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![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](https://image.slidesharecdn.com/multiplesclerosis-biplave-190401002125/75/Multiple-sclerosis-biplave-47-2048.jpg)
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Multiple sclerosis biplave
- 1. Multiple Sclerosis Dr. BIPLAVEKARKI RESIDENT, INTERNAL MEDICINE DHULIKHEL HOSPITAL
- 2. Introduction • A chronicimmune-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 350,000cases 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 incidencein 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 • VitaminD 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 susceptibility variants
- 6. Pathogenesis: Pathology Stage ofInflammation Stage of Demyelination Stage of Gliosis/Scarring
- 7. Pathogenesis: Pathology Stage ofinflammation • 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 ofdemyelination • 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 ofGliosis/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.
- 11. Clinical Manifestations • Onsetmay 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.
- 13. Weakness of thelimbs • 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 • Mayresult from Optic neuritis or Diplopia
- 16. Optic neuritis • Canbe 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 • Visualsymptoms 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 resultfrom – 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 Leftwardgaze Rightward gaze Upward gaze Downward gaze Adduction deficit in the right eye and nystagmus in the left eye
- 20. 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
- 21. Sensory symptoms • Sensoryimpairment 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
- 22. Ataxia • Limb ataxia •Cerebellar tremors • May also involve the head and trunk or the voice,producing a characteristic cerebellar dysarthria (scanning speech)
- 23. Bladder Dysfunction • In> 90% of patients • 1/3rd have weekly or more frequent episode of urinary incontinence • Detrusor hyperreflexia – causes urinary frequency, 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
- 24. GI Symptoms • Constipationoccurs in >30% of patients • Fecal urgency or bowel incontinence is less common ( < 15%)
- 25. Others • Cognitive dysfunction •Depression • Fatigue • Sexual dysfunction • Facial weakness • Vertigo • Hearing loss
- 26.
- 27. Heat sensitivity • Refersto 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 ( Uhthoff ‘s symptom) • MS symptoms worsen transiently, sometimes dramatically, during febrile ilInesses
- 28. Lhermitte's symptom • Anelectric 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
- 29. Paroxysmal symptoms • Briefduration( 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 symptom – Tonic contractions of a limb, face or trunk (tonic seizures) – Paroxysmal dysarthria and ataxia – Paroxysmal sensory disturbances
- 30. Others • Trigeminal neuralgia •Hemifacial spasm • Glossopharyngeal neuralgia • Facial myokymia
- 31.
- 32. Relapsing/remitting MS (RRMS) • Accountsfor 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.
- 33. Secondary progressive MS (SPMS) •Alwaysbegins 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.
- 34. 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
- 35. Progressive/relapsing MS (PRMS) • OverlapsPPMS 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
- 36. Effect of pregnancy •Pregnancy: – Fewer attacks than expected esp. in last trimester • Postpartum 3 months : – More attacks • Overall unaffected • DMAMS should be discontinued
- 37.
- 38. 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 •
- 39. MRI • Magnetic resonancespectroscopic 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
- 40. Magnetic Resonance Imaging Axialfirst-echo image from T2-weighted sequence demonstrates multiple bright signal abnormalities in white matter, typical for MS
- 41. Magnetic Resonance Imaging SagittalT2-weighted FLAIR demyelination appear high in signal as shown here in the corpus callosum.
- 42. Magnetic Resonance Imaging SagittalT2-weighted image of the thoracic spine demonstrates a high-signal-intensity lesion in the midthoracic spinal cord
- 43. Magnetic Resonance Imaging SagittalT1-weighted image obtained after the intravenous administration of gadolinium reveals focal areas of blood-brain barrier disruption, identified as high-signal-intensity regions
- 44. Magnetic Resonance Imaging Demyelinatingwhite matter plaques are arranged at right angles to the lateral ventricles, related to medullary veins Dawson finger with enhancement on T1WI
- 45. 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.
