Demyelinating

Multiple Sclerosis

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Multiple Sclerosis, MS

  • Epidemiology
  1. Top disabling condition of young adults (U.S.)
  2. Prevalence
    1. Northern U.S.: 110 cases per 100,000 persons
    2. Southern U.S.: 47 cases per 100,000 persons
    3. U.S. Total: 250,000-350,000 patients affected
  • Pathophysiology
  1. Acute attacks (relapsing remitting MS) are a result of inflammatory reaction
    1. Inflammatory cells (T Cells, B Cells and Macrophages) cross the blood-brain barrier at weakened vessel surfaces
    2. Immunoglobulins target the Myelin Sheath
    3. Macrophages damage the axons with free radical release
  2. Results
    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. Gender: Female > Male (2:1)
  3. High socioeconomic status
  4. Northern latitudes
  5. Environmental factors (toxins, viruses)
  6. Tobacco Abuse
  7. HLA histocompatible Antigens
  8. Vitamin D Deficiency (or less sunlight exposure)
    1. Munger (2006) JAMA 296:2832-2838 [PubMed]
  • 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. Depressed mood
  18. Fatigue
  19. Hearing Loss and Tinnitus
  20. Heat intolerance
  • 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 Nystagmus)
    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
  • Diagnosis
  • General Criteria
  1. Overview
    1. Diagnosis Requires 2 episodes and 2 CNS areas
    2. Episodes (Attacks) are discrete events lasting >24 hours and not associated with fever or infection
  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. Dissemination in space (DIS)
      1. Characteristic MS regions (periventricular, juxtacortical, infratemporal or spinal)
      2. Two CNS Areas or more are involved
    4. Dissemination in time (DIT)
      1. Two separate episodes of symptom clusters
        1. Involve different CNS areas
      2. Or Progression over at least 12 months
    5. No other explanation for CNS symptoms
      1. Not associated with fever or infection
    6. Age range 15 to 60 years
  3. Findings suggestive of alternative diagnosis (typically not due to Multiple Sclerosis)
    1. Abrupt, transient symptoms
    2. Seizures, Aphasia or other significant cortical findings
    3. Peripheral Neuropathy
    4. Non-neurologic involvement (e.g. cardiac)
  • Diagnosis
  • McDonald Criteria (2010)
  1. Definitive diagnosis: Relapsing Remitting
    1. Two or more attacks AND
    2. Two or more lesions or objective clinical evidence of one lesion and historical evidence of a prior attack
  2. Definitive diagnosis: Primary Progressive (PPMS)
    1. Insidious neurologic pregression of one year or more AND
    2. Additional criteria (2 of 3 required)
      1. One or more T2 lesion in characteristic MS regions (periventricular, juxtacortical, infratemporal or spinal)
      2. Two or more T2 lesions affecting the spinal cord
      3. Positive CSF findings (oligoclonal bands or elevated IgG Index)
  3. Presentations requiring a second attack for definitive diagnosis
    1. Dissemination in Time (DIT)
      1. Two or more attacks with objective evidence of one T2 lesion
      2. Lesion affects 2 of 4 characteristic MS regions (periventricular, juxtacortical, infratemporal or spinal)
    2. Dissemination in Space (DIS)
      1. One attack with objective evidence of two or more T2 lesions
        1. Simultaneous asymptomatic gadolinium-enhancing and nonenhancing lesions at a point in time OR
        2. New T2 or gadolinium-enhancing lesion on follow-up MRI
    3. One attack with objective evidence of one lesion
      1. Await additional attack with characteristics of one of the two presentations (DIT or DIS) as above
  4. References
    1. Polman (2011) Ann Neurol 69(2): 292-302 [PubMed]
  • Differential Diagnosis
  1. Degenerative disease
    1. Amyotrophic Lateral Sclerosis
    2. Huntington Disease
  2. Demyelinating disease
    1. Chronic inflammatory demyelinating Polyneuropathy
    2. Progressive Multifocal Leukoencephalopathy
  3. CNS Infection
    1. Tertiary Lyme Disease
    2. Tertiary Syphilis
    3. Human Immunodeficiency Virus (HIV)
    4. Mycoplasma
