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Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
Barts & The London Yr-4 medical student's lecture notes on MS
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Barts & The London Yr-4 medical student's lecture notes on MS

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MS lecture from the 17th December 2012

MS lecture from the 17th December 2012

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  • 1. 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 deficiency5. 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 reduced9. 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 Care10. 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.
  • 2. Multiple Sclerosis Professor Gavin Giovannoni
  • 3. Sexual Balance Restless Emotional Advanced Fertility Pregnancy Bladder dysfunction problems legs Tremor Insomnia lability Directive Breast Feeding Oscillopsia Vaccination Studying Bowel Gait Falls Spasticity Cognition Seizures Employment Swallowing PainRelationships Clinical trials Visual loss Travel Counselling Fatigue Driving Pressure sores Research Depression Fractures Exercise Occupational Nurse Rehab Therapy Anxiety specialists Diet Movement Insurance disorders Family Maintenance Escalation Induction Physio- counselling therapy Osteopaenia Side Effects Speech Alternative Risks therapy Palliative Care Medicine 2nd line Adverse Suprapubic DMTs 1st line events catheter Intrathecal Genetics Legal aid Genetic baclofern counselling Disease Smoking progression Intrathecal Social Lumbar Evoked Tendonotomy services Potentials Disease-free phenol Epstein Bar Virus puncture Colostomy Monitoring Gastrostomy Differential Vitamin D Diagnosis Relapses Functional Assisted neurosurgery suicide Diagnostic Criteria Blood MRI Terminal Tests Prevention DMT Diagnosis Symptomatic An holistic approach to MS; beta ver. 2.1 Therapist Counselling
  • 4. Reading material1. 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.
  • 5. Topics to be covered• Definition• Pathology• Epidemiology• Aetiology• Autoimmune pathogenesis• Clinical features• Treatment
  • 6. DefinitionPathological 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
  • 7. Gross Pathology
  • 8. Histopathology - inflammation
  • 9. Histopathology - demyelination
  • 10. Histopathology - gliosis
  • 11. 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
  • 12. Aetiology• Unknown• ? Infection• ? Autoimmune disease
  • 13. Risk Factors• Genes• Environment • Sunlight/UVB • vD • EBV • Smoking
  • 14. Migration studies Compston & Coles, Lancet 2008.
  • 15. Geographical distribution of MS: prevalence increases away from the equator 93 103 82 77 97 88 100 87 62 59 84 70 95 47 7 6 78 71 55 51 53 51 53 Vukusic S et al. J Neurol Neurosurg Psychiat 2007;78:707–709.
  • 16. Role of vD3: UVB and MS prevalence MS Prevalence by Department Against UVMED minimum 93 103 82 77 98 88 100 87 62 59 84 70 95 Department 47 76 UVMed MIN 78 71 3–4 4–6 55 6–7 51 53 51 7–9 10–11 11–13 45 14–16 1Jablonski NG, Chaplin G. J Hum Evol 2000;39:57–106. 2Chaplin G. Am J Phys Anthropol 2004;125:292–302.
  • 17. Month of Birth. 1Willer CJ et al. BMJ 2005;330:120–125.
  • 18. Familial Risk Compston & Coles, Lancet 2008.
  • 19. Epidemics or clusters of MSThe annual incidence of MS (per 100 000 inhabitants) in the Faroe Islands since 1940 12 10 8 6 4 2 0 1940 1945 1950 1955 1960 1965 1970 1975 1980 1985 1990 Kurtzke JF et al. Acta Neurol Scand 1993;88:161–173.
  • 20. Changing sex ratios Orton et al. Lancet Neurol 2006; 5: 932–36.
  • 21. Odds ratio of MS in subjects seronegative for EBV Ascherio et al. Ann Neurol 2007;61:288-299.
  • 22. Infectious mononucleosis Thacker et al. Ann Neurol 2006;59:499–503.
  • 23. Smoking is a risk factor for multiple sclerosis Hawkes CH, Mult Scler. 2007 Jun;13(5):610-5.
  • 24. 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
  • 25. 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
  • 26. Most embarrassing symptom
