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 - 3 rd / 4 th 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.
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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.
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.
• 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.
• 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)