MULTIPLE SCLEROSIS

(MS)
Fall 2023 – 2024
Beirut: Dr. Jihan Safwan – Dr. Maryline Mansour – Dr. Riwa Kfoury
Bekaa: Dr. Samar Younes
School of Pharmacy
Lebanese International University
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Learning Objectives
• At the end of the lecture, you will be able to:
• Identify the major differences between the different MS subtypes
• Recognize the place in therapy of the major pharmacological
agents
• Evaluate response to therapy and treatment side effects
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Multiple Sclerosis
• Immune-mediated, chronic, inflammatory disease
• Precipitated by unknown environmental factors in genetically
susceptible patients
• Hallmark of MS is inflammatory, demyelinating plaques, and axonal
loss in the CNS
• Plaque formation (sclerosed areas) attributed to immune
mechanisms that are triggered by autoimmune attacks against
antigens in the myelin membrane

• Characterized by relapses and remissions of neurological

symptoms and progression of disability over time
• Most common chronic neurologic disease of young adults
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Epidemiology
Worldwide Lebanon

• Approximately 400,000 • ~1,500 Lebanese patients

cases in the US are treated for MS and
2,000 with the disease in
• Estimates range from total
250,000 to 500,000
• Between 40 and 45
• Estimated 2.3 million individuals in every 100,000
cases worldwide have the disease
• Higher incidence in • >60% of patients develop
their first symptoms between
woman (≥3:1) 20 and 39 years
• ¾ cases present between • 2/3 cases affected are
ages 15 and 45 women
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Pathophysiology
• Pathologic hallmarks of MS
• Breakdown of the blood brain barrier
• Multifocal inflammation
• Demyelination & oligodendrocyte loss
• Axonal degeneration

• Major cause of disability is axonal loss

• MS plaques/lesions are:
• Areas of demyelination
• Followed by partial remyelination
• Location of lesions in the CNS dictates the type of clinical deficit
(infiltration of inflammatory cells in brainstem, optic nerves, spinal
cord…)
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Pathophysiology
Immune Dysregulation ➔ Autoimmune, neurodegenerative
disease of CNS

T‐Cells Myelin sheath Inflammation

Neurologic Nerve fiber

MRI lesions
symptoms scarring/sclerosis
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Clinical presentation
• General
– Most patients
• Non-specific complaints
• Vision problems
• Parasthesia

• Symptoms

Primary Signs / Symptoms
•Direct consequence of
conduction disturbances
produced by demyelination
and axonal damage
•Reflect the area of the brain
or spinal cord that is damaged
•Visual complaints/optic
neuritis
•Gait problems
•Paraesthesias
•Pain
•Spasticity
•Weakness
•Ataxia
•Speech difficulty
•Psychological changes
•Cognitive changes
•Fatigue
•Bowel/bladder dysfunction
•Sexual dysfunction
•Tremor
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Secondary Symptoms Tertiary Symptoms
•Complications resulting •Relate to the effect of
from primary symptoms the disease on the
•Ex: urinary retention (1⁰) patient’s everyday life
→ frequent urinary tract
infections (2⁰)
•Recurrent urinary tract •Financial problems
infections •Personal/social
•Urinary calculi problems
•Decubitus ulcer •Vocational problems
•Muscle contractures •Emotional problems
•Respiratory infections
•Poor nutrition
•Depression
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Diagnosis
• MS is a diagnosis of exclusion ➔ Diagnosis is mainly clinical
• Requires demonstration of “lesions separated in space and
time”
• Occurrence of at least two episodes of neurologic disturbance,
reflecting distinct sites of damage in the CNS, that cannot be explained
by another mechanism
• MRI
• Detection of MS lesions
• More sensitive compared to computed tomography (CT) scans
• Optic neuritis
• A common first symptom of MS
• Is indicative of a lesion or lesions localized on the optic nerve
• CSF evaluation
• Oligoclonal bands
• Blood tests
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Diagnosis
• McDonald criteria
Attacks Lesions Additional Criteria for MS diagnosis
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Clinical course/Classification
• Four categories
1. Clinically isolated syndromes
2. Relapsing-remitting MS
3. Secondary progressive MS
4. Primary progressive MS
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Clinical course/Classification
1. Clinically or Radiologically isolated syndromes
(CIS or RIS)
• CIS: is a first symptomatic episode compatible with
demyelination or multiple sclerosis (MS)
• Example: young adult with a single episode of CNS
dysfunction, such as unilateral optic neuritis
2. Relapsing-Remitting MS (RRMS)
• Episodes of acute worsening of neurologic function,
followed by a varying degree of recovery, with a
stable course between attacks; 85 – 90% of
patients at diagnosis

