By Dr. David Katz

1. WhatWhat’s New in Multiple’s New in Multiple
SclerosisSclerosis
David M Katz, MDDavid M Katz, MD
Bethesda Neurology, LLCBethesda Neurology, LLC
Associate Professor of Ophthalmology and Neurology atAssociate Professor of Ophthalmology and Neurology at
Howard University Hospital andHoward University Hospital and
Assistant Professor of Ophthalmology at GeorgetownAssistant Professor of Ophthalmology at Georgetown
UniversityUniversity
301-540-2700301-540-2700
Neuro-Ophthalmology ReviewNeuro-Ophthalmology Review
May 22, 2016May 22, 2016

2. DisclosuresDisclosures
 Clinical MS research supported by BiogenClinical MS research supported by Biogen
and Novartisand Novartis
 Clinical consultant for BiogenClinical consultant for Biogen

3. BackgroundBackground
 Multiple sclerosis (MS) is an autoimmune diseaseMultiple sclerosis (MS) is an autoimmune disease
typically causing attacks followed by remissions involvingtypically causing attacks followed by remissions involving
the central nervous system only, most often the opticthe central nervous system only, most often the optic
nerve(s).nerve(s).
 Symptoms and signs depend on where in the CNS theSymptoms and signs depend on where in the CNS the
lesion(s) are. For example, optic neuritis is caused bylesion(s) are. For example, optic neuritis is caused by
inflammation of an optic nerve, double vision due toinflammation of an optic nerve, double vision due to
brainstem lesions, transverse myelitis is caused bybrainstem lesions, transverse myelitis is caused by
inflammation of the spinal cord, ataxia is caused byinflammation of the spinal cord, ataxia is caused by
inflammation of the cerebellum or brainsteminflammation of the cerebellum or brainstem
 Optic neuritis presents most often in young females withOptic neuritis presents most often in young females with
unilateral pain on eye movement soon followed byunilateral pain on eye movement soon followed by
declining visual acuity, color vision, contrast sensitivitydeclining visual acuity, color vision, contrast sensitivity
and visual field over 7-10 days. Vision recovers toand visual field over 7-10 days. Vision recovers to
>>20/40 by six months in 95% of patients with or without20/40 by six months in 95% of patients with or without
high-dose steroid treatment based on results of the Optichigh-dose steroid treatment based on results of the Optic
Neuritis Treatment Trial 1988-92 (ONTT) andNeuritis Treatment Trial 1988-92 (ONTT) and
Longitudinal Optic Neuritis Study 1999-2004 (LONS)Longitudinal Optic Neuritis Study 1999-2004 (LONS)

4. Pre- 1993 MS Treatment:Pre- 1993 MS Treatment:
“Diagnose and Adios”“Diagnose and Adios”
 SymptomaticSymptomatic
treatment only:treatment only:
baclofen, benzos,baclofen, benzos,
Botox, gabapentinBotox, gabapentin
 PT/OT/rehabPT/OT/rehab
 IV Steroids toIV Steroids to
speedspeed
improvement fromimprovement from
relapses butrelapses but
ineffective atineffective at
reversing damagereversing damage

5. Martino et al. J Neuroimmunol 2000;109:3, Trapp et al. N Engl J Med 1998;338:278, Fisher et al. Neurology 2002;59:1412-20
Multiple Sclerosis:Multiple Sclerosis:
ImmunopathogenesisImmunopathogenesis
 InflammationInflammation
 Immune-mediatedImmune-mediated
 Facilitated by the entry of auto-reactive T and B cells and auto-Facilitated by the entry of auto-reactive T and B cells and auto-
antibodies from the bloodstream into the CNSantibodies from the bloodstream into the CNS
 DemyelinationDemyelination
 Primarily immune- and antibody-mediatedPrimarily immune- and antibody-mediated
 Mediated by cytokines produced by activated CD4 T cells andMediated by cytokines produced by activated CD4 T cells and
anti-myelin antibodies produced by activated B cells (ex. CD20)anti-myelin antibodies produced by activated B cells (ex. CD20)
 Axonal injury and lossAxonal injury and loss
 The effects of inflammation and demyelination lead to axonal injuryThe effects of inflammation and demyelination lead to axonal injury
and loss, and ultimately to brain atrophy and permanent disabilityand loss, and ultimately to brain atrophy and permanent disability

