Multiple sclerosis biplave

multiple sclerosis

1. Multiple Sclerosis Dr. BIPLAVE KARKI RESIDENT, INTERNAL MEDICINE DHULIKHEL HOSPITAL

2. Introduction A chronic immune-mediated disease characterized by inflammation, demyelination, gliosis (scarring), and neuronal loss. Relapsing-remitting or progressive course Lesions of MS typically occur at different times and in different CNS locations (i.e. disseminated in time and space)

3. Epidemiology Approximately 350,000 cases in US Estimated 2.5 million cases worldwide Higher prevalence in whites of Northern European ancestry Highest known prevalence for MS (250 per 100,000) in the Orkney Islands Prevalence of MS is 0.1–0.2% in other temperate zone Prevalence is often ten- to twenty fold less in the tropics

4. Epidemiology Higher incidence in woman (3:1) One of the most common causes of neurologic disabilities in young Onset is typically between 20 and 40 years (slightly later in men than in women)

5. Risk factors Vitamin D deficiency Exposure to Epstein-Barr virus (EBV) after early childhood Cigarette smoking High levels of dietary sodium Higher socioeconomic status Genetic susceptibility Polygenic Association with HLA-DRB 1 gene in the class II region of the MHC ; accounts for approximately 10% of the disease risk ~ 110 other MS s us ceptibility variants

6. Pathogenesis: Pathology Stage of Inflammation Stage of Demyelination Stage of Gliosis /Scarring

7. Pathogenesis: Pathology   Stage of inflammation Perivenular cuffing with inflammatory mononuclear cells (T cells & macrophages) with infiltration of surrounding white matter Disruption of blood brain barrier (but vessel wall is preserved, a contrast to vasculitis syndromes where vessel wall is damaged)

8. Pathogenesis: Pathology Stage of demyelination Demyelination is the hallmark of the pathology Cell-mediated immunity T-lymphocytes against Myelin Basic Protein (MBP ) Humoral immunity Myelin specific antibodies presence of elevated levels of locally synthesized immunoglobulins and oligoclonal antibodies, derived from clonally restricted CNS B cells and plasma cells, in the CSF are also characteristic of MS.

9. Pathogenesis: Pathology Stage of Gliosis/Scarring Astrocytic proliferation(gliosis) Relative sparing of axons is typical of MS Partial or total axonal destruction can also occur, especially within highly inflammatory lesions MS Plaques Oligodendrocyte precursor cells survive and in many lesions are present in even greater numbers than in normal tissue but fail to differentiate into mature myelin-producing cells Partial remyelination of surviving naked axons by surviving oligodendrocytes appearing as ‘shadow plaques’

10. Pathogenesis: Physiology

11. Clinical Manifestations Onset may be abrupt or insidious Symptoms Extremely varied Depend on the location and severity of lesions within the CNS Examination often reveals evidence of neurologic dysfunction, often in asymptomatic locations

12. Clinical Manifestations

13. Weakness of the limbs Loss of strength, speed or dexterity , as fatigue or as a disturbance of gait Exercise-induced weakness Characteristic symptom of MS UMN Type

14. Spasticity > 30 % of MS patients have moderate to severe spasticity, especially in the legs Commonly associated with spontaneous and movement-induced muscle spasms

15. Visual blurring May result from Optic neuritis or Diplopia

16. Optic neuritis Can be the first demyelinating event in approximately 20% of patients with MS Develops in approximately 40% of MS patients during the course of their disease Diminished visual acuity, dimness or decreased color perception (desaturation) in the central field of vision . May progress to severe visual loss

17. Optic neuritis Visual symptoms are generally monocular but may be bilateral Periorbital pain (aggravated by eye movement) often precedes or accompanies the visual loss. An afferent pupillary defect is usually present. Funduscopic examination : normal or reveal papillitis optic atrophy commonly follows ON

18. Diplopia May result from Internuclear ophthalmoplegia (INO ) or Sixth cranial nerve palsy (rarely the third or fourth) B/L INO is particularly suggestive of MS

19. INO Normal primary position Leftward gaze Rightward gaze Upward gaze Downward gaze Adduction deficit in the right eye and nystagmus in the left eye

20. Gaze Disturbances Horizontal gaze palsy One and a half syndrome conjugate horizontal gaze palsy in one direction plus an internuclear ophthalmoplegia in the other Acquired pendular nystagmus

21. Sensory symptoms Paresthesias e.g. Tingling,prickling sensations, formications, "pins and needles" or painful burning Hypesthesia e.g. reduced sensation, numbness or a "dead" feeling Unpleasant sensations e.g. feelings that body parts are swollen, wet, raw,or tightly wrapped

