Multiple Sclerosis

1. Epidemiology
   1. Top disabling condition of young adults (U.S.)
   2. Prevalence
      1. Northern U.S.: 191 cases per 100,000 persons (Olmstead County, Minnesota)
      2. Southern U.S.: 40 cases per 100,000 persons (Lubbock, Texas)
      3. U.S. Total: 1 Million patients affected
      4. Howard (2016) Neurol Clin 34(4): 919-39 [PubMed]
2. 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 inflammation and demyelination of white matter
         1. Periventricular and subpial white matter are particularly involved
      2. Gliosis
         1. Glial cell proliferation and activation
      3. Degeneration
         1. Axonal Loss
3. Risk Factors
   1. Race: White > Black
   2. Gender: Female > Male (2:1)
   3. High socioeconomic status
   4. Northern latitudes
   5. Environmental factors (toxins, viruses)
      1. Infectious Mononucleosis
   6. Tobacco Abuse
   7. HLA histocompatible Antigens
   8. Vitamin D Deficiency (or less sunlight exposure)
      1. Munger (2006) JAMA 296:2832-2838 [PubMed]
4. Symptoms
   1. Sensory loss of vibration, proprioception or nociception (37%)
   2. Optic Neuritis (36%)
   3. Focal Weakness (35%)
   4. Paresthesias with numbness or tingling Sensation (24%)
   5. Diplopia (15%)
   6. Ataxia or Incoordination (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%)
       1. Cognitive dysfunction is a late disease finding (consider alternative diagnosis if a concern at presentation)
       2. Findings may include Learning Difficulty, memory deficit, slowed processing speed
   12. Visual Loss (2%)
   13. Facial palsy (1%)
   14. Erectile Dysfunction or Sexual Dysfunction (1%)
   15. Myokymia (1%)
   16. Seizures (1%)
   17. Other findings
       1. Tremor
       2. Dysarthria
       3. Depressed mood
       4. Fatigue
       5. Hearing Loss or Tinnitus
       6. Heat intolerance
       7. Bowel Dsyfunction (e.g. Constipation)
5. 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
6. 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 or transient symptoms (<24 hours)
      2. Seizures, Aphasia or other significant cortical findings
      3. Peripheral Neuropathy
      4. Non-neurologic involvement (e.g. cardiac)
      5. Family History of neurologic disorder other than MS that may explain findings
      6. Progressive Ataxia
      7. Cognitive dysfunction
      8. Nonspecific neurologic symptoms that are difficult to localize
7. Diagnosis: McDonald Criteria (2017)
   1. Definitive diagnosis: Relapsing Remitting
      1. Two or more attacks AND
      2. Two or more lesions or objective clinical evidence of one lesion and clear-cut historical evidence of 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 OR
            3. Positive CSF-specific Oligoclonal Bands
      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]
      2. Thompson (2018) Lancet Neurol 17(2): 162-73 [PubMed]
8. Differential Diagnosis
   1. Degenerative disease
      1. Amyotrophic Lateral Sclerosis
      2. Huntington Disease
   2. Demyelinating disease
      1. Acute inflammatory demyelinating Polyneuropathy (Guillain Barre Syndrome)
      2. Chronic inflammatory demyelinating Polyneuropathy
      3. Neuromyelitis Optica
      4. Paraneoplastic Syndromes
   3. CNS Infection
      1. Tertiary Lyme Disease
      2. Tertiary Syphilis (Neurosyphilis)
      3. Human Immunodeficiency Virus (HIV)
      4. Mycoplasma
      5. Progressive Multifocal Leukoencephalopathy (JC Virus Infection)
   4. CNS Inflammation
      1. Sarcoidosis
      2. Systemic Lupus Erythematosus (SLE)
      3. Sjogren Syndrome
      4. Behcet Syndrome
      5. Susac Syndrome
      6. Granulomatosis with Polyangiitis
   5. CNS Vascular Disease
      1. Hypertension
