section name header

Info


A. Definition and Epidemiology [4]navigator

  1. Most prevalent severe neurological disease in young adults in USA
    1. Inflammatory demyelinating disease of the central nervous system (CNS)
    2. Lesions develop at distinct times and locations
  2. ~6000-9000 new cases annually in USA
    1. About 200,000 cases in USA currently (additional ~100,000 silent cases estimated)
    2. About 75,000 cases in United Kingdom
    3. Incidence lower in equatorial regions
    4. Prevalence higher in temperate zones, possibly related to early viral trigger
  3. Four Clinical Subtypes
    1. Relapsing and Remitting (RR-MS) - about 80% of younger patients (~40% overall prevalence)
    2. Benign type ~10%
    3. Chronic Primary Progressive (CP-MS) - typically beings at 45-50 years (~10% of MS)
    4. Chronic Secondary Progressive - progress from relapsing-remitting type (~45% of MS)

B. Pathology [2] navigator

  1. Presence of Localized Inflammatory Lesions [3]
    1. Likely that blood-brain barrier (BBB) disruption is initial event
    2. Gadolinium enhancement of MRI consistent with this hypothesis
    3. Antigen specific T cells enter the CNS recognize antigen
    4. This initiates a cytokine cascade that leads to BBB disruption (see below)
    5. Patchy CNS demyelination in active lesion areas
    6. Lesions are most commonly found around venules in the white matter
    7. Majority of early lesions are in periventricular distribution
  2. Histology of MS Lesions
    1. Lymphocyte and macrophage infiltration is found in most early lesions
    2. Macrophages are believed responsible for majority of myelin destruction
    3. Lymphocytes are mainly of T (CD4+ helper) cell type
    4. B cells are also present and secrete antigen specific IgG and IgM antibodies (Abs)
    5. Anti-myelin Abs are found, and may play a role in early demyelination
    6. Lack of correlation of anti-myelin Abs and progression to full-blown MS in pre-MS [9]
    7. During active lesions, CD4+ T helper cells produce mainly Type 1 cytokines
    8. T cells in healing lesions may express TGFß
    9. Inflammatory cells in active lesions account for T2 bright spots on MRI
  3. Classificaiton of MS Lesions [55]
    1. Type I: demyelination and macrophage related products (TNFa and others)
    2. Type II: Ig and complement
    3. Type III: early loss of myelin associated glycoprotein without remyelination
    4. Type IV: apoptosis of oligodendrocytes
  4. Longstanding Demyelination and Occasional Remyelination
    1. Oligodendrocytes are key cells here
    2. When remyelination fails, astrocytes replace the active lesion
    3. This accounts for the "sclerosis" or "plaques"
    4. In fresh brain slices, the astrocytic scar (sclerosis) feels firmer than white matter
    5. Scars are composed of cell cytoplasm with high water content
    6. Thus, scars account for T2 bright spots on MRI
    7. Remyelination by multipotential stem cells differentiating within chronic lesions
  5. Bystander Effects of Inflammation
    1. Axonal damage and neuron death (direct damage) may result from bystander effects
    2. Neuronal death may follow wallerian degeneration of axons
    3. Blood-brain barrier compromise is very common during acute inflammatory reactions

