Multiple Sclerosis: disease, investigations, treatment

Dr Trevor Pickersgill

Consultant Neurologist UHW

Overview

Summary History Pathology/causes Diagnosis and tests Range of disease Disease Modifying Treatments and

new treatments quackery

Multiple Sclerosis is…..

A nasty illness…. A benign illness…… Rapid… Slow…. Treatable…. Untreatable….. Popular: Yahoo 33.4M hits

Google 67.5M hits

….a mixed bag - unpredictable

What we really need is a medical…..

St Lidwina of Schiedam 1380-1433

Debilitating disease Fell skating 16 Mobility Headaches Violent tooth pains Paraplegic 19 Disturbed vision Died 53

Robert Carswell 1793-1857

Pathologist ‘strange lesions’ in

spinal cord

Jean Cruveilhier - parisian anatomist

Jean-Martin Charcot 1825-1893

Salpetriere La sclerose en plaque First to make

clinicopathological links 40 yrs after lesions

described Charcot’s (housekeeper’s)

Triad: Double vision Ataxia/unsteady Dysarthria/slurred

What Is MS? Inflammatory,

Demyelinating Disease

Specific to the Central Nervous System

Commonest cause of chronic neurological disability in young adults in the UK

20-40 yrs RR------->SP

What causes Multiple Sclerosis?

Chance Genes

Environment

Inflammation

Rubor

Calor

Dolor

Tumor

= Redness

= heat

= pain

= swelling

Cardinal feature: brain/spine inflammation

CNS Inflammation Blood-brain barrier

breached T Cell (white blood cell -

fight infection) sticks to lining

Migrates in Attracts more

inflammation cells and cytokines (attraction chemicals) produced

Inflammation causes demyelination

Demyelinating lesions in multiple sclerosis

Demyelination

Disturbs nerve messages

Slows conduction May cause block Interrupts normal

function of nerves May be silent I.e.

cause no problems

Putative Triggers

Virus/bacterial infection EBV/glandular fever?

Cross reactivity of virus coat proteins

Other environmental triggers Susceptible person ….all may trigger an

“autoimmune” process

An immune disease

White cell activation Complement (destroys cells)

activation Low level of immune activity

normally - CNS ‘naïve’ antibodies - various or ‘oligo’-

clonal in CSF F>M

Who Does MS Affect? Incidence 1 per 800 adult population 150/100,000 SE Wales (90-200 UK) 85,000 people in the UK Female to male 3:2

Age distribution by sex

Age group

Patient Nos

01020304050607080

0-14 15-24 25-34 35-44 45-54 55-64 65-74 >75

male

female

What about my children?

1 parent/sib/child: 2-4% 97% risk of not getting MS Risk is over lifetime - so

depends on their age If you are 50 you have lived

through most of the risk 1 non-immediate relative

Risk same as population

Diagnosis

Crucial is clinical story - dissemination in time and space…. I.e. multiple sclerosis

Poser criteria 1983 Definite Probable Possible Lab-supported/clinical

Diagnosis 2 - exclude other stuff

Lupus Sarcoid Strokes Functional illness e.g. anxiety Infection

How? - blood tests, chest Xray, MRI interpretation, lumbar puncture, symptoms

Is it MS? - case 1

F Age 14/15 tingling fingers Fatigue and weakness Ix KL and KCH

Age 21 Numb feet and fingers, fatigue UCC netball team Patch of sens forearms VEP normal, OB+

MRI 2000MRI 2005

Diagnosis?

1 attack 1 clinical lesion No paraclinical evidence of

other lesions - MRI/VEP CSF + - told she had MS

‘single’ myelitis - not MS Strictly not ‘clinically isolated

syndrome’

Multiple sclerosis: Brain MRI - changing lesions

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McDonald Criteria

Basically MRI can now clinch the diagnosis alone

Even in context of single episode (CIS) >3 months interval New lesions appearing or any dye enhancing =

Dissemination in Time Dissemination in space criteria now defined Mixture of old and new lesions on single

enhanced scan

Case 2 - is it MS? 26F 20th August 2004 10d h/o L arm feeling heavy, foot

dragging, bladder sensation Clumsy hand - typing Vision normal No headache 4 wks previously viral illness

with N+V, abdo pain Swollen optic discs

Investigations

Florid WM lesions No infratentorial CSF acellular Severe headache Resolved with IVMP 31/8/04 no signs DIAGNOSIS = first

episode CIS

Story continued

21/9/04 - foggy vision R eye Less than 1 month separation 16/17 Ishihara L nil else

Resolved over 10d until 1/11/04 R periorbital pain 3/11/04 VA 1/60 Rx IVMP 16/11/04 HM - large scotoma

MRI Dec 2004

Is it MS? ….yes

Dynamic disease

Constant lesion formation

Not all lesions cause symptoms (10%?)