  4. CNS Inflammation
    1. Sarcoidosis
    2. Systemic Lupus Erythematosus (SLE)
    3. Sjogren Syndrome
    4. Behcet Syndrome
  5. CNS Vascular Disease
    1. Hypertension
    2. Diabetes Mellitus
    3. Cerebrovascular Disease
    4. Migraine Headache
    5. Vasculitis
  6. CNS mass or structural disease
    1. Cervical Spondylosis
    2. Cervical Disc Disease
    3. CNS neoplasm
    4. Chiari Malformation
    5. Arteriovenous malformation
  7. Medications and recreational drugs
    1. Alcohol Abuse
    2. Cocaine Abuse
    3. Isoniazid
    4. Lithium
    5. Penicillin
    6. Phenytoin (Dilantin)
  8. Vitamin Deficiency
    1. Vitamin B12 Deficiency
    2. Folate Deficiency
    3. Vitamin E deficiency
  9. Psychiatric conditions
    1. Anxiety Disorder
    2. Conversion Disorder
    3. Somatization
  10. Genetic disorders
    1. Leukodystrophy
    2. Mitochondrial disease
  11. References
    1. Miller (2008) Mult Scler 14(9): 1157-74 [PubMed]
    2. Rolak (2007) Neurologist 13(2): 57-72 [PubMed]
  • Types
  • Course
  1. Relapsing remitting (90% of cases)
    1. Discrete attacks evolve over days to weeks
    2. Recovery for weeks to months in which there is no neurologic worsening between attacks
  2. Secondary progressive (50% of relapsing remitting cases)
    1. Starts as relapsing remitting disease
    2. Progresses to gradual neurologic deterioration outside of discrete, acute attacks
  3. Primary progressive (PPMS) and progressive relapsing (10% of cases)
    1. Steady functional decline from Multiple Sclerosis onset
    2. Termed primary progressive if no attacks occur
    3. Termed progressive relapsing if attacks occur
  4. References
    1. Lublin (1996) Neurology 46(4): 907-11 [PubMed]
  • Types
  • 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
          1. Around ventricles
          2. 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
  • Multiple Sclerosis Findings
  1. Cerebrospinal Fluid
    1. CSF is primarily used to exclude other causes on the differential diagnosis (e.g. Meningitis or Encephalitis)
    2. CSF Pleocytosis (>5 cells/microliter)
    3. 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
    4. 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 349:139-45 [PubMed]
  • Labs
  • Evaluation of differential diagnosis
  1. First-line tests
    1. Complete Blood Count
    2. Serum Vitamin B12 level
    3. Thyroid Stimulating Hormone (TSH)
    4. Erythrocyte Sedimentation Rate (ESR)
    5. Lyme Disease titer
    6. Rapid Plasma Reagin (RPR)
    7. Antinuclear Antibody
      1. Consider autoimmune evaluation
  2. Additional tests if indicated
    1. Angiotensin Converting Enzyme level (ACE Level) for Sarcoidosis
    2. Autoantibody assays for Behcet Syndrome, Sjogren Syndrome, Systemic Lupus Erythematosus and Vasculitis
      1. Antineutrophil Cytoplasmic Antibody (ANCA)
      2. Anticariolipin Antibody
      3. Antiphospholipid Antibody
      4. Anti-SS-A Antibody
      5. Anti-SS-B Antibody
    3. Human Immunodeficiency Virus Screening (HIV Test)
    4. Human T-CellLymphotropic virus type I (HTLV-1)
    5. Very Long chain Fatty Acid level for Adrenoleukodystophy
  • Management
  • Acute episode or relapse
  1. Evaluate for provocative event
    1. Acute Sinusitis
    2. Acute Bronchitis
    3. Urinary Tract Infection
    4. Emotional stressors may also provoke an event
  2. Corticosteroids: 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 daily for 3 days
      2. Next: 500 mg daily for 3 days
      3. Last: 250 mg daily for 3 days
    3. Alternative after first 3 days Methylprednisolone
      1. Prednisone 1 mg/kg/day orally daily for 14 days
  3. Plasmapheresis
    1. Indicated in cases refractory to Corticosteroids
    2. Plasma exchange performed every other day for 14 days
  • Management
  • Symptom-specific control
  1. Spasticity (70 to 80% of patients)
    1. Baclofen 10 to 40 mg orally three times daily
      1. Baclofen Intrathecal Pump may be preferred due to less sedation and greater effect
    2. Tizanidine 2 to 8 mg orally three times daily
    3. Gabapentin (Neurontin) 300 to 900 mg orally three times daily