C. Pathophysiology [1,2] navigator

  1. Overview
    1. Immune activation due to any of a variety of common pathogens in genetically susceptible
    2. Leads to acute inflammatory injury of glia and axons
    3. Recovery of function and structural repair
    4. Post-inflammatory gliosis and neurodegeneration
    5. Clinical manifestations probably 10-20 years after initial inciting event
    6. Genetic contribution based on twin studies (see below)
    7. Genetic predisoposition occurs with certain HLA subtypes
    8. Females more common than males (ratio is 1.8 to 1)
    9. Fundamental oligodendrocyte dysfunction appears involved in Lesions Types III and IV
  2. MS is likely to be a T Cell-Macrophage Initiated Autoimmune Disease [4]
    1. CD4+ T helper type 1 (Th1) lymphocytes appear to be involved
    2. Central memory T cells and effector memory T cells also involved
    3. Enter the CNS through internal caroticd artery, proceed into the CSF as well
    4. T cells specific for myelin basic protein (MBP) are found in nearly all patients with MS
    5. Extravasation of T cells into tissues through alpha4-beta1 integrin on cell surface
    6. Pathogenenic autoantibodies are produced late and found in cerebrospinal fluid (CSF) [3]
    7. Risk genetic alleles in various immune related genes identified (see below) [12]
  3. Th1 Mediated Inflammation
    1. Inflammatory response is amplified by T cell cytokines
    2. Effector stage initiated by Th1-like cytokines, leading to myelin damage
    3. Macrophages produce IL12 and TNFa, driving T helper cells to Th1 phenotype
    4. Major Th1 cytokines include interleukin 2 (IL-2), IL-23, interferon gamma (IFNg), tumor necrosis factor (TNFa) and lymphotoxin alpha (LTa, also called TNFß)
    5. Nitric oxide levels increase in lesions to maximal by 72 hours
    6. Nitric oxide may be key mediator of vasodilation, inflammation, axonal damage
  4. T Cell Specificities
    1. T cells specific for MBP and proteolipid protein and other CNS proteins have been found
    2. Antibodies against MBP and other proteins may be found in cerebrospinal fluid
    3. T cell specific MBP residues have been mapped in patients with HLA-DR2 and others
    4. A number of viral peptides have been shown to stimulate these T cells
    5. This suggests a mechanism for viral induction of anti-MBP T cells
    6. T cells specific for other CNS proteins have been found in MS patients' CSF
  5. Genetic Contributions
    1. Five-fold increased incidence in monozygotic versus dizygotic twins
    2. Genetic predisposition now widely accepted for MS
    3. Some HLA linkage: HLA-DR and -DQ as well as TNFa locus (all chromosome 17)
    4. Other loci poorly linked after numerous studies
    5. Likely polygenic susceptibility with environmental interaction
    6. In children with one affected parent, risk is about 1 in 200
    7. Increased risk in children with both parents affected (about 1 in 17) [17]
    8. Polymorphisms in IL1ß, IL1RA, and ApoE genes correlated with outcomes
    9. Risk alleles in genomewide study idenitified: IL2 receptor alpha and IL7 receptor alpha [12]
    10. Multiple alleles in HLA-DRA locus identified which confer hereditable risk [12]
  6. Myelin Sheath and Axonal Damage
    1. Myelin sheath destruction appears to be target of inflammatory response
    2. Oligodendrocytes may be destroyed
    3. Premyelinating oligodendrocytes are present in chronic MS lesions, however [31]
    4. Demyelination accounts for variable conduction block
    5. Normal saltatory conduction at Nodes of Ranvier is prevented
    6. Conduction block is known to increase with rise in temperature and decrease in pH
    7. Patients' symptoms may worsen after hot bath or with exercise
    8. Demyelinated axons in chronic MS lesions appear unreceptive to remyelination [31]
    9. Autoantibodies (autoAbs) to myelin basic protein (MBP) produced in most MS patients [3,5]
    10. AutoAbs against myelin oligodendrocyte glycoprotein (MOG) are more specific for clinically definite MS than anti-MBP autoAbs [5]
  7. Axonal Degeneration
    1. Major finding in the disease: damage is not restricted to myelin sheaths
    2. In RR-MS levels of neuronal n-acetyl aspartate (NAA) are reduced in areas of lesions
    3. In chronic progressive disease, global CNS levels of NAA are reduced
    4. Astrocytic scarring may also contribute in chronic lesions
    5. Progressive disability in MS may be due to neuronal death
    6. Neurons in chronic MS appear unreceptive to remyelination by oligodendrocytes [31]
  8. Role of Viral Infections
    1. No consistent association of most viral infections with MS risk
    2. No increased risk of spouses living with affected patients [17]
    3. Human herpesvirus 6 implicated but controversial results
    4. Antibodies to components of Epstein-Barr Virus (EBV) 1.5-4.0X increased in adults with MS compared with adults without MS [22] with similar associations in children [49]
    5. High titers of EBV viral capsid antigen or EBNA associated with >15X increased MS risk [6]
    6. Temporal relation between EBV titers (infection) and development of MS [29]
    7. Vaccination (including hepatitis B vaccine) does not increase MS risk or relapse [42,43]

