolar myelopathy MRI of Spine CSF Analysis: Elevated WBC or IgG index or OCB

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Patterns of Myelitis on Imaging

• There is broad differential for transverse myelitis

and basic CSF results are unlikely to help discriminate between etiologies

– There are now many possible antibodies and pathogens that can now be tested for – Test results may not return for weeks

• Patterns on imaging may help narrow differential

diagnosis

– Focus diagnostic evaluation – Allow for earlier initiation of empiric therapy

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Multiple Sclerosis

• Short lesions, spanning usually no more than 2

segments

• Located in periphery of spinal cord on axial

sequences, often asymmetric, involving dorsal or lateral columns

• During time of acute flare, lesions enhance with

gadolinium contrast

• Characteristic brain lesions

– Periventricular, juxta-cortical, infratentorial – Extending from corpus callosum

NMO Real 1

Neuromyelitis Optica

• Associated with aquaporin-4-antibody
• Longitudinally extensive, 3 or more segments
• Acute flare often associated with diffuse

contrast enhancement and cord edema

• On axial imaging, central cord usually

involved, both gray and white matter

• Can have brain lesions

– Hypothalamus, periventricular – Area postrema, around third/fourth ventricle

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Question #4

Which of the following statements is FALSE regarding imaging differences between MOG IgG myelitis and myelitis associated with multiple sclerosis or neuromyelitis optica?

• A. T2 signal change on axial imaging confined to gray

matter in an “H” pattern was more common in MOG IgG myelitis than multiple sclerosis B. Conus involvement was more common in MOG IgG myelitis than NMO C. Lesions associated with acute flares of MOG IgG myelitis more frequently demonstrated contrast enhancement than acute flares of multiple sclerosis

• D. Longitudinally extensive lesions spanning greater

than 3 vertebral segments was more common in MOG IgG myelitis than multiple sclerosis

T2 signal change on axial... Conus involvement was ... Lesions associated with ... Longitudinally extensive l...

22% 27% 46% 5%

MOG IgG Antibody Demyelination

• Myelin oligodendrocyte glycoprotein IgG antibody
• Found in 1/3rd of one series of aquaporin-4-IgG

antibody negative NMO spectrum disorder patients

• More likely to present as encephalitis and have seizures

than NMO or multiple sclerosis

• Acutely may present as “flaccid myelitis”
• More likely to have bilateral optic neuritis at once
• Affects younger patients on average
• Often post-infectious in pediatric population

MOG IgG Antibody Myelitis

• Frequently longitudinally extensive, but often

multiple lesions during acute flare

• Unlikely to enhance during acute flare
• More frequently (up to 30% of patients) to

have exclusive gray matter involvement on axial imaging, “H” pattern

• More likely to involve the conus
• Affects younger patients on average

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Question #5

The pattern of abnormalities and enhancement seen within the brainstem and periventricular white matter in this patient with encephalomyelitis has been described in association with which of the following autoantibodies?

• A. Glial Fibrillary Acidic Protein (GFAP)

antibody

• B. Double-stranded DNA antibodies
• C. Amphiphysin antibody
• D. Aquaporin-4 antibody (NMO)

Glial Fibrillary Acidic Prote.. Double-stranded DNA an... Amphiphysin antibody Aquaporin-4 antibody ...

43% 22% 26% 9%

2/15/2019 12

GFAP Astrocytopathy

• Clinically presents as encephalitis or myelitis or

both  seizures, memory loss, psychiatric

• Over 50% of patients had “a striking pattern of

linear perivascular radial gadolinium enhancement, extending outward from the ventricles”

– Some had similar pattern in cerebellum – Leptomeningeal, serpentine pattern also seen

• CSF usually with pleocytosis, high protein, and

with unique oligoclonal bands

GFAP Astrocytopathy

• About 1/3 in case series had associated neoplasm

– Ovarian teratoma, adenocarcinoma most common

• Some of the patients had prodromal viral illness
• Some had similar pattern in cerebellum
• Leptomeningeal, serpentine pattern also seen
• High percentage of co-existing antibodies including

NMDA-receptor-IgG and aquaporin-4-IgG

• Majority of patients improved with steroids

– IVIg and plasmapheresis used as adjunct

• Relapses off steroids not uncommon  steroid-sparing

therapy

2/15/2019 13

• Thank you for attention
• UCSF Neurohospitalist Division and Fellowship

– S. Andrew Josephson – Vanja Douglas – John Betjemann – Megan Richie – Nicole Rosendale – Elan Guterman – Maulik Shah

• Transfer Center at UCSF: 415-353-9166