Aunali S Khaku, M.D.

, MBA
Associate Professor of Neurology, University of Central
Florida College of Medicine
May 2020
 Served on Genzyme Pharmaceuticals Advisory Board
Aug 2015
 Identify the typical MS patient
(demographics)
 Outline the key features of the History
and Exam important in MS

 Recall the three elements necessary for

the diagnosis of MS
 Be able to correctly diagnose and treat
an MS exacerbation
 Recognize and treat common non -
neurologic symptoms of MS (spasticity,
neurogenic bladder, Sexual dysfunction,
Depression, Vitamin D deficiency,
Fatigue, Sleep Apnea...)

 Brief overview of MS DMT’s

 Demographics

 Etiology / Pathophysiology

 Spectrum of MS

 Diagnosing MS
 Historical features
 Physical exam
 Diagnostic tests
 Treatment
1396: Earliest recorded Western case of MS
1825-1893: Jean Martin Charcot (described MS)
1841: Brain Pathology of MS (Jean Cruveilhier)
 Typically Young Female

 95% of MS diagnosed between ages 15 and 55

 Prevalence: 0.1% of general population

 Females affected twice as often as male

 Genetic: risk is 2% with 1 affected 1st degree

relative and 9% with two affected relatives (HLA-
DR2)

 Environmental: Prevalence is proportional to

distance from Equator (*age 15)

 Etiology: Vitamin D? Virus? Magnetic Fields?

Chronic Cerebrospinal Venous Insufficiency?
(Zamboni), 2 Hit Hypothesis

 Progressive MS (older, male, spinal cord lesions,

min relapses, more disability)
 Genetic susceptibility + environ
factor (viral infxn?) in childhood

 Abnormal immune response

directed against oligodendrocytes

 Ab’s to specific myelin proteins:

myelin basic protein (MBP)

 Molecular mimicry (Glatiramer)

 Failure of clonal deletion during

development
 Hygiene Hypotheses (worms)
 Destruction of myelin: Multiple scarred foci (plaques) in the
white matter of the CNS

 Periventricular, optic nerves, chiasm, sp cord

 Paravenous Infiltration of inflammatory cells: Mononuclear

cells and lymphocytes

 Later, macrophages and microglia / astrocytes

 Myelin insulates neurons

 Saltatory Conduction: Nodes of

Ranvier

 Oligodendrocytes in CNS

 Schwann cells in PNS

 Autoimmune attack on
oligodendrocytes resulting in
multiple areas of demyelination
(molecular mimicry)
 I. Multiple sclerosis

 II. Neuromyelitis optica (Devic disease) and

progressive necrotic myelopathy

 III. Acute disseminated encephalomyelitis

(ADEM)
A. Postinfectious
B. Postvaccinal

 IV. Acute and subacute necrotizing hemorrhagic

encephalitis
• Originally thought to be a variant of MS, now considered a
different dz
• Lesions: optic nerves & confluent, longitudinally extensive (3
or more levels) spinal cord lesion (LETM)
• Autoantibody to aquaporin-4 channel / Anti-MOG
• CSF may show pleocytosis (>50 WBC/mL)
• Prognosis: worse than MS: 5-yr survival w more than one
attack is only 68%
• Tx: Immunosuppressive meds: cyclophosphamide, rituximab
/ PLEX / IVIG, Soliris (Newly FDA approved: Compliment
mediated)
• Monophasic demyelinating dz of the brain & cord
• Rapid progression of multifocal neuro deficits (hemiparesis,
aphasia, sensory loss, ataxia, optic neuritis)
• Toxic-appearing: fevers, meningismus, confusion:
(distinguishing it from typical MS)
• Post-infectious / post-vaccinal
• CSF: Incr pressure, oligoclonal bands, pleocytosis
• Prognosis: generally good w complete recovery
• Tx: high dose glucocorticoids like MS exacerbation
• Clinically isolated syndrome: The first episode of transient
neurological dysfunction prior to the diagnosis of MS
• Relapsing-remitting: Multiple episodes of transient neurological
dysfunction which may or may not completely resolve. There is no
progression in between relapses
• Primary progressive: No definite relapses and remissions.
Disease progresses relentlessly from the onset
• Secondary progressive: Patients with relapsing-remitting MS
may (after an average of 17 years) start to have some progression
between relapses marking a transition to secondary progressive
• Progressive-relapsing: Relentless progression from the onset, but
they may have rare clinical relapses
 Topographical Model of MS

 http://www.medscape.com/viewarticle/844354
 http://bcove.me/vb493n4i

 https://www.youtube.com/watch?v=MBjScktQD_8
 Need three things
 1) A Clinical history typical of MS (i.e. transient focal
neurologic dysfunction, not chronic pain or migraines
for instance)

