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Multiple Sclerosis: Some Basics

Worth Understanding COPE 52199-NO

A. Paul Chous, MA, OD, FAAO

4/18/17

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Mul$pleSclerosis:SomeBasicsWorthUnderstanding

A.   PaulChous,M.A.O.D.,FAAO,CDETacoma,WA

Disclosure n  I have been a consultant for, been on advisory

boards or spoken on behalf of the following: Alcon, Bausch & Lomb, Freedom Meditech, Glaxo Smith Kline, Kestrel, Kowa, Optos, Prodigy Diabetes Care, Regeneron, Risk Medical Solutions, VSP, Zeavision, Zeiss

My affiliations with these companies have not affected the materials within this lecture

33yofemale•  “IseedoublewhenIlookupatroadsigns”

•  BCVA20/20OD/OS•  PERRLAwithoutAPD•  Visiondimsintheshower

•  Eyesarestraightoncovertest

•  EOMsareabnormal

WhatIsThis??

Bilateral INO

WhatisMS?

•  AutoimmuneDiseaseoftheCNS•  Demyelina$onofwhitemaSer

Brain Spinal cord

WhatisMS?•  MSisanimmune-mediateddiseaseofthebrainandspinalcord– 450,000affectedinUS– 8,500-10,000newcases/yr

•  ImmunesystemaSacksanddestroysmyelinandaxons

•  Characterizedbydemyelina$onandaxonalloss

•  Demyelina$ngplaques:well-demarcatedareascharacterizedbylossofmyelin

MS Plaques

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WhatisMS?•  Dymyelina$onresultsin

– Paresthesia(numbness&weakness)– Lossofskeletalmusclecoordina$on– Lossofautonomicfunc$on

• Mul$plesitesofCNSinvolvement• Mul$pleaSacksover$me

Most Relevant Signs and Symptoms of MS in the Primary Care Setting

Pain

Vertigo Depression

Fatigue Numbness

Diplopia

Bladder Dysfunction

Gait impairments Cognitive Dysfunction

Sexual Dysfunction Bowel Dysfunction

Paresis

Epidemiology•  Prevalencethatrangesbetween2and291per100,000dependingonthecountryorspecificpopula$on

•  PrimarilyadiseaseofNorthernandCentral

Europeansandtheirdescendants

•  Sunlight&VitaminDintakeappeartolowerrisk

•  RareinEastAsiaandunknowninblacksinAfrica•  Migra$oninchildrenbeforetheageof15years

adopttherisksofthenewlocale

200 new cases per week in the US

Rates of MS in the US are twice as high above the 37th Parallel

MS rates in Canada are 3X higher than the US

MS World Wide Source: The Multiple Sclerosis Foundation

Post-pubertal females in Seattle are 30X more likely to get an MS diagnosis than post-pubertal females in Dallas

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Source: National MS Society

Peak diagnosis between 20-40 years of age

High cost due to medications and lost productivity due to disability

MSSubtypes

•  RelapsingRemibngMS(RRMS)•  SecondaryProgressive•  PrimaryProgressive•  ProgressiveRelapsing

•  MixedForms

ProgressionofMS

•  70%ini$allyrelapsingremibng

•  20-30%remainrelapsingremibng

•  40%transi$ontoaslow,chronicprogression(progressiverelapsingorsecondaryprogressive)

•  10-20%chronicprogressivefromoutset

•  20%benign

Gene$cs&Gender

•  7-20$mesmorecommonamongthosewithanaffectedfamilymember

•  Iden$caltwins=40%concordancerate

•  10%highrriskifT1DM,autoimmunethyroiddisease(Grave’s,Hashimoto’s),IBD

•  Women2:1 Am J Epidemiol (2005) 162 (8): 774-778.