      2. Diabetes Mellitus
      3. Cerebrovascular Accident
      4. Migraine Headache
      5. Vasculitis
      6. Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy (CADASIL)
   6. CNS mass or structural disease
      1. Cervical Spondylosis (or other Spinal Cord Syndromes)
      2. Cervical Disc Disease
      3. CNS neoplasm
      4. Arnold Chiari Malformation
      5. Arteriovenous Malformation
   7. Medications and recreational drugs
      1. Alcohol Abuse
      2. Cocaine Abuse
      3. Methanol Poisoning
      4. Isoniazid
      5. Lithium
      6. Penicillin
      7. Phenytoin (Dilantin)
      8. Anticholinergic Toxicity
      9. Biologic Agents
         1. Etanercept (Enbrel)
         2. Infliximab (Remicade)
   8. Vitamin Deficiency or Toxicity
      1. Vitamin B12 Deficiency
      2. Folate Deficiency
      3. Vitamin E deficiency
      4. Manganese Toxicity
   9. Psychiatric conditions
      1. Anxiety Disorder
      2. Conversion Disorder
      3. Somatization
   10. Genetic disorders
       1. Leukodystrophy
       2. Mitochondrial disease
   11. Miscellaneous
       1. Hypothyroidism
   12. References
       1. Miller (2008) Mult Scler 14(9): 1157-74 [PubMed]
       2. Rolak (2007) Neurologist 13(2): 57-72 [PubMed]
9. Types: Course
   1. Relapsing Remitting MS (85 to 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
      3. Recovery results from axonal changes, neuroplasty and remyelination
   2. Secondary progressive MS
      1. Starts as relapsing remitting (RRMS) and secondarily progresses in 50% of untreated RRMS cases
      2. Progresses to gradual neurologic deterioration outside of discrete, acute attacks
   3. Primary progressive (PPMS) and progressive relapsing (10-15% of cases)
      1. Steady functional decline from Multiple Sclerosis onset (and acute exacerbations may occur)
      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]
10. Types: Diagnostic Surety
    1. Definite Multiple Sclerosis
       1. All criteria fulfilled
    2. Clinically Isolated Syndrome
       1. First episode of acute or subacute symptoms characteristic of MS, lasting at least 24 hours
       2. Does not yet meet diagnostic criteria of MS
       3. Abnormal MRI predicts 80% progression to MS in 20 years (contrast with 20% if MRI normal)
       4. Probable Multiple Sclerosis: All criteria fulfilled except
          1. Only 1 neurologic sign (2 Symptomatic episodes) or
          2. Neurologic signs unrelated to 1 Symptomatic episode
       5. At risk for Multiple Sclerosis: All criteria fulfilled except
          1. Only 1 episode and
          2. No neurologic signs on exam
    3. Radiologically Isolated Syndrome
       1. Absent clinical symptoms, but incidental radiologic findings of inflammatory demyelination suspicious for MS
       2. Progression to MS or Clinically Isolated Syndrome in 30 to 40% of patients
11. Diagnostics
    1. MRI Head (preferred first line study)
       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
       1. Not nearly as useful as MRI Head
          1. Indicated when MRI is contraindicated or unavailable
       2. 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
12. 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)
          1. However, Oligoclonal bands can be used in place of one imaging lesion for MS diagnosis (see below)
       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]
13. 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. C-Reactive Protein (C-RP)
       6. Lyme Disease titer (Borelia titer)
       7. Rapid Plasma Reagin (RPR)
       8. 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. Sjogren Syndrome Antibodies (Anti-SS-A Antibody, 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)
