Multiple SclerosisDMW Dharmakeerthi (MD)Senior Registrar in clinicalNeurophysiology
EpidemiologyCompston A, et al. McAlpine‟s Multiple Sclerosis, 4th ed. Churchill Livingston, LondonPrevalence 5–200/100,000 populationSex distribution 70%–75% femaleAge at onset 20–40 yearsEthnic origin Predominantly Caucasian
The Basics - RevisionThe most common autoimmuneinflammatory demyelinating disease of theCNS.Episodes affecting different parts of thecentral nervous system at different times.Inflammation, leading to demyelinationand temporary conductionblock, symptomatic only if it occurs in aneloquent area.
PathogenesisPathogenesis of MS involves complex interactionsbetween genetic and environmental factorsMultiple genes are involvedTiming of environmental factors is important– The 1st event: in utero or early postnatal period– The 2nd event: after birth to age 15– The 3rd event: in adulthood (may be several)Vitamin D deficiency is a plausible candidate for the 1st factor; EBVinfection is a plausible candidate for the 2nd factorMS incidence has increased over the past 30 years due to a changein environmental exposure
Characterized pathologically by multifocalareas of demyelination with loss ofoligodendrocytes and astroglial scarring.Axonal injury is increasingly recognized asa prominent pathologic feature of MS.
Extravasationastrocytes BRAINTISSUEM Y E L IoligodendrocyteB cellRolling Adhesion4 IntegrinVCAMB L O O D F L O WLUMEN OFVENULEB A S A L L A M I N ACirculationActivated T cell ProteasesAntigen presenting cell(Astrocyte or Microglial cell)Activatedmicroglia/macrophagesT CELLREACTIVATIONActivatedMacrophageAutoantibodiesComplementIL-1, IL-12,chemokinesCytokines andchemokinesProteasesTNF-O2•-NO•AXONALDAMAGECourtesy of Sergio Baranzini, PhD.MS Disease Pathology
Pathogenesis of Multiple SclerosisMicroscopic PathologyCourtesy of D.P. Agamanolis, MD. http://neuropathology.neoucom.edu.
Some DefinitionsA Relapse:-Onset of new neurological symptoms, or a substantialdeterioration of previous symptoms, lasting more than 24hours, not explicable on the basis of infection or otherprocessClinically Isolated Syndrome:-Single neurological episode without clinical evidence ofprevious episodes, with a normal MRI scan has a ~20%chance of progressing to MS, with and abnormal scanfulfilling certain criteria has an 85% chance of developingMS
Some more definitionsRelapsing Remitting :- diseasecharacterised by relapses with substantialregression of symptoms afterwards – 70% startlike thisPrimary Progressive :- gradualprogressive disease from onset withoutrelapses. ~15% of MS casesSecondary Progressive :- progressivedisease following period or relapsing remittingdisease
2005 McDonald criteria revisions diagnostic criteria formultiple sclerosisClinical presentation Additional data needed for MS diagnosisTwo or more attacks*; objective clinical evidenceof two or more lesionsNone•Two or more attacks*; objective clinical evidenceof one lesionDissemination in space, demonstrated by: - MRIΔor- Two or more MRI-detected lesions consistentwith MS plus positive CSF or- Await furtherclinical attack* implicating a different siteOne attack*; objective clinical evidence of two ormore lesionsDissemination in time, demonstrated by: - MRIor- Second clinical attack*One attack*; objective clinical evidence of onelesion (monosymptomatic presentation; clinicallyisolated syndrome)Dissemination in space, demonstrated by:- MRIΔor- Two or more MRI-detected lesions consistentwith MS plus positive CSF and Dissemination intime, demonstrated by:- MRI or Second clinicalattack*Insidious neurological progression suggestive ofMSOne year of disease progression (retrospectivelyor prospectively determined) and Two of thefollowing:- Positive brain MRI (nine T2 lesions or four ormore T2 lesions with positive VEP)¥- Positivespinal cord MRI (two focal T2 lesions)- Positive CSF
CSFCSF total leukocyte count is normal in two-thirds ofpatientsCSF protein (or albumin) level is usually normalOligoclonal bandsAntimyelin antibodies - myelin oligodendrocyteglycoprotein (MOG) and myelin basic protein (MBP)
TimePreclinicalMRI ActivityRelapses/DisabilityMRI T2 Burden of DiseaseAxonal LossDisabilityCIS*Reprinted from Trapp BD, et al. Neuroscientist. 1999;5:48-57, with permission from Sage Publications.Relapsing-Remitting MSSecondary Progressive MSNatural History of MSClinical and MRI Measures
Acute relapsesIndications for treatment of a relapseinclude functionally disabling symptomswith objective evidence of neurologicimpairment.