- 46. Evoked Potentials • Recordingof 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
- 47. Cerebrospinal Fluid • CSFabnormalities 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
- 48. 2010 Revised McDonaldCriteria for the Diagnosis of Multiple Sclerosis Clinical Presentation Additional Data Needed for MS Diagnosis 2 or more attacks; Objective clinical evidence of 2 or more lesions or objective clinical evidence of 1 lesion with reasonable historical evidence of a prior attack None
- 49. 2010 Revised McDonaldCriteria for the Diagnosis of Multiple Sclerosis Clinical Presentation Additional Data Needed for MS Diagnosis 2 or more attacks; Objective 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
- 50. 2010 Revised McDonaldCriteria 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
- 51. 2010 Revised McDonaldCriteria 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
- 52. 2010 Revised McDonaldCriteria 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)
- 54. Prognosis • 15 yearsafter onset, only 20% of patients had no functional limitation • Between 1/3rd and 1/2 progressed to SPMS and required assistance with ambulation • 25 years after onset, 80% of MS patients reached this level of disability.
- 55. 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
- 56. Prognosis • Poor Prognosis –Patients with truncal ataxia, action tremor, pyramidal symptoms, or a progressive disease course – More MRI lesions during the early years of disease
- 57.
- 58. Kurtzke Expanded DisabilityStatus Score (EDSS) • Useful measure of neurologic impairment in MS
- 59. Kurtzke Expanded DisabilityStatus 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
- 60. Acute Attacks orInitial 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
- 61. Acute Attacks orInitial 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
- 62. Disease-modifying agents forMS (DMAMS) • Interferon beta-1a • Interferon beta-1b • Peginterferon beta-1a • Glatiramer acetate • Natalizumab • Mitoxantrone • Fingolimod • Teriflunomide • Dimethyl fumarate • Alemtuzumab
- 63. Interferon-ß • Immunomodulatory propertiesincluding – 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
- 64. 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.
- 65. 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
- 66. 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
- 67. Natalizumab • Humanized monoclonalantibody directed against the α4 subunit of α4ß1 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
- 68. Natalizumab • Dose: 300mcg 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
- 69. 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
- 70. 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
- 71. Teriflunomide • Active metaboliteof the drug leflunomide • Exerts 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
- 72. Mitoxantrone Hydrochloride • Exertsits 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)
- 73. Mitoxantrone Hydrochloride • Canbe 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/m2 q 3 months), the maximum duration of therapy can be only 2-3 years
- 74. Alemtuzumab • Humanized monoclonalantibody 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
- 75. Alemtuzumab • Dose – 1sttreatment course: 12 mg/day IV on 5 consecutive days (60 mg total dose) – 2nd 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 disease and membranous GN – Malignancies including thyroid cancer, melanoma, breast cancer,HPV-related cancers – Serious infections and infusion reactions.
- 78.
- 79. 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)
- 80. 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
- 81. References • Harrison’s Principlesof Internal Medicine 19th Edition • Davidson’s Principle and Practice of Medicne, 22nd Edition
- 82.
Editor's Notes
- #3 In most cases, the disease follows a relapsing-remitting pattern, with short-term episodes of neurologic deficits that resolve completely or almost completely. A minority of patients experience steadily progressive neurologic deterioration
- #4 with the highest known prevalence for MS (250 per 100,000) in the Orkney Islands, located north of Scotland. In other temperate zone areas (e.g., northern North America, northern Europe, southern Australia, and south New Zealand), the prevalence of MS is 0.1–0.2%. By contrast, in the tropics (e.g., Asia, equatorial Africa, and the Middle East), the prevalence is often ten- to twentyfold less.
- #6 At least three sequential (population-wide) environmental events are implicated in the causal pathway leading to MS. The first factor seems to occur either in utero or in the early postnatal period and is supported, in part, by the almost twofold increase in MS risk for dizygotic twins of MS probands (5.4%) compared to siblings (2.9%). It is also supported by the month-of-birth effect (in the northern hemisphere), in which May babies are significantly more likely, and November babies less likely, to develop MS compared to babies born in other months. Importantly, a recently published population-based study in the southern hemisphere (Australia) found a similar (but inverted) month-of-birth effect with the zenith in risk occurring for November/December babies and the nadir occurring for May/June babies. This month-of-birth effect provides evidence for an early environmental event, involved in MS pathogenesis, that is both coupled to the solar cycle and time-locked to birth. A second factor seems to occur during adolescence. Thus, several studies suggest that when individuals move (prior to their adolescent years) from an area of high MS prevalence to an area of low prevalence (or vice versa), their MS risk becomes similar to that of the region to which they moved. By contrast, when they make the same move after adolescence, their MS risk remains similar to that of the region from which they moved.