• RIS: an individual presents without overt clinical

symptoms but with MRI findings highly suggestive
of MS
• Example: incidental brain or spinal cord MRI findings that
are highly suggestive of MS
• MRI has been obtained for a completely unrelated
condition such as headaches or trauma

3. Secondary-Progressive MS (SPMS) 4. Primary-Progressive MS (PPMS)

• Initial relapsing-remitting disease course, followed
by progression with or without occasional relapses,
minor remissions, and plateaus; 50% of relapsing-
remitting patients develop secondary progression
within 10 – 20 years
• Gradual, almost continuous worsening with minor
fluctuations but no distinct relapses
• 10% of patients at diagnosis
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Clinical course
• Expanded Disability Status Scale (EDSS)
• Measures progression of the disease
• Multiple Sclerosis Functional Composite (MSFC)
• MRI is being used as an index of both disease activity and
progression

• Main factors which lead to a shorter than expected life span

• Development of secondary complications such as pneumonia or
septicemia
• Secondary to aspiration of mouth contents with swallowing difficulties,
decubitus ulcers, or urinary tract infections
• Rapid progression of primary lesions affecting respiratory function

• Suicide
• Suicide rates 7x the general population
• Correlate with progression of disease
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Prognostic Indicators in Multiple Sclerosis

Indicator Favorable prognosis Unfavorable prognosis

Age at onset <40 years >40 years

Gender Female Male

Optic neuritis or sensory Motor or cerebellar

Initial symptoms
symptoms symptoms

Attack frequency in
Low High
early disease

Course of disease Relapsing/remitting Progressive

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Goals of Disease Management

• Reduce relapses and slow progression
• Treat serious relapses
• Manage symptoms
• Improve QOL
• Hope for the future
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Nonpharmacological Treatment
• Occupational therapy may be useful to keep active
• Help improve the ability to complete the activities of daily living or
learn new techniques or tools to accomplish these tasks

• Physical therapy may improve muscle strength to help

patients improve their gait and balance

• Stretching exercises may help reduced muscle spasms or

help patients learn how to use mobility aid such as canes,
or walkers
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Treatment
CIS or RIS

RRMS
• Acute Relapses
• DMTs
• Symptomatic Therapy

Progressive MS
• SPMS
• PPMS
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Treatment – CIS or RIS

Symptoms consistent with MS
Clinically silent MRI lesions
CIS RIS
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Treatment
CIS or RIS

RRMS
• Acute Relapses
• DMTs
• Symptomatic Therapy

Progressive MS
• SPMS
• PPMS
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Treatment – RRMS (more common

presentation)
• Treatment of acute attacks
• Shorten the duration and
Acute
Relapses possibly decrease the severity
of the attack
• Disease-modifying therapies
Disease
Modifying • Alter the course of the illness
Therapies • Are most important to diminish
progressive disability over
Symptomatic
time
Therapies • Symptomatic management of
the disease
• Is of greatest importance to
maintain the patient’s quality of
life
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Acute Relapses For CS & ACTH ➔

• Corticosteroids (preferred) Rule out acute infection
• Intravenous methylprednisolone with or without a short prednisone taper
• Dose is 500 mg to 1000 mg/day as 1 dose or divided doses for 3–7 days
• Alternative is Oral prednisone with or without a short prednisone taper
• Dose is 625 to1250 mg/day given for 3 to 7 days
Neurologic recovery is the same with
• Side Effects of CS
or without an oral prednisone taper
• Relatively few side effects in most patients
• Mental status changes, unmasking of infection, and gastric disturbance may occur
• Fractures ➔ Repeated glucocorticoid therapy ➔ baseline and yearly bone density scans are
recommended

• Adrenocorticotropic hormone (ACTH) (alternative)

• Repository corticotropin injection gel IM or SC
• Indication ➔ Patients who cannot tolerate high-dose glucocorticoids or have poor
venous access or prefer self-injection
• 80 units for seven days, 40 units for four days, and 20 units for three days

• PLASMA EXCHANGE (last line)

• May be beneficial in patients with Acute central nervous system (CNS) inflammatory
demyelinating disease who do not respond to glucocorticoid therapy
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Disease Modifying Therapy

