Clinically Isolated Syndrome Emergency Lecture Series By: Laurence Poliquin-Lasnier Aug 7th 2013

CIS Definition: a first clinical episode characteristic of an MS attack (typically, optic neuritis, myelitis or a brainstem syndrome) without the requisite features of dissemination in time (DIT) or dissemination in space (DIS)

Multiple Sclerosis 4 types: 1. RRMS (80-85%) 2. PPMS (10-15%) 3. SPMS (majority will develop eventually) 4. Progressive relapsing MS (? Truly different from PPMS)

Definitions 1. RRMS: repeated, clearly defined acute attacks of neurologic symptoms and signs lasting >24 hours (relapses), each usually followed by full or partial recovery and a lack of disease progression between attacks 2. PPMS: progressive disease from the onset; can have occasional plateaus or minor improvements, but the overall trend is toward progressive disability 3. SPMS: progressive course that follows an initial period (often many years) of RRMS 4. Progressive relapsing MS: disease progression from onset with distinct acute relapses. The natural history is similar to that of PPMS

Multiple sclerosis Mean age of onset 30yo (70% have onset between yo) Prevalence 3X higher in F>M Prevalence in Canada: 50/ ( as opposed to 1:100,000 in equatorial regions)

What is an attack? Neurological disturbance typical for MS Subjective report or objective observation At least 24 hours duration in absence of fever or infection Excludes pseudoattacks or single paroxysmal symptoms (multiple episodes of paroxysmal sx occurring over 24 hours or more are acceptable as evidence) Some historical events with symptoms and pattern typical for MS can provide reasonable evidence of previous demyelinating event(s), even in absence of objective findings Time Between Attacks: 30 days between onset of event 1 and onset of event 2

Diagnosis History and physical exam Paraclinical tests: MRI CSF VEP

Revised 2010 McDonald Criteria These criteria should only be applied in patients who have experienced a typical CIS It is now possible to diagnose MS at the time of the CIS presentation CSF OCB no longer has a role in facilitating dx of RRMS but may be used to exclude other diagnoses

Revised 2010 McDonald Criteria

What provides evidence for DIS? ≥ 1 T2 lesion in at least two out of four areas of the CNS: periventricular, juxtacortical, infratentorial, or spinal cord Gadolinium enhancement of lesions is not required for DIS If a subject has a brainstem or spinal cord syndrome, the symptomatic lesions are excluded and do not contribute to lesion count

Revised 2010 McDonald Criteria Positive CSF: Oligoclonal IgG bands in CSF (and not serum) or elevated IgG index

Situations where VEP and CSF may be useful in RRMS 1. Pts >50 yrs or with vascular risk factors: brain MRI lesions can be present on the basis of age and/or ischemia. In addition to evidence from spinal cord MRI, where non-MS lesions are uncommon, presence or absence of OCB in CSF and/or abnormally prolonged latencies on VEP may aid in dx 2. Migraine: WM lesions frequently seen on brain MRI-> spinal cord, CSF and VEP may help 3. Pts with vague, non-specific symptoms such as dizziness, fleeting sensory phenomena, fatigue, subjective weakness, or cognitive issues. In addition to paraclinical tests, there is no substitute for repeat assessments over time (clinical and imaging) to come to a conclusive dx (MS or not MS). 4. When MRI access is limited or delayed

VITAMINDifferential Dx VascularAge, stroke, migraine, antiphospholip InfectiousLyme, HTLV-1, HIV, PML, Neurosyphilis, whipple, chronic meningitis (TB, fungal) Trauma/structuralArnold-Chiari, syrinx, cavernous malformation, disc herniation Autoimmune/InflammatorySLE, Sjogren, Behcet, Susac, Sneddon, PAN, ADEM, post-infectious myelitis, vasculitis Graulomatous: sarcoidosis, wegener, lymphomatoid granulomatosis MetabolicB12 deficiency, copper deficiency, celiac InheritedCADASIL, spastic paraparesis, Metachromatic or adreno leukodystrophy, Adrenomyeloleukodystrophy, Spinocerebellar disorders, mitochondrial disorders NeoplasticParaneoplastic encephalomyelopathies, brain or spinal cord tumor, CNS or intravascular lymphoma

Red flags HistoryExamInvestigations Positive family hx, fever, night sweats & wt loss, arthropathy, rash, mucocutaneous ulcers, dry mouth and eyes (sicca syndrome), ocular disease (uveitis, retinitis), severe and persistent H/A, stroke-like events, seizures, malabsorption syndrome Encephalopathy, meningismus, movement disorders (dystonia, myorrhythmia), LMN findings, findings confined to vascular territory, livedo reticularis, symmetric involvement, myopathy, neuropathy, renal dysfunction, diabetes insipidus, hypothalamic involvement, sensorineural hearing loss, pure cerebellar syndrome Significantly increased ESR or CRP, positive serology, abnormal CXR, CSF pleocytosis (WBC count >50/HPF), very high protein (>0.7 g/L), absent OCB in CSF, normal MRI brain/ cord, atypical MRI

Investigations MS is a dx of exclusion (*to consider dept on clinical presentation): CBC, electrolytes, TSH, LFT ANA, ENA, RF, C3, C4, ESR, CRP VitB12, *VitE, *Copper, *Zinc VDRL, HIV, Lyme, *HTLV1-2, *APLA, *ACLA (thrombophilia), Beta2M, *LDH, *Lactate *Chest imaging, ACE, *Calcium

Doctor, Do I have MS?

What is my risk of MS after a transverse myelitis? Acute complete TM Risk of MS of only 5% to 10% Partial or incomplete myelitis Abnormal brain MRI : 60% to 90% dx with MS at 3-5 yrs Normal brain MRI: 10% to 30% dx MS

What is my risk of MS after an optic neuritis? Optic Neuritis Treatment Trial 5-year cumulative probability of MS: 30% overall 16% with no brain MRI lesions 51% with three or more lesions Probability of developing MS by 10 years 38% overall 22% with no lesions 56% with 1 or more typical MS lesions Probability of developing MS by 15 years 50% overall cumulative probability 25% with no lesions on baseline brain MRI 72% with 1 or more lesions on MRI Risk of developing MS highest in first 5 years Probability of new MS dx at yr 15 in MS-free pts at 10-year 32% if 1 or more baseline lesions 2% if no baseline lesions

Treatment Acute: Solumedrol 1G IV qd X 3-5 days Faster recovery Does not change final outcome (based on ONTT) Long term: RCT in pts with CIS have shown that early treatment with beta interferons or copaxone can delay conversion to clinically definite MS However, it is unknown whether such treatments prevent or delay long-term disability

Figure Recommended algorithm for diagnosis of inflammatory demyelinating diseaseADEM = acute disseminated encephalomyelitis; CIS = clinically isolated syndrome; DIS = dissemination in space; DIT = dissemination in time; MS = multiple sclerosis; NMO = neuromyelitis optica. Selchen D et al. Neurology 2012;79:S1-S15 © 2013 American Academy of Neurology

References Selchen et al. MS, MRI, and the 2010 McDonald criteria. A Canadian expert commentary. Neurology. Vol 79, number 23, supplement 2, Dec 2012 Bradley Up to date