Multiple Sclerosis - Lecture 6 - Dr. Bhokasub

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Multiple Sclerosis - Lecture 6 - Dr. Bhokasub
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2013-04-08 18:05:03
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Describe the etiology and pathophysiology of MS  Recommend treatment for a patient with an acute exacerbation of MS  Compare and contrast all agents used to treat relapsing-remitting MS with respect to mechanism of action, side effects, efficacy, impact on disease progression, administration, and cost  Recommend therapy for symptomatic management for a patient with MS
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  1. Multiple sclerosis (MS) definition
    • neurodegenerative disease of the central nervous system (CNS)
    • demyelinating disease
    • - most common cause of chronic neurological disability in young adults
    • -affected areas of brain and spinal cord
    • -characteristic plaques or sclerosed areas
  2. high risk for MS (5)
    • 1. 15-45 years
    • 2. females (ratio 2:1)
    • 3. caucasians
    • 4. northern latitudes (higher)
    • 5. family members with MS
  3. etiology of MS
    • unknown - no cure***
    • could be:
    • biological: increased HLA, mutations in IL-2, IL-7 receptor genes, race, gender
    • environmental: location - high latitudes, smoking cigarettes, vitamin D, viral/bacterial infections (EBV)
  4. REMEMBER etiology 15 and MS
    • 1. genetically susceptible 15 yo in high-risk area ≥2 years exposed to crucial environmental agent = at risk
    • 2. migrates low to high < 15 yo = at risk
    • 3. migrates high to low > 15 yo = retains HIGH risk (vs lower if moved before 15).
  5. pathophysiology: inflammation
    infiltrate consisting of T and B lymphocytes, macrophages, antibodies, and complement
  6. pathophysiology: demyelination
    stripping of the myelin sheath surrounding CNS axons
  7. pathophysiology: axonal injury and transaction
    • damage to axons are irreversible when severed
    • neurodegeneration
    • gliotic sclerosis
  8. pathophysiology: autoimmune process directed against myelin and oligodendrocytes
    • T-cell entry into the CNS attract activated Th17 cells
    • actual mediator of myelin and axonal destruction has not been established 
    •  - combo of macrophages, antibodies, destructive cytokines, and reactive oxygen intermediates
    • number of T-regulatory (Treg) cells (suppressor activity) is reduced
  9. clinical presentation: primary
    visual complaints, gait problems, paresthesias (pins and needles), pain, spasticity, weakness, ataxia, speech difficulty, psychology changes, cognitive changes, fatigue, bowel/bladder dysfunction, sexual dysfunction, optioc neuritis
  10. clinical presentation: secondary
    recurrent urinary tract infections, urinary calculi, muscle contractures, respiratory infections, poor nutrition
  11. clinical presentation: tertiary
    financial, personal, social, vocational, and/or emotional problems
  12. Clinically isolated symptom (CIS)
    • 85% have first attacks that can last ≥24 hrs 
    • attacks may present separate from another symptom for 30 days, followed by remission
  13. Radiologically isolated symptom (RIS)
    patients who present atypically for MS but MRI results suggest MS
  14. Classification of MS (4)
    • 1. relapsing-remitting (RRMS)
    • 2. secondary-progressive (SPMS)
    • 3. primary-progressive (PPMS)
    • 4. progressive-relapsing (PRMS)
  15. definition: characterized symptoms that develop over a period of a few hours to a few days, followed by recovery and stale course between relapses
    Classification of MS: relapsing-remitting (RRMS)
  16. definition: characterized by gradual neurological deterioration with or without superimposed relapses and minor remissions
    Classification of MS: secondary-progressive (SPMS)
  17. definition: characterized by continual disease progression from onset with no superimposed relapses or remissions
    Classification of MS: primary-progressive (PPMS)
  18. definition: characterized by gradual neurological deterioration from the onset of symptoms and subsequent superimposed relapses
    Classification of MS: progressive-relapsing (PRMS)
  19. Exacerbation factors (10)
    unpredictable, infections, heat (fever), sleep deprivation, stress, malnutrition, anemia, organ dysfunction, exertion, childbirth
  20. clinical rating scale
    expanded disability status scale (EDSS)
  21. t/f MS is differential diagnosis (of exclusion)
    • T.
