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Multiple Sclerosis
Aka: Multiple Sclerosis, MS
- Epidemiology
- Top disabling condition of young adults (U.S.)
- Prevalence
- Northern U.S.: 110 cases per 100,000 persons
- Southern U.S.: 47 cases per 100,000 persons
- U.S. Total: 250,000-350,000 patients affected
- Pathophysiology
- Acute attacks (relapsing remitting MS) are a result of inflammatory reaction
- Inflammatory cells (T Cells, B Cells and Macrophages) cross the blood-brain barrier at weakened vessel surfaces
- Immunoglobulins target the Myelin Sheath
- Macrophages damage the axons with free radical release
- Results
- Focal regions of demyelination of white matter
- Particularly periventricular and subpial white matter
- Prognosis
- Relapse and remission cycles after first episode: 90%
- Benign course (1-2 relapses, then recovery): 20%
- Progressive course after 5 years of MS: 60-90%
- Progressive course from onset (10%)
- Rapidly progressive course from onset (very rare)
- Marburg Type
- Risk Factors
- Race: White > Black
- Gender: Female > Male (2:1)
- High socioeconomic status
- Northern latitudes
- Environmental factors (toxins, viruses)
- Tobacco Abuse
- HLA histocompatible Antigens
- Vitamin D Deficiency (or less sunlight exposure)
- Munger (2006) JAMA 296:2832-2838 [PubMed]
- Symptoms
- Sensory loss (37%)
- Optic Neuritis (36%)
- Weakness (35%)
- Paresthesias (24%)
- Diplopia (15%)
- Ataxia (11%)
- Vertigo (6%)
- Paroxysmal symptoms (4%)
- Urinary Incontinence (4%)
- Lhermitte Sign (3%)
- Electrical Sensation down spine on neck flexion
- Dementia (2%)
- Visual Loss (2%)
- Facial palsy (1%)
- Impotence (1%)
- Myokymia (1%)
- Seizures (1%)
- Depressed mood
- Fatigue
- Hearing Loss and Tinnitus
- Heat intolerance
- Signs
- Dysarthria
- Decreased pain, vibration and position sense
- Decreased coordination and balance
- Ataxia
- Difficult Tandem Walking
- Eye Exam
- Visual Field defects
- Decreased Visual Acuity
- Red color Perception
- Afferent Pupillary Defect
- Optic Nerve pallor (Optic Neuritis)
- Nystagmus (most commonly Horizontal Nystagmus)
- Bilateral Internuclear Ophthalmoplegia
- Nystagmus of abducting eye on lateral gaze
- Other eye with slow adduction
- Reflexes
- Deep Tendon Reflexes hyperactive
- Spasticity
- Abdominal reflexes lost
- Ankle Clonus present
- Babinski Reflex with up-going toes
- Charcot's Triad
- Intention Tremor
- Nystagmus
- Scanning speech
- Hot Bath Test
- Hot bath exacerbates visual signs
- Diagnosis: General Criteria
- Overview
- Diagnosis Requires 2 episodes and 2 CNS areas
- Episodes (Attacks) are discrete events lasting >24 hours and not associated with fever or infection
- Specific Criteria
- Objective findings on exam consistent with history
- Long white matter tracts predominately involved
- Pyramidal
- Cerebellar
- Medial Longitudinal Fasciculus (MLF)
- Optic Nerve
- Posterior Columns
- Dissemination in space (DIS)
- Characteristic MS regions (periventricular, juxtacortical, infratemporal or spinal)
- Two CNS Areas or more are involved
- Dissemination in time (DIT)
- Two separate episodes of symptom clusters
- Involve different CNS areas
- Or Progression over at least 12 months
- No other explanation for CNS symptoms
- Not associated with fever or infection
- Age range 15 to 60 years
- Findings suggestive of alternative diagnosis (typically not due to Multiple Sclerosis)
- Abrupt, transient symptoms
- Seizures, Aphasia or other significant cortical findings
- Peripheral Neuropathy
- Non-neurologic involvement (e.g. cardiac)
