Lecture Notes on Multiple Sclerosis - Professor Gavin Giovannoni (17 Dec 2012)

1. Definition

Pathological Definition: Inflammatory disease of the CNS characterised by demyelination and variable

degrees of axonal loss and gliosis.

Clinical Definition: Objective CNS dysfunction, i.e. involvement of two or more white matter structures

separated by time (1 months), with no other aetiology.

2. Pathology

Gross Pathology - plaques (periventricular white matter, optic nerves, brainstem, cerebellum, spinal cord)

Histopathology - perivascular inflammation (venules) extending into the white matter parenchyma (cell

mediated (lymphocytes and macrophages, rare plasma cells), demyelination, axonal loss and gliosis.

3. Aetiology

Unknown; complex disease involving genes and environment

Possible viral aetiology (disease clusters / migration studies) and/or autoimmune (definitive evidence of it

being autoimmune is lacking; but is the current dogma accepted by most people)

Genetic risk (concordance monozygotic twins 30% / dizygotic twins 5%, increased risk in family members)

4. Epidemiology

Age of onset - 3rd

/ 4th

decade (10 - 50 years)

Prevalence - ~125/100,000 (UK); varies with latitude (probably due to vD; i.e. vD is protective)

Life Span - slightly reduced (~10 year)

Sex - F > M (2:1) ; incidence appears to be increasing in females (not known why)

Race - Caucasians (uncommon in Chinese / ? Viking ancestral genes)

Risk factors – Genes (HLA and others), EBV infection and infectious mononucleosis, smoking and vitamin D

deficiency

5. Diagnosis

Clinical - typical clinical course / exclusion of other diseases

MRI - abnormal white matter

Evoked Potentials - delayed conduction

CSF - immunological abnormalities (intrathecal synthesis of oligoclonal IgG bands)

6. Clinical (Symptoms and Signs – positive and negative phenomena)

Motor - spasticity, weakness, gait abnormalities, spasms (clonic, tonic and flexor)

Sensory - positive (pins & needles, pain, etc) and negative sensory phenomena (loss of sensation).

Cerebellum - inco-ordination, ataxia, nystagmus, dysarthria, etc.

Brain Stem - diplopia, vertigo, nystagmus, dysarthria

Optic Nerves - optic neuritis (blurred vision, reduced colour vision, central or paracentral scotomas, reduced

visual acuity, afferent pupillary defect, optic disc pallor)

Bladder and Bowel – incontinence, frequency, urgency, hesitancy

Higher Functions - depression, poor concentration, forgetfulness, cognitive impairment

Fatigue – complex (exercise induced, temperature-related)

7. Course

Relapsing Remitting

Progressive (secondary or primary)

8. Prognosis

Highly variable - 30% benign disease / 10 yrs 30% wheel chair / 15 yrs 50%

Good prognosis - young, female, relapsing course, optic neuritis or sensory onset, long gap between first and

second relapses, good recovery from initial attack and low baseline lesion load on MRI.

Survival slightly reduced

9. Treatment

Disease Modifying

Acute Relapse - high dose corticosteroids

Relapsing cases - interferon beta, glatiramer acetate, natalizumab, fingolimod and mitoxantrone

Drugs in development: Teriflunomide, BG12, Laquinimod, Alemtuzumab, Ocrelizumab, Daclizumab

Progressive cases - immunosuppression (poor evidence base) there is a need for neuroprotection.

Symptomatic

Spastcity (Baclofen, tizanidine, gabapentin, diazepam, etc.)

Bladder and bowel care, fatigue, depression, pain, infections, skin and foot care

Physiotherapy

Occupational Care

10. Reading List:

Compston A, Coles A. Multiple sclerosis. Lancet. 2008 Oct 25;372(9648):1502-17.

Ramagopalan et al. Multiple sclerosis: risk factors, prodromes, and potential causal pathways. Lancet Neurol

2010; 9: 727–39.