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Lumbar Puncture

CSF/lumbar puncture analysis

Raised WBC sometimes

Protein normal/marginal

Characteristic IgG pattern

‘Band negative’ MS

“Types” of MS: are you a lumper or a splitter?

Types of MS

Benign retrospective diagnosis

relapsing/remitting(RR) 80% of those initially diagnosed will follow this disease course

secondary progressive (SP) 50-60% of PwMS will have this type

primary progressive (PP) 10-20% of PwMS. No relapses at onset, progressive disability.

Spinal disease. More severe.

Prognosis

Mean time to EDSS 6.0 Mean time to EDSS 6.0 -18yrs-18yrs

Relapses

New neurological symptoms and/or signs persisting for more than 24h not in the context of infection

Many mild, bothersome, irritating only

Some more severe - may need treatment

Some studies as low as 0.5/yr

Relapse treatment

Steroid tablets (Intravenous steroids) Wait and see Do not affect outcome

Outpatient Inpatient Rapid Access Clinic UHW

Disease Modifying Treatments

Licensed c.1999 NICE appraisal Modest usefulness 30% reduction

relapses ß-ifn:

Avonex Rebif Betaferon

Copolymer-1 Side effects

Eligibility:

Look for documentary evidence of new neurological deficit

>2 ‘disabling’ attacks 2yrs Assessment quite subjective

Eligibility 2

2+ disabling relapses /2yrs Ambulant 10m+ No/minimal background

progression No contraindications Willing to inject!

30% choose to withdraw

Newer Treatments:Campath-1H/alemtuzumab

Anti-T cell monoclonal antibody Not licensed for MS (yet) Treatment for leukaemia 80+ pts treated South Wales

Relapses reduce 90% study early disease v high dose ß-ifn -

55% better than IFN Side effects - long term Single treatment annually - drip once

a year

Newer Treatments - Tysabri/natalizumab

Reduces adhesion molecules in T cell migration

Prevents BBB breakdown Early studies promising MRI

data 2yr RCT early RRMS 68% reduction relapses Licensed NHS: ‘highly active’ Monthly drip - 15pts Cardiff

Cell migration

PML risk JC virus 40-80% of us have it Sits dormant in brain Reactivated when ‘normal’ immune system is

damaged (HIV) PML - untreatable - can be mild or fatal Peak after 2 yrs Risk 1:800 overall. Can test for virus

If negative 1:10,000 If positive, and had other drugs 1:100

150+ cases in 100,000 patients

New Drugs - oral [Cladribine] Fingolimod/Gilenya

Daily treatment Heart and skin and eye problems Licensed recently FDA USA Licensed EU April 2011 50% reduction relapses Recently approved NICE

Eligibility Interferon failure 1+ relapses 1yr and active MRI

Gilenya Once a day tablet £19,000/yr NICE appraisal - rejected - under

appeal - now approved First dose - risk of heart block ‘rapidly evolving severe MS’ or

interferon failure MS. Macular oedema/blood

pressure/infections 3500 Germany

Fampridine Oral tablet Improves walking efficiency

Speed Stride Fatigue

Works in 25% of pts Mechanism unsure £360/month - recently licensed Not yet approved NHS - company

hasn’t applied!

Vitamin D

Small studies show MASSIVE doses may reduce relapses

UK population deficient Month of birth studies - higher

risk of MS if born spring 1000 v 14,000 units/day Risks...pregnancy, heart

On the horizon.....

Teriflunomide Laquinimod Baclivuzumab Rituximab Daclizumab BG12

CCSVI....the latest wonder cure Italian doctor New technique

measuring jugular vein flow

‘100%’ accurate Experimented on his

wife Dozens of private

clinics Few large studies -

deaths?

CCSVI - facts Hugely conflicting results ‘too good to be true’ MS is an immune disease.....FACT! Sluggish blood flow could not cause

this.... But might be an after-effect Lots of money to be made.....treating

the rich and the desperate...

And then there was…. Goats’ serum LDN Omega 3 Vit D??? Sativex -

cannabis

Thank You

Acknowledgments:

NI team UHWMS Society CymruAll attendees today