Multiple sclerosis
Immunopathogenesis of MS
- Postulated mechanism
- Myelin-reactive T cell activated
- T cell crosses blood brain barrier
- T cell reactivates in the CNS
- Pathological subtypes of MS
- Demyelination
- Oligodendrocytes attacked
- Axonal injury
- Neuronal loss
- Neuroinflammation also important for neuroprotection ?neurotrophins,
regeneration
Epidemiology of
MS
- 3 female : 1 male
- Peak age of onset 30 years
- 85% relapsing-remitting, 15% primary
progressive
- Median 1 attack/year in first 5 years
- 50% become secondary progressive in 10
years
- 30-40% benign MS (EDSS < 4 at 10
years)
- Time to walking with cane 15-28
years
- Surival is 85-90% of normal population
- Genetic effects
- In high risk areas, some populations
are resistant (Amerindians, Inuit)
- Adoption studies (adopted children
carry risk of population)
- Half-sib studies (half sibs have half
risk of full sibs)
- Twin studies (25% concordance in
monozygotic, 5% in dizygotic twins)
- Birth-order status (no diff, against
the early exposure theory for infections)
- Conjugal studies (no concordance
between spouses)
- Environmental effects
- Latitude/sun exposure (? Vitamin D)
- Migration studies (risk of
destination if migrate <15 years)
Clinical
features of MS
- Motor manifestations
- Weakness, spasticity,
ataxia
- Somatosensory manifestations
- Positive and negative phenomena, in
same location or independent
- Visual symptoms
- Unilateral, painful optic neuritis,
with central scotoma
- Can be mild as colour desaturation, uncommonly total blindness
- Uveitis in 1% cases
- Diplopia from cranial nerve nuclei
involvement (internuclear ophthalmoplegia)
- Other eye findings: ocular contrapulsion, acquired convergence-evoked pendular nystagmus,
divergence insufficiency, nystagmus with oscillopsia (vestibular involvement)
- Cranial nerve/brain stem involvement
- Loss of taste, facial weakness, loss
of hearing, tinnitus, vertigo
- Also central hyperacusis
with phonophobia, dysarthria,
swallowing dysfunction, olfactory disturbance
- Cognitive/psychiatric disturbances
- Cognitive problems in 50-75% patients
- More severe with long-standing
disease and severe physical impairment
- Can occur independent of physical
disability
- Impaired attention, slowed
information processing, short-term memory loss, reduced visuospatial skills, impaired executive function
- Mood disturbance, suicide risk,
depression, emotional lability (frontal lobe)
- Bladder/bowel/sexual dysfunction
- Detrusor hyperactivity (urgency, frequency, nocturia)
- Detrusor-sphincter dyssynergia
(urinary hesitancy, postvoid residual,
retention)
- Both can cause urinary incontinence and
increased risk of UTIs
- Bowels: constipation or
urgency/incontinence
- Men with erectile dysfunction, women
with loss of libido and anorgasmia
- Fatigue
- Important source of disability
- Increased work of nerves to perform
routine tasks
- Uhthoffs phenomenon
- Depression, medications
- Systemic fatigue of unclear etiology ?soluble immune mediators in CNS
- Paroxysmal symptoms
- Focal or secondarily generalized
seizures in 1-5%
- Stereotyped movements from acute
inflammation, or ephaptic transmission from
chronically demyelinated fibers
- Paroxysmal motor phenomena - akinesia, tonic spasms, dystonia,
torticollis, ballism,
dysarthria, hemifacial
spasm, facial myokymia, segmental myoclonus, hiccups, episodic ataxia
- Paroxysmal sensory phenomena
neuralgic pain in cranial nerves (trigeminal or glossopharyngeal
neuralgia), radicular pain, Lhermittes
phenomenon, photopsias
- Pain
- Primary pain: neuralgic pain, dysesthetic pain, radicular
pain, tonic spasms, spasticity, optic neuritis
- Secondary pain: low back pain,
osteoporosis with fractures
- Ambulation
- Impaired ambulation, and even early
gait abnormalities on testing
- From leg weakness, spasticity, cerebellar/vestibular dysfunction, proprioceptive loss, visual disturbance
Clinical course
of MS
- Relapsing-remitting MS
- Primary progressive MS
- Secondary progressive MS
- Progressive-relapsing MS
- Marburg variant fulminant
MS, tumefactive MS
- Other related Balos
concentric sclerosis, concentric lacumar leukoencephalopathy, disseminated subpial
demyelination, myelinoclastic
diffuse sclerosis (Schilders disease), Devics neuromyelitis optica, clinically isolated syndromes (CIS) - ADEM,
transverse myelitis, optic neuritis
Diagnostic
criteria for MS
Schumacher Criteria for Definite MS
- Onset between 10-50 years
- CNS white matter disease
- Lesions disseminated in time and space
- Objective abnormalities on examination
- Course:
- attacks lasting >24 hours, spaced
>1 month apart
- gradual or stepwise progression over
6 months
- No alternative diagnosis
Poser Criteria
- Clinically-definite MS (CDMS)
- A1 2 relapses, 2 lesions
- A2 2 relapses, 1 lesion, 1 paraclinical
- Laboratory-supportive definite MS
(LSDMS)
- B1 2 relapses, 1 lesion, 1 paraclinical, CSF+
- B2 1 relapse, 2 lesions, CSF+
- B3 1 relapse, 1 lesion, 1 paraclinical, CSF+
- Clinically probable (CPMS)
- C1 2 relapses, 1 lesion, CSF-
- C2 1 relapse, 2 lesions, CSF-
- C3 1 relapsy,
1 lesion, 1 paraclinical, CSF-
- Laboratory-supported probable (LSPMS)
McDonald Criteria
Laboratory
tests for MS
- Basic blood tests CBC, ESR ANA, B12,
TSH, ACLA, Lyme serology, RF
- Additional bloods ACE, autoantibodies, vitE, VLCFA,
lactate, gene testing (mitochondria, notch-3)
- MRI brain and spinal cord
- CSF oligoclonal
banding with isoelectric focusing,
immunoglobulin G index (pair with serum sample)
- Neurophysiology VEP, SSEP
- Urologic studies (urinalysis, culture,
postvoid residual, bladder ultrasound, cystometrogram)
- CXR or chest CT, ECG
- Cognitive function testing
Management of
MS
- Steroids: Methylprednisolone
20-30mg/kg (max 1g) IV x3-5 days +/- PO
prednisone taper
- PLEX: Improves patients with severe
forms of demyelination not responsive to steroids
- Interferon beta-1b
- Betaseron 8mIU q2d SC
- Mechanism (postulated):
- Enhancement of suppressor T-cell
activity
- Decrease proinflammatory
cytokine production
- Downregulate antigen presentation
- Inihibition of lymphocyte trafficking through
BBB
- Decreased matrix metalloproteinase
production
- Side effects: flu-like symptoms, site
reaction, high LFTs, depression
- Contraindications: pregnancy,
depression (relative), hypersensitivity reaction, breastfeeding
- Neutralizing antibodies (rate 28-47%)
- RRMS improved 1/3 relative risk,
MRI. No effect on disability. ARR
17%
- SPMS early efficacy in decreasing
relapses
- Interferon beta-1a
- Avonex 30mcg qwk IM
- Neutralizing antibodies 2-6%
- RRMS improved 1/3 relative risk,
disability. No effect on MRI volume
- SPMS not efficacious
- Rebif 22/44mcg q2d SC
- Neutralizing antibodies 13-24%
- RRMS improved 1/3 relative risk,
disability, and MRI. ARR 15%
- SPMS decreases relapses, no effect
on progression
- Glatiramer acetate
- Copaxone 20mg qd SC
- Mechanism: switching TH1 (proinflam) to TH2 (anti-inflam)
helper T-cells
- Side effects: local skin reation, injection reaction (facial flushing, chest
tightness, palpitation, anxiety, dyspnea)
- No NABs
- RRMS improved relative risk, MRI
(not as impressive). No effect on disability
- Mitoxanthrone
- Immunosuppressant:
- Induces DNA breaking/crosslinking
- Interferes with RNA synthesis
- Inihibits topoisomerase
II (DNA repair)
- Side effects: dose-related cardiac toxicity, alopecia, amenorrhea,
leucopenia
- Cyclophosphamide (chemotherapy)
- Natalizumab (Tysabri 300mg IV qmonth)
- Blocks migration of WBC into the
brain by blocking alpha4-integrin from binding VCAM
- 50% decreased sustained disability,
70% decreased relapses
- Approved for patients with failed
management on interferon-beta
- Side effects: increased UTI, risk of
PML in combo with Avonex, transfusion
reactions, neutralizing antibodies
Symptomatic treatment
for MS
- Spasticity
- 70% patients have spasticity,
can be worsened by beta-interferons
- Can be detrimental (pain) or
beneficial (help with walking)
- Treat contributing factors UTIs, decubitus ulcers,
pain, constipation, tight-fitting clothes
- Physical therapy and stretching
- Baclofen (Lioresal)
- GABA analog, centrally-acting
skeletal relaxant
- Initial dose: 5 mg bid/tid
- Increase by 5-10mg q4-5 days until
effect or side effect
- Usual target range 40-120mg/day
- Common side effects: muscle
weakness, sedation, confusion
- Rare side effects: hepatotoxicity
- Sudden discontinuation can result in
seizures, confusion, hallucination, and increase tone
- Tizanidine (Zanaflex)
- Centrally-acting alpha-2-adrenergic
agonist
- Presynaptic inhibitor of spinal motor neurons
- Initial dose: 2-4mg qhs
- Increase by 2-4mg q2-3d, divided TID
or more
- Usual target dose 25mg/day, maximum
recommended 36mg/day
- Peak effect is 1-2 hours after
administration
- Common side effects: drowsiness, weakness,
dizziness, dry mouth, increased LFTs
- Monitor LFTs
at 1, 3, and 6 months, then q3-6months
- Combining baclofen
and tizanidine may improve efficacy and
decrease side effects
- Other potential drugs:
- Gabapentin 1200-2700mg/day
- Benzodiazepines (diazepam, clonazepam) more side effects (sedation)
- Dantrolene side effect of weakness, hepatotoxicity
- Botulinum toxin injections to local muscle
groups
- Intrathecal baclofen
can help legs for easier personal care and transfers
- Test dose of 50mcg and 100mcg
start if helpful
- Side effects - nausea/vomiting,
sedation, urinary retention, hypotension, seizures
- Usual target dose 300-800mcg/24h
- Weakness
- OT/PT
- 4-aminopyridine (experimental)
- K-channel blocker, sustained-release
form exists
- Enhances conduction across demyelinated fibers
- Dose response at 20-50mg
- Side effects 8% seizures
- Depression
- Routine screening for depression
- Psychotherapy and pharmacotherapy
- SSRIs less side effects than TCAs, but sometimes sedative effects of TCAs preferred
- Sexual dysfunction from SSRI may be
unacceptable
- Buproprion (NE and DA reuptake inhibitor) for
depression and fatigue
- Bipolar disorder, anxiety, abnormal
laugh/cry, euphoria also exist.
- Lithium or VPA for bipolar disorder
- Amitriptyline (25-75mg daily) for pathological
laughing/crying
Drug
|
Initial dose
|
Usual dose
|
Citalopram (Celexa)
|
20mg qd
|
20mg qd
|
Escitalopram (Lexapro)
|
10mg qd
|
10-20mg qd
|
Fluoxetine (Prozac)
|
20mg qd
|
20-60mg qd
|
Sertraline (Zoloft)
|
50mg qd
|
50-200mg qd
|
Buproprion (Wellbutrin)
|
100mg bid
|
100-150mg tid
|
Wellbutrin SR
|
150mg qd
|
150-200mg bid
|
- Fatigue
- Treat contributing factors sleep,
depression, physical deconditioning,
medications
- Limit activity in the afternoon
- OT for energy conservation strategies
- Amantadine (Symmetrel)
- NMDA receptor antagonist, dopaminergic properties
- 100mg BID
- Common side effects: nausea,
dizziness
- Modafinil (Provigil)
- Wake-promoting agent
- 100-200mg qd
- Common side effects: headache,
nausea, diarrhea, weakness, nervousness,
anxiety
- Other potential treatments
- Buproprion, nonsedating
SSRIs
- Methylphenidate (Concerta,
Metadate, Ritalin) does NOT help
- Acetyl L-carnitine
(1mg BID) experimental
- Pemoline (Cylert)
poorly tolerated, associated with hepatotoxicity
- Sexual dysfunction
- In up to 90% patients need to
screen
- Least likely in RRMS, but still
affects 2/3 of them
- Treat contributing factors fatigue,
medications
- Anticholinergies erectile dysfunction
- Baclofen erectile dysfunction, ejaculatory
dysfunction
- Carbamazepine decreased desire, erectile
dysfunction
- SSRI decreased desire,
ejaculatory/orgasmic dysfunction
- TCAs decreased desire, erectile
dysfunction, orgasmic dysfunction
- Sex therapy for communication
- Buproprion helpful in non-MS studies
- Sildenafil
(Viagra), vardenafil (Levitra), tadalafil (Cialis) PDE5 inhibitor
- Estrogen topical creams
or vaginal rings to help with dryness or sensitivity
- Cognitive dysfunction
- In up to 65% patients
- Screen, but MMSE not sensitive
- Cognitive remediation strategies to
compensate for deficits
- No effective treatments to date
- Possible treatments
- Donepezil (Aricept)
acetylcholinesterase inhibitor
- Disease-modifying agents that
minimize disease may help
- Bowel/bladder dysfunction
- In up to 75% patients, and disabling
in 15%
- Lesion above pons
detrusor hyperreflexia
/ overactive bladder
- Lesion between pons
and S2 reticulospinal pathways detrusor-sphincter dyssynergia
- Lesion lower sacral anterior horn
cells detrusor hypocontractility
- Screen for UTI if symptoms
- Nonpharmacological limit fluid intake, avoid caffeine,
pelvic floor exercises, biofeedback
- Overactive bladder treatments:
Medication
|
Initial dose
|
Usual dose
|
Anticholinergics
|
|
|
Oxybutynin (Ditropan)
|
5mg bid-tid
|
5mg bid-qid
|
Ditropan XL
|
5mg qd
|
5-30mg qd
|
Oxytrol transdermal patch
|
Biweekly patch
|
Biweekly patch
|
Tolterodine (Detrol)
|
2mg bid
|
1-2mg bid
|
Detrol LA
|
4mg qd
|
4mg qd
|
Alpha-adrenergic
antagonist
|
|
|
Doxazosin (Cardura)
|
1mg qd
|
1-8mg qd
|
Prazosin (Minipress)
|
1mg bid
|
1-10mg bid
|
Tamsulosin (Flomax)
|
0.4mg qd
|
0.4-0.8mg qd
|
Terazosin (Hytrin)
|
1mg qhs
|
1-10mg qhs
|
Antidiuretic hormone analog
|
|
|
Desmopressin
(DDAVP) tablet
|
0.5-1.0mg qhs or qd
|
0.2-0.6mg qhs or qd (huh?!)
|
DDAVP nasal spray
|
10mcg qhs or qd
|
10-20mcg qhs or qd
|
- Anticholinergics are main therapy. Side effects: dry
mouth, urinary retention
- DDAVP side effects: fluid retention,
hyponatremia
- Clean intermittent catheterization
also helpful
- Bladder botulinum
toxin toxin injections can also minimize
medication requirement
- Detrusor-sphincter dyssynergia
- Combination of anticholinergic
and alpha-adrenergic therapy
- Side effects: hypotension and
syncope better if titrate slowly
- Clean intermittent catheterization
helpful
Medication
|
Initial dose
|
Usual dose
|
Alpha-adrenergic
antagonist
|
|
|
Doxazosin (Cardura)
|
1mg qd
|
1-8mg qd
|
Prazosin (Minipress)
|
1mg bid
|
1-10mg bid
|
Tamsulosin (Flomax)
|
0.4mg qd
|
0.4-0.8mg qd
|
Terazosin (Hytrin)
|
1mg qhs
|
1-10mg qhs
|
- Detrusor hypocontractility
- Clean intermittent catheterization
or indwelling catheters
- Cranberry juice 8oz qd for frequent UTIs, or
prophylactic antibiotics if >3-4 infections/year
- Bowel dysfunction
- Fecal incontinence or constipation
- Constipation high fiber diet or supplementation, stool softeners (Colace 100mg bid), laxatives (Senekot
2 tabs qd or bisacodyl
(Dulcolax) 5-10mg qhs),
osmotic laxatives (lactulose, polyethylene
glycol), rectal suppositories and enemas (mineral oil, tap water)
- Incontinence high fiber diet and regular tap water enemas (better
formed stools), scheduled defecation after meals, loperamide
(Imodium) for loose stools
- Tremor
- Associated with other cerebellar
signs gait ataxia, dysmetria, dysdiadochokinesia, dysarthria
- Medications tried:
- Carbamazepine, clonazepam,
gabapentin, glutehimide,
isoniazid, levetiracetam,
ondansetron, primidone,
propranolol, tetrahydrocannabinol
- Poor effect of these medications
- Thalamotomy and thalamic deep brain stimulation
reported effective
- Paroxysmal symptoms
- Most commonly trigeminal neuralgia or
tonic spasms
- Treatment to suppress, then gradually
withdrawn
- If deemed an acute MS exacerbation,
IV steroids may be warranted
- Low dose anticonvulsants carbamazepine, dilantin, gabapentin
- Baclofen, benzodiazepines, and TCAs also tried, but more side effects
- Lamotrigine 75-400mg better tolerated and
effective than carbamazepine in trigeminal
neuralgia
- Misoprostol (Cytotec,
PGE1 analog) 200mcg TID (abortifacient, teratogenic!)
- Topiramate (Topamax)
100-200mg BID (starting dose 25mg BID)
- Percutaneous radiofrequency rhizotomy
if refractory trigeminal neuralgia, recurs in 30%
- Tiagabine (Gabitril,
5-30mg qday) in trials
- Botulinum toxin for refractory tonic spasms
- Pain
- IV steroids if associated with acute
attack
- Chronic neuropathic
pain anticonvulsants, TCAs, opioids, referral to pain specialist