    4. Onabotulinumtoxin A (Botox) injection
    5. Physical therapy
    6. Hydrotherapy
      1. Castro-Sanchez (2012) Evid Based Compliment Alternat Med 2012: 473963 [PubMed]
  2. Paroxysmal pain and other syndromes (85% of patients)
    1. Trigeminal Neuralgia
      1. Treat as with Trigeminal Neuralgia in non-Multiple Sclerosis patients
      2. Carbamazepine 100 to 600 mg orally three times daily
      3. Baclofen (Lioresal) 10 to 80 mg/day
    2. Dysesthetic limb pain
      1. Hydrotherapy (see spasticity above)
      2. Amitriptyline 10 to 150 mg orally at bedtime
      3. Gabapentin 300 to 900 mg orally three times daily
      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 10:434-41 [PubMed]
  3. Neurogenic Bladder
    1. Evaluate with post-void residual testing to distinguish failure to store from failure to empty
    2. Failure to store
      1. Detrol LA (Tolterodine LA) 2 to 4 mg orally daily
      2. Ditropan XL or Oxytrol XR (Oxybutynin XR) 5 to 10 to 30 mg orally daily
      3. Intranasal Desmopressin may be used for Nocturia
      4. Onabotulinumtoxin A (Botox) injection has been used in refractory cases
    3. Failure to empty
      1. Trial on alpha adrenergic blocker (e.g. Prazosin or Terazosin)
      2. Clean intermittent self cathetrization
  4. Neurogenic bowel
    1. Constipation: Manage aggressively
      1. Hydration and fiber supplementation
      2. Rectal stimulants and enemas as needed
    2. Fecal Incontinence
      1. Fiber supplementation
      2. Consider short-term anti-Diarrheal agent
      3. Colostomy has been used in refractory cases
  5. Fatigue (90% of patients)
    1. Evaluate for comorbid Major Depression, sleep disorder, Thyroid disease, Anemia, and Vitamin B12 Deficiency
    2. Amantadine 100 mg orally twice daily
      1. Peuckmann (2010) Cochrane Database Syst Rev (11): CD006788 [PubMed]
    3. Modafinil (Provigil) 100 to 200 mg orally each morning
      1. Variable efficacy
      2. Brown (2010) Ann Pharmacother 44(6): 1098-103 [PubMed]
  6. Major Depression
    1. Selective Serotonin Reuptake Inhibitor (SSRI)
  7. Sexual Dysfunction
    1. Affects >50% of men and >40% of women
    2. Men are typically prescribed Phosphodiesterase Inhibitors (e.g. Sildenafil or Viagra)
  • Management
  • Disease modifying agents for relapsing remitting Multiple Sclerosis
  1. Precautions
    1. All agents are very expensive, costing over $60,000 per year (except Mitoxantrone)
    2. Most disease modifying agents suppress T-cell Autoimmunity and have the potential for significant adverse effects
    3. Agents are typically selected, prescribed and monitored by neurologists with expertise in Multiple Sclerosis
    4. Vaccination
      1. Live Vaccines (e.g. Zostavax) should be administered >1 month before starting most of these MS agents
      2. Inactivated Vaccines may be given at any time
  2. Immunomodulatory agents: Interferon
    1. Longest track record (20 years) of the disease modifying agents
    2. Adverse Effects
      1. Local injection site inflammation
      2. Influenza-like symptoms (decreases after first 3 months)
      3. Lab abnormalities include Leukopenia and increased liver transaminases
      4. Exacerbation of depressed mood (including increased Suicidality)
    3. Interferon beta-1b
      1. Betaseron 0.25 mg SC every other day
      2. Modestly protects against exacerbation for 1 year
      3. Filippini (2003) Lancet 361:545-52 [PubMed]
    4. Interferon beta-1a
      1. Avonex 30 mcg IM once weekly
      2. Rebif 22 to 44 mcg SC three times per week
  3. Immunomodulatory agents: Non-Interferon agents
    1. Glatiramer (Copaxone)
      1. Adverse effects include local injection site inflammation, facial Flushing
      2. May also experience chest tightness, Dyspnea and Palpitations
      3. Dose: 20 mg SC daily
      4. Copolymer 1 that cross reacts with myelin basic protein
      5. Good track record of safety and greater efficacy than Interferon
  4. Oral Immunosuppressants
    1. Fingolimod (Gilenya)
      1. Adverse effects include Bradycardia, Hypertension, QTc Prolongation, elevated liver transaminases
