multiple scl aam

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Multiple Sclerosis ( MS)

Dr Shanthi Viswanathan

MBBS,MRCP ( Ire),Fellow ship inNeurology ( Malaysia)



Outline

• What is “Multiple Sclerosis

•

What is “Neuromyelitis Optica”

• Treatment ( Summary)



DIAGNOSIS



Post Gadoenhancement

Cavitation

On T1 post

Gad

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



M, T-cells activation, B-cells

BBB disruption (MRI: T1-Gd)

Inflammation

(MRI: T1-Gd, T2 active lesion, i.e. new+enlarging)

demyelination, axonal damage

axonal transection

disability

M clean up,gliosis occurs (MRI:T2 chronic lesions

Wallerian degeneration in normal

appearing white matter

recovery Repair

mechanisms

YES

NO

sv09 8

PATHOPHYSIOLOGY OF AN ACUTE RELAPSE & CHRONIC

PROGRESSION



Inflammation and Axonal

Degeneration in MS

Clinical symptoms

Subclinical degeneration

Time (years)

+

-

THERAPY A

x o n a l d a m a g e



Doinikow, 1915 Trapp, 1998

Terminal Axonal Bulbs:Evidence of Transected Axons

Doinikow B. D Zeitschr Nervenheilkunde 1915;26:233–47

Trapp BD. NEJM 1998;338:278–85



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 riskaccording 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’ ( plaquein 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 issueseg poor memory,attention probsDepression & anxiety.

• Bowel/bladder issues• Sexual problems, Fatigue



Clinical evidence

• Attack - An episode of neurological disturbance

lasting at least 24H

• Objective clinical evidence- objectively determinedclinical signs separated in time and space



Diagnosis: CLINICAL,CLINICAL, CLinical

• Must demonstrate dissemination in time & space of CNSlesions clinically & paraclinical evidence aided by MRIbrain, CSF analysis & EP’s

• Diagnosis of exclusion (inflammatory, infectious / postinfectious, 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



Relapsing-Remitting

Secondary-Progressive

Primary-

Progressive

Progressive-Relapsing

ProgressiveOnset

Exacerbating-Remitting

Onset

15 %

85 %

58 %

27 %

9 %

6 %

MS can be classified according to frequency and severity of

neurological symptoms, the ability of the CNS to recover, and

the accumulation of damage.



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

85% of

individuals

Miller et al Lancet

Neurology 0530 to 70% of these pts with CIS will convert to

CDMS



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%



Poser Diagnostic Criteria

DIAGNOSTIC CRITERIA FOR MULTIPLE SCLEROSIS

(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



Lesion should be at least 3mm

Original 2010

criteria



Ovoid

Perpendicular to the ventricles

Involve the corpus callosum

Callosalpericallosal



Callosal

/Pericallosal

lesions:Dawsons

fingers

Juxtacortical/

cortical lesionsPeriventricular lesions

ChronicMS



flair

PostGado

T2 blackhole



MRI cervicothoracic spine July 2002

Sagittal T2W

1 spinal cord lesion= 1

brain infratentorial (

posterior fossa) lesion

An enhancing spinal

cord lesion= an

enhancing brain lesion

Indvd spinal cord

lesions = can be

counted into No of T2

brain lesions

< 2 vs

,posterolateral

Paraclinical Investigations: What is a positive



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?

LEFT (P100-130)

Evoked potential testing(visual, auditory, orsomatosensory) is helpfulin

*detecting clinically silentlesions, and

The most sensitive are the

VEPs (50-90% sensitivity)and SSEPs (50-70%sensitivity).



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



Neuromyelitis Optica (NMO)Epidem: gender, age, race M=F, childhood-adult

Symptomatology

Severity

ON, TM or both

More severe, one/2 episodes of

ON & very quickly patient is

left with visual disability

CSF

Anti aquaporin 4 AB

Pleocytosis , > 50 WBC

OCB: 15-35%

60-90%

Natural Hx Monophasic: acute fulminant

Polyphasic: RR

Association Systemic ds (secondary NMO)Brain involvement

Spinal cord

May be atypical from

conventional MS

Length of lesion >= 3 vs

Necrosis,atrophy



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

Recurrent Optic neuritis with myelitis, Anti aquaporin status positive,

CSF OCB -ve , EDSS 3,steroids & azathioprine, severe tonic spasms,

better with tegretol

LESCLOwls nest

appearance



NMO MS

• AQP4 pos

• Worse outcome ( CNS destruction)

• Left with disability

• > 3 segments cord

• CSF: pleocytosis, OCB less

• Has relapsing & monophasic forms

• Can have brain involvement

• Pathology of the 2 conditions is also

different.

• AQP4 neg

• Better outcome

• Recovers quickly

• Cord: < 2 segments

• CSF: no pleocytosis; OCB

• Has relapsing forms

• Brain involvement present

Lancet Neurology

2007

Acute relapses with Steroids/PE



Acute relapses with Steroids/PE

Preventive, Maintenance therapy:

Immunosuppressants

Treatment of MS: Acute Rx/Preventive



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 onvisual 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 Administration No of pts % Reduction in

relapse rate (ARR)

Avonex 30g IM wkly 251 18%

Betaferon 1.6 MU 372 8%

Betaferon 8 MU 372 34%

Rebif 22 22g 3X/wk 540 29%

Rebif 44 44g 3X/wk 540 33%

Copaxone 20 mg od 251 29%

2 Conclusions : Interferons reduced relapse rates, severity of relapses

Dose –frequency relationship : High dose,more

more frequent dosing associated with less ARR



Fingolimod Natazulimab Mitoxantrone

Sphingosine 1

Phosphate inhibitor

Traps T-cells in the

lymph nodes

Acts on the alpha 4

integrin adhesion

molecule Px T cells

penetrating BBB

Targets proliferating

cells & prod

apoptosis of T/B

cells

Mode oral IV-monthly IV -3 monthly

Relapse rate

reduction

50-60% 60-80% 60-80%

MRI T2 lesion load 60-70% 70-80% 80%

Side effects First dose

bradycardia,macula

edema,LFT

increases,infections

Allergic reactions,

risk of PML (1:1000)

Cardiotoxicity

Acute leukemias

PML: infection with Jamestown cameron virus – producing

Progressive multifocal leukoencephalopathy



Algorithm for Treatment Failure

ESCALATION THERAPY

Fingolimod

Fingolimod



MultidisciplinaryApproach



Conclusion

• Get the Diagnosis correct : MS vs NMO

• Treat : Relapses Interferons 2nd line

drugs

• Treat the symptoms : spasticity,

pain,depression

multiple scl aam

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