Multiple Sclerosis – BB2 11th Jan 2013
Professor Gavin Giovannoni
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
Genetics
.
Increasing relatedness to an MS patient increases your risk of getting the disease
Willer et al, 2003
GWAS results in MS
.
IMSGC & WTCCC2, 2011
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
MS, Latitude and UV
.
Van der Mei et al, 2001
Age
-sta
nd
ard
ise
d M
S p
reva
len
ce
(pe
r 1
00
,00
0)
Latitude (degrees)
10
20
30
40
50
60
70
80
0 15 20 25 30 35 40 45 0
Latitude
Average annual bright sunshine (h)
5.5 0 6.0 6.5 7.0 7.5 8.0 8.5 9.0
10
20
30
40
50
60
70
80
0
Sunlight
Average annual ultraviolet radiation (kJ/m2/day)
UVB
2.0 0 2.5 3.0 3.5 4.0 4.5 5.0 5.5
10
20
30
40
50
60
70
80
0
Prevalence of MS in the UK
.
Ramagopalan et al, 2011
Relationship of MS Prevalence to Ultraviolet exposure
Ramagopalan et al, 2011
.
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
Infectious agents in MS
Ramagopalan et al 2009
.
Handel et al, 2010
19390 MS patients and 16007 controls, p < 10-54
Infectious mononucleosis and MS
Odds ratio of MS in subjects seronegative for EBV
Ascherio et al, 2007
Smoking is a risk factor for multiple sclerosis
Handel et al, 2010
Changing sex ratios
Orton et al. Lancet Neurol 2006; 5: 932–36.
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
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
Teach Neurology
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.