Multiple Sclerosis ( MS)

Dr Shanthi Viswanathan MBBS,MRCP ( Ire),Fellow ship in Neurology ( Malaysia)

Outline
What is Multiple Sclerosis What is Neuromyelitis Optica Treatment ( Summary)

DIAGNOSIS

Cavitation On T1 post Gad

Post Gado enhancement

Conventional MS

What is Multiple Sclerosis?

Idiopathic Inflammatory demyelinating disease of the central nervous system, with typical lesions disseminated in time and space Space : diff regions of CNS , Time: new lesions dev with passage of time Multiple Sclerosis Scleros Greek word Scars

What is Demyelination?
Inflammatory T cell Mediated attack ,? Trigger/BBB breached

Myelin attacked

Failure of conduction of impulses ( conduction block)

Symptoms produced

MS pathology
Perivenous inflammn Multifocal plaque like demyelination Reactive glial scar formation

Devoid of myelin stain

PATHOPHYSIOLOGY OF AN ACUTE RELAPSE & CHRONIC PROGRESSION

M, T-cells activation, B-cells BBB disruption (MRI: T1-Gd) NO Inflammation (MRI: T1-Gd, T2 active lesion, i.e. new+enlarging) YES demyelination, axonal damage Repair recovery mechanisms axonal transection M clean up, gliosis occurs (MRI:T2 chronic lesions Wallerian degeneration in normal appearing white matter disability
sv09 8

Inflammation and Axonal Degeneration in MS

+
Axonal damage

Clinical symptoms

THERAPY Subclinical degeneration Time (years)

Terminal Axonal Bulbs: Evidence of Transected Axons

Doinikow, 1915
Doinikow B. D Zeitschr Nervenheilkunde 1915;26:23347 Trapp BD. NEJM 1998;338:27885

Trapp, 1998

Epidemiology
Median age of onset 23 yrs ( 15 50yrs) Female: male= 1.77: 1 Very rare in children and > 60 yrs In Malaysia : F: M 6.6:1, Age of onset : 31 yrs Chong Tan Tin Neuro J SEA,97

Epidemiology

Incidence 1 in a million in low risk area 10 in 100,000 in high risk area High risk area: Europe, northern US, NZ, SE Australia Migration before age of 15 alters the risk according to the risk of adopted area

Aetiology
Unknown Genetic 20-30% monozygotic concordance Whites, HLA-DR2 Environmental ?viral ( HHV-6, mumps ,Epstein Barr Virus (EBV) ?autoimmune

Short segment lesion in cord of patients with MS

Clinical features: Optic Neuritis

Optic neuritis Loss of vision Eye pain Dyschromatopsia impaired color vision Movement & sound induced phosphenes

Fat Sat Axial MRI post Gad

Clinical features: motor

Weakness (80% West ,80% East) Paraparesis ( myelitis),Hemiparesis /monoparesis ( subcortical leisons) Spasticity/Tonic spasms /flexor spasms Feeling of feebleness aft exercise / heat exposure ( Uthoffs phenomenon)**

Clinical features: sensory

Numbness, tingling, pins and needles, tightness, coldness, swelling, intense itching ( 84% in West , 77% East) Lhermittes phenomenon : flexion of neck tingling in spine & limbs

Clumsy/useless hand : oppenheim hand ( plaque in dorsal column cervical cord)

Brain stem & Cerebellar inv Neurocognitive Issues,Sphincter problems

Internuclear ophthalmoplegia (INO) Vertigo (in 30-50% of patients) Gait /trunkal ataxia Tremor

Cognitive & psychiatric issues eg poor memory,attention probs Depression & anxiety. Bowel/bladder issues Sexual problems, Fatigue

Clinical evidence
Attack - An episode of neurological disturbance lasting at least 24H Objective clinical evidence- objectively determined clinical signs separated in time and space