Steroids in Acute RelapsesSpeed recovery from an acute relapseDo not alter the outcome at 6 monthsIf relapse severe + not improving in a few days– Exclude infection– Need adequate doses (>60mg)IV methyl pred 1g 3/7 or 500mg po for 5/7Gastric protection if a risk factorsAvoid oral tail-off unless prev. bad withdrawal– Avoid long term steroids– Counsel about long term side effects (incweakness, avascular necrosis)– PE for those not responding to steroids
Treatment of RRMSImmunomodulatory agentsA decreased relapse rateA reduced progression of disabilityA slower accumulation of lesions on MRIInterferon beta-1aInterferon beta-1bGlatiramer acetate
Current First-Line MS TherapiesInterferon beta-1b30 mcg Interferon beta-1a once weeklyGlatiramer acetateGenerally very safe and well toleratedAll require self-injection
When to treat?Potent immune modulation (alemtuzumab) given earlyin the disease appears not just to stop relapses but tohalt progression in the medium term (~5 years)Coles et al NEJM „08 359(17)The same treatment in patients with establishedsecondary progression stops relapses but fails to haltprogressionColes et al Annals Neurol. „99 46
Interferon beta-1b & 1aFirst medication approved by the US FDAAdministered EOD subcutaneously by selfinjectionInjection site necrosis and Flu-likesymptomsNeutralizing antibodies reduce thebioavailability of interferon
Glatiramer acetatePolymers of four amino acids competewith APC to T cellInducer of specific T helper 2 typesuppressor cellsInjection site reactions, chest pain,flushing, dyspnea, palpitationsNo laboratory monitoring is necessaryBEYOND, BECOME and REGARD trials
FingolimodSphingosine-1-phosphate receptor modulatorInduces rapid and reversible sequestration oflymphocytes in lymph nodes– Prevents activated and autoreactive cells frommigrating to target organsLymphocytes remain functional and may still beactivated as part of an immune responseCrosses blood brain barrier and may haveneuroprotective propertiesBrinkmann V, et al. J Biol Chem. 2002;277:21453-21457; Pinschewer DD, et al. J Immunol. 2000;164:5761-5770;Chiba K, et al. J Immunol. 1998;160:5037-5044.
FingolimodDaily oral tablet, first dose given in hospitaldue to potential for bradycardia and AVblockRelapse reduction 55% (0.18 cf 0.4relapse/yr)Macular oedema (?high dose only)Hypertension2 deaths from HSV/ZVZ encephalitisstopped two months prior to conceptionFREEDOMS TRANSFORMSPlacebo 0.40 /yr0.5 mg Fingolimod 0.18 /yr 0.16 /yr1.25 mgFingolimod0.16 /yr 0.20 /yrIFN-β1a (Avonex) 0.33 /yr
Fumaric Acid EstersDerived from common fumitory (Fumaria officinalis), aplant rich in fumaric acidUsed to treat skin disorders since the 17th centuryFumaric acid esters used in severe psoriasis– First reported by Schweckendiek in 1959Inhibits T-cell activity– Induction of activated lymphocyte apoptosis– Shift in cytokine profile from Th1 to Th2Effective in chronic experimental autoimmuneencephalomyelitisMay have neuroprotective properties by activatingantioxidant response genesSchilling S, et al. Clin Exp Immunol. 2006;145:101-107.