 2) Evidence of Lesion Dissemination in space

 3) Evidence of Lesion Dissemination in time

Criteria 2 and 3 can be fulfilled clinically or

radiographically
*Oligoclonal bands may replace 2 and 3 per the newst
McDonalds criteria
• Waxing and Waning (transient
episodes of (multi)focal
neurologic dysfunction):
numbness, paresthesia,
painful vision loss, clumsiness
(ataxia), weakness, diplopia,
gait, vertigo, fatigue, stiffness,
spasms bladder, bowel, sexual
dysfunction, tremor, heat
sensitivity, cognitive problems
• Symptoms come on gradually/
sub-acutely (hours to days)
• Resolve within days to weeks
• Rare to have aphasia or
seizures
• Ataxia is more common than
hemiparesis
 Limb sensory loss 31%
 Visual loss (optic neuritis) 16%
 Subacute weakness 9%
 Diplopia 7%
 Gait disturbance 5%
 Vertigo/balance problems 5%
 Acute weakness 4%
• Variable based on where the
patient has had lesions in the
past or what area is actively
inflamed

• Common findings include

spasticity, hyperreflexia,
Babinski sign, internuclear
ophthalmoplegia (INO), and
relative afferent pupillary defect
(RAPD)

• Charcot’s triad: SIN: scanning

(staccato) speech, intention
tremor, and nystagmus
 Vascular: embolic infarcts (endocarditis), malformations:
cavernous angiomas
 Infectious: PML, Lyme, brucellosis, meningitis (Bact,
Lyme, syphilitic, TB, Cryptococcal), Viral Encephalitides
 Neoplasm: lymphoma, Mets

 Inflamatory / CTD’s / Autoimmune: lupus,

antiphospholipid Ab, Sjögren’s, scleroderma, Polyarteritis
nodosa, CNS vasculitis, sarcoid, Behçets, Churg-Strauss
angiitis, Wegener’s (anti TNF medications)
 Spastic paraparesis

 Genetic / Metabolic: Leukodystrophies

• The first “attack” of ?MS

• Any sign / sx attributable to a CNS lesion

• Commonly optic neuritis / transverse myelitis

• Some evidence suggests treating results in better outcomes &

less disability, esp when +OCB

• Must do extensive workup to rule out other causes

• Demyelination of optic nerve (a CNS WM tract)

• Triad of decr acuity, dyschromatopsia, & eye pain

• Neuro exam: RAPD + possibly optic disc edema

• MRI: Increased T2 signal of the optic nerve and/or contrast

enhancement

• Prognosis: generally complete recovery expected

• R/o other causes

• Demyelination of the spinal cord WM tracts

• Typical Sx: sensory loss / heaviness in 1/both lower

extremities, Spastic / flaccid bladder

• Exam: variable based on location: but frequently: spasticity,

sensory level, upgoing toes, weakness

• L’hermitte’s phenomenon: lightning-like pain that radiates

down spine w head anteroflexion
• Three common diagnostic tests that are utilized with
multiple sclerosis are:

– Magnetic resonance imaging (Most Important)

– Lumbar puncture

– Visual evoked potentials

 Cell count w diff, protein, glucose: (usually wnl)

 Rarely cell count (and protein) is elevated w lymph predom,

but WBCs > 50 should prompt alternative Dx

• Oligoclonal bands (in CSF but not serum): incr synthesis of

Ab’s in csf with a small No. of resp Ag’s (present in 95% of
pt’s w definite MS) **

 Other tests: IgG

Index, Myelin Basic Protein, cultures,
VDRL, Fungal, AFB, cytology, ACE
• In the absence of a typical clinical picture for MS,
+OCB’s are not pathognomonic for MS
• UpToDate: “oligoclonal bands, may occur in any
disorder that disrupts the blood-brain barrier. …
Examples of other diseases that can cause oligoclonal
bands in the CSF include infections (eg, nervous
system Lyme disease), autoimmune diseases, brain
tumors, and lymphoproliferative diseases. Given how
many diseases can result in oligoclonal bands in
the CSF, the diagnostic utility of this finding is
limited”
 Visual evoked potential (VEP): Optic neuritis

 Visual stimuli presented & impulse over primary visual

cortex recorded

 If optic neuritis, VEP will show increased latency

(signal slowed from demyelination)
 MRI with and without Contrast: test of choice

 Lesion locations: periventricular, Juxtacortical, brainstem,

cerebellum, cervical cord

 T1: old lesions may appear hypointense (black holes)

 T2/FLAIR: Chronic lesions appear hyperintense

 T1 Post Contrast: Active demyelination during acute

exacerbations enhances post contrast
 Periventricular Cervical cord lesion at
“Dawson’s fingers” C1/C2
 Importance of FLAIR in MS. Periventricular lesions often
difficult to distinguish from CSF
• A new transient focal neuro deficit (not pain, or migraine)