6. Environmental
factors
(ex. northern latitudes,
Low vitamin D?)
Abnormal immunologic response
Genetic
predisposition
(ex. HLA-Dw2)
Infectious agent?
(HHV-6, HSV, EBV,
CMV, etc)
MS
Potential Triggers for Multiple SclerosisPotential Triggers for Multiple Sclerosis
Gilden DH Lancet Neurol 2005;4:195-202, Noseworthy et al. N Engl J Med 2000;343:938

7. Demyelination
Axonal Loss
Inflammation
(perivenous infiltrate)
Components of Multiple SclerosisComponents of Multiple Sclerosis
PathogenesisPathogenesis
Trapp et al. N Engl J Med 1998;338:278

8. MRI: FLAIR images aboveMRI: FLAIR images above
contrast images belowcontrast images below

9. MS is Inflammatory Early on,MS is Inflammatory Early on,
Degenerative LaterDegenerative Later
RelapsingSubclinical Progressive
TimeTime
MRI total T2 lesion areaMRI total T2 lesion area
MRI activityMRI activity
Measures of brain volumeMeasures of brain volume
Relapses and impairmentRelapses and impairment
Therapeutic window of opportunity

10. The newly discoveredThe newly discovered “Glymphatic” system helps“Glymphatic” system helps
explain how immune cells enter the CNSexplain how immune cells enter the CNS
Louveau A, et al Nature 2015Louveau A, et al Nature 2015

11. ““Glymphatics”Glymphatics”
 Before the first reports of a glympathic (glial-lymphatic)Before the first reports of a glympathic (glial-lymphatic)
system by Iliff et al in 2012, the CNS was thought not tosystem by Iliff et al in 2012, the CNS was thought not to
have a lymphatic system, yet we knew the immunehave a lymphatic system, yet we knew the immune
system somehow protects the CNS from infection and cansystem somehow protects the CNS from infection and can
cause autoimmune disease, ex. MScause autoimmune disease, ex. MS
 Lymphatic vessels were recently detected lining the duralLymphatic vessels were recently detected lining the dural
sinuses in mice, subsequently in humans, which carrysinuses in mice, subsequently in humans, which carry
immune cells to and from the CSFimmune cells to and from the CSF
 Classic MS lesions are typically perpendicular to theClassic MS lesions are typically perpendicular to the
lateral ventricles, termedlateral ventricles, termed “Dawson fingers” (1916), prior to“Dawson fingers” (1916), prior to
2012 the anatomic explanation was lacking for 96 years.2012 the anatomic explanation was lacking for 96 years.
The glymphatic system follows the same anatomicThe glymphatic system follows the same anatomic
distribution as Dawson fingersdistribution as Dawson fingers

12. Activation of Immune CellsActivation of Immune Cells
in the CNSin the CNS
Frohman EM et al. Arch Neurol 2005;62:1345-56, Martino et al. J Neuroimmunol 2000;109:3-9
 Upon antigen presentation inUpon antigen presentation in
CNS, CD4+ T cells differentiateCNS, CD4+ T cells differentiate
into autoreactive Th1 cells thatinto autoreactive Th1 cells that
release proinflammatoryrelease proinflammatory
cytokinescytokines
 This process leads to anThis process leads to an
inflammatory cascade andinflammatory cascade and
immune-mediated demyelinationimmune-mediated demyelination

13. When should MS treatmentWhen should MS treatment
begin?begin?
 1993-4 the first MS treatment, interferon-beta-1993-4 the first MS treatment, interferon-beta-
1b sq QOD (Betaseron) was made available by1b sq QOD (Betaseron) was made available by
lottery only due to small supply until 1995lottery only due to small supply until 1995
 1995-2001 Copaxone, Avonex, Rebif approved1995-2001 Copaxone, Avonex, Rebif approved
only for patients afteronly for patients after multiplemultiple clinical relapsesclinical relapses
 2002- Interferon beta 1a IM qwk (Avonex)2002- Interferon beta 1a IM qwk (Avonex)
approved afterapproved after firstfirst clinical MS relapseclinical MS relapse
 2014- MS treatment effective at2014- MS treatment effective at
delaying/preventing first clinical MS relapse indelaying/preventing first clinical MS relapse in
patients withpatients with “Radiological Isolated Syndrome”“Radiological Isolated Syndrome”

