MULTIPLE SCLEROSIS
Multiple Sclerosis A chronic, progressive neurologic disease characterized by scattered demyelination of nerve fibers in the brain and spinal cord.
Multiple Sclerosis Most common disabling condition in young adults Most common demyelinating disorder Progresses to disability in majority of cases Unpredictable course & variety of signs and symptoms; sometimes mistaken for psychiatric disorder
MS- Incidence Peak onset 20-40 years of age 70% between ages 21-40 Rarely prior to age 10 or after age 60 F > M (approx. 2:1) White > non-white (2:1)
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Risk factors Autoimmune process Viral infection Allergic reactions to infection Familial tendencies. Cool, temperature climates.
Etiology Autoimmune Viral T-cells activate against myelin Specific viral protein not yet identified Suspected “molecular mimicry” Roseola (HHV6) associated with demyelination in MS patients Viral infections known to provoke relapses
1. Research into the Causes of MS Genetic factors Environmental factors Immunological factors MS 10
Pathological Hallmarks Described in late 1800s by Dr. Charcot Inflammation and demyelination Plaques occur anywhere in the CNS Most frequent: optic nerve, brainstem, cerebellum, spinal cord Axon sparing within the plaques
Structure Of Plaques Outer layers of myelin sheath separate Degenerative changes in myelin Infiltration with macrophages Preservation of axons
Normal Conduction
Abnormal Conduction
Results Of Demyelination Conduction block at site of lesion Slower conduction time along affected nerve Increased subjective feeling of fatigue secondary to compensation for neurologic deficits
Initial Presentation of MS Incidence (%) Optic nerve inflammation 14–29 Poor balance (ataxia) 2–18 Dizziness (vertigo) 2–9 Weakness 10–40 Double visions (diplopia) 8–18 Bladder, bowel dysfunction 0–14 Pain 21–40 Sensory loss 13–39
Initial Symptoms Double vision / blurred vision Numbness Heat intolerance Motor weakness Fatigue Problems with bladder control Facial Palsy
Signs and Symptoms. Instability while walking Poor coordination Dizziness Tremors Spasticity of extremities **All symptoms can be precipitated by heat**
Signs and Symptoms Slurred speech Difficulty in chewing and swallowing Mental changes cognitive dysfunction Fecal or urinary incontinence or retention. Impotence
Classification Benign Multiple Sclerosis Mild infrequent sensory exacerbations with full recovery. Relapsing Remitting Multiple Sclerosis Episodes of exacerbations and remissions during which not all symptoms resolve completely.
Classification Secondary Chronic Progressive Relapses become more severe while remissions are less complete, shorter in duration, and eventually non-existent. The course of MS becomes steadily progressive. Primary Progressive No relapse. Disease begins with a slow progression of neurologic deficits.
Diagnostic tests CSF Analysis Magnetic resonance imaging Positron Emission Tomography Evoked Potential Studies
Dissemination in space and time MS Diagnosis Dissemination in space and time
Summarized Diagnostic Criteria 1. Dissemination in space: Objective evidence of neurological deficits localized to two separate parts of the CNS 2. Dissemination in Time: Onset of neurological deficits separated by at least one month 3. Rule out other explanations! August November 26 26 26
New Diagnostic Criteria Incorporate use of MRI Clinically Isolated Syndrom + MRI Dissemination in space + MRI Dissemination on time = Earlier MS Diagnosis DIS August November DIT 27 27 27
MRI - Dissemination in Space 3 of the following: 9 T2 or 1 Gd+ 3 Periventricular 1 Infratentorial 1 Juxtacortical lesion 28 28 28
MRI - Dissemination in Time Gd Gd > 3 months T2 T2 > 1 month > 1 month CIS Polman, 2005 29 29 29
DIAGNOSTIC WORK UP History & Physical Exam Brain and Spinal Cord MRI Labs: rule out mimics of MS Connective tissue diseases, infections, metabolic disorders Cerebrospinal Fluid (when clinical and MRI evidence inconclusive) Evoked Potentials: Identify damage to visual, auditory, & touch perception systems Less sensitive than MRI or cerebrospinal fluid 30 30 30