Diagnosis: CLINICAL,CLINICAL, CLinical

Must demonstrate dissemination in time & space of CNS lesions clinically & paraclinical evidence aided by MRI brain, CSF analysis & EPs Diagnosis of exclusion (inflammatory, infectious / post infectious, granulomatous etc) In RRMS :- neurological dysfxn separated in time & space with good recovery & minor disability in between attacks In Progressive MS: prog course > than 6/12

MS can be classified according to frequency and severity of neurological symptoms, the ability of the CNS to recover, and the accumulation of damage.
RelapsingRemitting

58 %

ExacerbatingRemitting Onset

85 %
Progressive Onset

SecondaryProgressive

27 %

9% PrimaryProgressive

6%

15 %

ProgressiveRelapsing

CLINICALLY ISOLATED DEMYELINATING SYNDROME

Clinically isolated Syndrome : Acute /subacute neurological event First ever expression of a CNS demyelinating event, occurs in 1/> sites ( WARNING OF MS/NMO)
Typical presentations Optic neuritis myelitis Cerebellar /Brainstem syndromes
30 to 70% of these pts with CIS will convert to CDMS

85% of individuals

Miller et al Lancet Neurology 05

Risk of MS after monosymptomatic episode

Optic neuritis
5 years cumulative risk
16% ( normal MRI brain) 51% ( 3 or more lesions on MRI brain)

Acute transverse myelitis

Complete: 5-10% Partial: 57-72%

DIAGNOSTIC CRITERIA FOR MULTIPLE SCLEROSIS Poser Diagnostic Criteria

(Poser C, et al Ann Neurol, 1983

enen

Revised 2001,2005 & 2010

Mc Donald criteria (2001/05)

Incorporating the use of MRI for the early diagnosis to Demonstrate dissemination in time & Dissemination in space

DIS

DIT

DIT &DIS

Original 2010 criteria

Lesion should be at least 3mm

Callosal pericallosal

Ovoid Perpendicular to the ventricles Involve the corpus callosum

Juxtacortical/ Periventricular lesions

cortical lesions

Chronic MS

Callosal /Pericallosal lesions:Dawsons fingers

flair

T2 black hole

Post Gado

1 spinal cord lesion= 1 brain infratentorial ( posterior fossa) lesion

< 2 vs ,posterolateral

An enhancing spinal cord lesion= an enhancing brain lesion

Indvd spinal cord lesions = can be counted into No of T2 brain lesions

MRI cervicothoracic spine July 2002 Sagittal T2W

Paraclinical Investigations: What is a positive CSF?

CSF :OCB Ig G -85- 90% , Ig G index > 0.7 in 90% Protein : raised 30% Cell count < 50 lymphocytes /mm3

Isoelectric focusing: the presence of bands in the FSC different from any such bands in serum and or the presence of an elevated Ig G index

Paraclinical Evidence : What is a positive VEP?

Evoked potential testing (visual, auditory, or somatosensory) is helpful in *detecting clinically silent lesions, and

The most sensitive are the VEPs (50-90% sensitivity) and SSEPs (50-70% sensitivity).
LEFT (P100-130)

Investigation to exclude other diagnoses

ESR P-ANCA, c-ANCA ANA, Rheumatoid factor Lupus anticoagulant, anticardiolipin antibodies Anti-Ro, anti-La HTLV-1 (CSF) HIV serology VDRL, TPHA CXR, serum and CSF ACE level Vit B12 Lymes serology

Differential diagnosis
SLE Sjorgens Synd Behchets Sarcoidosis CVA : thromboembolic ADEM NMO CADASIL,SCAs,Leukodystrophies,SACD

Neuromyelitis optica
Devic described it 19th century Historical definition : severe ON & myelitis ,close asscn. NOW WIDER : Relapsing forms Recurrent optic neuritis Recurrent transverse myelitis Brain inv ( Not MS like) #Recently : AB to aquaporin-4 water channel said to be sensitive & specfic for NMO 75% & 90% sensitive & specific for NMO

Neurology 2006

Mcdonalds 2010

Epidem: gender, age, race Symptomatology Severity

Neuromyelitis Optica (NMO)

M=F, childhood-adult ON, TM or both More severe, one/2 episodes of ON & very quickly patient is left with visual disability Pleocytosis , > 50 WBC OCB: 15-35% 60-90% Monophasic: acute fulminant Polyphasic: RR Systemic ds (secondary NMO) May be atypical from conventional MS Length of lesion >= 3 vs Necrosis,atrophy

CSF Anti aquaporin 4 AB Natural Hx Association Brain involvement

Spinal cord

Imaging

Long segment cord (> 3segments) : white and grey matter; cavitation

Brain: usually normal; or atypical of MS

When to suspect NMO in the brain?