- Diagnosis: McDonald Criteria (2010)
- Definitive diagnosis: Relapsing Remitting
- Two or more attacks AND
- Two or more lesions or objective clinical evidence of one lesion and historical evidence of a prior attack
- Definitive diagnosis: Primary Progressive (PPMS)
- Insidious neurologic pregression of one year or more AND
- Additional criteria (2 of 3 required)
- One or more T2 lesion in characteristic MS regions (periventricular, juxtacortical, infratemporal or spinal)
- Two or more T2 lesions affecting the spinal cord
- Positive CSF findings (oligoclonal bands or elevated IgG Index)
- Presentations requiring a second attack for definitive diagnosis
- Dissemination in Time (DIT)
- Two or more attacks with objective evidence of one T2 lesion
- Lesion affects 2 of 4 characteristic MS regions (periventricular, juxtacortical, infratemporal or spinal)
- Dissemination in Space (DIS)
- One attack with objective evidence of two or more T2 lesions
- Simultaneous asymptomatic gadolinium-enhancing and nonenhancing lesions at a point in time OR
- New T2 or gadolinium-enhancing lesion on follow-up MRI
- One attack with objective evidence of one lesion
- Await additional attack with characteristics of one of the two presentations (DIT or DIS) as above
- References
- Polman (2011) Ann Neurol 69(2): 292-302 [PubMed]
- Differential Diagnosis
- Degenerative disease
- Amyotrophic Lateral Sclerosis
- Huntington Disease
- Demyelinating disease
- Chronic inflammatory demyelinating Polyneuropathy
- Progressive Multifocal Leukoencephalopathy
- CNS Infection
- Tertiary Lyme Disease
- Tertiary Syphilis
- Human Immunodeficiency Virus (HIV)
- Mycoplasma
- CNS Inflammation
- Sarcoidosis
- Systemic Lupus Erythematosus (SLE)
- Sjogren Syndrome
- Behcet Syndrome
- CNS Vascular Disease
- Hypertension
- Diabetes Mellitus
- Cerebrovascular Disease
- Migraine Headache
- Vasculitis
- CNS mass or structural disease
- Cervical Spondylosis
- Cervical Disc Disease
- CNS neoplasm
- Chiari Malformation
- Arteriovenous Malformation
- Medications and recreational drugs
- Alcohol Abuse
- Cocaine Abuse
- Isoniazid
- Lithium
- Penicillin
- Phenytoin (Dilantin)
- Vitamin Deficiency
- Vitamin B12 Deficiency
- Folate Deficiency
- Vitamin E deficiency
- Psychiatric conditions
- Anxiety Disorder
- Conversion Disorder
- Somatization
- Genetic disorders
- Leukodystrophy
- Mitochondrial disease
- References
- Miller (2008) Mult Scler 14(9): 1157-74 [PubMed]
- Rolak (2007) Neurologist 13(2): 57-72 [PubMed]
- Types: Course
- Relapsing remitting (90% of cases)
- Discrete attacks evolve over days to weeks
- Recovery for weeks to months in which there is no neurologic worsening between attacks
- Secondary progressive (50% of relapsing remitting cases)
- Starts as relapsing remitting disease
- Progresses to gradual neurologic deterioration outside of discrete, acute attacks
- Primary progressive (PPMS) and progressive relapsing (10% of cases)
- Steady functional decline from Multiple Sclerosis onset
- Termed primary progressive if no attacks occur
- Termed progressive relapsing if attacks occur
- References
- Lublin (1996) Neurology 46(4): 907-11 [PubMed]
- Types: Subtypes
- Definite Multiple Sclerosis
- All criteria fulfilled
- Probable Multiple Sclerosis
- All criteria fulfilled except
- Only 1 neurologic sign (2 Symptomatic episodes) or
- Neurologic signs unrelated to 1 Symptomatic episode
- At risk for Multiple Sclerosis
- All criteria fulfilled except
- Only 1 episode and
- No neurologic signs on exam
- Diagnostics
- MRI Head (most useful)