CSF Increased immunoglobulin concentration Elevated IgG index Oligoclonal bands Elevated protein
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Evoked Potentials VER (visual evoked response)—75% abnormal BAER (brainstem auditory evoked response)—30% abnormal SSER (somatosensory evoked response) – 80% abnormal
MRI- Cerebellum
MRI- Spine
MRI- Spine
MRI- Optic Nerve
MRI- Cerebral Hemisphere
JUXTACORTICAL
MRI- Cerebral Hemisphere
T1 nn „black holes“
Differential Diagnosis Encephalomyelitis CNS Vasculitis Lyme Disease Lupus Erythematosus Spastic Paraparesis Behçet Syndrome Vitamin B-12 Deficiency and Syphilis Hereditary Degenerative Disorders
Standard Therapy Treatment of Relapses Corticosteroids- Methyl Prednisolone
Disease Modifying Therapies: 1993-2002 Glatiramer Acetate (Copaxone®) 1997 IFN -1b (Betaseron®) 1993 IFN -1a (Rebif®) 2002 IFN -1a (Avonex®) 1996 Type Polypeptide Recombinant Recombinant Recombinant mixture protein protein protein Indication Reduce freq. Reduce freq. Reduce freq. Slow prog. of relapses of relapses of relapses in relapsing in RRMS Slow Delay forms disability in disability in Prevent 2nd relapsing forms relapsing forms attack in CIS Injection SC SC SC IM Administration Daily Every other day 3x/week Weekly decrease relapses of MS by 33% Immunomodulatory Treatments The long-term data that was published on glatiramer acetate1 involves a 6-year interim analysis of the ongoing 10-year open-label study. Some 8-year data are available. An extension of the pivotal North American study of IFN -1b (Betaseron®) provided placebo-controlled data for up to 5 years (median treatment period, 48.0 months).2 More recently, data from the 4-year extension of the PRISMS trial suggest that IFN -1a SC (Rebif®) may be efficacious for up to 4 years.3 No long-term studies (>2 years) have been published describing neurologic outcomes following the long-term use of IFN -1a IM (Avonex®). 1. Johnson KP, Brooks BR, Ford CC, et al. Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 years. Mult Scler. 2000;6:255-266. 2. The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology. 1995;45:1277-1285. 3. The PRISMS (Prevention of Relapses and Disability by Interferon-- 1a Subcutaneously in Multiple Sclerosis) Study Group. PRISMS-4: long-term efficacy of interferon--1a in relapsing MS. Neurology. 2001;56:1628-1636. 54 54
Natalizumab-Tysabri Humanized monoclonal Antibody against 41 integrin Selective adhesion-molecule inhibitor (SAM) Prevents transendothelial migration of activated leukocytes from small venules into CNS
“68% relative reduction in the annualized rate of relapse produced by natalizumab was maintained at two years (P<0.001)” 56 56
Newer treatments for RRMS: the return of immunosuppression! Mitoxantrone Natalizumab Oral Treatments (Fingolimod)
Fingolimod (Gilenya) Sphingosine-1-phosphate receptor blocker; traps lymphocytes in lymph nodes Licenced for rapidly evolving MS (second line) 60% reduction in relapse rate Side effects include bradycardia, macula oedema, infections (esp herpes virus), skin cancers
Existing Therapies and Emerging Therapies for MS 2005 2006 2007 2010 2011 2012 2013 Orals Injectables BG 12 Oral Fumarate Oral Cladribine Rebif Teriflunomide Betaseron FTY 720 Laquinimod Copaxone Fampridine ambulation indication? SB683699 Avonex IV Novantrone IV Campath Tysabri Rituximab II - RRMS; III - PPMS Generic Mitoxantrone (oncology) (MS) Daclizumab MBP 8298 MLN1202 Filed approved In phase II In phase III
Complications Respiratory failure Pneumonia Neurologic deficits: paralysis. UTI Sexual dysfunction Contractures
Factors that influence prognosis Females Low rate of relapses per year Complete recovery from the first attack Long interval between first and second attack Low disability at 2 to 5 years from the disease onset
Factors that influence prognosis Symptoms predominantly from afferent systems (i.e.,. sensory symptoms) Younger age of onset Later cerebellar involvement Involvement of only one CNS system at the time of onset
What Happens? 50% of MS patients will need help walking within 15 years of disease onset Life Expectancy: 82.5% of normal 58 years old
Expanded Disability Status Scale
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