14. Management: General
    1. Involve a multidisciplinary team
       1. Neurologists (many tertiary centers have specialists in MS)
       2. Physical Therapy
       3. Occupational Therapy
       4. Speech and Language Therapy
       5. Mental Health providers
       6. Dietician
       7. Pharmacist
    2. Nonspecific 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
       7. Tobacco Cessation!
          1. Disability progression decreases with each year of being Tobacco free
             1. Tanasescu (2018) Nicotine Tob Res 20(5): 589-95 [PubMed]
          2. Risk of progression from RRMS to SPMS increases 4.7% per additional year of smoking after diagnosis
             1. Ramanujam (2015) JAMA Neurol 72(10): 1117-23 [PubMed]
15. 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. Initial 3 day course of Methylprednisolone IV or Oral (similar efficacy for oral dosing)
          1. Methylprednisolone 1000 mg orally daily (or in divided doses) for 3 days OR
          2. Methylprednisolone 1000 mg in 500 ml D5W infused over 4 to 6 hours each morning for 3 days
       2. Next: Steroid Taper after first 3 days (examples only, dosing varies widely, consult neurology for local protocol)
          1. Methylprednisolone 500 mg daily IV or Oral for 3 days, then 250 mg daily IV or Oral for 3 days OR
          2. Prednisone 1 mg/kg/day orally daily for 14 days OR
          3. No further Corticosteroids
    3. Plasmapheresis
       1. Indicated in cases refractory to Corticosteroids
       2. Plasma exchange performed every other day for 14 days
          1. Brochet (2020) J Clin Apher 35(4): 281-9 [PubMed]
16. 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
          1. Drug selection is a balance of effectiveness versus adverse effects given the underlying disease burden
          2. Moderately effective agents (e.g. Glatiramer, Interferon) are used in new RRMS with minimal disease burden
          3. Highly effective agents (e.g. Alemtuzumab, cladribine, natalizumab) are used in new rapidly progressive RRMS
       4. Expect to continue disease modifying agents lifelong
          1. Consider switching to more effective agent if inadequate benefit after 6 month trial
          2. Consider changing to alternative medication if significant adverse effects
          3. Conditions in which disease modifying agents may be discontinued
             1. Secondary progressive MS in a non-ambulatory, significantly disabled patient without relapse in 2 years
             2. Preconception Counseling prior to intended pregnancy (risk of MS relapse is decreased in pregnancy)
       5. 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 (starting in 1993) 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 (Betaseron, Extavia)
          1. Betaseron 0.25 mg SC every other day
          2. Modestly protects against exacerbation for 1 year
          3. Injection site reaction, Influenza-like symptoms, rare liver toxicity
          4. Generic Cost $6500 per month in 2022 (non-generic cost >$125,000/month)
          5. Filippini (2003) Lancet 361:545-52 [PubMed]
       4. Interferon beta-1a (Avonex, Rebif)
          1. Avonex 30 mcg IM once weekly (cost $7200 per month in 2022)
          2. Similar adverse effects to Interferon beta-1b
          3. Rebif 22 to 44 mcg SC three times per week (cost $35,000 per month in 2022)
          4. Peginterferon beta-1a (Plegridy) 125 mcg SQ every 2 weeks
    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/ml SQ daily or 40 mg/ml SQ three times weekly
          4. Copolymer 1 that cross reacts with myelin basic Protein and may act as a decoy for immune response
             1. Contains random length peptide chains with 4 Amino Acids found in myelin basic Protein
             2. Specifically, the Amino Acids are glutamic acid, lysine, alanine, and tyrosine
          5. Good track record of safety and greater efficacy than Interferon
          6. Generic Cost $4700 to $6000 per month in 2022 (non-generic costs >$22,000/month)
    4. Oral Immunosuppressants
       1. Fingolimod (Gilenya)
          1. Sphingosine-1-phosphate receptor blocker
          2. Costs $10,000 per month in 2022
          3. Adverse effects include Bradycardia, Hypertension, QTc Prolongation, elevated liver transaminases
