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
    • Uhthoff’s 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, Lhermitte’s 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 – Balo’s concentric sclerosis, concentric lacumar leukoencephalopathy, disseminated subpial demyelination, myelinoclastic diffuse sclerosis (Schilder’s disease), Devic’s 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)
    • D1 – 2 relapses, CSF+

 

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