Multiple Sclerosis

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Multiple Sclerosis

• Prepared by
• Dr. Sarwer Jamal Bajalan
• M.B.Ch.B, F.I.B.M.S(Neurology)

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Multiple Sclerosis

• Definition
• Epidemiology
• Pathogenesis
• Clinical features
• Diagnostic Criteria Evaluation
• Differential Diagnosis
• Management

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Definition of Multiple Sclerosis

• An inflammatory demyelinating disease of the CNS
  where there is
• Dissemination in space
• Dissemination in time
• No alternative neurologic disease
• MS is a clinical diagnosis

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• An immune-mediated autoimmunity, with
  secondary, significant axonal loss cerebral
  atrophy
• Occurs in genetically susceptible individuals who
  are exposed to an environmental agent at a young
  age
• Highly variable clinical course

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Epidemiology

• The most common progressive neurologic disease of
  young adults
• Affects 350,000 persons in the USA
• Most cases strike between ages 15 and 45
• Women outnumber men by as much as 2 to 31
• Risk Factors
• Female gender
• White race
• Northern latitude (USA)
• High socioeconomic status
• Scandinavian ancestry

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Pathogenesis

• MS involves genetic, environmental, and immune
  factors
• MS has inflammatory, demyelinating, and axonal
  damage components
• Pathogenesis is not clearly understood
• Immune modulation is most successful therapeutic
  approach supporting immune role in pathogenesis

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Signs and Symptoms of MS by Lesion Location
Optic nerve Monocular visual loss Scotoma Spinal
cord Limb weakness Spasticity and
hyper-reflexia Lhermittes sign Urinary urgency
and incontinence
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• Brainstem
• Diplopia (double vision)
• Pain (acute versus chronic)
• Trigeminal neuralgia, tic-like extremity pain
• Aching back pain, burning sensation, leg spasms
• Numbness of face and tongue
• Vertigo (sensation of moving around in space)
• Nystagmus (involuntary eye movements)
• INO (Inter Nuclear Ophthalmoplegia)

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• Cerebrum
• Impairment of concentration or memory
• Hemiparesis Hemisensory loss
• Visual field defect
• Cerebellum
• Incoordination of limbs
• Ataxic gate

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• Severe fatigue
• Experienced by 75 to 95 of MS sufferers
• Heat sensitivity
• Depression
• Etiology can be a
• Symptom
• Secondary complication
• Side effect of medications

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Secondary Complications

• Depression
• Urinary tract infection
• Accelerated lumbar spondylosis
• Aspiration pneumonia
• Pulmonary thromboembolism
• Pressure sores
• Limb contractures
• Gastroparesis

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MS Subtypes

• Asymptomatic
• Symptomatic
• Relapsing-remitting (85 at onset)
• Primary progressive (10)
• Secondary Progressive (transitional form 50 of
  RR)
• Progressive Relapsing (5)

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Multiple Sclerosis Subtypes
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Diagnosis

• Clinical findings
• History
• Neurologic exam
• Clinical picture
• Laboratory evaluations
• Magnetic resonance imaging (MRI)
• Evoked potentials
• Cerebrospinal fluid (CSF) analysis

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McDonald Diagnostic Criteria-1Relapsing
Remiting MS
Lesions disseminated in time(DIT) and
space(DIS) Time More than one attack separated
by at least one month Space CNS involvement of
more than one area Exclusion of other possible
causes
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McDonald Diagnostic Criteria - 2 Primary
Progressive MS

• Insidious course with steady progression of
  clinical deficits with paraclinical evidence of
• DIS by MRI in combination with VER positive CSF
• DIT by MRI or continued progression for 1 yr

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Imaging Lab Work-up for MS(Modified from
Fleming J, MS Its Masquerades, AAN-2003)

• Brain MRI with Gd
• Evoked Responses VER(VEP), BAER, SSER
• CBC, Chem 7, Liver enz, UA
• Lyme serology (based on exposure history)
• ANA, VDRL, ESR
• B12
• T3, T4, TSH
• HIV
• CSF (based on clinical and MRI)
• C T Spine MRI (if Brain MRI nl or indicated
  clinically)
• CXR

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MRI FLAIR T1 with Gadolinium
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MRI T1 Black Holes
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MRI Sagittal Views
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MRI Spinal Imaging
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MRI T2, T2, FLAIR, T1-Gd
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Visual Evoked Potentials
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CSF Studies

• Glucose Normal
• Protein Normal to Mild Elevation
• WBC Normal to Mild Mononuclear Pleocytosis
• Intrathecal Antibody Production
• Increased IgG Synthesis Rate,
• Oligoclonal Bands