D. Clinical Course [32,41]navigator

  1. Onset Usually in Young Adult
    1. Age ~20-40 years
    2. Females more frequently than males
    3. Most young persons begin with intermittant exacerbations (symptoms)
    4. This form is known as relapsing-remitting type (RR-MS)
    5. More than 50% of RR-MS develop chronic secondary progressive (CS-MS) over 10-15 years
    6. T2-weighted MRI-based lesion volume on presentation has some prognostic value [30]
    7. However, MRI-based lesion volume is not substantially specific for individual prognosis
  2. Progression of Neurologic Deficits and Disability [41]
    1. Neurologic deficits occur at different times affecting different parts of CNS
    2. Lack of association between anti-myelin Abs and progression to full-blown MS [9]
    3. In RR-MS, these deficits occur as exacerbations, with sudden severe symptoms/signs
    4. In CP-MS, deficits accrue more chronically and insidiously, with progressive decline
    5. Initial disability progression is much more rapid in CP-MS than in RR-MS
    6. When RR-MS transforms to CS-MS, progression is similar to CP-MS
    7. Thus, disability progression in CS-MS and CP-MS are similar
    8. Acute relapses do not significantly influence the progression of irreversible disability [41]
  3. Neurological deficits may be found in any area of CNS
    1. Optic Neuritis - may precede MS months to years earlier (60% risk of MS over 40 yrs) [7]
    2. Motor pathways - paresis (weakness) and/or plegias (paralysis)
    3. Sensory Pathways - paresthesias, dysesthesia, loss of sensation (anesthesia)
    4. Cerebellum - ataxia and dysmetria
    5. Transverse Myelitis (spinal cord lesions) variable
    6. Brown-Sequard Syndrome: loss of function on one side of spinal cord
    7. In Brown-Sequard, contralateral pain and temperature loss with ipsilateral paralysis
    8. MRI location of lesion and lesion volume show some correlation to deficits [30]
  4. Initial Presentation
    1. Paresthesias / Sensory Deficits 77%
    2. Gait Difficulty 35%
    3. Leg Weakness 17%
    4. Visual Loss 18% (see below)
    5. Arm Weakness 10%
    6. Double Vision 10%
    7. Poor balance
    8. Appearance of new symptoms and signs with rise in body temperature
  5. Ocular Symptoms
    1. Optic neuritis - damage to Cranial Nerve II [7]
    2. Scotomas or uncorrectable decrease in visual acuity
    3. Double Vision due to damage, CN III, IV and/or VI
    4. Uveitis occurs in ~1% of MS patients, typically posterior [50]
  6. Pregnancy and MS [28]
    1. Relapse rates are reduced ~70% in third trimester of pregnancy
    2. Relapse rates increase ~70% in first 3 months post-partum, then return to baseline
    3. May be related to Th2 shift in cytokine profiles during pregnancy
    4. Net effect of risk of MS relapse with pregnancy is minimal

E. Physical Examinationnavigator

  1. Performed after a careful history
    1. Elicit previously neglected, transient symptoms
    2. Focus particularly with heat or febrile illness
  2. Hyperreflexia 76%
  3. Leg Ataxia 57% (sensory or cerebellar)
  4. Poor Vibration Sense 47%
  5. Optic Neuritis 38%
  6. Nystagmus 35%
  7. Spasticity 21%
  8. Paraparesis 17%
  9. Intranuclear Ophthalmoplegia 11% (Medial Longitudinal Fasciculus Lesion in most cases)
  10. Neurogenic Bladder 10% (Incontinence)
  11. Lhermitte's Sign
    1. Acute flexion of neck causes shock down neck/arms/back/legs
    2. Implies cervical spinal cord (inflammatory) lesion
  12. Absent or asymmetric abdominal and/or cremasteric reflexes
  13. Positive Romberg test and/or poor tandem gait
  14. Worsening of symptoms / signs with hot bath or exercise (Uhthoff's phenomenon)
  15. History, MRI findings, and serology probably more accurate than physical examination