14. Clinically Isolated Syndrome (CIS),Clinically Isolated Syndrome (CIS),
i.e.i.e. “Single Sclerosis”“Single Sclerosis”
 MRI lesion load at presentation stratifies patients into high and low riskMRI lesion load at presentation stratifies patients into high and low risk
groupsgroups
 Even one lesion at presentation carries almost the same risk of MS at 5Even one lesion at presentation carries almost the same risk of MS at 5
years (80%) as >10 lesions at presentationyears (80%) as >10 lesions at presentation
0
20
40
60
80
100
5 10 14
0 Lesions
1-3 Lesions
4-10 Lesions
>10 Lesions

15. Early Treatment is important forEarly Treatment is important for
long-term control of MSlong-term control of MS
 Multiple well controlled studies indicate that early treatmentMultiple well controlled studies indicate that early treatment
of MS with immunomodulatory treatment (IMT) slowsof MS with immunomodulatory treatment (IMT) slows
progression of disease and lowers the risk of future disabilityprogression of disease and lowers the risk of future disability
 Patients with Clinically Isolated Syndrome (CIS), ie,Patients with Clinically Isolated Syndrome (CIS), ie, “Single“Single
Sclerosis” defined as a single event (ex. optic neuritis) withSclerosis” defined as a single event (ex. optic neuritis) with
an abnormal MRI have a lower risk of developing relapsingan abnormal MRI have a lower risk of developing relapsing
MS if treated with an IMTMS if treated with an IMT
 ““Radiological Isolated Syndrome (RIS)” ie, pre-symptomaticRadiological Isolated Syndrome (RIS)” ie, pre-symptomatic
MS includes patients undergoing MRI brain/spine forMS includes patients undergoing MRI brain/spine for
unrelated issues, most often trauma or migrainesunrelated issues, most often trauma or migraines
 A 5-year study of 451 RIS patients showed that 34%A 5-year study of 451 RIS patients showed that 34%
developed a clinical relapse, especially males with spinaldeveloped a clinical relapse, especially males with spinal
cord lesionscord lesions
Kappos L et al Neurol 2006; Okuda D, et al PloSone 2014Kappos L et al Neurol 2006; Okuda D, et al PloSone 2014

16. Interferon beta-1a IM qw (Avonex) inInterferon beta-1a IM qw (Avonex) in
Clinically Isolated SyndromeClinically Isolated Syndrome
PatientswithSecond
Exacerbation(%)
3 15 27
0
10
20
30
40
50 Placebo
IFN-beta 1a
Study Month
6 9 12 18 21 24 30 33 36
44%
in risk of
developing
MS
P=0.002
Jacobs et al. N Engl J Med 2000;343:898
IFN-beta 1a 193 164 143 112 73 41
Placebo 190 146 131 98 58 26
No. of Patients at Risk

17. MRI may be more informative than theMRI may be more informative than the
clinical examination as to whether an MSclinical examination as to whether an MS
patient is responding to treatmentpatient is responding to treatment
 Monthly MRIs on a large cohort of MS patients followedMonthly MRIs on a large cohort of MS patients followed
at the NIH showed lesions frequently developing andat the NIH showed lesions frequently developing and
spontaneously resolving (partially or completely) inspontaneously resolving (partially or completely) in
patients with no new symptoms or clinical findingspatients with no new symptoms or clinical findings
 PatientPatient’s symptoms and clinical examination therefore’s symptoms and clinical examination therefore
represent the “tip of the iceberg”; 80% of MS lesions onrepresent the “tip of the iceberg”; 80% of MS lesions on
MRI are clinically silentMRI are clinically silent
 A single MRI at diagnosis is therefore no longer felt to beA single MRI at diagnosis is therefore no longer felt to be
adequate to manage MS. Yearly or bi-annual MRIs areadequate to manage MS. Yearly or bi-annual MRIs are
now recommended. If new lesions are seen, a change innow recommended. If new lesions are seen, a change in
MS medication should be consideredMS medication should be considered
 I use the analogy of HTN: if you donI use the analogy of HTN: if you don’t check the BP’t check the BP
regularly on BP medication, how do you know if theregularly on BP medication, how do you know if the
medication is working?medication is working?