WhatisCIS?•  Theini$aldemyelina$ngeventisreferredtoas“ClinicallyIsolatedSyndrome”(CIS)

•  Commonpresenta$onsinclude:– Op$cneuri$s– Transversemyeli$s– Brainstemsyndromes(INO,cranialneuropathy,nystagmus)

TransverseMyeli$s

•  Ascendingnumbnessfromthefeetupthroughthetorsoorhandstothearms

•  Balanceproblems•  Par$alorcompletemotorparalysis•  L’HermiSe’sSign•  Bladder&sexualdysfunc$onarecommon

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Diagnostic Work-Up for Patients With Suspected CIS and/or MS

CSF: cerebrospinal fluid. Garcia Merino A, Blasco MR. Int MS J. 2007;14:58-63.

MRI imaging studies •  Brain w/ contrast •  Cervical spine w/ contrast •  Thoracic spine w/ contrast •  Areas where symptoms

manifest should guide imaging

CSF/lumbar puncture •  Assess degree of immune

cell infiltration of CNS

Blood tests •  Rule out MS mimetics,

other autoimmune diseases

Additional tests •  Evoked potential testing

–  Visual –  Auditory –  Somatosensory

•  Helpful in detecting multifocal disease

+

DiagnosisofMS

•  Requiresmul$plesitesofCNSinvolvementover$me

•  MRIofbrainandspinalcord– T2weightedFLAIR– T1weightedwithgadoliniumcontrast

•  NumberofMRIlesionsisthesinglemostimportantpredictorofconversiontoclinicallydefiniteMS(CDMS)anddisabilityprogression

T1-weighted à shorter Repetition Time (TR) and Time to Echo (TE) T2-wighted à longer TR and TE FLAIR à extremely long TR and TE

T1 = dark CSF T2 = light CSF Fluid attenuation = ésensitivity to pathology

T2-Weighted/FLAIR Brain MRI1-3

1. Image obtained from http://www.mslivingwell.org/new/understanding-your-mri. Accessed March 31, 2010. 2. Filippi M. Mult Scler. 2000;6:320-326. 3. Inglese M. Psychiatr Times. 2007;3(7). http://www.psychiatrictimes.com/display/ article/10168/56481?pageNumber=2. Accessed March 31, 2010.

•  Reveals hyperintense lesions •  Shows total number of lesions •  Indicative of disease burden •  Lesions may sometimes mimic

brain tumors •  Available scanning protocols

–  Sagittal Fluid Attenuated Inversion Recovery (FLAIR)

–  Axial FLAIR

Oldlesions

Newlesions

Baseline MRI Correlates With Risk of Conversion to MS

1. Tintore M et al. Neurology. 2006;67:968-972. 2. Brex PA et al. N Engl J Med. 2002;346:158-164. 3. Fisniku LK et al. Brain. 2008;131:808-817.

0

20

40

60

80

100

0 1 to 3 4 to 9 ≥10 Number of Lesions

Pat

ient

s C

onve

rting

to M

S, %

7 yearsa,1

14 yearsb,c,2

20 yearsb,c,3

a McDonald criteria. b Poser criteria. c Same patient cohort.

DisabilityfromMS•  ExtendedDisabilityStatusScore(EDSS)

– Scoringforeachof8func$onalsystems•  Pyramidal(abilitytowalk)•  Cerebellar(coordina$on)•  Brainstem(speechandswallowing)•  Sensory(touchandpain)•  Bowelandbladderfunc$ons•  Visual•  Mental•  Other(includesanyotherneurologicalfindingsduetoMS)

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Baseline MRI Correlates With Disability Progression

EDSS: Expanded Disability Status Scale. Tintore M et al. Neurology. 2006;67:968-972.

# of Lesions on Baseline MRI Patients With EDSS ≥ 3 at 5 years

0 5.8%

1-3 8.7%

4-9 11.1%

≥ 10 25.4%

DiagnosisofMS

•  LabteststoR/Omime$cs– SerumB12,ESR,Lyme$ter,ANA,RF,an$cardiolipin,TSH,NMO-IgG

•  LumbarpuncturewithCSFanalysis– Oligoclonalbanding:B-lymphocyteinfiltra$onofCNS

– ElevatedIgGIndex

•  95% of patients with MS have CSF OBs •  IgG index is rarely elevated in CSF OB-negative patients

Oligoclonal Bands (OBs) in CSF1,2

1. Link H, Huang YM. J Neuroimmunol. 2006;180:17-28. 2. Image adapted from: http://library.med.utah.edu/kw/ms/mml/ms_oligoclonal.html. Accessed February 25, 2010.