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Oligoclonal Bands
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Differential Diagnosis of MS
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• MANGEMENT OF
• MULTIPLE SCLEROSIS

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Treatment Goals

• Reduce (control) relapses
• Delay disease progression disability
• Alleviate symptoms

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Corticosteroids

• Symptomatic management for acute relapses
• Used in moderate-to-severe exacerbations
• IV methylprednisolone 500-1000 mg/day for 3-5
  days followed by oral prednisone (optional)
• Hasten clinical recovery
• Delay recurrence of neurologic events
• Does not alter the course of MS

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Disease Modifying Agents(Parentral)

• Betaseron? (interferon ?-1b)
• Avonex? (interferon ?-1a)
• Rebif? (interferon ?-1a)
• Copaxone? (glatiramer acetate)
• Novantrone? (mitoxantrone)
• 12 mg/m2 as short IV infusion
• Cumulative lifetime dose ? 140 mg/m2
• Tysabri? (Natalizumab)
• 300mg IV infusion over 1hr q 4 wks

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Disease Modifying Agents(Oral)

• Gilenya (Fingolimod)
• available since 2011
• 0.5 mg/day
• S/E
• Transitory slow heart rate
• macular edema
• Herpes infection 2 patients have died from it
• Aubagio (Terflunamide)
• 30 reduction in relapse frequency
• S/E diarrhea, nausea, hair loss and abnormal
  hepatic biochemistry
• Fumarate
• used in Germany for 10 years to treat psoriasis
  (Fumaderm)
• Laquinimod
• One dose 0.6 mg/day
• Modest effect 25 reduction in relapse frequency

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Interferon BetaMechanism of Action

• Reduce the production of the TNFa (tumor necrosis
  factor alpha) and T-cells, known to induce damage
  to myelin
• Reduce inflammation by
• Switching cytokine production from type 1
  (pro-inflammatory) to type 2 (anti-inflammatory)
  cells
• Increasing levels of interleuken 10 (IL-10)
• Decrease antigen presentation, to reduce the
  attack on myelin
• Reduce the ability of immune cells to cross the
  blood-brain barrier, by affecting adhesion
  molecules, chemokines, and proteases

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Betaseron (interferon beta-1b)(Betaferon)

• Indication Relapsing forms of MS
• Dose 8 million IU (250 mcg) SC every other day
• Reduces rate of clinical relapse
• Reduces the development of new lesions
• Delays the increase in the volume of lesions

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Immunomodulating Agents
IFNs
IFN ?-1a (Avonex)
IFN ?-1a (Rebif)
IFN ?-1b (Betaseron)
Glatiramer Acetate (Copaxone)
Type Recombinant Recombinant Recombinant Polypep
tide protein protein protein mixture Use
Slow Reduce Reduce Reduce accumulation
frequency frequency frequency of disability
of relapses of relapses of relapses
Injection IM SC SC SC Administration
Weekly 3 ?/week Every other day Daily Dosage
30 ?g 22 ?g 0.25 mg (8 MIU) 20 mg 44 ?g
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Symptomatic Treatments
Problem Management
Spasticity Remove irritating factors, Physical therapy, baclofen, diazepam, dantrolene
Paroxysmal phenomena carbamazepine, gabapentin, phenytoin
Fatigue Energy conservation, amantidine ,Modafinil ,Dalfampridine (Ampyra)
Depression Anti-depressants
Sexual dysfunction Behavioral therapy, Viagra(sildenafil), Muse(alprostadil)
Urinary dysfunction Tolterodine(Detrol), Oxybutynin(Ditropan), Bethanicol, Botox
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Prognosis

• Favorable
• Low attack rate
• Long interval to 2nd attack
• Complete recovery from 1st attack
• Younger age at onset
• Female sex
• Low disability at 2 and 5 years

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Multiple sclerosis - Disease progression (EDSS) -
years
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Whats New?
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The Therapy Pyramid in 2013
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References

• 1. Multiple Sclerosis Making the Diagnosis M.
  Wallin, MD, MPH Neurology Service VAMC,
  Washington, DC
• 2. Wallin M, et al Baker Clin Neurol CD-2003
• 3. David H. Snyder, M.D. Multiple Sclerosis
  Clinical Aspects 2005 dsnyder_at_nynapc.com
  212.794.2281
• 4. Multiple Sclerosis Janet Toth, MS, RPh Branch
  Manager, Specialty Pharmacy July 15, 2006
• 5. Harrison principles of internal medicine MS
• 6. Continuum multiple sclerosis. 2011
• 7. Clinical Neurology, Michael J. Aminoff, etal
• 8. Neurology
• 9. NEJM