Lesions involving corticospinal tract Extensive hemispheric lesions Periaqueductal lesions around the 3rd /4th ventricle Periependymal lesion around lateral ventricles Medullary with extensive spinal cord lesion Non specific brain disease In the absence of vasculitis, malignancy, infection and stroke Suspect NMO Vasogenic Edema

Neuromyelitis Optica

LESCL

Owls nest appearance

Recurrent Optic neuritis with myelitis, Anti aquaporin status positive, CSF OCB -ve , EDSS 3,steroids & azathioprine, severe tonic spasms, better with tegretol

NMO
AQP4 pos Worse outcome ( CNS destruction) Left with disability > 3 segments cord CSF: pleocytosis, OCB less Has relapsing & monophasic forms Can have brain involvement

MS
AQP4 neg Better outcome Recovers quickly Cord: < 2 segments CSF: no pleocytosis; OCB Has relapsing forms Brain involvement present

Pathology of the 2 conditions is also different. Lancet Neurology 2007

Acute relapses with Steroids/PE Preventive, Maintenance therapy: Immunosuppressants

Treatment of MS: Acute Rx/Preventive Rx : Non curative

2 relapses within 2 yrs/CIS with MRI CDMS

Acute Relapse
IV Methylprednisolone closure of BBB suppression of inflammation Reduces duration of attack no long term benefit Dose 500-1000 mg/day X 3-5 days Beck et al 99NEJM ONTT trial in ON use of IV steroids to hasten recovery, no effect on visual improvement ( NEJM 92)

Refractory relapses Further - IVMP after 4-8/52 Consider plasma exchange - 46% of refractory relapses at 8 wk improved with plasma exchange(Ann Neuro 99)

Prevent/ slow progression

Disease Modifying Drugs B-interferon Oral drugs : Fingolimod Natazulimab ( Tysabri)

Immunosuppressants Mitoxantrone # not talking about Rituximab,Alemtuzumab, IV Immunoglobulin

PRISMS, OWIMS , BENEFIT, EVIDENCE

Drug
Avonex Betaferon Betaferon Rebif 22 Rebif 44 Copaxone

Administration
30g IM wkly 1.6 MU 8 MU 22g 3X/wk 44g 3X/wk 20 mg od

No of pts
251 372 372 540 540 251

% Reduction in relapse rate (ARR)

18% 8% 34% 29% 33% 29%

2 Conclusions : Interferons reduced relapse rates, severity of relapses Dose frequency relationship : High dose,more more frequent dosing associated with less ARR

Fingolimod Sphingosine 1 Phosphate inhibitor Traps T-cells in the lymph nodes Mode Relapse rate reduction MRI T2 lesion load Side effects oral 50-60% 60-70% First dose bradycardia,macula edema,LFT increases,infections

Natazulimab Acts on the alpha 4 integrin adhesion molecule Px T cells penetrating BBB IV-monthly 60-80% 70-80%

Mitoxantrone Targets proliferating cells & prod apoptosis of T/B cells IV -3 monthly 60-80% 80%

Allergic reactions, Cardiotoxicity risk of PML (1:1000) Acute leukemias

PML: infection with Jamestown cameron virus producing Progressive multifocal leukoencephalopathy

Algorithm for Treatment Failure

ESCALATION THERAPY

Fingolimod

Fingolimod

Multidisciplinary Approach

Conclusion
Get the Diagnosis correct : MS vs NMO Treat : Relapses Interferons 2nd line drugs Treat the symptoms : spasticity, pain,depression