Normal Abnormal

CSF CSF Plasma Plasma

OBs absent

OBs present { {

B Lymphocyte Infiltration of CNS

OtherTests

•  EvokedPoten$als– Visual– Auditory– Somatosensory

•  OCT:meta-analysisshowsRNFLthinningandreducedlowcontrastacuityinptswithMS(with&w/opreviousop$cneuri$s)

Arch Neurol. 2009 Nov;66(11):1366-72.

Select Journal or Resource

37 yo woman with MS diagnosed x 8 years and no Hx of Optic Neuritis Brain January 20, 2011

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GC/IPLThinning•  Recentevidencesuggeststhinningoftheganglioncellandinnerplexiformlayersismoresensi$veforMSprogressionthanRNFLthinning Neurology. 2013 Jan 1;80(1):47-54

67 yo female with non-progressive MS x 35 years with Hx of right-sided optic neuritis. RNFL and Ganglion Cell Complex [GCC = thickness of GC + IPL] are grossly abnormal.

Source: A. Paul Chous, OD

MSProgression

EARLY•  Inflamma$on•  Demyelina$on•  Plaques

LATE•  Increasing$ssuedestruc$on

•  Axonalloss•  Atrophy

RELAPSES DISABILITY

Ambula$on&Mortality

• 90% of pts ambulatory at 10 years

• 75% ambulatory at 15 years

• Mean decrease in life expectancy: 5-10 years

OcularComplica$ons•  Op$cNeuri$s

– 40-55%ofMSptswillexperience–  Ini$aleventin20%ofpts

– Suddenlossofvisioninoneorbotheyes– Painoneyemovement– Colordesatura$on– Visualfielddefects

– Recoveryofacuityoverdaystoweeks– DDx:neuromyeli$sop$ca(Devic’sDisease)–NMOIgGan$bodies(targetscellularaquaporinreceptors)

OcularComplica$ons•  InternuclearOphthalmoplegia(INO)

– Brainstemdemyelina$on(MLF)– Lossofadduc$onwithintactconvergence

•  +HorizontalNystagmusofabduc$ngeye

– Diplopiaonlateralgaze

–  BilateralINOispathognomonic forMS,especiallyinyoungpts

Bull Soc Belge Ophtalmol. 2009;65-8.

Right INO

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OtherEyeFindings•  Nystagmuswithoscillopsia•  Cranialnervepalsies(typicallyCNVI)•  RNFLThinningandperimetricdefects

•  Reducedcontrastsensi$vity•  Phosphenes•  Uhtoff’sSign

•  OcularInflamma$on–  Parsplani$s–  Re$nalperiphlebi$s

Curr Opin Ophthalmol. 2005 Oct;16(5):315-20 Ocul Immunol Inflamm. 2004 Jun;12(2):137-42

MSTreatmentGoals•  Preventrelapses

•  Decreaseseverityandshortenrelapses

•  Decreasedisability

•  SloworpreventconversionfromRelapsingRemibng(RRMS)toSecondaryProgressive(SPMS)

Disease-ModifyingTherapy(DMT)

•  Interferons

•  Copaxone®•  Novantrone®•  Tysabri®•  Lemtrada®

•  Gilenya®•  Aubagio®•  Tecfidera®

§  Avonex®§  Betaseron®§  Extavia®§  Rebif®

FDA approved Oral Agents

Injected

IV Ocrevus®

Approved 3/2017

TreatmentofMS–1stLine•  DiseaseModifyingDrugs(DMDs)

–  InterferonΒ (1aand1b)•  Β 1aIM(AvonexTM)•  Β 1aSC(RebifTM)•  Β 1bIM(BetaseronTMExtaviaTM)

– Gla$rameracetate(CopaxoneTM)

– These3primaryDMDsdemonstratefairlyequivalentreduc$onineventrelapseratesandEDSSprogression(roughly35%reduc$on)