- Abnormal scan in >90% of Multiple Sclerosis patients
- Findings
- Plaque formation (Myelin Sheath loss)
- Spotty and irregular demyelination
- Distribution
- Involves Brainstem, Cerebellum, corpus callosum
- Other localized distribution
- Around ventricles
- Around gray-white junction
- Gadolinium enhancing if active inflammation
- CT Head (not as helpful as MRI Head)
- Findings
- Ventricular enlargement
- Low density periventricular abnormalities
- Focal enhancement
- Evoked Potentials
- Visual, auditory, somatosensory, and motor
- Visually evoked potentials are most useful
- One or more evoked potential abnormal in 80-90% of MS
- Labs: Multiple Sclerosis Findings
- Cerebrospinal Fluid
- CSF is primarily used to exclude other causes on the differential diagnosis (e.g. Meningitis or Encephalitis)
- CSF Pleocytosis (>5 cells/microliter)
- CSF IgG Increased (not specific for MS)
- Oligoclonal banding of CSF IgG by electrophoresis
- Oligoclonal bands >1 in 75-90% of MS patients
- CSF Myelin breakdown products present
- Serum titers predictive of Multiple Sclerosis
- Anti-Myelin oligodendrocyte glycoprotein (anti-MOG)
- Anti-Myelin basic protein (anti-MBP)
- Berger (2003) N Engl J Med 349:139-45 [PubMed]
- Labs: Evaluation of differential diagnosis
- First-line tests
- Complete Blood Count
- Serum Vitamin B12 level
- Thyroid Stimulating Hormone (TSH)
- Erythrocyte Sedimentation Rate (ESR)
- Lyme Disease titer
- Rapid Plasma Reagin (RPR)
- Antinuclear Antibody
- Consider autoimmune evaluation
- Additional tests if indicated
- Angiotensin Converting Enzyme level (ACE Level) for Sarcoidosis
- Autoantibody assays for Behcet Syndrome, Sjogren Syndrome, Systemic Lupus Erythematosus and Vasculitis
- Antineutrophil Cytoplasmic Antibody (ANCA)
- Anticariolipin Antibody
- Antiphospholipid Antibody
- Anti-SS-A Antibody
- Anti-SS-B Antibody
- Human Immunodeficiency Virus Screening (HIV Test)
- Human T-CellLymphotropic virus type I (HTLV-1)
- Very Long chain Fatty Acid level for Adrenoleukodystophy
- Management: Acute episode or relapse
- Evaluate for provocative event
- Acute Sinusitis
- Acute Bronchitis
- Urinary Tract Infection
- Emotional stressors may also provoke an event
- Corticosteroids: Methylprednisolone
- General
- Mix in 500 ml D5W
- Administer slowly over 4-6 hours in AM
- Taper schedule
- First: 1000 mg daily for 3 days
- Next: 500 mg daily for 3 days
- Last: 250 mg daily for 3 days
- Alternative after first 3 days Methylprednisolone
- Prednisone 1 mg/kg/day orally daily for 14 days
- Plasmapheresis
- Indicated in cases refractory to Corticosteroids
- Plasma exchange performed every other day for 14 days
- Management: Symptom-specific control
- Spasticity (70 to 80% of patients)
- Baclofen 10 to 40 mg orally three times daily
- Baclofen Intrathecal Pump may be preferred due to less sedation and greater effect
- Tizanidine 2 to 8 mg orally three times daily
- Gabapentin (Neurontin) 300 to 900 mg orally three times daily
- Onabotulinumtoxin A (Botox) injection
- Physical therapy
- Hydrotherapy
- Castro-Sanchez (2012) Evid Based Compliment Alternat Med 2012: 473963 [PubMed]
- Paroxysmal pain and other syndromes (85% of patients)
- Trigeminal Neuralgia
- Treat as with Trigeminal Neuralgia in non-Multiple Sclerosis patients
- Carbamazepine 100 to 600 mg orally three times daily
- Baclofen (Lioresal) 10 to 80 mg/day
- Dysesthetic limb pain
- Hydrotherapy (see spasticity above)
- Amitriptyline 10 to 150 mg orally at bedtime
- Gabapentin 300 to 900 mg orally three times daily
- Sativex (Available in Canada, not in U.S.)