  • 27. Society’s perspective
  • 28. MS is a severely debilitating disease with a major socio-economic burden EDSS and utilitya show a significant inverse relationship1,b  MS is one of the most common causes of neurological disability in young adults 2  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 disease 6aUtility 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. Horizontal eye movementsR L III MLF VI PPRF MLF = medial longitudinal fasiculus PPRF = parapontine reticular formation
  • 30. Case history 1• A 26 year old female, with previous history of myelitis, presents with double vision on looking to the left.
  • 31. Where is the lesion? Horizontal Eye Movements L R LR   R L III MLF Internuclear ophthalmoplegia VI PPRF
  • 32. Where is the lesion?R L R L R L III = = MLF R L VI PPRF Bilateral INO
  • 33. Where is the lesion?R L R L R L III MLF VI R L PPRF One and a half syndrome
  • 34. MRI
  • 35. MRI1. Three or more white matter lesions2. 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.
  • 36. Evoked potentials VEP BAEP SSEPNo. patients 1950 1006 1006No. series 26 26 31Rates of abnormality Definite MS 85% 67% 77% Probable MS 58% 41% 67% Possible MS 37% 30% 49% Asymptomatic 51% 38% 42% 58% (upper limbs)All patients 63% 46% 76% (lower limbs)
  • 37. Axonal plasticity - sodium channel Waxman SG. Nat Rev Neurosci. 2006 Dec;7(12):932-41.
  • 38. Reduced safety factor of conduction http://www.youtube.com/watch?v=wLSxS9THnGU http://www.youtube.com/user/ggiovannoni#p/a/u/1/iC9U0Obzhh4Videos courtesy Hugh Bostock, Inst. Neurol., UCL
  • 39. 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?
  • 40. 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.
  • 41. Wilhelm Uhthoff
  • 42. Circadian and hypothermia-induced effects on visual and auditory evoked potentials in multiple sclerosis Romani et al. Clinical Neurophysiology 111 (2000) 1602-1606.
  • 43. Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial Goodman et al. Lancet 2009; 373: 732–38.
  • 44. Intrathecal or central compartment IEF - Oligoclonal IgG Bands CSF normal / Serum polyclonal local OCBs local & systemic OCBs systemic OCBsSystemic or peripheral compartment
  • 45. CSF OCBsTest % AbnormalQuantitative Abnormal blood CSF barrier function 12% (Albumin quotient > 7 x 10-3) Increased IgG quotient 70-80% (IgG index > 0.88) Increased cell count 50% (> 4/ l)Qualitative Agarose 60% Acrylamide 75-85% IEF - oligoclonal bands 95-98%
  • 46. Clinical courserelapsing-remitting MS secondary progressive MS
  • 47. MS Expanded Disability Status Scale - EDSS
  • 48. 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
  • 49. 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 MRISurvival slightly reduced* old natural history data, which will have improved with DMTs
  • 50. Sexual Balance Restless Emotional Advanced Fertility Pregnancy Bladder dysfunction problems legs Tremor Insomnia lability Directive Breast Feeding Oscillopsia Vaccination Studying Bowel Gait Falls Spasticity Cognition Seizures Employment Swallowing PainRelationships Clinical trials Visual loss Travel Counselling Fatigue Driving Pressure sores Research Depression Fractures Exercise Occupational Nurse Rehab Therapy Anxiety specialists Diet Movement Insurance disorders Family Maintenance Escalation Induction Physio- counselling therapy Osteopaenia Side Effects Speech Alternative Risks therapy Palliative Care Medicine 2nd line Adverse Suprapubic DMTs 1st line events catheter Intrathecal Genetics Legal aid Genetic baclofern counselling Disease Smoking progression Intrathecal Social Lumbar Evoked Tendonotomy services Potentials Disease-free phenol Epstein Bar Virus puncture Colostomy Monitoring Gastrostomy Differential Vitamin D Diagnosis Relapses Functional Assisted neurosurgery suicide Diagnostic Criteria Blood MRI Terminal Tests Prevention DMT Diagnosis Symptomatic An holistic approach to MS; beta ver. 2.1 Therapist Counselling

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