Reducean

$genpres

enta$on

ReduceM

MPexpressio

n

InhibitTce

llprolifera

$on

TH1àTH2r

esponse

Ac$va$ono

fTregcells

TH=ThelpercellsBMJ. 2000 Aug 12; 321(7258): 424

Key Principles for Early Treatment With Disease-Modifying Therapies

Goodin DS, Bates D. Mult Scler. 2009;15:1175-1182.

l  Pa$entswhopresentwithCISareathighriskofdevelopingclinicallydefiniteMS

l  ThisriskisincreasediftheirbaselineMRIsuggeststhepresenceofmul$-focaldisease

l  TreatmentwithDMDsattheini$alepisodeofdemyelina$onmay:l PostponeprogressionofCIStoclinicallydefiniteMS

l Reduceriskofdisabilityprogression

AdverseEventswith1stLineDMDs

•  Depression(IFβ)•  Injec$onsitereac$ons(Both)•  Flu-likesymptoms(fever,chills,nausea)(IFβ)•  Elevatedliverfunc$ontests(IFβ)•  ChestPain&Shortnessofbreath(gla$ramer)

•  50%ofptsD/Cini$alDMDduetoAEs•  Management:pteduca$on;prophylaxan$-depressantswithInterferons;rotateinjec$onsites&warmmeds;dosereduc$on

lipoatrophy

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SecondLineAgents•  Natalizumab(TysabriTM):humanizedmonoclonal

an$bodyagainstα4-integrinCAM–  PreventsTcellegressthruBBB–  IVinfusionQ28days–  Smallriskofprogressivemul$focalleukoencephalopathy(PML)–698totalcasesasofDecember2016(opportunis$ctypicallyfatalviralinfec$on);increasedriskonimmunosuppressantsandpa$entswith+JCVirusan$bodies

•  Mitoxantrone(NovantroneTM):an$-cancerdrug(topoisomeraseinhibitor)usedin2°progressiveMS–  Cumula$vecardiactoxicity–  1in133ptsdevelopleukemia

Classic AAN Recommendations for DMTs in Patients With MS1

AAN: American Academy of Neurology. 1. Goodin DS et al. Neurology. 2002;58:169-178. 2. Goodin DS et al. Neurology. 2008;71:766-773.

First-Line Therapies

IFN β-1a IFN β-1b

GA

Second-Line Therapies

Natalizumab2 Mitoxantrone

Therapeutic Goals

Prevent future relapses Slow disease progression

Prevent long-term disability

l  TheAANdoesnotcurrentlyrecommendonefirst-linetherapyoveranother;thechoiceofIFNbetasorGAismadeatthediscre@onoftheclinicianandpa@ent

l  Natalizumabmaybeconsideredforfirst-linetherapyforpa@entswithan“aggressive”diseasecourse(ie,≥9lesionsonbaselineMRI)

NewOralAgentsforMS• Goal:equivalentorsuperiorefficacytoinjectableagents&convenience

•  FirstOral:Fingolimod(GilenyaTM)– PreventsegressofTcellsfromlymphnodes– Diminishesauto-aggressivelymphocy$cinfiltra$onofCNS

– Superiorreduc$onofrelapseswhencomparedhead-to-headwithInterferonβ-1a

–  Increasedriskofinfec$on,HTNandbradycardia– 0.5-1.5%incidenceofCME

Cohen JA et al. New Engl J Med. 2010;362:402-415. Kappos L et al. N Engl J Med. 2010;362:387-401.

Fingolimod Improves ARR, MRI Outcomes vs IFN β

•  MRIoutcomessignificantlyfavoredfingolimod–  Fewernew/enlarged

lesions,Gd-enhancinglesionsvsIFNβgroup

–  Lower12-moreduc@oninbrainvolumevsIFNβ

–  Disabilityprogressioninfrequentacrossall3groups

Cohen JA et al. New Engl J Med. 2010;362:402-415.