- Cannabis extract (THC) in oral spray form
- Rapid onset or relief
- FDA considers as Schedule I (illegal to import)
- Wade (2004) Mult Scler 10:434-41 [PubMed]
- Neurogenic Bladder
- Evaluate with post-void residual testing to distinguish failure to store from failure to empty
- Failure to store
- Detrol LA (Tolterodine LA) 2 to 4 mg orally daily
- Ditropan XL or Oxytrol XR (Oxybutynin XR) 5 to 10 to 30 mg orally daily
- Intranasal Desmopressin may be used for Nocturia
- Onabotulinumtoxin A (Botox) injection has been used in refractory cases
- Failure to empty
- Trial on alpha adrenergic blocker (e.g. Prazosin or Terazosin)
- Clean intermittent self cathetrization
- Neurogenic bowel
- Constipation: Manage aggressively
- Hydration and fiber supplementation
- Rectal stimulants and enemas as needed
- Fecal Incontinence
- Fiber supplementation
- Consider short-term anti-Diarrheal agent
- Colostomy has been used in refractory cases
- Fatigue (90% of patients)
- Evaluate for comorbid Major Depression, sleep disorder, Thyroid disease, Anemia, and Vitamin B12 Deficiency
- Amantadine 100 mg orally twice daily
- Peuckmann (2010) Cochrane Database Syst Rev (11): CD006788 [PubMed]
- Modafinil (Provigil) 100 to 200 mg orally each morning
- Variable efficacy
- Brown (2010) Ann Pharmacother 44(6): 1098-103 [PubMed]
- Major Depression
- Selective Serotonin Reuptake Inhibitor (SSRI)
- Sexual Dysfunction
- Affects >50% of men and >40% of women
- Men are typically prescribed Phosphodiesterase Inhibitors (e.g. Sildenafil or Viagra)
- Management: Disease modifying agents for relapsing remitting Multiple Sclerosis
- Precautions
- All agents are very expensive, costing over $60,000 per year (except Mitoxantrone)
- Most disease modifying agents suppress T-cell Autoimmunity and have the potential for significant adverse effects
- Agents are typically selected, prescribed and monitored by neurologists with expertise in Multiple Sclerosis
- Vaccination
- Live Vaccines (e.g. Zostavax) should be administered >1 month before starting most of these MS agents
- Inactivated Vaccines may be given at any time
- Immunomodulatory agents: Interferon
- Longest track record (20 years) of the disease modifying agents
- Adverse Effects
- Local injection site inflammation
- Influenza-like symptoms (decreases after first 3 months)
- Lab abnormalities include Leukopenia and increased liver transaminases
- Exacerbation of depressed mood (including increased Suicidality)
- Interferon beta-1b
- Betaseron 0.25 mg SC every other day
- Modestly protects against exacerbation for 1 year
- Filippini (2003) Lancet 361:545-52 [PubMed]
- Interferon beta-1a
- Avonex 30 mcg IM once weekly
- Rebif 22 to 44 mcg SC three times per week
- Immunomodulatory agents: Non-Interferon agents
- Glatiramer (Copaxone)
- Adverse effects include local injection site inflammation, facial Flushing
- May also experience chest tightness, Dyspnea and Palpitations
- Dose: 20 mg SC daily
- Copolymer 1 that cross reacts with myelin basic protein
- Good track record of safety and greater efficacy than Interferon
- Oral Immunosuppressants
- Fingolimod (Gilenya)
- Adverse effects include Bradycardia, Hypertension, QTc Prolongation, elevated liver transaminases
- Other adverse effects include Melanoma, Macular edema, HSV Encephalitis
- Dose: 0.5 mg orally daily
- Bradycardia risk (may present with Dizziness or Fatigue)
- Observe for 6 hours after first dose
- Avoid in those with known Arrhythmia or other heart disorder
- Avoid concurrent use with Digoxin, Diltiazem or Beta Blocker
