Multiple SclerosisJOHN D. SCHAEFFER, DO

PMG NEUROLOGY SPECIALISTS

Multiple Sclerosis

450,000 people in USA, 2.3 million worldwide

Female:Male - 3:1

Lifetime financial burden: $1.2 million

What is MS

Recurrent, subacute, focal neurologic symptoms and

signs that improve (to some extent) over several weeks or

months. These episodes (relapses) associated with

demyelination.

Also underlying progressive loss of axons and gray matter

Pathogenesis

Chronic Inflammatory disorder characterized by damage

of myelin sheath with axonal degeneration and neuronal

cell death18

Prevailing dogma: MS is an autoimmune disease

mediated by autoreactive CD4+ T-cells, but why do B-cell

depleting immunotherapies work?

Most researchers consider MS a primary organ-specific

autoimmune disease.

Pathogenesis

MS “develops in a genetically susceptible individual who

experiences a ‘sufficient set’ of environmental factors.”

HLA-DRB1*1501 increases risk by 3x

Northern European monozygotic twins concordance

rate of MS is 20-30% (versus 0.1-0.2% of general

population)

No single autoantigen, autoantibody, or infectious agent

has been unequivocally associated with MS.

Pathogenesis

Dozens of risk factors, which ones have evidence?: EBV: OR 3.6. Children (no sx), adults develop mono

Risk of MS in patients with h/o Mono is 2x gen population

Adolescent obesity: OR 2.0

Smoking (active [OR 1.6) and passive [1.3]). Dose dependent.

Vit D deficiency (OR 1.4)/low UV radiation exposure (OR 2.0)

MS incidence & prevalence are higher in higher latitudes

Shift work: OR 1.7.

Protective? Oral tobacco: one study found OR 0.5

Coffee: OR 0.7

Alcohol: OR 0.6

Multiple Sclerosis

Relapsing-remitting (RRMS) -85%

Secondary Progressive (SPMS)

- 80% of RRMS eventually (active vs. inactive)

Primary Progressive (PPMS) -

10% (active vs. inactive) Progressive-Relapsing (PRMS) -

5%

“Benign” MS

Recognized by autopsy cases in 1960s

Minimal disability (EDSS 2 or below) 20 years after

diagnosis.13

10-15% of MS

5 Principles of Diagnosis

1. Identification of a syndrome “typical” of MS-related

demyelination

2. Objective evidence of CNS involvement

3. Demonstration of Dissemination in Space (DIS)

4. Demonstration of Dissemination in Time (DIT)

5. No better explanation than MS

#1: Typical Syndromes - Questions to

ask patients

Have you ever experienced ________ that came on

subacutely and persisted for days to weeks and then

partially or fully resolved over days to weeks Monocular (usually painful) visual loss (optic neuritis)

Binocular diplopia

Limb weakness

Limb numbness

Vertigo

Lhermitte’s phenomenon

By definition, symptoms have to last 24 hours!!

#2: Objective Evidence - exam, MRI,

paraclinical

Optic neuritis:

Relative afferent pupillary defect (R-APD), abnormal

VEP

Double vision:

INO (internuclear ophthalmoplegia), CN6 palsy

Transverse Myelitis

Hemisensory level

The revised McDonald criteria affirmed that a radiographic abnormality that corresponds

to the correct anatomic location meets this criteria (i.e., T2 hyperinensity in spinal cord is objective evidence of myelitis)

#3: Dissemination in Space

Lesions in more than one distinct anatomic location within

the CNS

4 areas:

Periventricular

Cortical/Juxtacortical

Infratentorial

Spinal Cord

DIS is met with 1+ T2 hyperintense lesions in 2+ areas

#4: Dissemination in Time (DIT)

New CNS lesions over time

On-going disease rather than a monophasic disease

DIT can be met with:

A second clinical attack

Simultaneous enhancing and non-enhancing MS

typical lesions

New lesion on follow-up MRI ( 1 of every 8 are

symptomatic, on average)

2+ oligoclonal bands

Diagnosis – Space and Time

Old Criteria

Two clinical episodes in different parts of brain/spinal cord separated by at least 30 days.

On average takes about 2 years for the second clinical episode to occur, during which

time the disease is active.

About one of every eight new plaques is symptomatic.

Studies tell us that early treatment works better

Revised 2017 McDonald Criteria

Allow use of MRI and CSF findings to fulfill dissemination in space and time criteria

Allow diagnosis of MS much earlier in course so treatment can be started sooner

Also allow more room for diagnostic error (18 % in one recent study)

Caution

White matter abnormalities in a patient with

migraine or vascular risk factors should prompt

caution for interpretation. Remember that these

conditions may meet DIS and DIT but still require

a MS specific typical syndrome.