18. MRI in same patient over one yearMRI in same patient over one year
withoutwithout symptoms or treatmentsymptoms or treatment

19. Currently approved MS treatmentsCurrently approved MS treatments
 TheThe “platform treatments” first became available“platform treatments” first became available
in the mid-1990s and include interferon-betain the mid-1990s and include interferon-beta
injections (Betaseron, Avonex, Rebif, Extavia,injections (Betaseron, Avonex, Rebif, Extavia,
Plegridy), and a non-interferon, glatiramerPlegridy), and a non-interferon, glatiramer
acetate injections (Copaxone)acetate injections (Copaxone)
 Oral medication: fingolimod (Gilenya) approvedOral medication: fingolimod (Gilenya) approved
in 2010, teriflunomide (Aubagio) in 2012, andin 2010, teriflunomide (Aubagio) in 2012, and
dimethyl fumerate (Tecfidera) in 2013dimethyl fumerate (Tecfidera) in 2013
 The more potent MS medications: IVThe more potent MS medications: IV
natalizumab (Tysabri) and IV alemtuzumabnatalizumab (Tysabri) and IV alemtuzumab
(Lemtrada, aka Campath) unfortunately carry the(Lemtrada, aka Campath) unfortunately carry the
highest risk of serious side effects includinghighest risk of serious side effects including
Progressive Multifocal LeukoencephalopathyProgressive Multifocal Leukoencephalopathy
(PML) caused by the JC virus(PML) caused by the JC virus

20. Vitamin D and MSVitamin D and MS
 Ascherio et al prospectively followed 465 early MS patients forAscherio et al prospectively followed 465 early MS patients for
5 years and measured vitamin D levels every 6 months5 years and measured vitamin D levels every 6 months
Those patients with vitamin D levelsThose patients with vitamin D levels >>50 nmol/L had significantly50 nmol/L had significantly
fewer active MS lesions on MRI, less brain volume loss andfewer active MS lesions on MRI, less brain volume loss and
lower disability score (EDSS) than patients with levels <30lower disability score (EDSS) than patients with levels <30
 The well known finding of a higher incidence of MS furtherThe well known finding of a higher incidence of MS further
from the equator may be explained by lower vitamin D levelsfrom the equator may be explained by lower vitamin D levels
further from the equator. The contrary is also true: MS remainsfurther from the equator. The contrary is also true: MS remains
rare in countries near the equator.rare in countries near the equator.
 Beginning 20 years ago, the incidence of MS in Africa and theBeginning 20 years ago, the incidence of MS in Africa and the
Middle East began to increased significantly, perhaps followingMiddle East began to increased significantly, perhaps following
the advent of air conditioning in these regions, allowing peoplethe advent of air conditioning in these regions, allowing people
in warmer climates to stay inside during daylight hours,in warmer climates to stay inside during daylight hours,
thereby less UV exposure, therefore lower vitamin D levelsthereby less UV exposure, therefore lower vitamin D levels
Ascherio A et al Lancet NeurolAscherio A et al Lancet Neurol