Multiple Sclerosis

Professor Gavin Giovannoni

Epstein Bar Virus

Genetics

Vitamin D

Smoking

Risks

Adverse events

Differential Diagnosis

MRI

Evoked Potentials

Lumbar puncture

Blood Tests

Diagnostic Criteria

Cognition

Depression

Fatigue

Bladder

Bowel

Sexual dysfunction Tremor

Pain Swallowing

Spasticity Falls

Balance problems Insomnia

Restless legs Fertility

Clinical trials

Gait

Pressure sores

Oscillopsia

Emotional lability

Seizures

Gastrostomy

Rehab

Suprapubic catheter Intrathecal

baclofern

Physio- therapy

Speech therapy

Occupational Therapy

Functional neurosurgery

Colostomy

Tendonotomy

Studying

Employment Relationships

Travel

Vaccination

Anxiety

Driving

Nurse specialists

Counselling

Family counselling

Relapses

1st line

2nd line

Maintenance Escalation Induction

Monitoring

Disease-free

Disease progression

DMTs

Side Effects

Advanced Directive

Exercise

Diet

Alternative Medicine

Pregnancy Breast Feeding

Research

Insurance

Visual loss

Palliative Care

Assisted suicide

Social services

Legal aid Genetic counselling

Prevention

Diagnosis

DMT Symptomatic

Therapist

Terminal

Counselling An holistic approach to MS; beta ver. 2.1

Intrathecal phenol

Fractures

Movement disorders

Osteopaenia

Reading material

1. Compston A, Coles A. Multiple sclerosis. Lancet 2008 ;372:1502-17.

2. Ramagopalan et al. Multiple sclerosis: risk factors, prodromes, and potential causal pathways. Lancet Neurol 2010; 9: 727–39.

Topics to be covered

• Definition

• Pathology

• Epidemiology

• Aetiology

• Autoimmune pathogenesis

• Clinical features

• Treatment

Definition

Pathological Definition: Inflammatory disease of the CNS characterised by demyelination and variable degrees of axonal loss and gliosis.

Clinical Definition: Objective CNS dysfunction, i.e. involvement of two or more white matter structures separated by time (1 months)*, with no other aetiology.

* At least 1 month

Gross Pathology

Histopathology - inflammation

Histopathology - demyelination

Histopathology - gliosis

Epidemiology

• Age of onset - 3rd / 4th decade (16 - 50 years)

• Prevalence - ~125/100,000 (latitude dependent)

• Life Span - slightly reduced (~ 10 years)

• Sex - F > M

• Race - Caucasians

(uncommon in Chinese / ? Viking ancestral genes)

• Geography - Northern European Disease

• Familial clustering

Aetiology

• Unknown

• ? Infection

• ? Autoimmune disease

Risk Factors

• Genes

• Environment

• Sunlight/UVB

• vD

• EBV

• Smoking

Compston & Coles, Lancet 2008.

Migration studies

Geographical distribution of MS: prevalence increases away from the equator

Vukusic S et al. J Neurol Neurosurg Psychiat 2007;78:707–709.

53

55

70

47 76 71 78

51 53 51

59

77 88

103

97 100

84

93

87

95

62

82

Role of vD3: UVB and MS prevalence

1Jablonski NG, Chaplin G. J Hum Evol 2000;39:57–106. 2Chaplin G. Am J Phys Anthropol 2004;125:292–302.

45

55

70

47 76

71 78

51 53 51

59

77

62

88

103

98 100

84

82

93

87

95

MS Prevalence by Department Against UVMED minimum

3–4

4–6

6–7

Department UVMed MIN

7–9

10–11

11–13

14–16

.

Month of Birth

1Willer CJ et al. BMJ 2005;330:120–125.

Compston & Coles, Lancet 2008.

Familial Risk

Epidemics or clusters of MS

The annual incidence of MS (per 100 000 inhabitants) in the Faroe Islands since 1940

Kurtzke JF et al. Acta Neurol Scand 1993;88:161–173.

0

2

4

6

8

10

12

1940 1945 1950 1955 1960 1965 1970 1975 1980 1985 1990

Changing sex ratios

Orton et al. Lancet Neurol 2006; 5: 932–36.