- #7 Whites are inherently at higher risk for MS than Africans or Asians, even when residing in a similar environment. MS also aggregates within some families, and adoption, half-sibling, twin, and spousal studies indicate that familial aggregation is due to genetic, and not environmental, factors
- #8 New MS lesions begin with perivenular cuffing by inflammatory mononuclear cells， predominantly T cells and macrophages，which also infùtrate the surrounding white matter. At sites of inflammation，the blood-brain barrier (BBB) is disrupted， but unlike vasculitis， the vessel wall is preserved. Involvement of the humoral immune system is also evident; small numbers of B Iymphocytes also infiltrate the nervous system， myelin-specific autoantibodies are present on degenerating myelin shea出s， and complement is activated. Demyelination is the hallmark of the pathology， and evidence of myelin degeneration is found at the earliest time points of tissue injury. A remarkable feature of MS plaques is that oligodendrocyte precursor cells survive-and in many lesions are present in even greater numbers than in normal tissue-but these cells fail to differentiate into mature myelin-producing cells. In some lesions， surviving oligodendrocytes or those that differentiate from precursor cells partially remyelinate the surviving naked axons， producing so-called shadow plaques. As lesions evolve， there is prominent astrocytic proliferation (gliosis) . Over time， ectopic Iymphocyte follicle-like structures， consisting of aggregates of T and B cells resembling secondary Iymphoid tissue， appear in the meninges and especially overlying deep cortical sulci and also in perivascular spaces. Although relative sparing of axons is typical of MS， partial or total axonal destruction can also occur， especially within highly inflammatory lesions. Thus MS is not solely a disease of myelin， and neuronal patholo窃T is increasingly recognized as a major contributor to irreversible neurologic disability. Inflammation， demyelination， and plaque formation are also present in the cerebral cortex， and significant axon loss indicating death of neurons is widespread， especially in advanced cases (see "Neurodegeneration，" below)
- #9 New MS lesions begin with perivenular cuffing by inflammatory mononuclear cells， predominantly T cells and macrophages，which also infùtrate the surrounding white matter. At sites of inflammation，the blood-brain barrier (BBB) is disrupted， but unlike vasculitis， the vessel wall is preserved. Involvement of the humoral immune system is also evident; small numbers of B Iymphocytes also infiltrate the nervous system， myelin-specific autoantibodies are present on degenerating myelin shea出s， and complement is activated. Demyelination is the hallmark of the pathology， and evidence of myelin degeneration is found at the earliest time points of tissue injury. A remarkable feature of MS plaques is that oligodendrocyte precursor cells survive-and in many lesions are present in even greater numbers than in normal tissue-but these cells fail to differentiate into mature myelin-producing cells. In some lesions， surviving oligodendrocytes or those that differentiate from precursor cells partially remyelinate the surviving naked axons， producing so-called shadow plaques. As lesions evolve， there is prominent astrocytic proliferation (gliosis) . Over time， ectopic Iymphocyte follicle-like structures， consisting of aggregates of T and B cells resembling secondary Iymphoid tissue， appear in the meninges and especially overlying deep cortical sulci and also in perivascular spaces. Although relative sparing of axons is typical of MS， partial or total axonal destruction can also occur， especially within highly inflammatory lesions. Thus MS is not solely a disease of myelin， and neuronal patholo窃T is increasingly recognized as a major contributor to irreversible neurologic disability. Inflammation， demyelination， and plaque formation are also present in the cerebral cortex， and significant axon loss indicating death of neurons is widespread， especially in advanced cases (see "Neurodegeneration，" below)
- #10 MMUNOLOGY A proinflammatory autoimmune response directed against a component of CNS myelin， and perhaps other neural elements as well， remains the cornerstone of current concepts of MS pathogenesis. AUTOREA CηVE T L YMPHOCY陀5 Myelin basic protein (MBP)， an intracellular protein involved in myelin compaction， is an important T cell antigen in experimental allergic encephalomyelitis (EA日， a laboratory model， and probably also in human MS. Activated MBP-reactive T cells have been identified in the blood， in cerebrospinal fluid (CSF) ，and within MS lesions. Moreover， DRB1 水15:01 may influence the autoimmune response because it binds with high affinity to a fragment of MBP (spanning amino acids 89-96)， stimulating T cell responses to this self-protein. Two different populations of proinflammatory T cells are likely to mediate autoimmunity in MS. T-helper type 1 (TH 1 ) cells producing interferon '1 (IFN-y) are one key effector population， and more recently， a role