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

Stacey L. Clardy MD PhDStaff Neurologist, Salt Lake City VAAssistant Professor of Neurology, University of UtahDirector, Autoimmune Neurology Fellowship

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

• 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

Objectives

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

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

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

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

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

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)

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

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.

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

Myelopathy in the national VA populationFirst large, population-based epidemiology study in the US in 30 years

719 CONFIRMED cases (from 4000 caseswith ICD code related to TM)

Mean age 53, median 54

Ethnicity N=723White 479 (66.25)African American 149 (20.61)Hispanic/Latino 25 (03.46)

American Indian/Alaska Native

5 (00.69)

Pacific Islander/Asian American

10 (01.38)

Unknown 53 (07.33)

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)

Myelopathy in the national VA population

Modified Rankin #

Modified Rankin at time of attack

Modified Rankin at most recent visit

0 0 17 (02.35)1 30 (4.14) 128 (17.70)2 127 (17.57) 188 (26.00)3 143 (19.78) 138 (19.09)4 186 (25.73) 138 (19.09)5 44 (06.09) 18 (02.49)6 0 17 (02.35)Unknown 193 (26.69) 79 (10.93)

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

Tobin et.al. Curr Op Neurol 2014

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

(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). 

Myelopathy – Compressive

Tobin et.al. Curr Op Neurol 2014

LETM• Sarcoidosis ▫ Many with posterior column▫ Many with isolated

myelopathy▫ Contrast enhancement,

persistent▫ Leptomeningeal

enhancement (~50%)▫ Trident sign

Tobin et.al. Curr Op Neurol 2014

MRI: Clardy patient files

Zawlewski et al Neurology 2016

Neurosarcoidosis- Contrast enhancement, persistent- Neoplastic & Sarcoid have greater

PET-FDG uptake than other inflammatory myelitis

Neurosarcoidosis plus …

Pre-treatment Post-treatment

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

Pekcevik et.al. Mult Scler 2015; Tobin et.al. Curr Op Neurol 2014

MRI: Clardy patient files

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. 2012 Feb 28;78(9):665-71.

• 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

Diagnosis

• 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

Revised NMOSD Criteria (2015)

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

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

NMO Spectrum DisorderBeyond optic neuritis and transverse myelitis

Kearney et al. Nat Rev Neurol 2015; Banwell, Lennon and Pittock et al. Neurology 2008; Jarius et al J Neuroinflamm. 2016

NMO in Veterans227 patients coded

Neuromyelitis Optica (NMO) ICD‐9  341.0 

Criteria NOT met

154 patients

● > 75% diagnosed with MS. ● Other: myelopathy, neurosarcoidosis, pseudotumor, headache, dementia, optic neuritis NOS, transverse myelitis  NOS, uveitis, optic atrophy, paraneoplastic, MG, vertigo, SLE.

NMO58 patients

● Age of Onset  40.5 years (range 21‐75 years) ● 38 male, 20 female 

● 20 Caucasian, 35 African American, 3 Latino ● Presenting symptom(s): ON – 43; LETM – 17; 

N/V/H – 7

Seropositive43 patients

Seronegative (or never tested)

15 patients

Indeterminate15 patients

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).

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. 2016.

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

• 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!!)

Treatments

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)

SummaryReview 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.

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).

Thank you!

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