22. Sensory symptoms Sensory impairment of the trunk and legs below a horizontal line on the torso (a sensory level) Indicates that the spinal cord is the origin of the sensory disturbance. Often accompanied by a bandlike sensation of tightness around the torso Pain a common symptom of MS, in > 50 % can occur anywhere on body and can change locations over time

23. Ataxia Limb ataxia Cerebellar tremors May also involve the head and trunk or the voice,producing a characteristic cerebellar dysarthria (scanning speech)

24. Bladder Dysfunction In > 90% of patients 1/3 rd have weekly or more frequent episode of urinary incontinence Detrusor hyperr efl ex ia causes urin ary fr e quency , urgency,nocturia and uncontrolled bladder emptying Detrusor sphincter dyssynergia causes difficulty in initiating and/or stopping the urinary stream, producing hesitancy, urinary retention, overflow incontinence,and recurrent infection

25. GI Symptoms Constipation occurs in >30% of patients Fecal urgency or bowel incontinence is less common ( < 15%)

26. Others Cognitive dysfunction Depression Fatigue Sexual dysfunction Facial weakness Vertigo Hearing loss

27. Ancillary Symptoms

28. Heat sensitivi ty Refers to neurologic symptoms produced by an elevation of the body's core temperature e.g. unilateral visual blurring may occur during a hot shower or with physical exercise ( Uhtho ff ‘s symptom ) MS symptoms worsen transiently, sometimes dramatically, during febrile ilInesses

29. Lhermitte's symptom An electric shock-like sensation ( typically induced by flexion or other movements of the neck) that radiates down the back into the legs; rarely radiating into the arms Generally self-limited but may persist for years

30. Paroxysmal symptoms B rief duration( 10 s to 2 min ) High frequency (5-40 episodes per day) Lack of any alteration of consciousness or change in background EEG during episodes A self-limited course (generally lasting weeks to months) May include Lhermitte's s ym ptom Tonic contractions of a limb, face or trunk (tonic seizures) Paroxysmal dysarthria and ataxia Paroxysmal sensory disturbances

31. Others Trigeminal neuralgia Hemifacial spasm Glossopharyngeal neuralgia Facial myokymia

32. Disease course

33. Relapsing/remitting MS (RRMS) Accounts for 85% of MS cases at onset Discrete attacks that generally evolve over days to weeks (rarely over hours). With initial attacks, there is often substantial or complete recovery over the ensuing weeks to months, but as attacks continue over time recovery may be less evident. Between attacks, patients are neurologically stable.

34. Secondary progressive MS (SPMS) Always begins as RRMS At some point however, the clinical course changes so that the patient experiences a steady deterioration in function unassociated with acute attacks (which may continue or cease during the progressive phase) . SPMS produces a greater amount of neurologic disability than RRMS. For a patient with RRMS, the risk of developing SPMS is -2% each year, meaning that the great majority of RRMS ultimately evolves into SPMS. SPMS appears to represent a late stage of the same underlying illness as RRMS

35. Primary progressive MS (PPMS) Accounts for 15% of cases. These patients do not experience attacks but only a steady functional decline from disease onset. Compared to RRMS, the sex distribution is more even, the disease begins later in life (mean age -40 years), and disability develops faster (at least relative to the onset of the first clinical symptom) Despite these differences， PPMS appears to represent the same underlying illness as RRMS

36. Progressive/relapsing MS (PRMS) Overlaps PPMS and SPMS and accounts for -5% of MS patients. Like patients with PPMS, these patients experience a steady deterioration in their condition from disease onset. However, like SPMS patients, they experience occasional attacks superimposed upon their progressive course

37. Effect of pregnancy Pregnancy: Fewer attacks than expected esp. in last trimester Postpartum 3 months : More attacks Overall unaffected DMAMS should be discontinued

38. DIAGNOSTlC TESTS

39. Magnetic Resonance Imaging Characteristic abnormalities are found in >95% of patients, although more than 90% of the lesions visualized by MRI are asymptomatic Lesions larger than 6 mm located in typical distribution of white matter lesion Corpus callosum Periventricular white matter Infratentorial (brainstem,cerebellum) Spinal cord

40. MRI Magnetic resonance spectroscopic imaging ( MRSI ): can quantitate molecules such as N-acetyl aspartate, which is a marker of axonal integrity. Magnetization transfer ratio (MTR): imaging may be able to distinguish demyelination from edema

41. Magnetic Resonance Imaging Axial first-echo image from T2-weighted sequence demonstrates multiple bright signal abnormalities in white matter, typical for MS

42. Magnetic Resonance Imaging Sagittal T2-weighted FLAIR demyelination appear high in signal as shown here in the corpus callosum.