    • ≥ 2 episodes of neurologic disturbance reflecting distinct sites of damage in the CNS that cannot be explained by another mechanism
  22. ____ criteria for diagnosis for MS
    • Mcdonald Criteria
    • - Brain magnetic resonance imaging (MRI)
    • - Cerebrospinal fluid (CSF)
    • - Visual-evoked potential (VEP) studies
    • - with physical exam + history
    • - no specific labs
  23. diagnosis: MRI
    • images of brain and spine
    • est. dx and px
    •   - plaques, atrophy, lesions
    • single demyelination attack and ≥3 T2-weighted lesions: 90% likelihood of developing a second attach (clinically definite MS) over 15 years
    • Similar individuals with normal brain MRIs: 19% likelihood of developing MS over 15 years
  24. diagnosis: CSF
    • oligoclonal banding
    • -level increased in CSF
    • -level normal in serum
    • -atypical clinical scenarios
    • -possible MS diagnosis: > 50x106/mL (50x109/L) mononuclear cells in the CSF usually indicates a diagnosis other than MS
  25. diagnosis: VEP
    • detect clinically silent areas
    •  - slowed conductance of visual, brainstem, and somatosensory
    • << sensory and specificity
    • blood studies
    •  - antimyelin antibodies
    •  -help define px
    •  -rule out differentials
  26. Prognosis: good
    • long interval between 1st and 2nd attack
    • no residual neurologic deficits from the 1st attack
    • relatively benign 2- and especially 5-year course of MS
    • early onset <40 years
    • absence of cerebrospinal oligoclonal IgG bands
    • normal or low MRI scan disease burden at the time of diagnosis
  27. Prognosis: bad
    • frequent attacks
    • disabling early attacks
    • prolonged or permanent residual disability
    • 5-year history of active MS
    • early involvement of cerebellar pathways
    • later onset >40 years
    • presence of CSF oligoclonal IgG bands
    • high MRI disease burden at diagnosis
  28. 5 goals of treatment for MS
    • 1. decrease severity, intensity, and duration of exacerbations
    • 2. enhance recovery from exacerbations
    • 3. prevent relapses and the onset of progressive disease
    • 4. provide symptomatic relief from complications
    • 5. maintain the patient's quality of life (disease-modifying therapies - DMTs, treatment of acute exacerbations, symptomatic therapy)
  29. goals of THERAPY for MS
    • early therapy is most effective
    • -relapsing - Avonex, Betaseon (or Extavia), Copaxone, Rebif (ABC-R) therapy immediately after the diagnosis
  30. 9 medications for MS
    • AABCEGNRT
    • Avonex (interferon beta-1a)
    • Aubagio (teriflunomide)
    • Betaseron (interferon beta-1b)
    • Copaxone (glatiramer acetate)
    • Extavia (interferon beta-1b)
    • Gilenya (fingolimod)
    • Novantrone (mitoxantrone)
    • Rebif (interferon beta-1a)
    • Tysabri (natalizumab)
  31. MOA: suppresses the autoimmune destruction of myelin; slows accumulation of disability and decreases the frequency of clinical exacerbations
    hint: interferon B-1a
    • Avonex: IM weekly, RRMS, category C
    • Rebif: SC TIW, RRMS, category C
    • (room temp up to 30 days)
  32. MOA: suppresses T-cell proliferation through immunoregulatory activity, reduces pro-inflammatory mediators, and decreases BBB permeability
    hint: interferon B-1b
    • Betaseron: SC QOD, RRMS, category C
    • Extavia: SC QOD, RRMS, category C
  33. Adverse reactions for Interferons in MS
    • common: 