for highly proinflammatory T H 1 7 T cells has been established. T H 17 cells are induced by transforming growth factor ß (TGF-ß) and 1L-6 and are amplified by 1L- 2 1 and 1L-23. TH 1 7 cells， and levels of their corresponding cytokine 1L- 1 7， are increased in MS lesions and also in the circulation of people with active MS. High cir culating levels of IL- 1 7 may also be a marker of a more severe course of MS. TH 1 cytokines， including 1L-2， tumor necrosis factor (TNF)-α， and 1FN-y， also play key roles in activating and maintaining autoimmune responses， and TNF-α and 1FN -'1 may directly injure oligodendrocytes or the myelin membrane. HUMORAL A U TOIMMUNITY B cell activation and antibody responses also appear to be necessarγ for the full development of demyelinating lesions to occur， both in experimental models and in human MS. Clonally restricted populations of activated， antigen-experienced， memory B cells and plasma cells are present in MS lesions， in lymphoid follicle-like structures in the meninges overlying the cerebral cortex， and in the CSF. Similar or identical clonal populations are found in each compartment， indicating that a highly focused B cell response is occurring locally within the CNS in MS. Myelin-specific autoantibodies， some directed against an extracellular myelin protein， myelin oligodendrocyte glycoprotein (MOG)， have been detected bound to vesiculated myelin debris in MS plaques. 1n the CSF， elevated levels of locally s严ühesized immunoglobulins and oligoclonal antibodies，derived from clonally restricted CNS B cells and plasma cells， are also characteristic of MS. The pattern of oligoclonal banding is unique to each individual， and attempts to identi命the targets of these antibodies have been largely unsuccessful.
- #11 . Over time, ectopic lymphocyte follicles appear in perivascular and perimeningeal regions, consisting of aggregates of T and B cells and resembling secondary lymphoid structures. Although relative sparing of axons is typical of MS, partial or total axonal destruction can also occur, especially within highly inflammatory lesions. Thus, MS is not solely a disease of myelin, and neuronal pathology is increasingly recognized as a major contributor to irreversible neurologic disability. Inflammation and plaque formation are present in the cerebral cortex, and significant axon loss indicating death of neurons is widespread, specially in advanced cases
- #12 Nerve conduction in myelinated axons occurs in a saltatory manner, with the nerve impulse jumping from one node of Ranvier to the next without depolarization of the axonal membrane underlying the myelin sheath between nodes. This produces considerably faster conduction velocities (70 m/s) than the slow velocities (1 m/s) produced by continuous propagation in unmyelinated nerves. Conduction block occurs when the nerve impulse is unable to traverse the demyelinated segment. This can happen when the resting axon membrane becomes hyperpolarized due to the exposure of voltage-dependent potassium channels that are normally buried underneath the myelin sheath. A temporary conduction block often follows a demyelinating event before sodium channels (originally concentrated at the nodes) redistribute along the naked axon. This redistribution ultimately allows continuous propagation of nerve action potentials through the demyelinated segment. Conduction block may be incomplete, affecting high- but not low-frequency volleys of impulses. Variable conduction block can occur with raised body temperature or metabolic alterations and may explain clinical fluctuations that vary from hour to hour or appear with fever or exercise. Conduction slowing occurs when the demyelinated segments of the axonal membrane is reorganized to support continuous (slow) nerve impulse propagation
- #13 Symptoms may be severe or seem so trivial that a patient may not seek medical attention for months or years. Indeed， at autopsy， approximately 0 . 1 % of individuals who were asymptomatic during life will be found， unexpectedly，to have pathologic evidence of MS. Similarly， in the modern era， an MRI scan obtained for an unrelated reason may show evidence of asymptomatic MS. Examination often reveals evidence of neurologic dysfunction， often in asymptomatic locations. For example， a patient may present with symptoms in one leg but signs in both
- #15 The weakness is of the upper motor neuron type is usually accompanied by other pyramidal signs such as spasticity， hyperreflexia， and Babinski signs. Occasionally a tendon reflex may be lost (simulating a lower motor neuron lesion) if an MS lesion disrupts the afferent reflex fibers in the spinal cord
- #16 Spasticity is commonly associated with spontaneous and movement-induced muscle spasms. More than 30% of MS patients have moderate to severe spasticity， especially in the legs. This is often accompanied by painful spasms interfering with ambulation， work， or self-care. Occasionally spasticity provides support for the body weight during ambulation， and in these cases， treatment of spastiαty may actually do more harm than good.