Odds ratio of MS in subjects seronegative for EBV

Ascherio et al. Ann Neurol 2007;61:288-299.

Infectious mononucleosis

Thacker et al. Ann Neurol 2006;59:499–503.

Smoking is a risk factor for multiple sclerosis

Hawkes CH, Mult Scler. 2007 Jun;13(5):610-5.

Clues to autoimmunity

• Autoimmune disease

• MHC associations

• Possible associations with other autoimmune diseases

• Females > males

• Autoreactive T-cells and B-cells

• Affected by pregnancy and viral infections

• Animal models (EAE)

• Pathology

• Unable to transfer disease

Clinical Presentation - symptoms & signs

• Motor - spasticity, weakness and gait abnormalities.

• Sensory - positive (pins & needles) and negative sensory phenomena (loss of sensation).

• Cerebellum - inco-ordination and unsteady gait.

• Brain Stem - diplopia, vertigo, nystagmus, dysarthria

• Optic Nerves - optic neuritis (blurred vision)

• Bladder and Bowel - incontinence

• Higher Functions - depression, poor concentration, forgetfulness, etc.

• Fatigue

Most embarrassing symptom

Society’s perspective

MS is a severely debilitating disease with a major socio-economic burden

MS is one of the most common causes of neurological disability in young adults2

Natural history studies indicate that it takes a median time of 8, 20 and 30 years to reach the irreversible disability

levels of EDSS 4, 6 and 7, respectively3

Up to 75% increased annualized divorce rate4

Life expectancy is reduced by 5-10 years5

In a 2004 study, 2 out of 3 patients with RRMS were unemployed due to the disease6

EDSS and utilitya show a significant inverse relationship1,b

aUtility measures are derived from EQ-5D using the EuroQoL instrument. bAdapted from Orme et al 2007. Error bars depict 95% confidence intervals. Half points on EDSS are not shown on graph axis, except at EDSS 6.5.

1.Orme M et al. Value In Health. 2007;10:54-60. 2.WHO. 2008.[TK] 3. Confavreaux, Compston. 2005.[TK] 4. Coles et al. 2001.[TK] 5. Confavreaux, Vukusic. 2006.[TK] 6. Morales-Gonzales. Mult Scler. 2004;10:47-54.

Horizontal eye movements

R L

III

VI

PPRF

MLF

MLF = medial longitudinal fasiculus PPRF = parapontine reticular formation

Case history 1

• A 26 year old female, with previous history of myelitis, presents with

double vision on looking to the left.

Where is the lesion?

R L

III

VI

PPRF

MLF

Horizontal Eye Movements

R L

L R

Internuclear ophthalmoplegia

Where is the lesion?

R L

R L

L R

R L

III

VI

PPRF

MLF = =

Bilateral INO

Where is the lesion?

R L

R L

L R

R L

III

VI

PPRF

MLF

One and a half syndrome

MRI

MRI

1. Three or more white matter lesions

2. At least two of the following

i. At least 1 lesion abutting body of lateral ventricle

ii. At least 1 infratentorial lesion

iii. A lesion > 6mm

Sensitivity = 81%

Specificity = 96%

Callosal lesions

Offenbacher H, et al. Neurology 1993;43:905-9.

Evoked potentials

VEP BAEP SSEP

No. patients 1950 1006 1006

No. series 26 26 31

Rates of abnormality

Definite MS 85% 67% 77%

Probable MS 58% 41% 67%

Possible MS 37% 30% 49%

Asymptomatic 51% 38% 42%

All patients 63% 46% 58% 76%

(upper limbs) (lower limbs)

Axonal plasticity - sodium channel

Waxman SG. Nat Rev Neurosci. 2006 Dec;7(12):932-41.

Videos courtesy Hugh Bostock, Inst. Neurol., UCL

Reduced safety factor of conduction

http://www.youtube.com/watch?v=wLSxS9THnGU http://www.youtube.com/user/ggiovannoni#p/a/u/1/iC9U0Obzhh4

Case study 1

• 29 year male with early MS complains of difficulty playing squash:

• 10 – 15 minutes after starting to play he keeps missing the ball.