White matter lesions can be a part of normal

aging

Seen in patients with migraine, hypertension,

diabetes, hyperlipidemia, head injury, …

Not Quite MS

1. Radiologically Isolated Syndrome (RIS)

a. Classic radiographic findings with no typical symptoms

2. Clinically Isolated Syndrome (CIS): one clinical event.

a. 90% will have second attack within 3 years

Why does it matter?

Currently available DMTs seem to be mostly ineffective

once the relapsing phase of MS is over.”

MS Relapses

Relapses defined as new or worsening neurologic

symptoms that occur in absence of fever/infection, last >

24 hours, and are preceded by 30 days of relative

neurologic stability.2

Sensory system (48%) Optic (20%)

Brainstem (21%) Motor (18%) Cerebellar (6%)

Bowel/bladder (3%)3

Pseudorelapse

Have to differentiate!

Recurrence of symptoms from a previous relapse

Tend to occur with heat (Uhthoff phenomenon),

infection, exercise, fatigue

Should resolve with time/removal of trigger

Interesting

Relapse risk increases with systemic infections, perceived stress,

postpartum trimester, and assisted reproductive techniques.

Viral/bacteria infections increase T-cell type 1 immune response

(parasitic infections do not, T-cell type 2).

Encourage MS patients to get vaccinated (inactivated)

Live attenuated vaccines may increase risk of relapse

High-dose influenza vaccine is not recommended for MS

Wait 4-6 weeks after relapse

Relapses and Treatment Response

MS relapse treatments:

Corticosteroids

- There is no convincing evidence that steroids

change long term outcome.

ACTH

PLEX

Not every relapse requires treatment

Corticosteroids

High doses (500-1000 mg methylprednisolone) hasten

neurologic recovery

One placebo controlled meta-analysis showed a 0.76 point

improvement in EDSS 5-7 days after treatment and 0.85

points 2-4 weeks later.

IV infusions for 3 days averages $2400

Oral steroids are no less effective per COPOUSEP trial (2015)

1000 mg methylprednisolone = 1250 mg prednisone = 192

mg dexamethasone

Tapering is not necessary (no suppression of HPA axis)

AE: metallic taste, facial flushing, GI disturbance, insomnia.

Avoid in first trimester (cleft palate)

ACTH

IM injection

No head to head studies

One vial cost $40 in 2001, $34,000 in 2014 = infrequent use

Plasma Exchange (PLEX)

Most patients don’t fully recovery to baseline after relapse

Those with severe impairments after steroids

PLEX: “significant improvement” in 42% (5% of sham)

There are risks with PLEX

Disease Modifying Treatments (DMTs)

f

3 strategies

1. Escalation

2. Start with highly effective therapy

3. Induction

DMTs: 1st line Interferon Beta (Betaseron, Avonex, Rebif, Plegridy)

Flulike symptoms, injection site reactions, liver toxicity, worsening of depression and spasticity.

CBC w/ diff and LFTs 1, 3, 6 months then annually

RRMS and active SPMS

Glatiramer acetate (Copaxone) 20 mg daily or 40 mg 3x/weekly Injection site reactions, lipoatrophy, injection

fatigue, chest pain. No monitoring labs RRMS

DMTs: 1st line (Fumarates) Dimethyl fumarate (Tecfidera)

240 mg BID

Nrf-2 activation?

AE: flushing (ASA 81), abd pain, nausea, diarrhea, infections (VZV)

PML: 6 cases. All had prolonged lymphopenia (ALC < 0.5)

Labs: CBC, LFT’s q6months. CBC/LFTs prior to start.

RRMS and active SPMS

Diroximal fumarate (Vumerity)

Fewer GI adverse effects

Less frequent by about 10-15%

Less severe. Discontinuation rate down to 1.6% vs. 6%

Same baseline labs and monitoring as Dimethyl

DMTs: 1st line

Teriflunomide (Aubagio) Pyrimidine synthesis inhibitor 7 or 14 mg BID

AE: hair thinning, HA, nausea, diarrhea, HTN, neuropathy, liver failure.

1 PML.

Teratogen: requires use of two effective birth control methods in

women. Cholestyramine washout. Also detectable in semen.

Labs: TB, LFTs, CBC prior to start. LFTs monthly x 6 months, CBC q3-6

months.

RRMS and active SPMS

DMTs: 2nd line (Mods)

Fingolimod (Gilenya)

0.5 mg daily PO

Sequesters lymphocytes in lymph nodes

RRMS and active SPMS

Initiation: first dose monitoring, ophtho exam x 2, CBC w/ diff,

LFTs, BUN, Cr, Varicella IgG (if not immune vaccinate and

wait 3 months).

Monitoring: CBC and LFTs q3-6m

AE: liver, PRES, macular edema, skin cancer, HTN. Infection?