- #17 may result from ON or diplopia (double vision) ; if the symptom resolves when either eye is covered， the cause is diplopia
- #18 Optic neuritis (ON) can be the first demyelinating event in approximately 20% of patients with MS. ON develops in approximately 40% of MS patients during the course of their disease Much less commonly, patients with ON may describe phosphenes (transient flashes of light or black squares) lasting from hours to months. Phosphenes may occur before or during an ON event or even several months following recovery.
- #21 The patient had an adduction deficit in the right eye and nystagmus in the left eye on leftward gaze (Panel A). He also had an adduction deficit in the left eye and nystagmus in the right eye on rightward gaze (Panel B). Upward gaze (Panel C), downward gaze (Panel D), and normal primary position (Panel E) were unremarkable
- #24 Transverse myelitis can be a rare complication following cat scratch disease.[6] It can also be associated with: Bacterial Infections - Mycoplasma pneumoniae, Lyme borreliosis, syphilis (tabes dorsalis), tuberculosis Viral Infections - herpes simplex, herpes zoster, cytomegalovirus, Epstein-Barr virus, enteroviruses (poliomyelitis, Coxsackie virus, echovirus), human T-cell, leukemia virus, human immunodeficiency virus, influenza, rabies Post-Vaccination - Rabies, cowpox Multiple sclerosis Paraneoplastic syndromes Vascular - thrombosis of spinal arteries, vasculitis secondary to heroin abuse, spinal arteriovenous malformations
- #26 Detrusor hyperrefexia due to impairment of suprasegmental inhibition， causes urinary frequency, urgency,nocturia and uncontrolled bladder emptying Detrusor sphincter dyssynergia, due to loss of synchronization between detrusor and sphincter muscles, causes difficulty in initiating and/or stopping the urinary stream,producing hesitancy, urinary retention, overflow incontinence,and recurrent infection
- #28 Cognitive dysfunction can include memory loss; impaired attention; difficulties in executive functioni吨， memory， and problem solving; slowed information processing; and problems shifting between cognitive tasks. Euphoria (elevated mood) was once thought to be characteristic of MS but is actually uncommon， occurring in <20% of patients. Cognitive dysfunction sufficient to impair activities of daily living is rare. Facial weakness due to a lesion in the pons may resemble idiopathic Bell's palsy) . Unlike Bell's palsy， facial weakness in MS is usually not associated with ipsilateral loss of taste sensation or retroauricular pain. Vertigo may
- #29 Something that is subordinate, auxiliary, or supplementary.
- #30 from transient conduction block (see above) .
- #31 Lhermitte’s phenomenon (LP), (“Lhermitte’s sign”, “barber chair sign” or “barber shop sign”) also seen in cervical lesions. Typical LP; Post-traumatic LP (contusion of the spinal cord from neck trauma); Reverse LP (extrinsic compression of the cervical spinal cord during neck extension); Inverse LP (upward moving paresthesia induced by neck flexion) Reverse LP is defined when symptoms are induced by neck extension, not flexion. LP represents spinal demyelination disorders, reverse LP is induced by extrinsic compression of the cervical cord, and neck collar immobilization rather than intravenous or oral medication is recommended
- #33 Trigeminal neuralgia, hemifacial spasm and glossopharyngeal neuralgia can occur when the demyelinating lesion involves the root entry (or exit) zone of the fifth, seventh and ninth cranial nerve，respectively. Trigeminal neuralgia (tic douloureux) is a very brief lancinating facial pain often triggered by an afferent input from the face or teeth. Most cases of trigeminal neuralgia are not MS related; however， atypical features such as onset before age 50 years， bilateral symptoms， objective sensory loss， or nonparoxysmal pain should raise the possibility that MS could be responsible. Facial myokymia consists of either persistent rapid flickering contractions of the facial musculature (especially the lower portion of the orbicularis oculus) or a contraction that slowly spreads across the face. It results from lesions of the corticobulbar tracts or brainstem course of the facial nerve.