    • injection site pain, redness and swelling, flu-life symptoms last for 24 hours
    • infrequent:
    • dyspnea, tachycardia, depression, liver-thyroid, abnormalities, leukopenia
  34. monitoring parameters for interferons in MS (3)
    • 1. CBC with PLT
    • 2. LFTs
    • 3. TFTs 
    • baseline, every 3 months for a year, then every 6 months thereafter
  35. MOA: active metabolite of leflunomide. Inhibits a mitochondrial enzyme, thus interfering with DNA synthesis --> reduced lymphocyte activation
    Aubagio (teriflunomide): oral QD, RRMS, category X
  36. BLACK BOX WARNING: hepatotoxicity and teratogenicity 
    drug for MS
    • Aubagio (teriflunomide)
    • recommended: transaminase and bilirubin obtained PRIOR to treatment (up to 6 months) for the first 6 months
  37. AE for Aubagio (teriflunomide)
    • short term:
    • abnormal LFT(5%) - reversible, alopecia, diarrhea, influenza, nausea, paresthesias
    • long term:
    • no specific issues have been seen in patients with MS
    • Major:
    • Stevens Johnsons Syndrome (SJS), increase BP, fetal malformations, elevated serum hepatic transaminases (BBW)
  38. MOA: blocks myelin-specific autoimmune responses and likely serves as a "decoy" that blocks myelin-damaging T-cells
    Copaxone (Glatiramer acetate): SC QD, RRMS, category B
  39. AE for Copaxone (Glatiramer acetate)
    • mild pain/pruritis (10%)
    • Chest tightness/dyspnea (10-15%, transient)
    • flushing
    • no lab monitoring needed
    • (room temp up to 1 week)
  40. MOA: partial agonist at the sphingosine-1-phosphate receptor 1
    -internal sequester lymphocytes in the lymphoid tissue
    - reduces the infiltration of T-lymphocytes and macrophages into the CNS
    -bind to SP-1 receptor in the CNS to promote remyelination
    Gilenya (fingolimod): oral QD, relapsing form, category C
  41. AE for Gilenya (fingolimod)
    • general:
    • h/a, migraine, back pain, diarrhea
    • major:
    • first dose bradycardia, infections, macular edema, decrease in forced expiratory volume over 1 second, LFT elevation, BP elevation, lymphoma (rare - reversible 2-4 weeks after d/c)
  42. monitoring parameters for Gilenya (fingolimod) (5)
    • CBC, LFTs, ophthalmologic examinations, pulse and BP, ECG
    • *patient should be observed for 6 hours after first dose
    • *ECG is mandatory prior to first dose and after the 6 hours observation period
  43. MOA: anthrocenedione chemotherapeutic agent (inhibiting DNA and RNA synthesis)
    Novantrone (mitoxantrone): IV Q3months (body surface area), monotherapy for SPMS, worsening RRMS, PRMS, max cumulative dose 140 mg/m2, category D, may cause blue discoloration
  44. AE for Novantrone (mitoxantrone)
    • cardiotoxicity: obtain left ventricular function (prior, before each does, after accumulated dosage of 100 mg/m2), if heart failure signs/symptoms develop)
    • nausea, alopecia, menstrual disorder, amenorrhea, URI, UTI, leukopenia, hair thinning
    • BBW: cardiotoxicity, secondary acute myelogenous leukemia
  45. MOA: blocks alpha-4-integrin which inhibits the trafficking of immune cells into the CNS
    Tysabri (natalizumab): IV Q4W in NaCl over 1 hour, relapsing form, category C
  46. Touch Program for which MS drug
    • Tysabri (natalizumab)
    • -educate on risk of PML (progressive multifocal leukoencephalopathy)
    • -provide medication guide
    • -diagnose PML, if indicated
    • -obtain signatures