43. Magnetic Resonance Imaging Sagittal T2-weighted image of the thoracic spine demonstrates a high-signal-intensity lesion in the midthoracic spinal cord

44. Magnetic Resonance Imaging Sagittal T1-weighted image obtained after the intravenous administration of gadolinium reveals focal areas of blood-brain barrier disruption, identified as high-signal-intensity regions

45. Magnetic Resonance Imaging Demyelinating white matter plaques are arranged at right angles to the lateral ventricles , related to medullary veins Dawson finger with enhancement on T1WI

46. Magnetic Resonance Imaging Black holes indicates chronic stage with white matter destruction, axonal loss and irreversible clinical outcome. Black holes may be a marker of irreversible demyelination and axonal loss.

47. Evoked Potentials Recording of the timing of CNS responses to specific stimuli Visual evoked potentials (VEPs) Somatosensory evoked potentials (SSEPs) Brainstem auditory evoked potentials (BAEPs ) EP abnormalities Non specific to MS Marked delay in the latency of a specific EP component is suggestive of demyelination

48. Cerebrospinal Fluid CSF abnormalities found in MS include: A mononuclear cell pleocytosis Increased level of intrathecally synthesized IgG IgG index = [IgG (CSF) / IgG (serum)] / [Albumin (CSF) /Albumin (serum)] Total CSF protein is usually normal Presence of oligoclonal bands

49. Diagnostic Criteria Dawson criteria: 1916 Schumacher criteria: 1965 Poser criteria: 1983 McDonald criteria: 2001 Revised McDonald criteria: 2005, 2010

50. 2010 Revised McDonald Criteria for the Diagnosis of Multiple Sclerosis Clinical Presentation Additional Data Needed for MS Diagnosis 2 or more attacks; Objective clinical e vidence of 2 or mor e le sions or objective clinical e vidence of 1 lesion with reasonable historical evidence of a prior attack None

51. 2010 Revised McDonald Criteria for the Diagnosis of Multiple Sclerosis Clinical Presentation Additional Data Needed for MS Diagnosis 2 or more attacks; Obj ective clinical evidence of 1 lesion Dissemination in space, demonstrated by ≥ 1 T2 lesion on MRI in at least two out of four MS-typical regions of the CNS (periventricular, juxtacortical, infratentorial, or spinal cord) OR Await a further clinical attack implicating a different CNS site

52. 2010 Revised McDonald Criteria for the Diagnosis of Multiple Sclerosis Clinical Presentation Additional Data Needed for MS Diagnosis 1 attack; objective clinical evidence of 2 or more lesions Dissemination in time, demonstrated by Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time OR A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan OR Await a second clinical attack

53. 2010 Revised McDonald Criteria for the Diagnosis of Multiple Sclerosis Clinical Presentation Additional Data Needed for MS Diagnosis 1 attack; objective clinical evidence of 1 lesion (clinically isolated syndrome) Dissemination in space and time, demonstrated by For dissemination in space ≥ 1 T2 lesion in at least two out of four MS-typical regions of the CNS (periventricular, juxtacortical , infratentorial , or spinal cord) OR Await a second clinical attack implicating a different CNS site AND For dissemination in time Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time OR A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan OR Await a second clinical attack

54. 2010 Revised McDonald Criteria for the Diagnosis of Multiple Sclerosis Clinical Presentation Additional Data Needed for MS Diagnosis Insidious neurologic progression suggestive of MS (PPMS) One year of disease progression (retrospectively or prospectively determined) PLUS Two out of the three following criteria Evidence for dissemination in space in the brain based on ≥ 1 T2+ lesions in the MS-characteristic periventricular, juxtacortical, or infratentorial regions Evidence for dissemination in space in the spinal cord based on 2 T2+ lesions in the cord Positive CSF (isoelectric focusing evidence of oligoclonal bands and/or elevated IgG index)

55. Prognosis 15 years after onset, only 20% of patients had no functional limitation Between 1/3 rd and 1/2 progressed to SPMS and required assistance with ambulation 25 years after onset, 80% of MS patients reached this level of disability.