- #34 Relapsing/remitting MS (RRMS) (Fig. A) Accounts for 85% of MS cases at onset and is characterized by 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. 2. Secondary progressive MS (SPMS) always begins as RRMS (Fig. B) 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. 3. Primary progressive MS (PPMS) (Fig. C) 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. 4. 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
- #39 Disease modifying agents for multiple sclerosis (DMAMS)
- #42 magnetization transfer ratio (MTR) imaging and proton magnetic resonance spectroscopic imaging (MRSI)
- #44 Sagittal T2-weighted FLAIR (fluid attenuated inversion recovery) image in which the high signal of CSF has been suppressed. CSF appears dark, while areas of brain edema or demyelination appear high in signal as shown here in the corpus callosum (arrows)
- #46 Sagittal T1-weighted image obtained after the intravenous administration of gadolinium DTPA reveals focal areas of blood-brain barrier disruption, identified as high-signal-intensity regions (arrows)
- #47 MRI feature in multiple sclerosis where demyelinating white matter plaques are arranged at right angles to the lateral ventricles. The unique orientation of these plaques is thought to be related to medullary veins. Dawson means son of david
- #48 T1 black holes are hypointense lesions commonly seen on T1WI in patients withmultiple sclerosis, and indicates the chronic stage with white matter destruction, axonal loss and irreversible clinical outcome. Black holes may be a marker of irreversible demyelination and axonal loss
- #49 VEPs are performed by having a patient focus on a reversing black-and-white checkerboard pattern. Delays in latencies indicate demyelination in the anterior visual pathways. VEPs are not typically necessary for patients with clear clinical evidence of optic neuritis (ON). SSEPs evaluate the posterior column of the spinal cord, the brainstem, and the cerebral cortex. Delays in latencies of various peaks indicate demyelination in the correlated pathway of the spinal cord or brain. BAEPs are performed to evaluate ipsilateral asymptomatic MS lesions in the auditory pathways. They are less sensitive than VEPs and SSEPs. EP abnormalities are not specific to MS,although a marked delay in the latency of a specific EP component (as opposed to a reduced amplitude or distorted wave-shape) is suggestive of demyelination
- #50 A pleocytosis of >75 cells/μL， the presence of polymorphonuclear leukocytes， or a protein concentration >1 g/L (> 100 mg/dL) in CSF should raise concern that the patient may not have MS. IgG Index normal (0.30 to 0.67) as well as abnormal (0.50 to 0.89 The measurement of oligoclonal bands (OCBs) by agarose gel electrophoresis in the CSF also assesses intrathecal production of IgG. Two or more discrete OCBs， not present in a paired serum sample， are found in >75% of patients with MS. OCBs may be absent at the onset of MS， and in individual patients， the number of bands may increase with time.
