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Multiple SclerosisAka: MS

Epidemiology
1. Top disabling condition of young adults (U.S.)
2. Prevalence: 250,000-350,000 (U.S.)
Pathophysiology
1. Focal regions of demyelination of white matter
2. Particularly periventricular and Subpial white matter
Prognosis
1. Relapse and remission cycles after first episode: 90%
2. Benign course (1-2 relapses, then recovery): 20%
3. Progressive course after 5 years of MS: 60-90%
4. Progressive course from onset (10%)
5. Rapidly progressive course from onset (very rare)
  1. Marburg Type
Risk Factors
1. Race: White > Black
2. Sex: Female > Male (2:1)
3. High socioeconomic status
4. Northern latitudes
5. Environmental factors (toxins, viruses)
6. HLA histocompatible antigens
Symptoms
1. Sensory loss (37%)
2. Optic Neuritis (36%)
3. Weakness (35%)
4. Paresthesias (24%)
5. Diplopia (15%)
6. Ataxia (11%)
7. Vertigo (6%)
8. Paroxysmal symptoms (4%)
9. Urinary Incontinence (4%)
10. Lhermitte Sign (3%)
  1. Electrical sensation down spine on neck flexion
11. Dementia (2%)
12. Visual Loss (2%)
13. Facial palsy (1%)
14. Impotence (1%)
15. Myokymia (1%)
16. Seizures (1%)
17. Depression
Signs
1. Dysarthria
2. Decreased pain, vibration and position sense
3. Decreased coordination and balance
  1. Ataxia
  2. Difficult tandem walking
4. Eye Exam
  1. Visual field defects
  2. Decreased Visual Acuity
  3. Red color perception
  4. Afferent pupillary defect
  5. Optic Nerve pallor (Optic Neuritis)
  6. Nystagmus (most commonly horizontal)
  7. Bilateral Internuclear Ophthalmoplegia
    1. Nystagmus of abducting eye on lateral gaze
    2. Other eye with slow adduction
5. Reflexes
  1. Deep Tendon Reflexes hyperactive
  2. Spasticity
  3. Abdominal reflexes lost
  4. Ankle clonus present
  5. Babinski Reflex with up-going toes
6. Charcot's Triad
  1. Intention Tremor
  2. Nystagmus
  3. Scanning speech
7. Hot Bath Test
  1. Hot bath exacerbates visual signs
Diagnostic Criteria
1. Overview
  1. Diagnosis Requires 2 episodes and 2 CNS areas
2. Specific Criteria
  1. Objective findings on exam consistent with history
  2. Long white matter tracts predominately involved
    1. Pyramidal
    2. Cerebellar
    3. Medial longitudinal fasciculus (MLF)
    4. Optic Nerve
    5. Posterior columns
  3. Two CNS Areas or more are involved
  4. Timing
    1. Two separate episodes of symptom clusters
      1. Involve different CNS areas
    2. Or Progression over at least 6 months
  5. No other explanation for CNS symptoms
  6. Age range 15 to 60 years
Differential Diagnosis
1. CNS Infection
  1. Tertiary Lyme Disease
  2. Tertiary Syphilis
  3. Human Immunodeficiency Virus (HIV)
2. CNS Inflammation
  1. Sarcoidosis
  2. Systemic Lupus Erythematosus (SLE)
  3. Sjogren's Disease
3. CNS Microvascular Disease
  1. Hypertension
  2. Diabetes Mellitus
4. CNS mass
  1. Cervical Spondylosis
  2. CNS neoplasm
  3. Chiari Malformation
5. Miscellaneous
  1. Vitamin B12 Deficiency
  2. Genetic condition (e.g. Leukodystrophy)
Subtypes
1. Definite Multiple Sclerosis
  1. All criteria fulfilled
2. Probable Multiple Sclerosis
  1. All criteria fulfilled except
    1. Only 1 neurologic sign (2 Symptomatic episodes) or
    2. Neurologic signs unrelated to 1 Symptomatic episode
3. At risk for Multiple Sclerosis
  1. All criteria fulfilled except
    1. Only 1 episode and
    2. No neurologic signs on exam
Diagnostics
1. MRI Head (most useful)
  1. Abnormal scan in >90% of Multiple Sclerosis patients
  2. Findings
    1. Plaque formation (myelin sheath loss)
    2. Spotty and irregular demyelination
    3. Distribution
      1. Involves brainstem, cerebellum, corpus callosum
      2. Other localized distribution
        
