1. Multiple Sclerosis

2. Inflammatory demyelinating disease of the central nervous system. Most common cause of neurological disability in young adults.

3. Multiple Sclerosis Epidemiology: 940 patients followed at the multiple sclerosis clinic of the Montreal Neurological Institute:

4. Multiple Sclerosis Epidemiology: Sex ratio: F:M = 1.77:1.00 Prevalence ranges from <5 to 60 per 100 000. Higher in Europe and North America. South Africa: White population: 5-25/100 000. Genetics: Sibs 3-5% risk. Monozygotic twins 20-38% risk

5. Multiple Sclerosis Temporal patterns Relapsing-remitting (RR) MS: 55% Secondary progressive (SP) MS: 31% Primary progressive (PP) MS: 9% Progressive relapsing (PR) MS: 5%

6. Multiple Sclerosis Pathophysiology: Demyelination

7. Multiple Sclerosis Pathophysiology: –Consequences of demyelination: Slowing of conduction Conduction block Uhthoff’s phenomenon – Temperature Mechanical stimulation

8. Multiple Sclerosis Pathophysiology: –Axonal injury Usually occurs later, but also evidence of early loss.

9. Multiple Sclerosis Pathophysiology: –Recovery: Early – Resolution of oedema, cytokines, pH Intermediate – Increase in internodal Na channels Later – Remyelination

10. Multiple Sclerosis Pathophysiology: –Immunological disease: Complex, not fully elucidated, various patterns. Disruption of perivenular BBB. Migration of T cells (CD8+CD4) and macrophages. Macrophages occur in centre of lesion, associated with oligodentrocyte destruction and demyelination. In periphery of lesion – Remyelination by surviving oligodendrocytes and even oligodendrocyte proliferation. Plaques: Discreet areas of demyelination, macrophage, and T- cell infiltration, astrocytosis.

11. Multiple Sclerosis Radiological features

12. Multiple Sclerosis Clinical features : –Cranial nerve deficits: Optic neuritis – common Oculomotor involvement: –Isolated nerves: VI>III>IV –Internuclear ophthalmoplegia –Nystagmus Trigeminal neuralgia Facial palsy, but Taste not affected. Hemifacial spasma and myokemia Pseudobulbar palsy – common in later stages

13. Multiple Sclerosis Clinical features: –Sensory symptoms: Common Various patterns Often paresthesias, dysesthesias and other positive symptoms. Plaques involving dorsal root entry zones are common – radicular pain or severe loss of proprioception: useless hand with normal power.

14. Multiple Sclerosis Clinical features: –Motor features: Usually later than sensory Hemiparesis with cerebral or brainstem lesions Acute partial myelitis. Gradually progressive paraparesis characteristic of progressive forms of MS. –Cerebellar features - common

15. Multiple Sclerosis Clinical features: –Impairment of Bladder, Bowel, and Sexual Functions: Urgency and urgency incontinence Dyssynergic voluntary sphincter activity With involvement of sacral spinal segments – Hypotonic bladder with overflow incontinence. Constipation > fecal incontinence Sexual dysfunction

16. Multiple Sclerosis Clinical features: –Cognitive Impairment: Subtle and underreported. Subcortical: Abstract conceptualization, recent memory, attention, and speed of information processing –Affective Disorders: Depression – 50% risk. Higher than with other chronic neurological diseases. –Fatigue

17. Multiple Sclerosis Clinical features: –Characteristic positive features: Lhermitte’s phenomenon - Electric shock radiating down the spine or into the limbs on flexion of the neck. Uhthoff’s phenomenon – Worsening of existing symptoms Trigeminal neuralgia, central pain, paraspinal spasms, myokemia, phosphenes and a variety of other paroxysmal neurological symptoms.

18. Multiple Sclerosis Diagnostic Criteria: Revised McDonald et al. (2005) Diagnostic Criteria for Multiple Sclerosis CLINICAL (ATTACKS) OBJECTIVE LESIONSADDITIONAL REQUIREMENTS TO MAKE DIAGNOSIS 2 or more None. Clinical evidence alone will suffice; additional evidence desirable but must be consistent with MS 2 or more1Dissemination in space by MRI or 2 or more MRI lesions consistent with MS plus positive CSF or await further clinical attack implicating other site 12 or moreDissemination in time by MRI or second clinical attack 11Dissemination in space by MRI or 2 or more MRI lesions consistent with MS plus positive CSF AND dissemination in time by MRI or second clinical attack 0 (progression from onset) 1 or moreDisease progression for 1 year (retrospective or prospective) AND 2 out of 3 of the following: Positive brain MRI (9 T2 lesions or 4 or more T2 lesions with positive VEP) Positive spinal cord MRI (2 or more focal T2 lesions) Positive CSF

19. Multiple Sclerosis Diagnostic Criteria: –Positive MRI = 3 or more: 1 gadolinium-enhancing brain or cord lesion or 9 T2 hyperintense brain and/or cord lesions if there is no gadolinium-enhancing lesion 1 or more brain infratentorial or cord lesions 1 or more juxtacortical lesions 3 or more periventricular lesions Note: Individual cord lesions can contribute along with individual brain lesions to reach required number of T2 lesions.

20. Multiple Sclerosis Diagnostic Criteria: –MRI EVIDENCE OF DISSEMINATION IN TIME : A gadolinium-enhancing lesion detected in scan at least 3 months after onset of initial clinical event at a site different from initial event - or - A new T2 lesion detected in a scan done at any time compared to a reference scan done at least 30 days after initial clinical event

21. Multiple Sclerosis Prognosis: –Poor prognostic indicators: Male Older onset Progressive from start Frequent initial relapses Pyramidal or brainstem rather that optic neuritis or sensory symptoms. –Pure optic neuritis, without brain lesions has good prognosis, only 16 % progress to MS in 5 years. Compared to 51% with 3+ lesions.

22. Multiple Sclerosis Treatment: –Acute attacks: Methyl-Prednisolone: 500mg to 1000mg daily x3-5/7.

23. Multiple Sclerosis Treatment: –Disease modifying treatment in RRMS: Interferon beta-1a (Avonex) 30ug IMI/w Interferon beta 1a (Rebif) 22-44ug SC 3x/w Interferon beta-1b (Betaferon) 8MIU alt days Glatirimer acetate (Copaxone) 20mg daily Mitoxanthrone Natalizumab (Tysarbi)

24. Multiple Sclerosis Treatment: –Disease modifying treatment in SP and PRMS: Mitoxanthrone Interferon beta-1b (Betaferon) Cyclophosphamide ?? Azathioprine ?? Methotrexate ?? Monthly – 3 monthly pulses of Solumedrol ??

25. Multiple Sclerosis Treatment: –Disease modifying treatment in PPMS: ???