F. Diagnosisnavigator

  1. Revised Criteria allow classification of individual as:
    1. MS (definite)
    2. Possible MS
    3. Not MS
  2. Two or more episodes separated in space and time required [1]
    1. However, if initial lesion is clinical, then other lesion does not have to be clinical
    2. Magnetic resonance imaging (MRI) is part of current diagnostic criteria
    3. Analysis of cerebrospinal fluid (CSF) is also critical
    4. Visually evoked potential (VEP) testing can also be done
    5. One neurologic event with MRI consistent with MS and presence of anti-MOG or anti-MBP autoAbs predicts early conversion to clinically definite MS [5]
  3. Brain and Spinal Cord (MRI)
    1. Brain MRI is abnormal in >95% of cases of MS
    2. >95% of MS patients have lesions with high signal on T2 weighted scans
    3. MS T2 lesions found in white matter, usually in periventricular region
    4. T2 lesions are due to high water content
    5. Total area of high T2 signal called "lesion load"
    6. T2 weighted MRI - high signal in fresh lesions due to edema or presence of inflammatory cells
    7. T2 weighted MRI - high signal in old lesions due to replacement of myelin (lipid) with astrocytes (water)
    8. T1 weighted MRI - "holes" where high lipid content is lost due to myelin breakdown
    9. Spinal cord lesions on MRI often in cervical region but may be anywhere
    10. Gadolinium MRI scan - gadolinium is an MRI contrast agent and shows increased uptake in areas of blood-brain barrier breakdown
    11. Gadolinium MRI differentiates active from old lesions in diagnosis of MS
    12. Gadolinium MRI lesion load predicts relapses well, but is a poor predictor of the development of cumulative impairment (disability) [41]
    13. MRI alone is probably not accurate enough for ruling MS in or out
  4. Optic Neuritis and MRI Lesions [7]
    1. High risk MS in patients with optic neuritis and at least one demyelinating lesion on MRI
    2. Overall MS risk in optic neuritis patients is ~38% in 10 years
    3. Interferons are approved for treating optic neuritis + MRI lesions; reduce MS risk [14,39]
  5. Serological tests for anti-MBP and anti-MOG autoAbs are highly predictive for early conversion to clinically definite MS [5]
  6. CSF Examination (Lumbar Puncture)
    1. Intrathecal IgG: oligoclonal bands (increased IgG, L chains and myelin damage) in >80%
    2. MBP may be found in CSF during active disease (may occur with any CNS inflammation)
    3. Low grade lymphocytosis in active disease
  7. Demyelination
    1. Nerve conduction delays in CNS detected with various evoked potentials:
    2. Visual (VEP), brainstem auditory (BSAEP) and sensory (SEP) evoked potentials
    3. Specific findings on MRI
  8. Poor Prognostic Factors
    1. Male Sex
    2. Age >40 years at onset
    3. Motor dysfunction
    4. Relatively high number of attacks in first 2 years
    5. Rapid progression of disability measured by expanded disability status scale (EDSS)
    6. Cerebellar involvement is frequently irreversible

G. Differential Diagnosisnavigator

  1. Metabolic Disorders
    1. Vitamin B12 Deficiency
    2. Leukodystrophies
  2. Autoimmune Disroders
    1. Systemic Lupus Erythematosus
    2. Behcet's Disease
    3. Sarcoidosis
    4. Sjogren's Syndrome
    5. Chronic inflammatory demyelinating polyneuropathy (CIDP)
    6. Polyradiculopathy associated with CNS demyelination
    7. Antiphospholipid Antibody Syndrome
  3. Infection
    1. HIV associated myelopathy
    2. HTLV-1 associated myelopathy
    3. Lyme Disease
    4. Syphilis (neurovascular)
  4. Vascular Disorders
    1. Spinal dural arteriovenous fistula
    2. Cavernous hemangiomata
    3. CNS Vasculitis
    4. Cerebral autosomal dominant arteriopathy (CADASIL)
  5. Genetic Diseases
    1. Hereditary ataxias and paraplegias
    2. Leber's optic atrophy
    3. Other mitochondrial disorders
  6. Posterior Fossa and Spinal Cord Lesions
    1. Arnold-Chiari malformation
    2. Spondylotic and other myelopathies
  7. Neoplastic Disorders
    1. Spinal cord tumors
    2. CNS lymphoma
    3. Paraneoplastic disorders
  8. Psychiatric: conversion reaction, malingering