        Around ventricles
        
        Around gray-white junction
    4. Gadolinium enhancing if active inflammation
2. CT Head (not as helpful as MRI Head)
  1. Findings
    1. Ventricular enlargement
    2. Low density periventricular abnormalities
    3. Focal enhancement
3. Evoked Potentials
  1. Visual, auditory, somatosensory, and motor
  2. Visually evoked potentials are most useful
  3. One or more evoked potential abnormal in 80-90% of MS
Labs
1. Cerebrospinal Fluid
  1. CSF Pleocytosis (>5 cells/microliter)
  2. CSF IgG Increased (not specific for MS)
    1. Oligoclonal banding of CSF IgG by electrophoresis
    2. Oligoclonal bands >1 in 75-90% of MS patients
  3. CSF Myelin breakdown products present
2. Serum titers predictive of Multiple Sclerosis
  1. Anti-Myelin oligodendrocyte glycoprotein (anti-MOG)
  2. Anti-Myelin basic protein (anti-MBP)
  3. Berger (2003) N Engl J Med 349:139
3. Lab evaluation for differential diagnosis
  1. Vitamin B12
  2. Thyroid Stimulating Hormone (TSH)
  3. Erythrocyte Sedimentation Rate (ESR)
  4. Lyme Disease titer
  5. Rapid Plasma Reagin (RPR)
  6. Antinuclear Antibody
    1. Consider autoimmune evaluation
Management: Acute episode or relapse
1. Evaluate for provocative event
2. Methylprednisolone
  1. General
    1. Mix in 500 ml D5W
    2. Administer slowly over 4-6 hours in AM
  2. Taper schedule
    1. First: 1000 mg qd for 3 days
    2. Next: 500 mg qd for 3 days
    3. Last: 250 mg qd for 3 days
  3. Alternative after first 3 days Methylprednisolone
    1. Prednisone 1 mg/kg/day PO for 14 days
Management: Symptom-specific control
1. Spasticity
  1. Baclofen 10 to 40 mg po tid
  2. Tizanidine 2 to 8 mg po tid
  3. Gabapentin 300 to 900 mg po tid
2. Paroxysmal pain
  1. Amitriptyline 10 to 150 mg po qhs
  2. Gabapentin 300 to 900 mg po tid
  3. Carbamazepine 100 to 600 mg po tid
  4. Sativex (Available in Canada, not in U.S.)
    1. Cannabis extract (THC) in oral spray form
    2. Rapid onset or relief
    3. FDA considers as Schedule I (illegal to import)
    4. Wade (2004) Mult Scler 10:434
3. Urinary urgency
  1. Oxybutynin 5 mg po qd to 20 mg/day in divided doses
  2. Tolterodine 2 to 4 mg po bid
4. Bowel disorders
  1. Constipation: Manage aggressively
  2. Fecal Incontinence
    1. Fiber supplementation
    2. Consider short-term anti-Diarrheal agent
5. Fatigue
  1. Amantadine 100 mg po bid
  2. Modafinil 100 to 200 mg po qAM
6. Major Depression
  1. Selective Serotonin Reuptake Inhibitor (SSRI)
Management: New Medications to slow MS progression
1. Interferon beta-1b (Betaseron) 0.25 mg SC qOther day
  1. Modestly protects against exacerbation for 1 year
  2. Filippini (2003) Lancet 361:545
2. Interferon beta-1a
  1. Avonex 30 mcg IM once weekly
  2. Rebif 22 to 44 mcg SC three times per week
3. Glatiramer (Copaxone) 20 mg SC daily
  1. Copolymer 1
  2. Cross reacts with myelin basic protein
  3. More efficacious than Interferon
4. Mitoxantrone (Novantrone) 5 to 12 mg/m2 IV q3 months
5. Natalizumab (Tysabri, Antegren) IV once monthly
  1. Blocks CNS entry of immune response to nerve cells
  2. Reduces relapse rate by >60%
  3. Very expensive: $2000/month
  4. Risk of hypersensitivity, infection, depression
  5. (2004) Neurology 62:2038
6. Immunoglobulin IV
  1. Delays recurrent events
  2. Achiron (2004) Arch Neurol 61:1515
General Supportive Measures
1. Keep Cool
2. Regular Exercise
3. Pursuit of wellness and positive attitude
4. Education regarding the disease
5. Support from family and MS support groups
Resources
1. National Multiple Sclerosis Society
  1. http://www.nmss.org
References
1. Pirko in Goetz (2003) Clinical Neurology, p. 1060-76
2. Wilson (1991) Harrison's IM, p. 657-8
3. (1995) Neurology 45:1268
4. Calabresi (2004) Am Fam Physician 70:1935
5. Frohman (2003) Med Clin North Am 87:867
6. Hawker (2004) Prim Care 31:201
7. O'Connor (2002) Neurology 59:s1

Multiple Sclerosis (C0026769)
Definition (MSH)	An autoimmune disorder mainly affecting young adults and characterized by destruction of myelin in the central nervous system. Pathologic findings include multiple sharply demarcated areas of demyelination throughout the white matter of the central nervous system. Clinical manifestations include visual loss, extra-ocular movement disorders, paresthesias, loss of sensation, weakness, dysarthria, spasticity, ataxia, and bladder dysfunction. The usual pattern is one of recurrent attacks followed by partial recovery (see MULTIPLE SCLEROSIS, RELAPSING-REMITTING), but acute fulminating and chronic progressive forms (see MULTIPLE SCLEROSIS, CHRONIC PROGRESSIVE) also occur. (Adams et al., Principles of Neurology, 6th ed, p903)
Definition (CSP)	chronic disease characterized by presence of numerous areas of demyelination in the central nervous system with symptoms such as weakness, incoordination, paresthesis, and speech disturbances; the etiology is unknown.
Definition (NCI)	A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid), serving as a nerve insulator and helping in the transmission of nerve signals.
Concepts	Disease or Syndrome (T047)
ICD9	340
Basque	ESKLEROSIA PLAKAN
Danish	Dissemineret sklerose
Dutch	Multipele sclerose
English	Disseminated Sclerosis, Generalised multiple sclerosis, Generalized multiple sclerosis, insular sclerosis, MS, Multiple Sclerosis, SCLEROSIS MULTIPLE
Finnish	MULTIPPELISKLEROOSI
French	Sclerose en plaques
German	Multiple Sklerose
Hungarian	sclerosis multiplex
Italian	Sclerosi multipla
Norwegian	MULTIPPEL SKLEROSE
Portuguese	Esclerose multipla
Spanish	esclerosis en placas, esclerosis mÃºltiple, esclerosis mÃºltiple generalizada, Esclerosis multiple, esclerosis multiple generalizada
Swedish	MULTIPPEL SKLEROS/MS
Credits	Derived from the NIH UMLS (Unified Medical Language System)

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Multiple SclerosisAka: MS

Multiple Sclerosis (C0026769)

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