             1. Other adverse effects include Melanoma, Macular edema, HSV Encephalitis
          4. Dose: 0.5 mg orally daily
          5. 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
          2. Dose 2 mg orally once daily
       3. Ozanimod (Zeposia)
          1. Released in 2020 and similar to Fingolimod
          2. Dose 0.92 mg orally once daily
       4. Ponesimod (Ponvory)
          1. Released in 2021 and similar to Fingolimod
          2. Dose 20 mg orally once daily ($8300 per month in 2022)
       5. 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
       6. Dimethyl Fumarate (Tecfidera)
          1. Generic in 2020 ($130 per month in 2022)
          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
       7. Monomethyl Fumarate (Bafiertam)
          1. Released in 2020 and similar to Dimethyl Fumarate
          2. Dose: 190 mg orally twice daily
       8. Diroximel Fumarate (Vumerity)
          1. Released in 2020 and similar to Dimethyl Fumarate
          2. Dose 231 mg orally twice daily
          3. Similar adverse effects to Dimethyl Fumarate
       9. Cladribine (Mavenclad)
          1. Dose: 1.75 mg/kg orally twice yearly (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. Malignancy risk
             4. Nausea, Headache, flu-like symptoms, severe lymphopenia, Shingles, Tuberculosis
    5. Parenteral immunosuppressants for refractory disease: Monoclonal Antibodies
       1. Alemtuzumab (Lemtrada)
          1. Monoclonal Antibody dosed IV 12 mg/day for 5 days (then, in 12 months, repeat 12 mg/day for 3 days)
          2. Risk of infusion reaction, infection risk, Thyroid disorder, renal dysfunction
          3. Also risk of Venous Thromboembolism, immune Thrombocytopenia
       2. Daclizumab (Zinbryta)
          1. Monoclonal Antibody dosed SQ once monthly
          2. Hepatotoxicity risk (monitor Liver Function Tests)
       3. Natalizumab (Tysabri, Antegren)
          1. Monoclonal Antibody dosed 300 mg IV once every 4 weeks
          2. Adverse effects include Hypersensitivity, infusion reaction, Headache, Fatigue
          3. Risk of Progressive Multifocal Leukoencephalopathy
          4. Blocks CNS entry of immune response to Nerve Cells
          5. Reduces relapse rate by >60%
          6. (2004) Neurology 62:2038 [PubMed]
       4. Ocrelizumab (Ocrevus)
          1. First-line only in primary progresive MS (only one FDA approved in primary progressive MS)
          2. Dosed 600 mg IV once every 6 months (administered over 3.5 hours)
          3. Pretreatment with Methylprednisolone and Diphenhydramine
          4. Adverse effects: Severe infusion reactions, herpetic infection, PML, malignancy risk
       5. Ofatumumab (Kesimpta)
          1. Monoclonal Antibody to CD20
          2. Dose 20 mg SQ at week 0, 1 and 2, then as of week 4, start 20 mg per month
          3. Adverse effects include liver injury, PML, infection risk
    6. Parenteral immunosuppressants for refractory disease: Miscellaneous Agents
       1. Mitoxantrone (Novantrone)
          1. Adverse effects include myelosuppression, elevated liver transaminases, CHF and Leukemia
          2. Dose: 5 to 12 mg/m2 IV every 3 months
          3. Costs $900/year
    7. Other interventions
       1. Hematopoietic Stem Cell Transplant (experimental in 2022)
          1. Burt (2019) JAMA 321(2): 165-74 [PubMed]
17. 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. Cannabinoids
       6. Non-pharmacologic Management
          1. Physical therapy or Physiotherapy
          2. Transcutaneous Nerve Stimulation
          3. Transcranial Magnetic Stimulation
          4. Structured Exercise Program
          5. Hydrotherapy
             1. Castro-Sanchez (2012) Evid Based Compliment Alternat Med 2012: 473963 [PubMed]
    2. Ataxia
       1. Baclofen
       2. Tizanidine
       3. Dantrolene
       4. Threonine
       5. Cannabinoids
       6. Vestibular Rehabilitation
       7. Deep Brain Stimulation
    3. Ambulatory Dysfunction
       1. Dalfampridine XR (Ampyra)
       2. Physiotherapy
       3. Occupational Therapy
       4. Supervised Resistance Training
    4. Tremor
       1. Onabotulinum Toxin A (local Tremors)
       2. Beta Blockers
       3. Diazepam
       4. Isoniazid
    5. Visual Problems (Oscillopsia)
       1. Gabapentin (Neurontin, first-line)
       2. Memantine (Namenda, second-line)