H. Treatment [32]navigator

  1. Goals of Treatment [1]
    1. Reduce relapse rates
    2. Prevent fixed disability directly attributable to relapse
    3. Prevent disability acquired through progression
    4. Treat established progression
    5. Provide symptomatic management of fixed neurological deficits (see below)
  2. General Overview [4]
    1. Not all MS patients require active medical therapy
    2. Only patients with active inflammation in form of relapses or clear activity on MRI
    3. In general, first line therapy with glatiramer acetate or IFNß, although natalizumab appears to be more effective than either of these agents [4]
    4. Natalizumab should be used with RR-MS who have failed on first line therapy
    5. Unclear if natalizumab has benefit in progressive forms of MS
    6. Mitoxantrone or cyclophosphamide, are used in progressive or refractory MS
    7. Glucocorticoids are for acute exacerbations, remission induction
  3. Glucocorticoids
    1. Proven to accelerate remission and help terminate exacerbations
    2. Minimal (or no) retardation of overall progression of disease
    3. Exacerbations are usually treated with high dose, daily glucocorticoids
    4. Typical regimen consists of 3-5 days of 500-1000mg daily IV methylprednisolone
    5. Oral prednisone 60mg po qd x 7 days, with 50% taper every 7 days, was as effective in reducing disability as IV steroid therapy [15]
    6. High dose glucocorticoids IV slowed progression of optic neuritis but baseline MRI findings in control versus active groups were significantly different [7,16]
    7. Glucocorticoids likely most effective when given within 48-72 hours of symptoms [1]
    8. Other anti-inflammatory agents such as methotrexate may be active
  4. Interferon ß (IFN-ß) [11,35]
    1. Mechanism of action may involve interferance with IFNg activation of macrophages
    2. IFN-ß treatment may shift T helper cell profile towards Th2 lymphokine production
    3. Induces expression of tumor necrosis factor related apoptosis inducing ligand (TRAIL)
    4. May also block blood-brain barrier openings in MS
    5. Early and sustained induction of TRAIL in MS patients receiving IFNß is a marker for response [35]
    6. Overall, IFN-ß reduces relapse and progression 30-35%
    7. IFN-ß1a once weekly intramuscular (Avonex®) reduces relapse rate AND slows disease progression in relapsing remitting MS [10,34]
    8. IFN-ß1a (Avonex®) IM weekly after first clinical event reduces onset of definite MS and delays progression [39]
    9. IFN-ß1a (Rebif®) given subcutaneously weekly after first clinical event reduces onset of definite MS by ~20% and delays progression [14]
    10. Rebif® prevented relapses in 62% versus 52% for Avonex® at 48 weeks [11]
    11. IFN-ß1b (betaseron®) decreases relapse rates and progression rates 35% in secondary progressive MS [8,33]
    12. IFN-ß1b (betaseron®) 250µg (8 MIU) sc qod reduced risk of relapse, new T2 lesions on MRI, and probably delayed disease progression compared with Avonex® [44]
    13. IFN-ß1b given after first clinical event (usually optic neuritis) substantially reduced disability compared with delayed IFN-ß1b given after definitive MS diagnosis [24]
    14. betaseron® and Rebif® are more effective at preventing relapses within 2 years than Avonex®, likely due to doses used [33]
    15. Flu-like symptoms are major problem with interferons, preventable with acetaminophen
    16. Anti-IFNß antibodies develop in ~20-30% of patients on sc IFN-ß1b, <10% of patients on weekly IFN-ß1a (Avonex®) but ~25% of patients on Rebif® [11]
    17. Presence of anti-IFNß antibodies appears to reduce effectiveness of INFß in MS [47]
    18. Anti-IFNß antibody titers usually diminish over time
    19. In patients whose anti-IFNß titers do not diminish, consider changing therapy [47]
  5. Copolymer 1 (glatiramer acetate, Copaxone®) [18]
    1. Random synthetic peptides containing four negatively charged amino acids found in MBP
    2. Likely mimics MBP by binding to myelin / proteolipid protein-specific T lymphocytes
    3. Binding of Copolymer 1 peptides to T cells may block antigen-specific stimulation
    4. Given 20mg / day subcutaneous injections
    5. ~30% reduction in relapses without reduction in disability progression
    6. Systemic reaction with flushing, chest tightness, palpitations in 10% of persons
    7. Pain and erythema at injection site is common
    8. Approved for relapsing-remitting MS
  6. Mitoxantrone (Novantrone®)
    1. Mitoxantrone + glucocorticoids significantly reduced MRI lesions and disease flares in secondary progressive MS [20]
    2. Mitoxantrone alone 12mg/m2 IV q3 months for 24 months reduced progression, disability, number of relapses and other clinical variables >50% in progressive MS [45]
    3. Anti-emetics (ondansetron, others) are used with infusion
    4. Blood cell counts must be monitored
    5. Generally well tolerated and appears quite effective
  7. Natalizumab (Tysabri®; formerly Antegren®) [4,21,46]
    1. Anti-alpha4 Integrin monoclonal antibody (mAb) prevents T cell migration into CNS (see above)
    2. Natalizumab q4 weeks IV monotherapy reduced progression from 29% to 17% (NNT=9) at 2 years [21]
    3. With monotherapy, likelihood of remaining relapse-free was 67% versus 41% placebo at 2 years (NNT=4) [21]
    4. Reduced new T2-enhancing MRI lesions by 83% over 2 years (see within 6 weeks)
    5. Natalizumab q4 weeks added to standard IFNß1a (Avonex®) reduced clinical relapses >50% and new T2 MRI enhancing lesions ~80% versus IFNß1a alone over 2 years [13]
    6. Adverse events include slighltly increased fatigue and allergic reactions (9% versus 4%), and increases in white blood cell counts in serum, due to integrin blockade
    7. Rare cases of progressive multifocal leukoencephalopathy (PML) in patients on natalizumab±IFNß or other immunsuppressive agents [4,27,52,53,54]
    8. Overall risk of PML ~1:1000 and warning on label [4,27]
    9. Currently should not be combined with other immunosuppressives
    10. Most effective agent currently available to reduce progression and relapse in MS [13,21]
    11. Patients on natalizumab must be registered under the TOUCH program
  8. Rituximab (Rituxan®) [25]
    1. Anti-CD20 mAb depletes B lymphocytes
    2. Dose 1000mg IV on days 1 and 15 reduces gadolinium enhancing lesions, relapses at 48 weeks
    3. Well tolerated with minimal injection site reactions and flu-like symptoms
    4. Highly significant reductions in gadolinium lesions and volume with good tolerability
    5. Consider use of ribuximab in relapsing patients (Phase III studies to be initiated)
  9. Other Anti-Inflammatory Therapies
    1. None have been studied as carefully as the above treatments
    2. Little incentive to study these closely - expensive trials with MRIs in large cohorts
    3. Azathioprine - goal doses of 2-4 mg/kg/day oral, some benefit on relapses
    4. Methotrexate - 7.5-15mg q week im or po
    5. Intravenous Ig (IVIg) - some relapse prevention, possible reduced progression [19]
    6. IVIg had no benefit in secondary progressive MS [26]
  10. Therapeutic Plasma Exchange
    1. May be beneficial in MS associated primarily with antibody/complement demyelination
    2. Appears to be of benefit in ~45% of glucocorticoid-resistant flares
    3. Retrospective analysis of plasma exchange shows good efficacy in antibody/complement demyelination pattern (see above) [55]
  11. Ineffective Treatments
    1. Cyclophosphamide efficacy results disputed; high side effects
    2. Oral Tolerance (Myloral®) - Phase III trial failed
    3. Plasmapheresis is not effective