• Interferons (IFNs)
• Glatiramer acetate
I. Injectables • Daclizumab
• Ofatumumab
• OTHER TREATMENTS
• Azathioprine
• Fingolimod, Siponimod, ozanimod,
• Cyclophosphamide
ponesimod
• Teriflunomide
• Glucocorticoids
II. Oral • Dimethyl fumarate, Diroximel fumarate,
Monomethyl fumarate
• Intravenous immune
• Cladribine globulin
• Laquinimod
• • Stem cell transplantation
III. •
Mitoxantrone
Natalizumab
• Alemtuzumab
Intravenous • Ocrelizumab

First Generation Self-injectables Interferons, Glatiramer acetate

Agents IV Infusion Mitoxantrone
Fingolimod, Siponimod, ozanimod, ponesimod,
Oral Agents Teriflunomide, Dimethyl fumarate, Diroximel fumarate,
Second Generation Monomethyl fumarate, cladribine
Agents IV Infusion Natalizumab, Alemtuzumab, Ocrelizumab
Self-injectable Daclizumab, Ofatumumab
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Brand Indicati Administr Monitoring

Drug SE Comments
name on ation Parameters
First-generation agents
Self-injectables
Interferon- Avonex® RRMS IM once • Avonex®: Low potency IFN
β1a CIS weekly • Rebif® , Plegridy®,
Betaseron®: High potency
Interferon- Rebif® RRMS SC TIW IFN
β1a CIS • Avoid use in untreated
severe depression
• Depression, flu-
Pegylated Plegridy® RRMS SC q 14 • Electrolytes, • Suicide risk
like sx,
Interferon- CIS days CBC, LFTs, • Can premedicate or
leukopenia,
β1a injection site
thyroid function, concurrently use an
depression antipyretic/analgesic for flu-
Interferon- Betaseron RRMS SC QOD reaction
® like symptoms
β1b CIS • Neutralizing antibodies
Extavia® • Develop in some patients
18–24 months after trx
begins
• Preg. Cat. C
Glatiramer Copaxone RRMS SC QD or • Injection site • Postinjection • Chest tightness, urticaria can
acetate ® CIS SQ TIW reactions, reaction occur at any dose
infection, • Preg. Cat. B
urticaria, chest
tightness
IV infusion
Mitoxantr Novantron SPMS IV infusion • Bone marrow • CBC, ECG, • Lifetime dose should not
one e® PRMS suppression, LVEF exceed 140 mg/m2 due to
Worsen cardiotoxicity, cardiac toxicity
ing AML • Secondary leukemia
RRMS • Preg. Cat. D
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Brand Indicati Administ Monitoring

Drug SE Comments
name on ration Parameters
Second-generation agents
Oral agents
Fingolimod Gilenya® RRMS • Lymphocytopenia, • REMS
macular retinal • CBC, ECG, • Fing: Requires first dose
Siponimod CIS,
edema, AV block, BP, ophthalmic observation for bradycardia at
RRMS,
Ozanimod first dose examination, hospital
SPMS
bradycardia, LFTs • Fing: Preg. Cat. C
Ponesimod infection
Teriflunomi Aubagio® RRMS • Steven–Johnson • CBC, LFTs, • Possibility of TB reactivation
de syndrome, liver BP, • Active metabolite of leflunomide
failure, neutropenia, pregnancy, TB • Preg. Cat. X ➔ CI in pregnancy
activation of TB test • It is found in semen
(transvaginal absorption)
• Men and women who wish to
conceive a child ➔ SHOULD
D/C teriflunomide and undergo
PO an accelerated drug elimination
procedure using cholestyramine
or activated charcoal powder for
11 days
Dimethyl Tecfidera® RRMS • Flushing, rash, GI • CBC, LFTs • Taking with food decreases
fumarate discomfort, incidence of flushing
lymphocytopenia, • Preg. Cat. C
Diroximel CIS,
increased LFTs
fumarate RRMS,
SPMS
Monomethy CIS,
l fumarate RRMS,
SPMS
Cladribine RRMS, • Infections, tumors • CBC
SPMS
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Brand Indicati Administr Monitoring

Drug SE Comments
name on ation Parameters
Second-generation agents
IV infusion
Natalizuma Tysabri® RRMS IV infusion • Depression, fatigue, • JCV antibody, • REMS: Risk of PML (progressive
b hepatotoxicity infection, MRI, LFTs multifocal leukoencephalopathy)
• PML • Preg. Cat. C
• Rapidly progressive viral
CNS infection by JCV JCV: John
• Usually results in death or Cunningham
permanent disability virus ➔ Type of
polyomavirus