       3. Vestibular rehabilitation
    6. Paroxysmal pain and other syndromes (85% of patients)
       1. Trigeminal Neuralgia
          1. Treat as with Trigeminal Neuralgia in non-Multiple Sclerosis patients
          2. First-Line
             1. Carbamazepine 100 to 600 mg orally three times daily
             2. Oxcarbazepine (Trileptal)
          3. Second-Line
             1. Baclofen (Lioresal) 10 to 80 mg/day
             2. Gabapentin
             3. Lamotrigine (Lamictal)
       2. Dysesthetic limb pain or Neuropathic Pain
          1. Hydrotherapy (see spasticity above)
          2. Amitriptyline or Nortriptyline
          3. Gabapentin 300 to 900 mg orally three times daily
          4. Pregabalin (Lyrica)
          5. Venlafaxine (second-line)
          6. 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]
    7. Neurogenic Bladder
       1. Evaluate with post-void residual testing to distinguish failure to store from failure to empty
       2. Failure to store (detrusor spasm)
          1. Avoid spicy or acidic foods, Caffeine and Alcohol
          2. Bladder Training
          3. Sacral neuromodulation
          4. Detrol LA (Tolterodine LA) 2 to 4 mg orally daily
          5. Ditropan XL or Oxytrol XR (Oxybutynin XR) 5 to 10 to 30 mg orally daily
          6. Onabotulinumtoxin A (Botox) injection has been used in refractory cases
       3. Nocturia
          1. Intranasal Desmopressin
       4. Failure to empty (outlet disorder)
          1. Trial on alpha adrenergic blocker (e.g. Prazosin or Terazosin)
          2. Cannabinoids
          3. Clean intermittent self cathetrization
    8. Neurogenic bowel
       1. Constipation: Manage aggressively
          1. DocusateSodium (Colace)
          2. Bisacodyl (Dulcolax)
          3. Magnesium Citrate or Magnesium Oxide
          4. Polyethylene glycol (Miralax)
          5. Hydration and fiber supplementation (e.g. Psyllium)
          6. Rectal stimulants and enemas as needed
          7. Lubiprostone (Amitiza)
          8. Other measures
             1. Abdominal massage
             2. Biofeedback or electrostimulation of abdominal Muscles
             3. Planned toilet times
       2. Fecal Incontinence
          1. Fiber supplementation
          2. Consider short-term anti-Diarrheal agent
          3. Colostomy has been used in refractory cases
    9. 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]
       4. Other agents to consider
          1. Selective Serotonin Reuptake Inhibitor or SSRI (e.g. Escitalopram, Fluoxetine, Sertraline)
          2. Dextroamphetamine
          3. Methylphenidate (Ritalin)
       5. Other non-pharmacologic therapy
          1. Aerobic Exercise
          2. Avoid excessive heat, over-exertion and stress
          3. Mindfulness Training
    10. Major Depression or Emotional Lability
        1. Selective Serotonin Reuptake Inhibitor or SSRI (e.g. Escitalopram, Fluoxetine, Sertraline)
        2. Serotonin Norepinephrine Reuptake Inhibitor or SNRI (e.g. Venlafaxine, Duloxetine)
        3. Bupropion (Wellbutrin)
        4. Cognitive Behavioral Therapy
    11. Sexual Dysfunction
        1. Affects >50% of men and >40% of women
        2. Men
           1. See Erectile Dysfunction
           2. Phosphodiesterase Inhibitors (e.g. Sildenafil or Viagra)
           3. Intercavernous Vasodilator
        3. Women
           1. See Female Sexual Dysfunction
           2. Duloxetine
           3. Vaginal lubrication, clitoral vibratory stimulation
    12. Cognitive Impairment or Dementia
        1. Donepezil (Aricept)
        2. Other agents have not shown benefit (e.g. Rivastigmine, ginkgo, Amantadine)
        3. Consider neuropsych rehabilitation
        4. Consider occupational therapy
18. 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, Marburg Type)
    6. Overall decreased Life Expectancy by 7 to 8 years in women diagnosed at a young age (e.g. 35 years old)
19. 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/
20. 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. Hauser (2020) Am J Med 133(12): 1380-90 [PubMed]
    9. Hawker (2004) Prim Care 31:201-26 [PubMed]
    10. OConnor (2002) Neurology 59:s1-33 [PubMed]
    11. Saguil (2014) Am Fam Physician 90(9): 644-52 [PubMed]
    12. Saguil (2022) Am Fam Physician 106(2): 173-83 [PubMed]