PML: 20 cases (1 : 12,000). No markers are known to predict

risk.

DMTs: 2nd line (Mods)

Siponimod (Mayzent) Mostly same baseline and monitoring studies

No FDO unless HR<55, AV block, MI, CHF Need genotyping of metabolic enzyme to determine dose

RRMS and active SPMS

Ozanimod

Very similar to Fingolimod

No cardiac events

Ponesimod Appears to have fewer AE’s than Fingolimod

DMTs: 2nd line (CD20 MAB)

Ocrelizumab (Ocrevus)

CD20 MAB. 300 mg IV q2w (x2) then 600 mg q6m

RRMS and (active?) PPMS

AE: infusion rxn, infection, Hep B reactivation (0), breast

cancer(?) Infusion: 34-40% will have flushing/throat irritation (B-cell lysis). Slow rate.

PML: 0 cases

Initiation: Hep B core and surface antigen.

Monitor: annual CBC

DMTs: 2nd line (CD20 MAB)

Ofatumumab Submitted to FDA Differences from Ocrevus?

Ublituximab

Ongoing studies

DMTs: 2nd line

Natalizumab (Tysabri)

MAB against alpha integrin (IgG4 subclass).

Prevents leukocytes from entering CNS

Initiation: JCV, LFTs. Monitor: JCV q6m

PML: risk based on 3 factors

Time on drug

Prior immunosuppression

JC virus index

Rebound. 3-6 months after last dose. Start another DMT 4

weeks after last dose

DMTs: 2nd line

Alemutuzumab (Lemtrada) CD52 MAB, 12 mg daily x 5 days. One year later for 3 days. If

relapse occurs, repeat for 3 days (separated by 1 year)

RRMS with “inadequate” response to 2+ DMTs

AE: autoimmune diseases, malignancy Initiation: CBC w/ diff, LFTs, BUN, Cr, Varicella titer, UA w/ micro, TB

test, derm referral. Vaccines should be administered 6 weeks prior to

treatment

Monitor: CBC w/ diff, Cr, UA w/ micro qmonth x 48 months. TSH and

thyroid exam q3m x 48 months. Derm & Pap smear annually.

DMTs: 2nd line

Cladribine (Mavenclad) Purine analog, concentrated in lymphocytes and

monocytes (only) – causes DNA breaks

FDA approved for RRMS and active SPMS (inadequate

response to other meds)

Rarely used due to malignancy rate (2X placebo)

Mitoxantrone

Causes DNA crosslinks and strand breaks

Cardiotoxic and AML

Active SPMS

Minocycline

If DMT is delayed due to cost, consider “Bridging” with

minocycline 100 mg BID

2017 phase 3 RCT showed it was effective between 3-

12 months, no benefit at 24 months.

Monitor LFTs periodically

DMTs: 2nd line

Not FDA approved

Rituximab (Rituxan)

Mouse moiety CD20 MAB (more immunogenic than

Ocrevus)

HERMES trial

500-1000 mg IV q6m

DMTs: Other

Bone Marrow/Stem Cell

Mobilize and collect patient stem cells

Chemo to ablate bone marrow

Reconstitute bone marrow with collected stem cells

Mortality about 2.8%

Best “no evidence of disease activity” (NEDA); ~70% at 5 years

NEDA is no relapses, no new or enlarging plaques on MRI, no

disability progression

Only phase II studies so far

On DMT, now what?

Monitor patient tolerance of side effects

Consider insurance, pregnancy, lactating

Monitor effectiveness

DMTs take between 6 weeks to 6 months to start

working.

MRI brain W/O contrast 6 months after treatment

initiation then annual

I just monitor brain, rely on symptom/exam for C/T

spine

NEDA?

Stopping DMTs

Stopping DMTs

Patient preference, intolerance, progressive disease

Natural history of MS: risk of new episodes of CNS

demyelination is highest at onset and decreases with age.

By age 50 the risk is < 10%

DMTs have only been studied in age 55 and younger

Increased risk in elderly

Downside: MS relapse

Stopping DMTs

“Discontinuation of DMT may be safe and appropriate in

older individuals, especially those who have been

quiescent clinically, with no relapses and no new activity

on MRI scans for significant periods of time.”

RCT results expected in 2021.

Protective

Biotin

B vitamin (B7)

May promote remyelination and energy production

Modestly improved EDSS in one phase III trial. Additional studies planned.

Simvastatin

43% less brain volume loss in phase II study of SPMS

Mechanism of action unclear

Phase III study in progress

Protective

Ibudilast

Suppresses cytokines

Less volume loss in both PPMS and SPMS

Phase III study planned

Failed

Riluzole

Amiloride

Fluoxetine

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