56. Prognosis Favourable prognosis Optic Neuritis or sensory symptoms at onset Fewer than two relapses in the first year of illness Minimal impairment after 5 years Fewer MRI lesions during the early years of disease

57. Prognosis Poor Prognosis Patients with truncal ataxia, action tremor, pyramidal s ym ptoms , or a progressive disease course More MRI lesions during the early years of disease

58. Treatment

59. Kurtzke Expanded Disability Status Score (EDSS) Useful measure of neurologic impairment in MS

60. Kurtzke Expanded Disability Status Score (EDSS) Patients with EDSS scores <3.5 have RRMS, walk normally, and are generally not disabled Patients with EDSS scores >5.5 have progressive MS (SPMS or PPMS), are gait-impaired and typically are occupationally disabled

61. Acute Attacks or Initial Demyelinating Episodes Pseudoexacerbations vs new disease activity Pseudoexacerbation: Glucorticoid treatment inappropriate Glucocorticoids To manage first attack or acute exacerbations Provide short term benefit Long term benefit unclear Dose: IV methyl prednisolone: 500- 1000 mg/d for 3-5 days, either without a taper or followed by a course of oral prednisone beginning at a dose of 60-80 mg/d and gradually tapered over 2 weeks

62. Acute Attacks or Initial Demyelinating Episodes Plasma exchange (5 to 7 exchanges : 40-60 mL/kg per exchange, every other day for 14 days) may benefit patients with fulminant attacks of demyelination that are unresponsive to glucocorticoids High Cost Conclusive evidence of efficacy lacking

63. Disease-modifying agents for MS (DMAMS) Interferon beta-1a Interferon beta-1b Peginterferon beta-1a Glatiramer acetate Natalizumab Mitoxantrone  Fingolimod Teriflunomide Dimethyl fumarate Alemtuzumab

64. Interferon-ß Immunomodulatory properties including Downregulating expression of MHC molecules on APC Reducing proinflammatory and increasing regulatory cytokine levels Inhibiting T cell proliferation Limiting the trafficking of inflammatory cells in the CNS Reduces the attack rate and improves disease severity measures such as EDSS progression and MRI-documented disease burden Should be considered in patients with either RRMS or SPMS with superimposed relapses

65. Interferon-ß Doses: IFN -ß-1 a : 30 mcg IM qw or 44 mcg SC tiw IFN-ß-1 b : 250 mcg SC qod (the first drug for MS, 1993) Peg IFN -ß-1 a ( FDA Approved on 2014 Aug) Common side effects include Flu like symptoms(e.g. Fevers, chills, and myalgias ) Mild abnormalities on routine laboratory evaluation (e.g. elevated liver function tests or Iymphopenia ). Rarely, more severe hepatotoxicity Reactions at the injection site Development of neutralizing antibodies to IFN-ß should not affect the treatment if patient Is doing well on therapy.

66. Glatiramer Acetate Synthetic , random polypeptide composed of four amino acids (l-glutamic acid, l-lysine, l-alanine, and l-tyrosine ) Mechanism of action may include Induction of antigen-specific suppressor T cells Binding to MHC molecules, thereby displacing bound MBP Altering the balance between proinflammatory and regulatory cytokines . Should be considered in RRMS patients Reduces the attack rate (whether measured clinically or by MRI) in RRMS May also benefit disease severity measures An equally effective alternative to IFN-ß in RRMS patient Usefulness in progressive disease is entirely unknown

67. Glatiramer Acetate Dose: SC injection of either 20 mg qd or 40 mg thrice weekly Side Effects: Injection-site reactions Approximately 15% of patients experience one or more episodes of flushing, chest tightness, dyspnea, palpitations, and anxiety after injection

68. Natalizumab Humanized monoclonal antibody directed against the α4 subunit of α4 ß1 integrin, a cellular adhesion molecule expressed on the surface of lymphocytes Prevents lymphocytes from binding to endothelial cells, thereby preventing lymphocytes from penetrating the BBB and entering the CNS. Indicated as monotherapy for the treatment of patients with relapsing forms of MS Recommended only for JC antibody-negative patients, unless they have failed alternative therapies or if they have a particularly aggressive disease course

69. Natalizumab Dose: 300 mcg IV infusion q monthly Associated with progressive multifocal leukocephalopathy ( PML) in ~ 0.3 % of patients Risk of PML seems to increase with a history of previous immunosuppression, duration of exposure to natalizumab beyond 2 years, and JC virus antibody positivity < 10 % devlop hypersensitivity reactions (including anaphylaxis) and 6% develop neutralizing antibodies to the molecule

70. Fingolimod A sphingosine-1-phosphate (S1P) inhibitor Prevents the egress of lymphocytes from the secondary lymphoid organs such as the lymph nodes and spleen Fingolimod reduces the attack rate and significantly improves all measures of disease severity in MS Approved as first line therapy Dose : 0.5 mg PO q day Adverse Effects: Mild elevation of LFTs or lymphopenia First and second degree heart block and bradycardia Macular edema Disseminated VZV infection