Fingolimod at 2 dosing levels improves ARR vs IFN β

OtherOralTherapies:

•  Aubagio™(teriflunomide)–inhibitsTcellmitosis

•  Tecfidera™(dimethylfumarate)–inhibitsCAMsandinflamma$on;ac$vatesNrf2pathwayñantioxidant defense

Relative Efficacy of oral agents assessed by ARR and % without relapse:

Gilenya = Tecfidera > Aubagio

Alemtuzumab: Newer 2nd or 3rd line Tx Ocrelizumab: 1st drug for PPMS

•  Lemtrada®andOcrevus®•  AnnualIVinfusionx2years(orQ6mos)•  Humanmonoclonalan$bodytoCD52proteinonsurfaceofTandBlymphocytes

•  50+%reduc$oninARRcomparedwithinterferonβ1a

•  30%developautoimmunethyroidi$swithLemtradaand3XhigherrateofneoplasmwithOcrevus Mult Scler. 2015 Jan; 21(1): 22–34

N Engl J Med. 2017 Jan 19;376(3):209-220..

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Alterna$ve/ComplementaryStrategies

•  Dietary– SwankDiet:lowfat(<20g/d)showed84%reduc$oninMSmortalityover34years

– BestBetDiet:lowsaturatedfat,correc$onofleakygut,elimina$onoffoodallergens(gluten,eggs,addedsugars)usingELISA

– Bothdietsrecommendelimina$onofeggs,legumes,dairy

– Ac$vateNrf2

DietaryAc$vatorsofNrf2

•  Nrf2isthemasternuclearregulatoryfactorofan$oxidantdefense

•  Upregulatedby:– polyphenols-greentea,curcumin,resveratrol– Sulforaphane–broccoli,cabbage,kale– Allicin–garlic– Lycopene–tomatoes

– Protandim™–patenteddietarysupplementwith‘phytochemicalNrf2ac$vators’

Alterna$veMeds•  LowDoseNaltrexone(LDN)–opioidantagonist

–  VerypopularamongstMSbloggers–  Lotsofanecdotalevidenceofbenefit–  Limitedscien$ficevidenceforimprovedQoL

•  Estrogen&TestosteroneTherapies–  ReducedMRIlesionsandrelapsesduringpregnancy(estrioleffect)andlowerAIDzinmen

–  UCLApilotandPhase2studiesshowdrama$cimprovementinRRMSMRIlesionsand50%addi$onaldropinARRwithsupplementalestriolinwomenwhenaddedtoCopaxone

.J Immunol. 2003 Dec 1;171(11):6267-74. Arch Neurol. 2007 May;64(5):683-8. Lancet Neurol. 2016 Jan;15(1):35-46.

Ann Neurol. 2010 Aug;68(2):145-50

Impact of Vitamin D on MS •  Should you add vitamin D to your MS

treatment regimen? – Vitamin D deficiency is a risk factor for MS;

multivitamin is recommended (1,000-2,000 IU/day vitamin D3)

– One cohort study showed significant reduction in ARR with increased serum vit D in patients on Tysabri™ (n = 170, p = 0.02)

Higher serum 25-OH vitamin D levels are associated with up to a 54% decrease in MS Dx

54% risk reduction @ 54 ng/ml 25(OH)-vitamin D

Mult Scler Relat Disord. 2016 Nov;10:169-173.