21. Natalizumab (Tysabri) IV q4wkNatalizumab (Tysabri) IV q4wk
 Efficacy at six months: 90% reduction in new T2 and gad+Efficacy at six months: 90% reduction in new T2 and gad+
lesions (interferon-beta (IFB)=80% reduction)lesions (interferon-beta (IFB)=80% reduction)
 Relapses were reduced by 68% at one year (IFB=30%)Relapses were reduced by 68% at one year (IFB=30%)
 Progression of disability reduced by 42% at 2 yearsProgression of disability reduced by 42% at 2 years
(IFB=<30% at 2 years)(IFB=<30% at 2 years)
 Natalizumab is a monoclonal antibody that inhibits alpha-4-Natalizumab is a monoclonal antibody that inhibits alpha-4-
mediated cell adhesion of leukocytes to the VCAM-1mediated cell adhesion of leukocytes to the VCAM-1
receptors and thereby blocks movement of inflammatory Treceptors and thereby blocks movement of inflammatory T
cells into the CNScells into the CNS
 However, without adequate T cell migration into the CNSHowever, without adequate T cell migration into the CNS
the risk of infection rises: 1/200-500 develop PML if JCV+the risk of infection rises: 1/200-500 develop PML if JCV+
for > 2 yearsfor > 2 years
Goodin D, et al Neurol 2008Goodin D, et al Neurol 2008

22. Multiple SclerosisMultiple Sclerosis
ImmunopathogenesisImmunopathogenesis
Frohman EM et al. Arch Neurol 2005;62:1345-56

23. Penetration of the blood-brain barrierPenetration of the blood-brain barrier
 Breakdown of BBB permits entry from the glymphaticBreakdown of BBB permits entry from the glymphatic
system into the CNSsystem into the CNS
 Auto-reactive T and B cellsAuto-reactive T and B cells
 Antibody and complementAntibody and complement
Frohman EM et al. Arch Neurol 2005;62:1345-56

24. Fimgolimod (Gilenya)Fimgolimod (Gilenya)
 Fimgolimod 0.5 mg/d was the first oral agentFimgolimod 0.5 mg/d was the first oral agent
approved for MS, in 2010. It is a sphingosine-1-approved for MS, in 2010. It is a sphingosine-1-
phosphate receptor blocker which inhibitsphosphate receptor blocker which inhibits
release of T cells from lymph nodesrelease of T cells from lymph nodes
 Side effects:Side effects: macular edemamacular edema <3 months into<3 months into
treatment in 1/400, bradycardia <6 hrs first dose,treatment in 1/400, bradycardia <6 hrs first dose,
increased risk of infections, especially zoster,increased risk of infections, especially zoster,
UTIs, sinus infections, 5 cases of PML to dateUTIs, sinus infections, 5 cases of PML to date

25. Teriflunomide (Aubagio)Teriflunomide (Aubagio)
 Second oral agent 14 mg/d, approved inSecond oral agent 14 mg/d, approved in
20122012
 Inhibits pyrimidine synthesis therebyInhibits pyrimidine synthesis thereby
reducing inflammatory leukocytesreducing inflammatory leukocytes
 Side effects: liver toxicity, alopecia,Side effects: liver toxicity, alopecia,
headache, diarrhea, category X forheadache, diarrhea, category X for
pregnancy (males and females)pregnancy (males and females)
 Not as effective as fingolimod andNot as effective as fingolimod and
permanently affects the immune system,permanently affects the immune system,
so used less oftenso used less often

26. Dimethyl Fumarate (Tecfidera)Dimethyl Fumarate (Tecfidera)
 Approved for MS in 2013, 240 mg po bidApproved for MS in 2013, 240 mg po bid
 Used in Europe for 10 years for psoriasis andUsed in Europe for 10 years for psoriasis and
RA, and used to prevent mold buildup on leatherRA, and used to prevent mold buildup on leather
until banned in 1998 due to contact dermatitisuntil banned in 1998 due to contact dermatitis
 Mode of action unclear: activation of nuclearMode of action unclear: activation of nuclear
derived factor 2, thereby acting as anti-derived factor 2, thereby acting as anti-
inflammatory and antioxidantinflammatory and antioxidant
 Side effects: GI, flushing, leukopenia, increasedSide effects: GI, flushing, leukopenia, increased
LFTs. 4 cases of PML to dateLFTs. 4 cases of PML to date

