References 1. Feng S et al. Journal of Thoracic Oncology 2017; 12: Spain L et al. Annals of Oncology 2017; 28:

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1 Maulik Shah, MD February 15, 2019 Patient Presentation: Progressive Sensory Disturbance In early 2018, this 57 year old man was sent to the Emergency Department after complaining in the oncology clinic of progressive sensory deficits, subjective weakness, and marked impairment of gait including recurrent falls. He was unable to walk unsupported by his family or without a walker. He had a history of mandibular squamous cell carcinoma and small cell lung cancer with known metastatic disease to the supratentorial brain presumably related to the latter. He had been treated with local surgical resection and radiation and had been treated with ipilimumab and nivolumab starting two months prior to hospital admission. Of note, ipilimumab targets cytotoxic T lymphocyte associated antigen 4 and nivolumab targets programmed death 1 receptor. He reports that shortly after his first treatment with checkpoint inhibitor therapy, he noted numbness in his left hand. This progressed slowly initially over a month to involve left leg as well, but over last few weeks, spread to the right leg and then the right hand. He felt clumsy and dyscoordinated and reported recurrent falls at home. On neurologic examination, he had a normal mental status exam but had a withdrawn affect and was visibly frustrated with his deficits. He was noted to have mild guttural dysarthria and nystagmus with far lateral gaze on both sides. He was cachetic with reduced muscle bulk throughout but had normal tone and no clear focal motor weakness. His left and right finger and foot taps were clumsy and dysrhythmic and he had dysmetria with finger nose finger and heel to shin testing on both sides, worse on the left compared to the right side. On sensory examination, he had diminished pinprick sensation in distal hands and feet but more marked impairment of proprioception and joint position sense in his fingers, wrist, toes and ankles. Deep tendon reflexes were absent in the arms and legs. He was unable to stand up without assistance. Laboratory work up was notable for SIADH and mild hyponatremia. Lumbar puncture for CSF analysis revealed WBC 30 (95% lymphoctyes), glucose 48, and protein 184. An EMG/NCS study showed evidence of non length dependent generalized sensory neuropathy versus neuronopathy with multifocal involvement of the motor nerves and nerve roots with mild features suggestive of demyelination. MRI Brain showed overall improvement in the burden of metastatic disease. MRI Total Spine showed T2 hyperintensity and cord edema from C3 C7 segments, prominently involving the dorsal columns on both sides with tract specific homogenous enhancement with gadolinium contrast, as well as enhancement of exiting nerve roots and dorsal root ganglia. A diagnostic test result was reported.. References 1. Feng S et al. Journal of Thoracic Oncology 2017; 12: Spain L et al. Annals of Oncology 2017; 28:

2 3. Kao JC et al. JAMA Neurology 2017; 74: Vitt JR et al. Neurology 2018; 91: Hampton CW et al. Neurol Neuroimmunol Neuroinflamm 2015; 2: e Flanagan EP et al. Neurology 2011; 76: Flanagan EP et al. Continuum Neurology 2011; 7: Dubey D et al. JAMA Neurology 2018; epub e1 e9. 9. Flanagan EP et al. Ann Neurol 2017, 81:

3 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 1

4 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 Question #1 Which of the following has been reported as a neurologic complication of checkpoint inhibitor cancer therapy? (1) Acute demyelinating polyneuropathy (2) Cerebellitis (3) Limbic encephalitis (4) Myasthenia gravis (5) All of the above have been reported in the literature 2

5 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 lymphocyteassociated 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 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 3

6 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 4

7 Question #2 Which of the following etiologies is of primary concern given results of diagnostic testing and MRI spine imaging? (1) Viral myelitis (2) Autoimmune / paraneoplastic myelitis (3) Metastatic disease with intramedullary involvement (4) Compressive spondylotic myelopathy (5) Metabolic myelopathy 5

8 Question #3 Which of the following MR imaging pattern of findings would be most suggestive of a paraneoplastic cause of myelitis? (1) Owl s eye appearance and hyperintensity of anterior spinal cord (2) Nodular leptomeningeal and exiting nerve root enhancement (3) Short segment peripherally based asymmetric homogenously enhancing single lesion (4) Longitudinally extensive tract specific symmetric T2 hyperintensity and contrast enhancement on T1 6

9 Case, continued CSF testing returned positive for CRMP 5 IgG antibody Treated with high dose IV steroids followed by oral 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 7

10 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 oligoclonal 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 of 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 MRI of Spine CSF Analysis: Elevated WBC or IgG index or OCB 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 8

11 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 9

12 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 10

13 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 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? (1) T2 signal change on axial imaging confined to gray matter in an H pattern was more common in MOG IgG myelitis than multiple sclerosis (2) Conus involvement was more common in MOG IgG myelitis than NMO (3) Lesions associated with acute flares of MOG IgG myelitis more frequently demonstrated contrast enhancement than acute flares of multiple sclerosis (4) Longitudinally extensive lesions spanning greater than 3 vertebral segments was more common in MOG IgG myelitis than multiple sclerosis 11

14 MOG IgG Antibody Demyelination Myelin oligodendrocyte glycoprotein IgG antibody Found in 1/3 rd 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 12

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17 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? (1) Glial Fibrillary Acidic Protein (GFAP) antibody (2) Double stranded DNA antibodies (3) Amphiphysin antibody (4) Aquaporin 4 antibody (NMO) 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 15

18 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 16

19 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: