Demyelinating
Multiple Sclerosis
search
Multiple Sclerosis
, MS
Epidemiology
Top disabling condition of young adults (U.S.)
Prevalence
Northern U.S.: 110 cases per 100,000 persons
Southern U.S.: 47 cases per 100,000 persons
U.S. Total: 250,000-350,000 patients affected
Pathophysiology
Acute attacks (relapsing remitting MS) are a result of inflammatory reaction
Inflammatory cells (T Cells,
B Cell
s and
Macrophage
s) cross the blood-brain barrier at weakened vessel surfaces
Immunoglobulin
s target the
Myelin Sheath
Macrophage
s damage the axons with free radical release
Results
Focal regions of demyelination of white matter
Particularly periventricular and subpial white matter
Prognosis
Relapse and remission cycles after first episode: 90%
Benign course (1-2 relapses, then recovery): 20%
Progressive course after 5 years of MS: 60-90%
Progressive course from onset (10%)
Rapidly progressive course from onset (very rare)
Marburg Type
Risk Factors
Race: White > Black
Gender: Female > Male (2:1)
High socioeconomic status
Northern latitudes
Environmental factors (toxins, viruses)
Tobacco Abuse
HLA histocompatible
Antigen
s
Vitamin D Deficiency
(or less sunlight exposure)
Munger (2006) JAMA 296:2832-2838 [PubMed]
Symptoms
Sensory loss (37%)
Optic Neuritis
(36%)
Weakness (35%)
Paresthesia
s (24%)
Diplopia
(15%)
Ataxia
(11%)
Vertigo
(6%)
Paroxysmal symptoms (4%)
Urinary Incontinence
(4%)
Lhermitte Sign
(3%)
Electrical sensation down spine on neck flexion
Dementia
(2%)
Visual Loss (2%)
Facial palsy (1%)
Impotence
(1%)
Myokymia (1%)
Seizure
s (1%)
Depressed mood
Fatigue
Hearing Loss
and
Tinnitus
Heat intolerance
Signs
Dysarthria
Decreased pain, vibration and position sense
Decreased coordination and balance
Ataxia
Difficult tandem walking
Eye Exam
Visual Field
defects
Decreased Visual Acuity
Red color perception
Afferent Pupillary Defect
Optic Nerve
pallor (
Optic Neuritis
)
Nystagmus
(most commonly
Horizontal Nystagmus
)
Bilateral
Internuclear Ophthalmoplegia
Nystagmus
of abducting eye on lateral gaze
Other eye with slow adduction
Reflexes
Deep Tendon Reflex
es hyperactive
Spasticity
Abdominal reflexes lost
Ankle Clonus
present
Babinski Reflex
with up-going toes
Charcot's Triad
Intention Tremor
Nystagmus
Scanning speech
Hot Bath Test
Hot bath exacerbates visual signs
Diagnosis
Gene
ral Criteria
Overview
Diagnosis Requires 2 episodes and 2 CNS areas
Episodes (Attacks) are discrete events lasting >24 hours and not associated with fever or infection
Specific Criteria
Objective findings on exam consistent with history
Long white matter tracts predominately involved
Pyramidal
Cerebellar
Medial Longitudinal Fasciculus
(MLF)
Optic Nerve
Posterior Column
s
Dissemination in space (DIS)
Characteristic MS regions (periventricular, juxtacortical, infratemporal or spinal)
Two CNS Areas or more are involved
Dissemination in time (DIT)
Two separate episodes of symptom clusters
Involve different CNS areas
Or Progression over at least 12 months
No other explanation for CNS symptoms
Not associated with fever or infection
Age range 15 to 60 years
Findings suggestive of alternative diagnosis (typically not due to Multiple Sclerosis)
Abrupt, transient symptoms
Seizure
s,
Aphasia
or other significant cortical findings
Peripheral Neuropathy
Non-neurologic involvement (e.g. cardiac)
Diagnosis
McDonald Criteria (2010)
Definitive diagnosis: Relapsing Remitting
Two or more attacks AND
Two or more lesions or objective clinical evidence of one lesion and historical evidence of a prior attack
Definitive diagnosis: Primary Progressive (PPMS)
Insidious neurologic pregression of one year or more AND
Additional criteria (2 of 3 required)
One or more T2 lesion in characteristic MS regions (periventricular, juxtacortical, infratemporal or spinal)
Two or more T2 lesions affecting the spinal cord
Positive CSF findings (oligoclonal bands or elevated IgG Index)
Presentations requiring a second attack for definitive diagnosis
Dissemination in Time (DIT)
Two or more attacks with objective evidence of one T2 lesion
Lesion affects 2 of 4 characteristic MS regions (periventricular, juxtacortical, infratemporal or spinal)
Dissemination in Space (DIS)
One attack with objective evidence of two or more T2 lesions
Simultaneous asymptomatic gadolinium-enhancing and nonenhancing lesions at a point in time OR
New T2 or gadolinium-enhancing lesion on follow-up MRI
One attack with objective evidence of one lesion
Await additional attack with characteristics of one of the two presentations (DIT or DIS) as above
References
Polman (2011) Ann Neurol 69(2): 292-302 [PubMed]
Differential Diagnosis
Degenerative disease
Amyotrophic Lateral Sclerosis
Huntington Disease
Demyelinating disease
Chronic inflammatory demyelinating
Polyneuropathy
Progressive Multifocal Leukoencephalopathy
CNS Infection
Tertiary
Lyme Disease
Tertiary Syphilis
Human Immunodeficiency Virus
(HIV)
Mycoplasma
CNS Inflammation
Sarcoidosis
Systemic Lupus Erythematosus
(SLE)
Sjogren Syndrome
Behcet Syndrome
CNS Vascular Disease
Hypertension
Diabetes Mellitus
Cerebrovascular Disease
Migraine Headache
Vasculitis
CNS mass or structural disease
Cervical Spondylosis
Cervical Disc Disease
CNS neoplasm
Chiari Malformation
Arteriovenous malformation
Medications and recreational drugs
Alcohol Abuse
Cocaine Abuse
Isoniazid
Lithium
Penicillin
Phenytoin
(
Dilantin
)
Vitamin Deficiency
Vitamin B12 Deficiency
Folate Deficiency
Vitamin E
deficiency
Psychiatric conditions
Anxiety Disorder
Conversion Disorder
Somatization
Gene
tic disorders
Leukodystrophy
Mitochondrial disease
References
Miller (2008) Mult Scler 14(9): 1157-74 [PubMed]
Rolak (2007) Neurologist 13(2): 57-72 [PubMed]
Types
Course
Relapsing remitting (90% of cases)
Discrete attacks evolve over days to weeks
Recovery for weeks to months in which there is no neurologic worsening between attacks
Secondary progressive (50% of relapsing remitting cases)
Starts as relapsing remitting disease
Progresses to gradual neurologic deterioration outside of discrete, acute attacks
Primary progressive (PPMS) and progressive relapsing (10% of cases)
Steady functional decline from Multiple Sclerosis onset
Termed primary progressive if no attacks occur
Termed progressive relapsing if attacks occur
References
Lublin (1996) Neurology 46(4): 907-11 [PubMed]
Types
Subtypes
Definite Multiple Sclerosis
All criteria fulfilled
Probable Multiple Sclerosis
All criteria fulfilled except
Only 1 neurologic sign (2 Symptomatic episodes) or
Neurologic signs unrelated to 1 Symptomatic episode
At risk for Multiple Sclerosis
All criteria fulfilled except
Only 1 episode and
No neurologic signs on exam
Diagnostics
MRI Head
(most useful)
Abnormal scan in >90% of Multiple Sclerosis patients
Findings
Plaque
formation (
Myelin Sheath
loss)
Spotty and irregular demyelination
Distribution
Involves
Brainstem
,
Cerebellum
, corpus callosum
Other localized distribution
Around ventricles
Around gray-white junction
Gadolinium enhancing if active inflammation
CT Head
(not as helpful as
MRI Head
)
Findings
Ventricular enlargement
Low density periventricular abnormalities
Focal enhancement
Evoked Potentials
Visual, auditory, somatosensory, and motor
Visually evoked potentials are most useful
One or more evoked potential abnormal in 80-90% of MS
Labs
Multiple Sclerosis Findings
Cerebrospinal Fluid
CSF is primarily used to exclude other causes on the differential diagnosis (e.g.
Meningitis
or
Encephalitis
)
CSF
Pleocytosis
(>5 cells/microliter)
CSF IgG Increased (not specific for MS)
Oligoclonal banding of CSF IgG by electrophoresis
Oligoclonal bands >1 in 75-90% of MS patients
CSF Myelin breakdown products present
Serum titers predictive of Multiple Sclerosis
Anti-Myelin oligodendrocyte glycoprotein (anti-MOG)
Anti-Myelin basic protein (anti-MBP)
Berger (2003) N Engl J Med 349:139-45 [PubMed]
Labs
Evaluation of differential diagnosis
First-line tests
Complete Blood Count
Serum
Vitamin B12
level
Thyroid Stimulating Hormone
(TSH)
Erythrocyte Sedimentation Rate
(ESR)
Lyme Disease
titer
Rapid Plasma Reagin
(RPR)
Antinuclear Antibody
Consider autoimmune evaluation
Additional tests if indicated
Angiotensin Converting Enzyme
level (
ACE Level
) for
Sarcoidosis
Autoantibody assays for
Behcet Syndrome
,
Sjogren Syndrome
,
Systemic Lupus Erythematosus
and
Vasculitis
Antineutrophil Cytoplasmic Antibody
(
ANCA
)
Anticariolipin
Antibody
Antiphospholipid Antibody
Anti-SS-A Antibody
Anti-SS-B Antibody
Human Immunodeficiency Virus
Screening (
HIV Test
)
Human
T-Cell
Lymphotropic virus type I (HTLV-1)
Very Long chain
Fatty Acid
level for Adrenoleukodystophy
Management
Acute episode or relapse
Evaluate for provocative event
Acute Sinusitis
Acute Bronchitis
Urinary Tract Infection
Emotional stressors may also provoke an event
Corticosteroid
s:
Methylprednisolone
Gene
ral
Mix in 500 ml D5W
Administer slowly over 4-6 hours in AM
Taper schedule
First: 1000 mg daily for 3 days
Next: 500 mg daily for 3 days
Last: 250 mg daily for 3 days
Alternative after first 3 days
Methylprednisolone
Prednisone
1 mg/kg/day orally daily for 14 days
Plasmapheresis
Indicated in cases refractory to
Corticosteroid
s
Plasma exchange performed every other day for 14 days
Management
Symptom-specific control
Spasticity (70 to 80% of patients)
Baclofen
10 to 40 mg orally three times daily
Baclofen Intrathecal Pump
may be preferred due to less sedation and greater effect
Tizanidine
2 to 8 mg orally three times daily
Gabapentin
(
Neurontin
) 300 to 900 mg orally three times daily
Onabotulinumtoxin A (
Botox
) injection
Physical therapy
Hydrotherapy
Castro-Sanchez (2012) Evid Based Compliment Alternat Med 2012: 473963 [PubMed]
Paroxysmal pain and other syndromes (85% of patients)
Trigeminal Neuralgia
Treat as with
Trigeminal Neuralgia
in non-Multiple Sclerosis patients
Carbamazepine
100 to 600 mg orally three times daily
Baclofen
(
Lioresal
) 10 to 80 mg/day
Dysesthetic limb pain
Hydrotherapy (see spasticity above)
Amitriptyline
10 to 150 mg orally at bedtime
Gabapentin
300 to 900 mg orally three times daily
Sativex (Available in Canada, not in U.S.)
Cannabis
extract (THC) in oral spray form
Rapid onset or relief
FDA considers as Schedule I (illegal to import)
Wade (2004) Mult Scler 10:434-41 [PubMed]
Neurogenic
Bladder
Evaluate with post-void residual testing to distinguish failure to store from failure to empty
Failure to store
Detrol
LA (
Tolterodine
LA) 2 to 4 mg orally daily
Ditropan
XL or Oxytrol XR (
Oxybutynin XR
) 5 to 10 to 30 mg orally daily
Intranasal
Desmopressin
may be used for
Nocturia
Onabotulinumtoxin A (
Botox
) injection has been used in refractory cases
Failure to empty
Trial on alpha adrenergic blocker (e.g.
Prazosin
or
Terazosin
)
Clean intermittent self cathetrization
Neurogenic bowel
Constipation
: Manage aggressively
Hydration and fiber supplementation
Rectal stimulants and enemas as needed
Fecal Incontinence
Fiber
supplementation
Consider short-term anti-
Diarrhea
l agent
Colostomy has been used in refractory cases
Fatigue
(90% of patients)
Evaluate for comorbid
Major Depression
, sleep disorder,
Thyroid
disease,
Anemia
, and
Vitamin B12 Deficiency
Amantadine
100 mg orally twice daily
Peuckmann (2010) Cochrane Database Syst Rev (11): CD006788 [PubMed]
Modafinil
(
Provigil
) 100 to 200 mg orally each morning
Variable efficacy
Brown (2010) Ann Pharmacother 44(6): 1098-103 [PubMed]
Major Depression
Selective Serotonin Reuptake Inhibitor
(
SSRI
)
Sexual Dysfunction
Affects >50% of men and >40% of women
Men are typically prescribed
Phosphodiesterase Inhibitor
s (e.g.
Sildenafil
or
Viagra
)
Management
Disease modifying agents for relapsing remitting Multiple Sclerosis
Precautions
All agents are very expensive, costing over $60,000 per year (except Mitoxantrone)
Most disease modifying agents suppress T-cell
Autoimmunity
and have the potential for significant adverse effects
Agents are typically selected, prescribed and monitored by neurologists with expertise in Multiple Sclerosis
Vaccination
Live Vaccine
s (e.g.
Zostavax
) should be administered >1 month before starting most of these MS agents
Inactivated
Vaccine
s may be given at any time
Immunomodulatory agents:
Interferon
Longest track record (20 years) of the disease modifying agents
Adverse Effects
Local injection site inflammation
Influenza
-like symptoms (decreases after first 3 months)
Lab abnormalities include
Leukopenia
and increased liver transaminases
Exacerbation of depressed mood (including increased
Suicidality
)
Interferon
beta-1b
Betaseron 0.25 mg SC every other day
Modestly protects against exacerbation for 1 year
Filippini (2003) Lancet 361:545-52 [PubMed]
Interferon
beta-1a
Avonex 30 mcg IM once weekly
Rebif 22 to 44 mcg SC three times per week
Immunomodulatory agents: Non-
Interferon
agents
Glatiramer (Copaxone)
Adverse effects include local injection site inflammation, facial
Flushing
May also experience chest tightness,
Dyspnea
and
Palpitation
s
Dose: 20 mg SC daily
Copolymer 1 that cross reacts with myelin basic protein
Good track record of safety and greater efficacy than
Interferon
Oral Immunosuppressants
Fingolimod (Gilenya)
Adverse effects include
Bradycardia
,
Hypertension
,
QTc Prolongation
, elevated liver transaminases
Other adverse effects include
Melanoma
,
Macula
r edema,
HSV Encephalitis
Dose: 0.5 mg orally daily
Bradycardia
risk (may present with
Dizziness
or
Fatigue
)
Observe for 6 hours after first dose
Avoid in those with known
Arrhythmia
or other heart disorder
Avoid concurrent use with
Digoxin
,
Diltiazem