71. Dimethyl Fumarate (DMF) Mechanism of action not fully understood it seems to have anti-inflammatory effects through its modulation of the expression of proinflammatory and anti-inflammatory cytokines. Reduces the attack rate and significantly improves all measures of disease severity Dose : 240 mg PO bd Side Effects Gastrointestinal side effects ( abdominal discomfort, nausea,vomiting , flushing and diarrhea) Mild elevation of LFTs or lymphopenia / neutropenia

72. Teriflunomide Active metabolite of the drug leflunomide E xerts its antiinflammatory effects by limiting the proliferation of rapidly dividing T and B cells FDA Approved in 2012 Reduces the attack rate and significantly improves all measures of disease severity Dose: 7 or 14 mg PO q day Side effects: headache, alopecia, diarrhea, nausea, increased ALT, influenza, and paresthesias Pregnancy: Category X

73. Mitoxantrone Hydrochloride Exerts its antineoplastic action by Intercalating into DNA and producing both strand breaks and interstrand cross-links Interfering with RNA synthesis Inhibiting topoisomerase II ( involved in DNA repair) Indicated for use in SPMS, in PRMS and in patients with worsening RRMS ( defined as patients whose neurologic status remains significantly abnormal between MS attacks )

74. Mitoxantrone Hydrochloride Can be cardiotoxic (e.g ., cardiomyopathy,reduced LVEF and irreversible congestive heart failure) > 40 % of women will experience amenorrhea ， which may be permanent Risk of acute leukemia ,at least a 1 % lifetime risk Not be used as a first-line agent in either RRMS or relapsing SPMS Dose: At currently approved doses ( 12 mg/m 2 q 3 months ), the maximum duration of therapy can be only 2-3 years

75. Alemtuzumab Humanized monoclonal antibody directed against the CD 52 antigen which is expressed on both lymphocytes and monocytes FDA approval in November 2014 Reserve use for patients who have an inadequate response to ≥2 other drugs for MS

76. Alemtuzumab Dose 1 st treatment course: 12 mg/day IV on 5 consecutive days (60 mg total dose) 2 nd treatment course: 12 mg/day on 3 consecutive days (36 mg total dose) given 12 months after the first treatment course Serious Side effects Autoimmune diseases including thyroiditis, Graves' disease, Thrombocytopenia, hemolytic anemia, pancytopenia, anti GBM dis ease and membranous GN Malignancies including thyroid cancer, melanoma, breast cancer, HPV-related cancers Serious infections and infusion reactions .

77. Symptomatic Therapy

78. Symptoms Treatment Pain 1. Anticonvulsants (carbamazepine, 100–1000 mg/d; phenytoin, 300–600 mg/d; gabapentin, 300–3600 mg/d; or pregabalin, 50–300 mg/d) 2. Antidepressants (amitriptyline, 25–150 mg/d; nortriptyline, 25–150 mg/d; desipramine, 100–300 mg/d; or venlafaxine, 75–225 mg/d) 3. Antiarrhythmics (mexiletine, 300–900 mg/d) Weakness K Channel Blockers such as 4-aminopyridine ( 10-40 mg/d) and 3,4-diaminopyridine (40-80 mg/d) Ataxia/Tremor Clonazepam, 1 .5-20 mg/primidone, 50-250 mg/d; propranolol, 40-200 mg/d; or ondansetron,8- 1 6 mg/d Spasticity and spasms Baclofen (20- 120 mg/d); diazepam (2-40 mgl/d; tizanidine (8-32 mg/d); dantrolene (25-400 mg/d), and cyclobenzaprine hydrochloride (10-60 mg/d) Cognitive problems Donepezil hydrochloride ( 10 mg/d) Bladder Dysfunction Antispasmodic Agents like propantheline bromide (10- 15 mg/dl); oxybutynin (5- 5 mg/d); hyoscyamine sulfate(0.5-0.75 mg/d); tolterodine tartrate (2-4 mg/d); or solifenacin (5 一 1 0 mg/d)

79. Promising experimental therapies Numerous clinical trials are currently underway Monoclonal antibodies against CD20 ( ocrelizumab ) Selective oral sphingosine-1-phosphate receptor antagonists such as laquinimod , ozanimod , ponesimod , and siponimod   Ofatumumab is also a CD20 inhibitor Daclizumab , an interleukin-2 inhibitor Estriol Molecules to promote remyelination Bone marrow transplantation

80. References Harrison’s Principles of Internal Medicine 19 th Edition Davidson’s Principle and Practice of Medicne, 22 nd Edition

81. Thank You