• Rule out pseudo-exacerbations: Fever, UTI, CXR

• MRI with contrast (Gd+ lesions suggest a flare)

• CIS or MS exacerbation should be treated with IV methylprednisolone

(Solumedrol) one gram per day for three to five days. (Recent RCT 2014:
Ramo-tello et al MS Journal: Oral Methyprednosolone 1250 mg po x3d = IV
Solumedrol)
• Oral prednisone associated with a higher rate of subsequent attacks (for optic
neuritis).
• Steroids do not alter natural history or progression of disease, but hastens the
rate of recovery. Thus not to be used for minor symptoms like numbness
(weigh risk of steroids w benefit)
• Acthar? / PLEX, IVIG?
 These medications slow the disease, reduce relapse
rate, may prevent disability
 These medications do not:
 Cure the disease
 Necessarily make people feel better
 Necessarily alleviate symptoms
 Most data suggests treating early as soon as possible
reduces the risk of irreversible damage
 Important to address other risks (smoking, obesity,
diet, heat, Vitamin D)
Platform
Therapies
"ABCs" / Moderate
Strongest agents
injections agents - oral
– IV infusions
interferon beta teriflunomide Natalizumab
1a and b fingolimod Alemtuzumab
Plegridy Ocrelizumab
Siponimod** Daclizumab
Glatiramer (20 Ozanimod ?Rituximab
&40 MG) ?stem cells
dimethyl
Glatopa fumarate Cladribin**

Stronger medication often = more immunosuppression (risk of

infection)
 First generation DMT’s (ABC’s / Platform Therapies)
 Decrease relapse rate by ~ 30%

 IFN’s: (SE: flu like illness, injection site rxn, migraine)

 Interferon beta 1a
 Avonex: One shot IM Q wk
 Rebif: One shot SC three times a week
 Interferon beta 1b
 Betaseron: One shot SC QOD
 Extavia: One shot SC QOD
 Plegridy: Pegylated Avonex: 125 mcg SC Q 14 days

 Copaxone (glatiramer): peptide chain consisting amino acids within myelin

basic protein: (SE: flushing, Chest Pain, SOB, palpitations, anxiety)
• 20 mg SC QD vs 40 mg TIW (multiple generics including glatopa)
 Fingolimod / Gilenya: 0.5 mg PO q daily, (SE: ha, colds,
fatigue, lymphopenia, bradycardia, skin ca, encephalitis,
death?) PML, VZV
 Dimethylfumarate / Tecfidera: (12 or 240 mg twice daily)
PML, Flushing, GI Upset, Lymphopenia
 Teriflunomide / Aubagio: 7 or 14 mg once daily
Teratogenic, Liver Failure, TB, alopecia
 Natalizumab / Tysabri: 300 MG every 4 weeks, Monoclonal
AB: SE: PML (TOUCH program: JCV Status, Prior
Immunosupressants)
 Lemtrada (alemtuzumab) (Campath): 12 mg daily for 5
consecutive days (total 60 mg), followed 12 months later by
12 mg daily for 3 consecutive days (total 36 mg);
Monoclonal AB: Two lifetime doses. More? SE:
autoimmune diseases, thyroid disease,vasculitis, CVA
Glomrulonephritides, ?PML, malignancies
 Ocreluzimab (Ocrevus): 300 mg on day 1, followed by 300
mg 2 weeks later; subsequent doses of 600 mg are
administered once every 6 months. Humanized Rituximab.
Relapsing and Primary Prog MS: PML, Breast Ca, Hepatitis
B…
 Dalfampyridine / Ampyra: walking
drug in MS, Potassium channel
current prolonger: Renal disease,
Seizures,
 Others: IVIG, PLEX, Pulsed steroids,
Azathioprine, Celcept
 Others: Siponimod, Ozanimod,
Ofatunumab, Laquinimod,
Ublituximab, Cladribine
 Anti Lingo Drugs:
 Secondary Progressive MS?
 Study age criteria
 2010 sudy, no FDA approval
 Defnition of SPMS based on EDSS?
 Mitoxantrone: Secondary Prog MS: (SE: 1/135 risk of
Acute leukaemia, Cardiotoxicity)

 Daclizumab: fatal Hepatitis, Death, inflammatory

brain disease
 Most common chronic symptom in MS
 Physical Exhaustion
 Other Causes: Depression, medications, heat, thyroid,
OSA
 Conservative measures: Exercise, Cooling Vests, naps
 Medications: Modafinil, Armodafinil, Amantadine,
Stimulants
 Several studies show high
vitamin D levels reduce risk of
MS and new lesions

