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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 inflamm’n • 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;26:233–47 Trapp BD. NEJM 1998;338:278–85

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) • Lhermitte’s 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 & EP’s • 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 Lyme’s serology

Differential diagnosis
• • • • • • • • SLE Sjorgens Synd Behchets Sarcoidosis CVA : thromboembolic ADEM NMO CADASIL,SCA’s,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
30g IM wkly 1.6 MU 8 MU 22g 3X/wk 44g 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