- Siponimod (Mayzent)
- Released in 2020 and similar to Fingolimod
- Ozanimod (Zeposia)
- Released in 2020 and similar to Fingolimod
- Teriflunomide (Aubagio)
- Adverse effects include Alopecia, Diarrhea, Nausea, Leukopenia, elevated liver transaminases, Peripheral Neuropathy
- FDA Black Box warning for hepatotoxicity (monitor Liver Function Tests)
- Teratogenic and requires reliable Contraception
- Dose: 7 to 14 mg orally daily
- Dimethyl Fumarate (Tecfidera)
- Generic in 2020
- Adverse effects include Abdominal Pain, Diarrhea, Nausea, lymphocytopenia, elevated liver transaminases
- Flushing is common, and decreases over time (consider taking Aspirin 30 min before dose)
- Monitor Complete Blood Count
- Dose: 120 to 240 mg orally twice daily
- Monomethyl Fumarate (Bafiertam)
- Released in 2020 and similar to Dimethyl Fumarate
- Diroximel Fumarate (Vumerity)
- Released in 2020 and similar to Dimethyl Fumarate
- Cladribine (Mavenclad)
- Oral dose given over 2 year treatment course with dosing cycles
- Indicated in refractory cases and not first line
- Similar efficacy to Dimethyl Fumarate
- Adverse Effects
- Teratogenic! (requires Pregnancy Testing before each course of medication)
- Progressive Multifocal Leukoencephalopathy (PML)
- Nausea, Headache, flu-like symptoms, severe lymphopenia, Shingles
- Parenteral immunosuppressants for refractory disease: Monoclonal Antibodies
- Daclizumab (Zinbryta)- Monoclonal Antibody - SQ once monthly
- Hepatotoxicity risk (monitor Liver Function Tests)
- Natalizumab (Tysabri, Antegren) - Monoclonal Antibody - IV once monthly
- Adverse effects include Hypersensitivity, infusion reaction, Headache, Fatigue
- Risk of Progressive Multifocal Leukoencephalopathy
- Blocks CNS entry of immune response to Nerve Cells
- Reduces relapse rate by >60%
- (2004) Neurology 62:2038 [PubMed]
- Ocrelizumab (Ocrevus)
- First-line only in primary progresive MS
- Dosed IV once every 6 months (administered over 3.5 hours)
- Pretreatment with Methylprednisolone and Diphenhydramine
- Adverse effects: Severe infusion associated reactions, infection, Progressive Multifocal Leukoencephalopathy
- Parenteral immunosuppressants for refractory disease: Miscellaneous Agents
- Mitoxantrone (Novantrone)
- Adverse effects include myelosuppression, elevated liver transaminases, decreased Cardiac Function and Leukemia
- Dose: 5 to 12 mg/m2 IV every 3 months
- Costs $900/ year in contrast to more than $60,000/year for other agents
- Management: General Supportive Measures
- Keep Cool
- Regular Exercise
- Pursuit of wellness and positive attitude
- Education regarding the disease
- Support from family and MS support groups
- Vitamin D Supplementation may help prevent exacerbations
- Resources
- National Multiple Sclerosis Society
- http://www.nmss.org
- NIH Multiple Sclerosis
- http://www.ninds.nih.gov/disorders/multiple_sclerosis/multiple_sclerosis.htm
- Multiple Sclerosis Association of America (MSAA)
- http://www.mymsaa.org/
- Multiple Sclerosis Foundation
- http://www.msfocus.org/
- References
- (2017) Presc Lett 24(9): 53
- (2020) Presc Lett 27(11): 65
- Pirko in Goetz (2003) Clinical Neurology, p. 1060-76
- Wilson (1991) Harrison's IM, p. 657-8
- (1995) Neurology 45:1268-76, 1277-85 [PubMed]
- Calabresi (2004) Am Fam Physician 70:1935-44 [PubMed]
- Frohman (2003) Med Clin North Am 87:867-97 [PubMed]
- Hawker (2004) Prim Care 31:201-26 [PubMed]
- OConnor (2002) Neurology 59:s1-33 [PubMed]
- Saguil (2014) Am Fam Physician 90(9): 644-52 [PubMed]