I. Treatment of Symptoms navigator

  1. Bladder Incontinence
    1. Need to determine if problem is detrusor spasm or lack of contraction
    2. For detrusor spasm (dyssynergy), anti-cholinergic agents such as oxybutynin (Ditropan®) are recommended
    3. Residual volume in bladder >100mL indicates poor contractile activity
    4. Intermittant self catheterization typically recommended for poor contraction
    5. Many patients have combination of detrusor spasm and poor contraction
    6. For poor contraction alone, cholinergic agonists (urocholine) may be considered
  2. Fatigue
    1. Very debilitating for some patients
    2. Amantadine
    3. Pemoline
    4. Amphetamine analogs have been used
  3. Pain
    1. Typically shooting, lancinating in nature
    2. Carbamazapine
    3. Gabapentin
    4. Mexilitine
  4. Muscle Spasm Therapy
    1. Main problem is progressive, often severe spasticity
    2. Graded (pyramidal) approach has been advocated
    3. Physical measures are critical in all stages
    4. Tizanidine (Zanaflex®) - newer antispasmotic for low back pain and MS (first line)
    5. Other first line: diazepam (Valium®), dantrolene, baclofen (Lioresal®)
    6. Second line: carisoprodal (Soma®), cyproheptadine, clonidine
    7. Intrathecal baclofen can be used for generalized spasticity
    8. Chemodenervation with botulinum toxin or phenol may be used for focal spasticity
    9. Selective posterior rhizotomy or other surgical intervention may be used
    10. Exercise and rehabilitation are of utmost importance