FumarateConclusionsFumarate reduced the cumulative number ofGad+ lesions, with a trend toward reducedrelapsesAdverse effects profile favorable withdiscontinuations due to nausea, flushing,headache, nasopharingitis (known effects inpsoriasis)Phase III trials are actively recruiting, completionexpected in 2011, launch in 2012
TeriflunomideLeflunomide parent compound used in treatmentof rheumatoid arthritisInhibits pyrimidine synthesis– Binds dihydroorotate dehydrogenase, the fourthenzyme in de novo pyrimidine synthesisInhibits T-cell divisionInhibits murine experimental autoimmuneencephalomyelitisZeyda M, et al. Arthritis Rheum. 2005;52:2730-2739.
Teriflunomide Phase IIPrimary Outcome13.45.2 5.30246810121416Placebo 7 mg/day 14 mg/dayCumulativeNo.ofUniqueActiveLesions61%, P <0.03O‟Connor PW, et al. Neurology.
Teriflunomide ConclusionsReduced cumulative number of Gad + lesions withfavorable trends for relapse rate reduction and disabilityOverall well tolerated with acceptable adverse effectprofileTeriflunomide is teratogenic in animalsReproductive toxicity in humans is not fully understood– Women are advised not to become pregnant and mencautioned not to parent children while on therapyWomen who wish to become pregnant– Washout with cholestyramine or activated charcoal andconfirmation of acceptable plasma levels ofteriflunomide– Without washout up to 2 years before plasma levelsdecrease sufficientlyO‟Connor PW, et al. Neurology.2006;66:894-900.
SummaryCumulative Number ofGad+ lesionsAnnualizedRelapse RateFingolimod (1.25 mg)(3-arm study, N = 277)-43%, P <0.001 -55%, P =0.009Teriflunomide (7 mg)(3-arm study, N = 178)-61%, P <0.03 -32%, NSLaquinimod (0.6 mg)(3-arm study, N = 306)-38%, P =0.005 -32%, NSFumarate (720 mg)(4-arm study, N = 256)-69%, P <0.001 -32%, NSCladribine (2.1 mg)(2-arm study, N = 52)-94%, P <0.001 -32%, P =0.011. Kappos L, et al. N Engl J Med. 2006;355:1124-1140. 2. O‟Connor PW, et al.Neurology. 2006;66:894-900. 3. Comi G, et al. 59th AAN Meeting; April 28-May 5,2007. Abstract S02.002. 4. Kappos L, et al. 22nd ECTRIMS 2006; September 27-
Natalizumab TysabriIntegrin α4 blockadeStops circulating lymphocytes entering the CNSWell tolerated monthly infusionsEffective relapse suppression (68% cf placebo)Risk of PML appears to increase with time ontreatment:-Very low in first yearBy 2 years around 1 in 1000 per year of treatmentRisk of rebound disease activity when stopped
MitoxantroneOriginally suggested for highly activeRRMS and possibly early progression50% reduction in relapse rateCardiotoxicity, less common with newerregimesRisk of Leukaemia – particularlyPromyelocytic leukaemia ?0.3%++
Alemtuzumab CampathAnti CD52 monoclonal depletes alllymphocytes,Prolonged immunomodulationHighly effective relapse reduction (78% cfIFNβ1a)Stops progressive disability when given early30% risk of AutoimmunityITPThyroid
Campath (Alemtuzumab)– Unlicensed, and cheap! (at present)No effect on established progressionMarked reduction in relapse rate for thosewith highly active disease – 74% cf IFNMost convincing effect on progression ofany drug, when started early enough25% occurrence of other autoimmunedisease (Graves, ITP etc)
AzathioprineOne small, open-label study found thatazathioprine up to 3 mg/kg per day waswell tolerated and reduced the rate of newgadolinium-enhancing brain lesions inpatients with RRMS
CyclophosphamideLimited observational evidence supportsthe use of pulse (eg, monthly) IVcyclophosphamide for RRMS
ConclusionsTo date, treatment has been successful insuppressing relapses and enhancing MRIlesionsEarly treatment with effective immunetherapy may alter the course of disease,preventing/ delaying later disability