 Target levels 50-100

 In a meta-analysis (11 studies, 2138 participants)
spasticity due to MS with, greater average
improvement on the Ashworth scale for spasticity
compared with placebo, but not statistically significant
 Randomized controlled trial in pain due to MS (58
participants): small, nonsignificant difference in
number of responders
 Placebo control trial in PPMS (CUPID): no effect
 12-week randomized trial (MUSEC) 279 patients: relief
from muscle stiffness was greater with cannabis
 Canabis impairs cognition
 More studies needed
 Fatigue: (Rule out OSA, hypothyroidism, B12 deficiency): Tx w
amantadine / modafinil / pemoline / Adderall / Ritalin
 Vitamin D Defficiency: Extensive research. (Goal in MS > 50)

 Bladder dysfunction : (rule out UTI) urinary retention: bethanechol /

intermittent catheterization, urinary urgency / frequency (spastic
bladder), propantheline (Pro-Banthine) or oxybutynin
 Sexual Dysfunction (r/o depression), Tx w PDE inhibitors
 Pain: CBZ / Gabapentin / Opioids?

 Spasms / Contractures: BTX / Baclofen (oral / intrathecal)/Tizanidine /

Flexeril / Dorsal rhizotomy, myelotomy, crushing of obturator nerves
 Tremor: ventrolateral thalamotomy / DBS / INH / Pyridoxine / CBZ /
KZP / limb weights on wrists
 Depression: SSRI’s, Psychotherapy

 Constipation
• Extremely variable from person to person

• Prior to DMTs, pt’s were commonly bedridden in 15-20 yrs.

Now 90% are independent at 10 yrs

• Female sex, relapsing-remitting subtype, optic neuritis at

onset, & infrequent exacerbations are good prognostic signs

• Spinal lesions, African American or Hispanic race, Male Sex

tend to be worse prognosis

• Life expectancy is just slightly lower than the gen population

with aspiration pna playing a huge role
 Medlink neurology

 Adams & Victor text book of neurology, MS; Ch 36

 AAN’s Continuum on Multiple Sclerosis

 UpToDate

 C Ramo-Tello et al A randomized clinical trial of oral versus intravenous methylprednisolone for

relapse of MS. Multiple Sclerosis Journal 2014, Vol. 20(6) 717–725
 Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults Author:Michael J
Olek, DOSection Editor:Francisco González-Scarano, MDDeputy Editor:John F Dashe, MD, PhD Apr
12, 2018.

 Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple
sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee
of the American Academy of Neurology. Rae-Grant A, Day GS, Marrie RA, Rabinstein A, Cree BAC,
Gronseth GS, Haboubi M, Halper J, Hosey JP, Jones DE, Lisak R, Pelletier D, Potrebic S, Sitcov C,
Sommers R, Stachowiak J, Getchius TSD, Merillat SA, Pringsheim T. Neurology. 2018 Apr
24;90(17):777-788.
 Oral tablet taken once daily

 Must have TB test prior to starting and avoid live vaccines during therapy

 Birth defects can occur (for both male and female patients)

 Can cause liver failure. LFTs required monthly for first 6 months of therapy

 Hair thinning or more rarely hair loss can occur

 Accelerated elimination: cholestyramine 8g three times daily for 11 days

 *Nonformulary*
 Oral capsule taken once daily

 Minimum 6 hour cardiac monitoring after first dose

 Common/serious adverse reactions

 AV block and bradyarrhythmias
 Abdominal discomfort
 Decreased liver function
 Immunosuppression with risk for Progressive Multifocal
Leukoencephalopathy (PML)
 Oral capsule taken twice daily initially started at 120mg
for tolerance then increased 240mg

 Common adverse effects and ways to prevent them

 Flushing – take with food or premedicate with aspirin
 GI upset – take with food
*flushing and GI upset will usually get better with time*
 Immunosuppression with risk of PML
 One hour IV infusion every 4 weeks

 Common adverse reactions

 Rash
 GI upset
 Arthralgia
 Immunosuppressive – highest risk for PML!
 Patient, provider, pharmacy, and infusion clinic must be
actively enrolled in TOUCH program to avoid risk of PML.
 12 mg/day 4 hour IV infusion for 3-5 days depending on
course

 This was chemotherapy (Campath ®) that was relabeled

for MS

 Adverse reactions: Severe immunosuppression, low

platelets, autoimmune disorders, cancer risk

 Patients, providers, pharmacies, and infusion clinics must

be enrolled in the Lemtrada REMS program
 Infusion every 6 months (1st infusion is split into 2
half-infusions 2 weeks apart
 First agent demonstrating benefit in PPMS
 Wipes out CD 20 B-cell for 6-9-12 months
 Infusion reactions
 pre-treat with steroids, Tylenol, Benadryl
 Risk of infections, Hepatitis B (Vaccinate 6wks prior)
 No live vaccines when on Ocrevus
 Thus far no PML cases in ocrelizumab + on rituximab.
 breast cancer and other