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

Multiple Sclerosis

Multiple Sclerosis

• Inflammatory demyelinating disease of the central nervous system.

• Most common cause of neurological disability in young adults.

Multiple Sclerosis

• Epidemiology:940 patients followed at the multiple sclerosis clinic of the Montreal Neurological Institute:

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

Multiple Sclerosis

• Temporal patterns• Relapsing-remitting (RR) MS: 55%

• Secondary progressive (SP) MS: 31%

• Primary progressive (PP) MS: 9%

• Progressive relapsing (PR) MS: 5%

Multiple Sclerosis

• Pathophysiology: Demyelination

Multiple Sclerosis

• Pathophysiology:– Consequences of demyelination:

• Slowing of conduction

• Conduction block

• Uhthoff’s phenomenon – Temperature

• Mechanical stimulation

Multiple Sclerosis

• Pathophysiology:– Axonal injury

• Usually occurs later, but also evidence of early loss.

Multiple Sclerosis

• Pathophysiology:– Recovery:

• Early – Resolution of oedema, cytokines, pH

• Intermediate – Increase in internodal Na channels

• Later – Remyelination

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.

Multiple Sclerosis

Radiological features

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

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.

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

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

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

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.

Multiple Sclerosis• Diagnostic Criteria:  Revised McDonald et al. (2005) Diagnostic Criteria for Multiple Sclerosis

CLINICAL (ATTACKS)

OBJECTIVE LESIONS ADDITIONAL REQUIREMENTS TO MAKE DIAGNOSIS

2 or more 2 or more None. Clinical evidence alone will suffice; additional evidence desirable but must be consistent with MS

2 or more 1 Dissemination in space by MRI or 2 or more MRI lesions consistent with MS plus positive CSF or await further clinical attack implicating other site

1 2 or more Dissemination in time by MRI or second clinical attack

1 1 Dissemination 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 more Disease 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

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.

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

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.

Multiple Sclerosis

• Treatment:– Acute attacks: Methyl-Prednisolone: 500mg to

1000mg daily x3-5/7.

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)

Multiple Sclerosis

• Treatment:– Disease modifying treatment in SP and PRMS:

• Mitoxanthrone

• Interferon beta-1b (Betaferon)

• Cyclophosphamide ??

• Azathioprine ??

• Methotrexate ??

• Monthly – 3 monthly pulses of Solumedrol ??

Multiple Sclerosis

• Treatment:– Disease modifying treatment in PPMS:

• ???