transverse myelitis and myelopathy in the va system...
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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