Legend: All percentages reference a common baseline of 25 ng/ml as shown on the chart. %’s reflect the disease prevention % at the beginning and ending of available data. Example: Breast cancer incidence is reduced by 30% when the serum level is 34 ng/ml vs the baseline of 25 ng/ml. There is an 83% reduction in incidence when the serum level is 50 ng/ml vs the baseline of 25 ng/ml. The x’s in the bars indicate ‘reasonable extrapolations’ from the data but are beyond existing data. References: All Cancers: Lappe JM, et al. Am J Clin Nutr. 2007;85:1586-91. Breast: Garland CF, Gorham ED, Mohr SB, Grant WB, Garland FC. Breast cancer risk according to serum 25-Hydroxyvitamin D: Meta-analysis of Dose-Response (abstract).American Association for Cancer Research Annual Meeting, 2008. Reference serum 25(OH)D was 5 ng/ml. Garland, CF, et al. Amer Assoc Cancer Research Annual Mtg, April 2008,. Colon: Gorham ED, et al. Am J Prev Med. 2007;32:210-6. Diabetes: Hyppönen E, et al. Lancet 2001;358:1500-3. Endometrium: Mohr SB, et al. Prev Med. 2007;45:323-4. Falls: Broe KE, et al. J Am Geriatr Soc. 2007;55:234-9. Fractures: Bischoff-Ferrari HA, et al. JAMA. 2005;293:2257-64. Heart Attack: Giovannucci et al. Arch Intern Med/Vol 168 (No 11) June 9, 2008. Multiple Sclerosis: Munger KL, et al. JAMA. 2006;296:2832-8. Non-Hodgkin’s Lymphoma: Purdue MP, et al. Cancer Causes Control. 2007;18:989-99. Ovary: Tworoger SS, et al. Cancer Epidemiol Biomarkers Prev. 2007;16:783-8. Renal: Mohr SB, et al. Int J Cancer. 2006;119:2705-9. Rickets: Arnaud SB, Copyright GrassrootsHealth, 10/16/08 www.grassrootshealth.org.

VitaminD3inOp$cNeuri$sPts

•  30subjectswithONweregivenweeklydosesof50,000IUD3orplacebo

•  68%lessconversiontoCDMSinthTxgroup(p=0.007)ayer12months

•  VitaminDmayhelppreventprogressionfromop$cneuri$stoclinicallydefiniteMS

Acta Neurol Belg. 2013 Sep;113(3):257-63

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CoimbroProtocol•  CiceroCoimbro,MD,PhD

– SaoPaolo,Brazil– Protocolusedin4000+pa@entswithCDMS

•  1,000IUvitaminD3perKgbodyweight– Driveparathyroidhormonetolowendofnormalrangeandadjust

– Co-supplementa@onwithvitaminB2(riboflavin),lowcalciumdietand2.5Lwater/day

•  Claims95%ofpa@entsgointosymptoma@c&radiologicremission

HALT-MSTrial

•  Asingleroundofhi-doseimmunosuppressivetherapycombinedwithautologousinfusionofpa@ents’ownstemcells-ànorelapses,MRIlesionsorworseningdisabilityin69%ofpa@entsacer5years

•  n=24withRRMS

JAMA Neurology DOI: 10.1001/jamaneurol.2014.3780 (2014).

Cannabis

•  Cannibis–smallstudiesshowreducedmusclespas$citythataffects80%ofMSpa$entspersurveys(13%aresevere)

•  Recentevidencesuggestscannabisusemayacceleratecogni$vedysfunc$onassociatedwithreduc$oninbrainvolume

CMAJ. 2012 Jul 10;184(10):1143-50. J Neurol Neurosurg Psychiatry. 2012 Nov;83(11):1125-32

Neuroimage Clin. 2015 Apr 9;8:140-7.

SleepApnea•  Mul@plestudies(includingpublica@onsfromtheMidAmericaNeuroscienceIns@tuteinKansasCity)showthatOSASisatleastdoublycommoninMSpa@ents

•  Sleepapneamaycontributetofa@guecommonlyexperiencedbyMSpa@ents

•  InquireaboutOSASsymptoms(day@mesleepiness,snoring,etc.)

J Clin Sleep Med. 2014 Feb 15;10(2):155-62

GoodOptometricTeststoHelpDxandMonitorProgression

•  Contrastsensi$vity– Vistech,Pelli-Robson,M&STechnologies

•  Colorvision– RabinConeContrastTest(InnovaSystems)– ColorDx(Konan)

•  sdOCT•  VEP(Konan,Diopsys)

•  GoodCaseHistory:Uhtoff’s,L’HermiSe’s

Conclusions

•  OcularfindingsarecommoninMS

•  Optometristsshouldbeawareofthepharmacologicandnon-pharmacologicmanagementofMS

•  Encouragingpa$entstocon$nuewithDMTmayhelpreducedisability

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