• Why?

Carl Pulfrich (1858 to 1927)

The Pulfrich effect is a psychophysical percept wherein

lateral motion of an object in the field of view is interpreted by the visual cortex as having a depth component, due to a relative difference in signal timings between the two eyes.

Wilhelm Uhthoff

Circadian and hypothermia-induced effects on visual and auditory evoked potentials in multiple sclerosis

Romani et al. Clinical Neurophysiology 111 (2000) 1602-1606.

Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial

Goodman et al. Lancet 2009; 373: 732–38.

IEF - Oligoclonal IgG Bands

local OCBs

local & systemic OCBs

systemic OCBs

normal / polyclonal

CSF

Serum

Intrathecal or central compartment

Systemic or peripheral compartment

CSF OCBs

Test % Abnormal

Quantitative Abnormal blood CSF barrier function (Albumin quotient > 7 x 10-3)

12%

Increased IgG quotient (IgG index > 0.88)

70-80%

Increased cell count (> 4/ l)

50%

Qualitative Agarose 60% Acrylamide 75-85%

IEF - oligoclonal bands 95-98%

relapsing-remitting MS secondary progressive MS

Clinical course

MS Expanded Disability Status Scale - EDSS

Treatment Disease Modifying

– Acute Relapse - high dose corticosteroids

– Relapsing cases - interferon beta & glatiramer acetate

– Highly active cases – fingolimod, natalizumab, mitoxantrone

– Drugs in development – Teriflunomide, BG12, laquinimod, alemtuzumab,

ocrelizumab, daclizumab

– Progressive cases – nothing licensed; need for effective neuroprotectants

– Prevention – strategies need to be tested

– Cure –early aggressive immune system rebooters have the greatest chance of a

cure

Symptomatic

– Spasticity (baclofen, etc.)

– Bladder and bowel function

– Fatigue

– Depression

– Infections

– Skin and foot care

– Pain

– Physiotherapy

– Occupational Care

Prognosis

Highly variable*

– 30% benign disease (depends on follow-up)

– 15 yrs ~30% wheel chair

– 20 yrs ~50% wheel chair

– 50% unemployment rate 8-10 yrs post diagnosis

Good prognostic

– young, female

– relapsing course

– optic neuritis or sensory onset

– long gap between first and second relapses.

– full recovery from initial attack

– low baseline lesion load on MRI

Survival slightly reduced

* old natural history data, which will have improved with DMTs

Epstein Bar Virus

Genetics

Vitamin D

Smoking

Risks

Adverse events

Differential Diagnosis

MRI

Evoked Potentials

Lumbar puncture

Blood Tests

Diagnostic Criteria

Cognition

Depression

Fatigue

Bladder

Bowel

Sexual dysfunction Tremor

Pain Swallowing

Spasticity Falls

Balance problems Insomnia

Restless legs Fertility

Clinical trials

Gait

Pressure sores

Oscillopsia

Emotional lability

Seizures

Gastrostomy

Rehab

Suprapubic catheter Intrathecal

baclofern

Physio- therapy

Speech therapy

Occupational Therapy

Functional neurosurgery

Colostomy

Tendonotomy

Studying

Employment Relationships

Travel

Vaccination

Anxiety

Driving

Nurse specialists

Counselling

Family counselling

Relapses

1st line

2nd line

Maintenance Escalation Induction

Monitoring

Disease-free

Disease progression

DMTs

Side Effects

Advanced Directive

Exercise

Diet

Alternative Medicine

Pregnancy Breast Feeding

Research

Insurance

Visual loss

Palliative Care

Assisted suicide

Social services

Legal aid Genetic counselling

Prevention

Diagnosis

DMT Symptomatic

Therapist

Terminal

Counselling An holistic approach to MS; beta ver. 2.1

Intrathecal phenol

Fractures

Movement disorders

Osteopaenia