    • -makes copies and send report
    • -evaluate at 3 months and 6 months, then every 6 months
    • CHANGES: recommend blood and CSF screen at baseline and every 6 months to assess the presence of JC and BK virus DNA
  47. treatment of acute exacerbations of MS
    • mild acute exacerbations that do not produce functional decline may not require tx
    • if functional ability is affected: IV high-dose corticosteroids 
    • -Methylprednisolone 500-1000 mg/d IV
    • (duration 3-10 days, 3-5 days for signs of improvement)
  48. AE for methylprednisolone in MS
    • sleep disturbance, a metallic taste, GI upset, INC glucose
    • long term use AE: acne, fungal infections, mood alteration, GI hemorrhage
  49. symptomatic therapy: fatigue
    • most COMMON complaint (disabling for some)
    • commonly occurs mid-late afternoon (heat exposure, exertion, intercurrent infection, spasticity, weakness, and depression)
    • TX:
    • 1. amantadine hydrochloride: 100 mg BID
    • 2. methylphenidate (Ritalin): and related
    • 3. modafinil (Provigil): 100 mg BID
  50. symptomatic therapy: impaired gait
    • dalfampridine (AMPYRA):
    • 10 mg PO BID, improve walking, not restricted on stage of MS
    • safety profile: urinary tract infections, insomnia, dizziness, h/a, nausea, weakness
    • contraindications: history of seizures or moderate-severe kidney disease
  51. symptomatic therapy: spasticity - jerking (6)
    • legs >> arms
    • 1. baclofen: 10 mg TID titrated up to 40-80 mg/d
    • 2. tizanidine (Zanaflex): titrate over 2-4 weeks up to 2-36 mg/d (AE: sedation, dizziness, dry mouth)
    • 3. diazepam (Valium): 2-10 mg/d (addiction/CNS depression)
    • 4. clonazepam (Klonopin): 1-3 mg/d
    • 5. dantrolene sodium (Dantrium): 100-400 mg/d
    • 6. gabapentin (Neurontin): 1800-3600 mg/d
  52. symptomatic therapy: neurologic bladder (7)
    • 1. darifenacin (Enablex): 7.5-15 mg/d
    • 2. fesosterodine (Toviaz): 4-8 mg/d
    • 3. oxybutynin (Ditropan): 10-20 mg/d
    • 4. solifenacin (Vesicare): 5-10 mg/d
    • 5. tolterodine (Detrol): 2-4 mg/d
    • 6. trospium (Sanctura): 40 mg/d
    • 7. dicyclomine hydrochloride (Bentyl): 30-80 mg/d
  53. symptomatic therapy: neurogenic bowel
    • 1. conservative measures:
    • timed bowel evacuation, dietary fiber, bulk-forming agents, biofeedback, physical activity, hydration
    • 2. medical therapies:
    • stool softeners, rectal stimulants, laxatives, enemas
    • *common occurrence with increase use of narcotics and/or anticholinergic medications
  54. symptomatic therapy: sexual dysfunction (3)
    • sildenafil (Viagra): 4 hrs 1/2 life  
    • tadalafil (Cialis): longest half-life (17.5 hrs) and duration (24-36 hrs)
    • vardenafil (Levitra): more CYP2C, 4 hrs 1/2 life
    • all rapid bioavailability, CYP3A4
  55. MOA: reduces inflammation caused by the MS immune response and protects nerves against injury 
    hint: emerging therapy
    • Tecfidera: oral 2-3x daily
    • AE: flushing and hot flashes, GI-upset, diarrhea, nausa, abdominal pain, h/a
  56. MOA: humanized monoclonal antibodies, targeting CD 20 (ex: depletion of B-cells and reduction in antigen presentation) (3)
    • 1. rituximab
    • 2. ocrelizumab
    • 3. ofatumumab
    • IV infusions
    • AE: impaired antibody response, infections, PML
  57. second line therapy for side effects (2)
    • mitoxantrone
    • natalizumab

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