Alemtuzum Lemtrad RRMS IV infusion • Infections, thyroid disorders, • CBC, thyroid • REMS
ab a® • BBW function, TB prior to • May premedicate with high-dose CS
• Infusion reactions trx, infusion • Preg. Cat. C
• Autoimmune: immune- reactions
mediated
thrombocytopenic purpura
• Malignancy
Ocrelizuma Ocrevus RRMS IV infusion • Infusion reactions, URTIs, • Monitor for infusion • REMS
b ® & PPMS oral herpes activation, reactions • Risk of PML
neoplasms • Preg. Cat.: fetal risk can’t be ruled out

Brand Indicati Administrat

Drug SE Monitoring Parameters Comments
name on ion
Second-generation agents
Self-injectable
Daclizuma Zinbryta® RRMS SC once • Infection, • LFTs and bilirubin • REMS (monitor LFTs)
b monthly depression, rash • Removed from market in 2018
• BBW: Hepatic injury
(increased ALT)
Ofatumum RRMS, SC once • URTI, injection site • Screen for infections • Treat infections before
ab SPMS monthly reactions prior to trx administering drug
STRATEGIES FOR
THERAPY SELECTION
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Current MS Treatment Guideline

• Draft proposals have been released by both American
Academy of Neurology (AAN) and European Academy of
Neurology

• WHY NO EXISTING GUIDELINES??

• Diagnosis is complex
• Clinical
• Radiographic
• Substantial variability exists
• Patient presentation
• Disease course
• Limited head-to-head data among FDA-approved medications
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Efficacy / Toxicity Illustration

High Natalizumab Alemtuzumab
Efficacy
Ocrelizumab
Fingolimod
Dimethyl
Fumarate Daclizumab
Efficacy
Interferons Teriflunomide

Glatiramer
Low
Efficacy

Low Toxicity High

Toxicity Toxicity
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MS Suggested Treatment Algorithm

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Symptomatic therapies
• Patients may experience:
• Fatigue
• Spasticity
• Walking impairment
• Urinary incontinence
• Pain
• Depression
• Cognitive impairment
• Fecal incontinence
• Constipation
• Sexual dysfunction
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Symptomatic therapies
Fatigue

• Nonpharmacologic ➔ rest, assistive devices, cooling strategies, exercise, stress management

• Pharmacologic ➔ amantadine or methylphenidate

Spasticity: consequence of dysfunction of CNS ➔ characterized by muscle

over activity and high tone spasms

• Therapies must be centrally acting

• First line: Baclofen(skeletal muscle relaxant), tizanidine (short acting muscle relaxant)
• Second line: Dantrolene (skeletal muscle relaxant), diazepam
• Third line: Intrathecal baclofen
• Focal spasticity (impairment & activity limitation in one joint): Botulinum toxin

Walking impairment

• Dalfampridine (Ampyra)
• Indication: improve walking in patients with multiple sclerosis by improving walking speed
• MOA: Potassium channel blocker (prolong action potential)
• Dose: 10 mg orally 2 times/day; extended-release tablets
• Contraindication: patients with a history of seizures or moderate or severe renal impairment
• Adverse effects: Seizures, urinary tract infections, insomnia
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Treatment
CIS or RIS

RRMS
• Acute Relapses
• DMTs
• Symptomatic Therapy

Progressive MS
• SPMS
• PPMS

SPMS
Main Recommendation
• Treat active SPMS with
an approach similar to
how you treat RRMS
• Therapeutic options include
all DMTs approved for RRMS
and SPMS
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Suboptimal Response
• For patients with active
SPMS who have a
suboptimal response to
DMT (evidence of ongoing
disease activity with attacks
(relapses) and/or the
development of new MS
lesions) ➔ switching to a
different DMT is a
reasonable option
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PPMS
• Ocrelizumab
• Used in PPMS patients who are ≤55 years or have active disease
on MRI
• Using ocrelizumab in older patients with inactive disease was less
likely to benefit and more likely to experience SE

• Trials of DMTs used in RRMS ➔ NO BENEFIT in PPMS

• Other treatments have been tried for PPMS

• Examples: glucocorticoid pulses, methotrexate, intravenous
immune globulin, mitoxantrone
• Lack convincing clinical trial evidence of effectiveness; most
MS experts do not use these medications for PPMS on a routine
basis
THANK YOU!