- #55 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
- #56 Polmantly sensitivity and specificity of McDonald's criteria are 46% and 63% re
- #60 Mortality as a direct consequence of MS is uncommon,although it has been estimated that the 25-year survival is only 85% of expected The likelihood of having benign MS is thought to be <20%. In patients with their first demyelinating event (i.e.， a clinically isolated syndrome)， the brain MRI provides prognostic information With three or more typical T2-weighted lesions， the risk of developing MS after 20 years is -80%. Conversely， with a normal brain MRI， the likelihood of developing MS is <20%. Similarly， the presence of two or more Gd-enhancing lesions at baseline is highly predictive of future
- #64 When patients experience acute deterioration， it is important to consider whether this change reflects new disease activity or a "pseudo exacerbation" resulting from an increase in ambient temperature， fever， or an infection. When the clinical change is thought to reflect a pseudoexacerbation， glucocorticoid treatment is inappropriate Side effects of short-term glucocorticoid therapy include fluid retention， potassium loss， weight gain， gastric disturbances， acne and emotional lability. Concurrent use of a low-salt， potassium-rich diet and avoidance of potassium-wasting diuretics are advisable. Lithium carbonate (300 mg oral iv bid) may help to manage emotional lability and insomnia associated with glucocorticoid therapy. Patients with a history of peptic ulcer disease may require cimetidine (400 mg bid) or ranitidine ( 150 mg bid). Proton pump inhibitors such as pantoprazole (40 mg oral iv bid) may reduce the likelihood of gastritis， especially when large doses are administered oral iv. Plasma exchange (five to seven 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. However， the cost is high， and conclusive evidence of efficacy is lacking.
- #68 In patients with SPMS but without relapses efficacy has not been established. In Europe and Canada, higher doses of subcutaneous interferon beta-1a (Rebif) were studied in the Prevention of Relapse and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) Study. Interferon beta-1a reported a 27% reduction in the relapse rate in patients receiving 66 µg/wk and a 33% reduction in those receiving 132 µg/wk. In the Evidence of Interferon Dose-response: European North American Comparative Efficacy (EVIDENCE) trial, which compared 2 preparations of interferon beta-1a (Rebif and Avonex), relapse occurred less frequently with 44 µg 3 times weekly (Rebif) than with 30 µg once weekly (Avonex) (25% vs 37%).[82] In addition, the mean number of active unique MRI lesions per patient per scan was lower in the Rebif than in the Avonex group (0.17 vs 0.33). Patients on Rebif experienced fewer flulike symptoms, but more injection site reactions, hepatic function disorders, and white blood cell disorders ADVANCE trial of >1,500 patients with MS over a 2-year period, in the first year of the trial, peginterferon beta-1a dosed every 2 weeks significantly reduced annualized relapse rate (ARR) at 1 year by 36% compared with placebo (P = 0.0007). Peg IFN -ß-1 a ( FDA Approved on 2014 Aug) Day 1: 63 mcg SC once, Day 15: 94 mcg SC once, Beginning on day 29 and thereafter: 125 mcg SC q2wk. Common side effects of IFN-ß therapy include flu like symptoms (e.g.， fevers， chills， and myalgias) and mild abnormalities on routine laboratory evaluation (e.g.， elevated liver function tests or lymphopenia). Rarely， more severe hepatotoxicity may occur. Subcutaneous IFN-ß also causes reactions at the injection site (e.g .， pain， redness， induration， or， rarely， skin necrosis). Side effects can usually be managed with concomitant nonsteroidal anti-inflammatory medications, Depression， increased spasticity， and cognitive changes have been reported， although these symptoms can also be due to the underlying disease. Approximately 2-10% of IFN-ß-1 a (Avonex) recipients, 15-25% IFN-ß-1 a (Rebif) recipients， and 30-40% of IFN-ß-1 b (Betaseron/extavia) recepients develop neutralizing antibodies to IFN-B, which may disappear over time.
- #70 REGARD and BEYOND study
- #71 Indicated as monotherapy for the treatment of patients with relapsing forms of MS, to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations prevents lymphocytes from binding to endothelial cells, thereby preventing lymphocytes from penetrating the BBB and entering the CNS Nata l izumab is hig h ly effective i n red ucing the attack rate and significantly improves a l l measures of disease severity in MS (both c l i n ical and MRI). . Moreover， it is wel l-tolerated， and the dosing sched u l e of monthly intravenous infusions ma kes it very convenient for patients.