or
Beta Blocker
Siponimod (Mayzent)
Released in 2020 and similar to Fingolimod
Ozanimod (Zeposia)
Released in 2020 and similar to Fingolimod
Teriflunomide (Aubagio)
Adverse effects include
Alopecia
,
Diarrhea
,
Nausea
,
Leukopenia
, elevated liver transaminases,
Peripheral Neuropathy
FDA Black Box warning for hepatotoxicity (monitor
Liver Function Test
s)
Teratogen
ic and requires reliable
Contraception
Dose: 7 to 14 mg orally daily
Dimethyl Fumarate (Tecfidera)
Gene
ric in 2020
Adverse effects include
Abdominal Pain
,
Diarrhea
,
Nausea
, lymphocytopenia, elevated liver transaminases
Flushing
is common, and decreases over time (consider taking
Aspirin
30 min before dose)
Monitor
Complete Blood Count
Dose: 120 to 240 mg orally twice daily
Monomethyl Fumarate (Bafiertam)
Released in 2020 and similar to Dimethyl Fumarate
Diroximel Fumarate (Vumerity)
Released in 2020 and similar to Dimethyl Fumarate
Cladribine (Mavenclad)
Oral dose given over 2 year treatment course with dosing cycles
Indicated in refractory cases and not first line
Similar efficacy to Dimethyl Fumarate
Adverse Effects
Teratogen
ic! (requires
Pregnancy Test
ing before each course of medication)
Progressive Multifocal Leukoencephalopathy
(PML)
Nausea
,
Headache
, flu-like symptoms, severe lymphopenia,
Shingles
Parenteral immunosuppressants for refractory disease: Monoclonal Antibodies
Daclizumab (Zinbryta)-
Monoclonal Antibody
- SQ once monthly
Hepatotoxicity risk (monitor
Liver Function Test
s)
Natalizumab (Tysabri, Antegren) -
Monoclonal Antibody
- IV once monthly
Adverse effects include
Hypersensitivity
, infusion reaction,
Headache
,
Fatigue
Risk of
Progressive Multifocal Leukoencephalopathy
Blocks CNS entry of immune response to
Nerve Cell
s
Reduces relapse rate by >60%
(2004) Neurology 62:2038 [PubMed]
Ocrelizumab (Ocrevus)
First-line only in primary progresive MS
Dosed IV once every 6 months (administered over 3.5 hours)
Pretreatment with
Methylprednisolone
and
Diphenhydramine
Adverse effects: Severe infusion associated reactions, infection,
Progressive Multifocal Leukoencephalopathy
Parenteral immunosuppressants for refractory disease: Miscellaneous Agents
Mitoxantrone (Novantrone)
Adverse effects include myelosuppression, elevated liver transaminases, decreased
Cardiac Function
and
Leukemia
Dose: 5 to 12 mg/m2 IV every 3 months
Costs $900/ year in contrast to more than $60,000/year for other agents
Management
Gene
ral Supportive Measures
Keep Cool
Regular
Exercise
Pursuit of wellness and positive attitude
Education regarding the disease
Support from family and MS support groups
Vitamin D
Supplementation may help prevent exacerbations
Resources
National Multiple Sclerosis Society
http://www.nmss.org
NIH Multiple Sclerosis
http://www.ninds.nih.gov/disorders/multiple_sclerosis/multiple_sclerosis.htm
Multiple Sclerosis Association of America (MSAA)
http://www.mymsaa.org/
Multiple Sclerosis Foundation
http://www.msfocus.org/
References
(2017) Presc Lett 24(9): 53
(2020) Presc Lett 27(11): 65
Pirko in Goetz (2003) Clinical Neurology, p. 1060-76
Wilson (1991) Harrison's IM, p. 657-8
(1995) Neurology 45:1268-76, 1277-85 [PubMed]
Calabresi (2004) Am Fam Physician 70:1935-44 [PubMed]
Frohman (2003) Med Clin North Am 87:867-97 [PubMed]
Hawker (2004) Prim Care 31:201-26 [PubMed]
OConnor (2002) Neurology 59:s1-33 [PubMed]
Saguil (2014) Am Fam Physician 90(9): 644-52 [PubMed]
Type your search phrase here