J. Experimental Therapies navigator

  1. Alemtuzumab (Campath®) [38]
    1. Antibody to CD52 found on lymphocytes and monocytes
    2. Depletes these white cell populations
    3. Single pulse of Campath 1H suppresses MRI markers of inflammation in MS
    4. The single pulse has activity for at least 6 months
    5. May be combined with non-depleting anti-CD4 T cell antibody
    6. CD4 and CD8 T cell populations are depleted for >18 months
    7. Converts T helper populations from Th1 to Th2
    8. Benefit seen in about 50% of patients; remaining 50% progress
    9. About 35% of patients develop anti-thyroid hormone receptor antibodies [38]
    10. This autoimmune thyroid (Graves') disease was responsive to carbimazole
  2. Fingolimod (FTY720) [56,57]
    1. Sphingosine 1-phosphate agonist results in lymphocyte sequestration in lymph nodes
    2. Causes reversible lymphopenia by modifying lymphocyte migration
    3. Does not appear to increase in infection risk
    4. Fingolimod 1.25 or 5mg po qd for 6 months reduced relapses by ~50%, and reduced number of new T1-weighted MRI lesions by >40% [57]
    5. Adverse effects: asympatomic aminotransferase elevations, dyspnea, nasal discharge, headache , diarrhea, nausea [57]
    6. Very promising oral agent for treatment of MS
  3. Laquinimod [23]
    1. Novel immunomodulatory agent
    2. Probably acts by inducing a Th1 to Th2 shift
    3. Lquinimod 0.6mg qd (buty not 0.3mg qd) in RR-MS for 36 weeks reduced cumulative number of gadolinium enhanced MRI lesions by 40% with very good tolerability
    4. Also reduced T1 hypointense lesions
    5. No effect on expanded disability scale (EDSS) but trend to reduction in anualized relapses
  4. Cannabanoids [48]
    1. Showed some promise in Phase II studies on spacticity associated with MS
    2. No effect on spasticity (measured by Ashworth Scale) in 611 patient MS study
    3. Objective improvement in mobility and patient well-being was observed
    4. Generally well tolerated with side effects similar to placebo
  5. Anti-CD11 Antibodies
  6. Remyelination strategies - under development

References navigator

  1. Compston A and Coles A. 2002. Lancet. 359(9313):1221 abstract
  2. Frohman EM, Racke MK, Raine CS. 2006. NEJM. 354(9):942 abstract
  3. Antel JP and Bar-Or A. 2003. NEJM. 349(2):107 abstract
  4. Ransohoff RM. 2007. NEJM. 356(25):2622 abstract
  5. Berger T, Rubner P, Schautzer F, et al. 2003. NEJM. 349(2):139 abstract
  6. Levin LI, Munger KL, Rubertone MV, et al. 2003. JAMA. 289(12):1533 abstract
  7. Balcer JC. 2006. NEJM. 354(12):1273 abstract
  8. IFNB Multiple Sclerosis Study Group. 1995. Neurology. 45:1277 abstract
  9. Kuhle J, Pohl C, Mehling M, et al. 2007. NEJM. 356(4):371 abstract
  10. Jacobs LD, Cookfair DL, Rudick RA, et al. 1996. Neurology. 39:285 abstract
  11. beta Interferons for Multiple Sclerosis. 2002. Med Let. 44(1141):88 abstract
  12. International Multiple Sclerosis Genetics Consortium. 2007. NEJM. 357(9):851 abstract
  13. Rudick RA, Stuart WH, Calabresi PA, et al. 2006. NEJM. 354(9):911 abstract
  14. Comi G, Filippi M, Barkhof F, et al. 2001. Lancet. 357(9268):1576 abstract
  15. Barnes D, Hughes RAC, Morris RW, et al. 1997. Lancet. 349:902 abstract
  16. Beck RW. 1995. Arch Ophthalmol. 113:136 abstract
  17. Robertson NP, O'Riordan JI, Chataway J, et al. 1997. Lancet. 349:1587 abstract
  18. Glatiramer Acetate. 1997. Med Let. 39(1004):61 abstract
  19. Fazekas F, Deisenhammer F, Strasser-Fuchs S, et al. 1997. Lancet. 349:589 abstract
  20. