Transverse Myelitis and Myelopathy in the VA system: Etiology and Epidemiology

Transcription

1 Transverse Myelitis and Myelopathy in the VA system: Etiology and Epidemiology Stacey L. Clardy MD PhD Staff Neurologist, Salt Lake City VA Assistant Professor of Neurology, University of Utah Director, Autoimmune Neurology Fellowship

2 Disclosures - Podcast Editor for the journal Neurology - Site investigator for the Alexion clinical trial for Eculizumab in Relapsing NMO patients - Research Funding from the Western Institute for Biomedical Research and the Transverse Myelitis Association - Consulting (under $1000 US): Adivo Associates * May discuss off-label use of medications

3 Objectives Discuss approach to comprehensive evaluation of myelitis and myelopathy of unclear etiology Have a better understanding of the different causes of non-traumatic spinal cord injury Epidemiology of Myelitis and Myelopathy within the VA and DoD Treatment approaches to Myelopathy and Myelitis

4 What is Myelitis? Diagnostic criteria being revisited, but otherwise not revisited since 2002 Historically, definition vague, complicated by transverse requirement Transverse first described in case in 1948 Referred to clinical finding of band-like area of altered sensation -- not the extent of spinal cord involvement on imaging Suchett-Kaye, 1948; Kerr, 2010

5 What is Myelitis? Historically, Varied Definitions: Some requiring bowel/bladder involvement, or motor involvement Time limitation for symptom onset Some excluding vascular Some excluding complete or partial lesions

6 2002 TM Diagnostic Criteria Inclusion criteria problematic: Bilateral symptoms Clearly defined sensory level Progression to nadir between 4 hr - 21 days Cord inflammation required Not allowed to use oligoclonal bands or elevated protein to meet this criteria Exclusion: Systemic disorders, Infectious etiology

7 Myelitis vs. Myelopathy What s in a name? itis vs. opathy Clinician approach Start at myelopathy, rule in/out myelitis Patient understanding Diagnostic implications --? etiology Treatment implications Myelopathy is not always Myelitis Vascular Myelitis not always Demyelinating Acute Flaccid Paralysis

8 Nomenclature & Nosology Myelitis, Myelopathy Acute, Idiopathic, Secondary Partial, Complete Longitudinally Extensive Transverse Myelitis Vascular Trampoline and Surfers Myelopathy Acute Flaccid Myelitis Location: Rostral-Caudal (long vs short) Partial vs. Complete White vs Grey Matter vs. Mixed vs. Central

9 Who gets Myelitis? Age depends on underlying etiology: Acute demyelinating encephalomyelitis preferentially presents in children under the age of 10 (Banwell et al., 2007) MS mean age of onset of 30 (Weinshenker et al., 1989) Neuromyelitis optica (NMO) usually presents a little later in life at 40 (Mealy et al., 2012)

10 Myelopathy Clinical assessment matters! CSF, MRI, spinal angiography help CSF: Non-inflammatory (WBC normal; no OCB) Infarct, Dural AVF, Spondylosis, tumor, B12 Inflammatory ( WBC; +/- OCB s) MS, NMOSD, infectious, sarcoid Markedly CSF protein; normal cell count Spinal block (tumor/spondylosis); Guillain Barre Glucose Meningomyelitis Barreras et.al. Annals 2014

11 457 patients referred to a myelopathy center with presumptive diagnosis of TM *Of all predictors, the temporal profile of symptoms contributed the most to the increased discriminatory power.

12 Time to nadir matters! Acute/hyperacute <12 hrs to nadir Spinal cord infarct Time to nadir: 1-21 days Inflammatory: Transverse myelitis, MS, NMOSD Progression over >21 days Spondylosis Tumor Dural AVF Relapsing/Remitting Caution Misdiagnosis of Guillain Barre Syndrome still common

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14 Myelopathy in the national VA population First large, population-based epidemiology study in the US in 30 years 719 CONFIRMED cases (from 4000 cases with ICD code related to TM) Ethnicity N=723 White 479 (66.25) African American 149 (20.61) Hispanic/Latino 25 (03.46) American Indian/Alaska 5 (00.69) Native Pacific Islander/Asian 10 (01.38) American Unknown 53 (07.33) Mean age 53, median 54

15 Myelopathy in the national VA population Diagnosis N=723 Indeterminate 152 (21.02) MS 117 (16.18) NMO 28 (03.87) Sjögren's 3 (00.41) SLE 7 (0.97) Sarcoid 11 (01.52) Infection 44 (06.09) Paraneoplastic 5 (00.69) Idiopathic 318 (43.98) ADEM 15 (02.07) Other 22 (03.04) Modified Rankin # Modified Rankin at time of attack Modified Rankin at most recent visit (02.35) 1 30 (4.14) 128 (17.70) (17.57) 188 (26.00) (19.78) 138 (19.09) (25.73) 138 (19.09) 5 44 (06.09) 18 (02.49) (02.35) Unknown 193 (26.69) 79 (10.93)

16 Functional loss = Clue to etiology Complete loss of spinal cord function Acute compressive lesion, a necrotizing myelitis, or trauma Central cord lesion: autonomic dysfunction, spinothalamic deficits, pyramidal distribution weakness below level of lesion Syrinx or possibly NMO Anterior spinal cord syndrome w/ acute flaccid weakness, spinothalamic dysfunction but preserved dorsal column function Anterior spinal artery occlusion Isolated loss of vibration & joint position sense Vitamin B12 /copper deficiency, nitrous oxide toxicity Isolated tract involvement other than dorsal columns Possible paraneoplastic Brown-Sequard syndrome (hemicord): ipsilateral motor weakness, vibration & joint position sensory loss; contralateral pain & temperature loss Often MS or Compressive Jacob and Weinshenker, 2008; Kumar, 2010; Pittock et al., 2005; West et al. 2012

17 Tobin et.al. Curr Op Neurol 2014

18 Myelopathy - Vascular Vascular Vascular causes more common than appreciated AVM/fistula, Venous thrombosis, Stroke Many LETM Hyperacute + Chronic presentations Spinal angiogram likely underutilized* Average time to diagnosis of Dural AVF in Mayo Clinic series: 2 years Red Flags: Worsening symptoms with Plasma Exchange/Steroids MRI: Clardy patient files

19 Myelopathy Compressive (a) T2 sagittal and (b) T1 postcontrast sagittal images demonstrate high signal & associated degenerative disk disease and 'pancake like' enhancement at point of maximal stenosis (arrows). Tobin et.al. Curr Op Neurol 2014

20 LETM Sarcoidosis Many with posterior column Many with isolated myelopathy Contrast enhancement, persistent Leptomeningeal enhancement (~50%) Trident sign MRI: Clardy patient files Zawlewski et al Neurology 2016 Tobin et.al. Curr Op Neurol 2014

21 Neurosarcoidosis - Contrast enhancement, persistent - Neoplastic & Sarcoid have greater PET-FDG uptake than other inflammatory myelitis

22 Neurosarcoidosis plus Pre-treatment Post-treatment

23 LETM NMO: More likely to involve ½ cross sectional area of cord Enhance and centrally located Both central and peripheral in cord T1 hypointense Gray matter involvement Mass effect MRI: Clardy patient files Pekcevik et.al. Mult Scler 2015; Tobin et.al. Curr Op Neurol 2014

24 NMO Evolving Diagnostic Assays Aquaporin-4 testing, sensitivity by method: Flow cytometry - 77% (46 of 60) Visual observation by CBA - 73% (44 of 60) Fluorescence immunoprecipitation assay and tissue-based immunofluorescence assay - 48%- 53% Commercial assays: CBA - 68% (41 of 60) and ELISA -60% 72% (43 of 60) when used in combination Waters PJ, McKeon A, Leite MI, et.al. Serologic diagnosis of NMO: a multicenter comparison of aquaporin-4-igg assays. Neurology Feb 28;78(9):

25 Diagnosis NMO Spectrum disorders present with variable phenotypes Frequently misdiagnosed NMO patients: Overlap syndromes Sjogren s, Lupus, Myasthenia Gravis Prolonged Nausea, Vomiting, or Hiccups Area postrema lesions Hydrocephalus Narcolepsy/Anorexia Brainstem Syndromes Recurrent myalgias with hyperckemia

26 Revised NMOSD Criteria (2015) New nomenclature: NMO spectrum disorders (NMOSD), stratified further by serologic testing (with or without AQP4-IgG). NMOSD WITH AQP4-IgG include: Clinical syndromes and/or MRI findings, related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations. NMOSD WITHOUT AQP4-IgG: More stringent clinical criteria, with additional neuroimaging findings, required

27 Revised NMOSD Criteria: AQP4-IgG Seronegative Patients Clinical disease affecting 2+ regions Consensus definition under revision Optic Neuritis (ON) + LETM (current definition) Other syndromes anchored to at least 1 core presentation Isolated recurrent ON / isolated recurrent LETM do not qualify Caveats Serological retesting Competing diagnoses

28 NMO Spectrum Disorder Beyond optic neuritis and transverse myelitis Why are the diagnostic criteria relevant? - Appropriate treatment - Accurate data in Clinical trials - Further define the spectrum of disease - Avoid misdiagnosis - Neurosarcoidosis, paraneoplastic myelopathy, mitochondrial/genetic diseases, spinal AVM, nutritional - Short Transverse Myelitis (STM) - MRI sagittal T2 lesion <3 vertebral segments - MS is commonest cause - Adult MS almost always STM; Pediatric MS has long lesions in up to 15% - Caution -- STM often considered incompatible with NMOSD, but 15% are STM - Image too early short / Image too late discontinuous Kearney et al. Nat Rev Neurol 2015; Banwell, Lennon and Pittock et al. Neurology 2008; Jarius et al J Neuroinflamm. 2016

29 NMO in Veterans 227 patients coded Neuromyelitis Optica (NMO) ICD Criteria NOT met 154 patients NMO 58 patients Indeterminate 15 patients > 75% diagnosed with MS. Other: myelopathy, neurosarcoidosis, pseudotumor, headache, dementia, optic neuritis NOS, transverse myelitis NOS, uveitis, optic atrophy, paraneoplastic, MG, vertigo, SLE. Age of Onset 40.5 years (range years) 38 male, 20 female 20 Caucasian, 35 African American, 3 Latino Presenting symptom(s): ON 43; LETM 17; N/V/H 7 Seropositive 43 patients Seronegative (or never tested) 15 patients

30 NMO in Veterans Coexisting autoimmunity : Lupus, 4; Sjogren s syndrome, 1; myasthenia gravis, 2; thyroid disease, 4; vitiligo, 1. Prior misdiagnoses: MS, optic neuritis not otherwise specified (NOS), transverse myelitis NOS. Coexistent cancer in 4 patients Malignancies: bladder, SCC, lymphoma, synovial cell sarcoma Malignancy predating NMO symptoms in 3 patients 12 patients deceased of NMO complications (average age death 54, range 30-77) *Reflects pre-treatment era Indeterminate NMO patients (n=15): Followed outside VA (4) or incomplete evaluation (11).

31 New myelopathies on the block MOG - Monophasic or relapsing acute ON, myelitis, brainstem encephalitis, or encephalitis, or any combination of these syndromes GFAP - May have tremor, optic disc edema - CSF most sensitive/specific - NMDA, AQP4 antibodies may coexist - Steroid-responsive Kitley, Vincent, Palace et al. JAMA Neurol 2014; Jarius et al. J Neuroinflamm 2016; Fang B et.al. JAMA Neurol

32 Treatments *OFF-LABEL Neurosarcoidosis: Acute: Prolonged corticosteroid, +/- Infliximab, with or without methotrexate Cyclophosphamide for refractory cases Caution: CVID NMOSD (including MOG): Acute: IV methylprednisolone, PLEX Rituximab > Mycophenolate > Azathioprine 3 trials on going (CD-19, IL-6, and complement) GFAP: Corticosteroid

33 Treatments Compressive Surgical decompression/stabilization Neoplastic (Lymphoma, other): Standard cancer-directed therapy Paraneoplastic Standard cancer-directed therapy, +/- corticosteroid targeting neurologic symptoms Vascular: Repair dural AV fistula (surgical) Metabolic: Replace deficiency (B12, copper, etc.) ( plus Rehabilitation and Symptomatic therapies!!)

34 Summary Start at myelopathy Don t delay treatment However -- Index of suspicion required for vascular etiology Suspect if worsening with steroids/plex Can have inflammatory CSF findings, including bands Skilled angiographer Rule in/out Myelitis Pay attention to Season and Geography History is KEY Save CSF and Serum!! (prior to immunotherapy)

35 Summary Review the Imaging in Detail axial and sagittal, + post-contrast imaging LP rule: If you are going to stick a needle in someone s back Get extra CSF Always order oligoclonal bands Empiric treatment often warranted, but treatment will interfere with ability to achieve a diagnosis so ALWAYS save pretreatment serum and CSF.

36 Summary Systemic Autoimmunity (Rheumatology) often manifests in the CNS If immune-mediated, be patient (recovery time) It is all in the History COMPLETE Personal and Family Infections frequently have an exposure. Autoimmunity tends to run in families. Course of the illness is always informative (acute/subacute/chronic/stuttering).

37 Thank you!

38 Acute Flaccid Myelitis Updated definition: Acute onset of focal limb weakness and an MRI showing spinal cord lesion largely restricted to gray matter, spanning one or more spinal segments, regardless of age. Some positive for EV D68 (5 of 12 at Colorado) Fever, flaccid paralysis, prolonged and incomplete recovery No pathogen consistently detected in CSF CDC did not consistently detect EV-D68, but was certainly involved in some cases