27. MS treatments on the near horizonMS treatments on the near horizon
 Rituximab blocks CD19 and CD20 B cells: available off-Rituximab blocks CD19 and CD20 B cells: available off-
label for MSlabel for MS
 Ocrelizumab (humanized rituximab): FDA approvalOcrelizumab (humanized rituximab): FDA approval
expected 2016 for relapsing andexpected 2016 for relapsing and primaryprimary progressive MSprogressive MS
 Daclizumab (Zinbryta, formerly Zenapax) blocks CD25Daclizumab (Zinbryta, formerly Zenapax) blocks CD25
and IL-2 activated T cells. FDA approval expected 2016and IL-2 activated T cells. FDA approval expected 2016
 Vitamin D has anti-inflammatory properties. A trial of lowVitamin D has anti-inflammatory properties. A trial of low
dose vs high dose vitamin D with glatiramer (Copaxone)dose vs high dose vitamin D with glatiramer (Copaxone)
is ongoingis ongoing
 Autologous bone marrow transplant is highly effective inAutologous bone marrow transplant is highly effective in
aggressive cases of MS but to date carries an 8% fatalityaggressive cases of MS but to date carries an 8% fatality
rate due to opportunistic infectionsrate due to opportunistic infections

28. Anti-LINGOAnti-LINGO
 A monoclonal Ab that blocks a CNSA monoclonal Ab that blocks a CNS
-specific glycoprotein that inhibits-specific glycoprotein that inhibits
remyelination by oligodendrocytesremyelination by oligodendrocytes
 Anti-LINGO IV 100mg/kg q4w x 24w in 33Anti-LINGO IV 100mg/kg q4w x 24w in 33
patients improved the latency on visualpatients improved the latency on visual
evoked potential test by 7.6 ms (p=0.05)evoked potential test by 7.6 ms (p=0.05)
over 36 placebo patients, suggesting anti-over 36 placebo patients, suggesting anti-
LINGO may promote remyelinationLINGO may promote remyelination
 No effect on visual acuity or OcularNo effect on visual acuity or Ocular
Coherence Tomography (OCT) of theCoherence Tomography (OCT) of the
optic discoptic disc

29. Phenytoin (Dilantin) for MSPhenytoin (Dilantin) for MS
 Blocks Na entry into demyelinated axons, thereby protectingBlocks Na entry into demyelinated axons, thereby protecting
them from further injurythem from further injury
 A phase II trial in optic neuritis is ongoingA phase II trial in optic neuritis is ongoing
(don(don’t let Martin Shkreli find out, he’ll buy the rights to Dilantin’t let Martin Shkreli find out, he’ll buy the rights to Dilantin
and charge $5,000 a pill like he did with pyrimethamineand charge $5,000 a pill like he did with pyrimethamine
(Daraprim) for HIV patients…)(Daraprim) for HIV patients…)

30. SummarySummary
 MS traditionally was, and in some cases still is a progressiveMS traditionally was, and in some cases still is a progressive
CNS disease causing disability over many yearsCNS disease causing disability over many years
 Current immunomodulatory medication significantly reduceCurrent immunomodulatory medication significantly reduce
relapses, MRI progression, and slow disability but do not haltrelapses, MRI progression, and slow disability but do not halt
the disease in all patientsthe disease in all patients
 Early treatment is more effective than delaying 2-5 years byEarly treatment is more effective than delaying 2-5 years by
reducing the risk of relapses and lowering the risk of long-reducing the risk of relapses and lowering the risk of long-
term disease progressionterm disease progression
 Yearly neurological examination and MRIs help guideYearly neurological examination and MRIs help guide
immunomodulatory treatmentimmunomodulatory treatment
 The current standard is NEDA (No Evidence of DiseaseThe current standard is NEDA (No Evidence of Disease
Activity) clinically and by MRI and can be achieved in 1/3 ofActivity) clinically and by MRI and can be achieved in 1/3 of
patients if treated early with an effective medicationpatients if treated early with an effective medication
 The future holds promise for agents to reverse disability byThe future holds promise for agents to reverse disability by
repairing damaged myelin and axons (anti-LINGO?)repairing damaged myelin and axons (anti-LINGO?)

31. Thank YouThank You
David M Katz, MDDavid M Katz, MD
301-540-2700301-540-2700