        1. Other adverse effects include Melanoma, Macular edema, HSV Encephalitis
      2. Dose: 0.5 mg orally daily
      3. Bradycardia risk (may present with Dizziness or Fatigue)
        1. Observe for 6 hours after first dose
        2. Avoid in those with known Arrhythmia or other heart disorder
        3. Avoid concurrent use with Digoxin, Diltiazem or Beta Blocker
    2. Siponimod (Mayzent)
      1. Released in 2020 and similar to Fingolimod
    3. Ozanimod (Zeposia)
      1. Released in 2020 and similar to Fingolimod
    4. Teriflunomide (Aubagio)
      1. Adverse effects include Alopecia, Diarrhea, Nausea, Leukopenia, elevated liver transaminases, Peripheral Neuropathy
      2. FDA Black Box warning for hepatotoxicity (monitor Liver Function Tests)
      3. Teratogenic and requires reliable Contraception
      4. Dose: 7 to 14 mg orally daily
    5. Dimethyl Fumarate (Tecfidera)
      1. Generic in 2020
      2. Adverse effects include Abdominal Pain, Diarrhea, Nausea, lymphocytopenia, elevated liver transaminases
      3. Flushing is common, and decreases over time (consider taking Aspirin 30 min before dose)
      4. Monitor Complete Blood Count
      5. Dose: 120 to 240 mg orally twice daily
    6. Monomethyl Fumarate (Bafiertam)
      1. Released in 2020 and similar to Dimethyl Fumarate
    7. Diroximel Fumarate (Vumerity)
      1. Released in 2020 and similar to Dimethyl Fumarate
    8. Cladribine (Mavenclad)
      1. Oral dose given over 2 year treatment course with dosing cycles
      2. Indicated in refractory cases and not first line
      3. Similar efficacy to Dimethyl Fumarate
      4. Adverse Effects
        1. Teratogenic! (requires Pregnancy Testing before each course of medication)
        2. Progressive Multifocal Leukoencephalopathy (PML)
        3. Nausea, Headache, flu-like symptoms, severe lymphopenia, Shingles
  5. Parenteral immunosuppressants for refractory disease: Monoclonal Antibodies
    1. Daclizumab (Zinbryta)- Monoclonal Antibody - SQ once monthly
      1. Hepatotoxicity risk (monitor Liver Function Tests)
    2. Natalizumab (Tysabri, Antegren) - Monoclonal Antibody - IV once monthly
      1. Adverse effects include Hypersensitivity, infusion reaction, Headache, Fatigue
      2. Risk of Progressive Multifocal Leukoencephalopathy
      3. Blocks CNS entry of immune response to Nerve Cells
      4. Reduces relapse rate by >60%
      5. (2004) Neurology 62:2038 [PubMed]
    3. Ocrelizumab (Ocrevus)
      1. First-line only in primary progresive MS
      2. Dosed IV once every 6 months (administered over 3.5 hours)
      3. Pretreatment with Methylprednisolone and Diphenhydramine
      4. Adverse effects: Severe infusion associated reactions, infection, Progressive Multifocal Leukoencephalopathy
  6. Parenteral immunosuppressants for refractory disease: Miscellaneous Agents
    1. Mitoxantrone (Novantrone)
      1. Adverse effects include myelosuppression, elevated liver transaminases, decreased Cardiac Function and Leukemia
      2. Dose: 5 to 12 mg/m2 IV every 3 months
      3. Costs $900/ year in contrast to more than $60,000/year for other agents
  • Management
  • 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
  6. Vitamin D Supplementation may help prevent exacerbations
  • Resources
  1. National Multiple Sclerosis Society
    1. http://www.nmss.org
  2. NIH Multiple Sclerosis
    1. http://www.ninds.nih.gov/disorders/multiple_sclerosis/multiple_sclerosis.htm
  3. Multiple Sclerosis Association of America (MSAA)
    1. http://www.mymsaa.org/
  4. Multiple Sclerosis Foundation
    1. http://www.msfocus.org/
  • References
  1. (2017) Presc Lett 24(9): 53
  2. (2020) Presc Lett 27(11): 65
  3. Pirko in Goetz (2003) Clinical Neurology, p. 1060-76
  4. Wilson (1991) Harrison's IM, p. 657-8
  5. (1995) Neurology 45:1268-76, 1277-85 [PubMed]
  6. Calabresi (2004) Am Fam Physician 70:1935-44 [PubMed]
  7. Frohman (2003) Med Clin North Am 87:867-97 [PubMed]
  8. Hawker (2004) Prim Care 31:201-26 [PubMed]
  9. OConnor (2002) Neurology 59:s1-33 [PubMed]
  10. Saguil (2014) Am Fam Physician 90(9): 644-52 [PubMed]