bb2 ms lecture - barts and the london med school - 11th jan 2013
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Multiple Sclerosis – BB2 11th Jan 2013
Professor Gavin Giovannoni
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Topics to be covered
• Definition
• Pathology
• Epidemiology
• Aetiology
• Autoimmune pathogenesis
• Clinical features
• Treatment
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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
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Gross Pathology
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Histopathology - inflammation
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Histopathology - demyelination
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Histopathology - gliosis
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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
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Aetiology
• Unknown
• ? Infection
• ? Autoimmune disease
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Risk Factors
• Genes
• Environment
• Sunlight/UVB
• vD
• EBV
• Smoking
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Genetics
.
Increasing relatedness to an MS patient increases your risk of getting the disease
Willer et al, 2003
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GWAS results in MS
.
IMSGC & WTCCC2, 2011
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Compston & Coles, Lancet 2008.
Migration studies
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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
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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
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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
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Prevalence of MS in the UK
.
Ramagopalan et al, 2011
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Relationship of MS Prevalence to Ultraviolet exposure
Ramagopalan et al, 2011
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.
Month of Birth
1Willer CJ et al. BMJ 2005;330:120–125.
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Compston & Coles, Lancet 2008.
Familial Risk
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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
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Infectious agents in MS
Ramagopalan et al 2009
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.
Handel et al, 2010
19390 MS patients and 16007 controls, p < 10-54
Infectious mononucleosis and MS
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Odds ratio of MS in subjects seronegative for EBV
Ascherio et al, 2007
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Smoking is a risk factor for multiple sclerosis
Handel et al, 2010
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Changing sex ratios
Orton et al. Lancet Neurol 2006; 5: 932–36.
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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
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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
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Most embarrassing symptom
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Society’s perspective
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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.
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Horizontal eye movements
R L
III
VI
PPRF
MLF
MLF = medial longitudinal fasiculus PPRF = parapontine reticular formation
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Case history 1
• A 26 year old female, with previous history of myelitis, presents with
double vision on looking to the left.
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Where is the lesion?
R L
III
VI
PPRF
MLF
Horizontal Eye Movements
R L
L R
Internuclear ophthalmoplegia
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MRI
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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.
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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)
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Axonal plasticity - sodium channel
Waxman SG. Nat Rev Neurosci. 2006 Dec;7(12):932-41.
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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
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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?
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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.
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Wilhelm Uhthoff
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Circadian and hypothermia-induced effects on visual and auditory evoked potentials in multiple sclerosis
Romani et al. Clinical Neurophysiology 111 (2000) 1602-1606.
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Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial
Goodman et al. Lancet 2009; 373: 732–38.
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IEF - Oligoclonal IgG Bands
local OCBs
local & systemic OCBs
systemic OCBs
normal / polyclonal
CSF
Serum
Intrathecal or central compartment
Systemic or peripheral compartment
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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%
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relapsing-remitting MS secondary progressive MS
Clinical course
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MS Expanded Disability Status Scale - EDSS
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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
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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
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Teach Neurology
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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.