- #72 However， prog ressive mu ltifocal leukoencephalopa thy (PML)， a l ife-threatening condition resulting from i nfection by the John Cunningham (JC) virus， has occu rred in a pproximately 0.3% of patients treated with nata l izumab. The i ncidence of PML is very low i n the first yea r of treatment but then rises by the second yea r to reach a level of a bout 2 cases per 1 000 patients per yea r N evertheless， the measurement of antibodies against the JC virus i n the serum can be used to stratify this risk. Thus， in patients who do not have these a nti bod ies， the risk of PML is either m i n i m a l or nonexistent (as long as they rema i n JC a nti body free). Conversely， in patients who have these antibodies (especia l ly those who have them in high titer)， the risk may be as high as 0.6% or g reater. The risk is also high in patients who have previously received i m m unosuppressive
- #73 A sphingosine-1-phosphate (S1P) inhibitor and it prevents the egress of lymphocytes from the secondary lymphoid organs such as the lymph nodes and spleen. Its mechanism of action is probably due, in part, to the trapping of lymphocytes in the periphery and the prevention, thereby, of lymphocytes reaching the brain. Mild abnormalities on routine laboratory evaluation (e.g., elevated liver function tests or lymphopenia) are more common than in controls. Although rarely severe, sometimes discontinuation of the medication is necessary. First-degree heart block and bradycardia can also occur, the latter necessitating the prolonged (6-h) observation of patients receiving their first dose Egress (the action of going out of or leaving a place)
- #74 DEFINE & CONFIR M Trial inhibits the ubiquitylation and degradation of nuclear factor E2-related factor 2 (N rf2)-a transcription factor that binds to the antioxidant response elements (AREs) located on the DNA and thereby induces the transcription of several antioxidant proteins inhibits the ubiquitylation and degradation of nuclear factor E2-related factor 2 (Nrf2)—a transcription factor that binds to the antioxidant response elements (AREs) located on the DNA and thereby induces the transcription of several antioxidant proteins. DMF also used in Psoriasis
- #75 TEMSO trial Terifl u nomide i n h i bits the m itochondrial enzyme di hyd ro-orotate dehyd rogenase， which is a key pa rt of the pathway for de novo pyrimidine biosynthesis from carba moyl phosphate and aspartate. It is the active meta bol ite of the d rug lefl u nomide (FDA-a pproved for rheu matoid a rth ritis)， and it exerts its a ntiinfl a m matory effects by l i miting the prol iferation of ra pidly divid ing T and B cells. This enzyme is not i nvolved i n the so 日l I ed 飞a lvage pathway，" by which existi ng pyri midine pools a re recycled for DNA and RNA synthesis in resting and homeostatica l ly prol iferating cells. Consequently， terifl u nomide is considered to be cytostatic rather than cytotoxic A major l i m itation， especia l ly in women of childbearing age， is its possible teratogenicity (preg na ncy category X); terifl u nomide can rema i n in the bloodstrea m for 2 yea rs， and it is recom mended that exposed men and women who wish to conceive receive cholecystyra m i n e or activated charcoa l to e l i m i nate residual drug.
- #80 Ca n i n c l u d e tria l s of d i忏ere nt preparatio n s of i nterferon ß ( I F N-ß， pa rtic u l a rly adva nc i n g fro m o nce-weekly (Avo nex) to a more fr巴q uent (e.g.， Rebif， Beta sero n/Extavia) d o s i n g r巳g i m e n . O pti o n s a l so i n c l u d e use of nata l iz u m a b i n J C viru s-positive patients. MRI， m a g n etic res o n a n ce i m a g i n g
- #81 Azathioprine (2-3 mg/kg per day) Methotrexate (7.5-20 mg/week) Cyclophosphamide (700 mgl肘， every other month) Intravenous immunoglobulin (IVlg， administered in monthly pulses (up to 1 g/kg) for up to 2 years， ethylprednisolone， administered in one study as monthly highdose intravenous pulses，reduced disability progression (see above Cyclophosphamide has shown benefit in PPMS in some trials.
- #83 Ataxia/tremor : often intractable , Hand weights reduce tremor ; Thalamotomy/DBS with mixed success Spasticity :Physical therapy, regular exercise, and stretching cholinesterase i n h i bitor donepezil hydroch loride ( 1 0 mg/d)
- #84 monoclonal antibodies against CD20 to deplete B cells and against the IL-2 receptor selective oral sphingosine-1-phosphate receptor a ntagonists to sequester Iymphocytes in secondary Iymphoid organs; (3) estriol to induce a pregnancy-like state; (4) molecules to promote remyelination;and (4) bone marrow transplantation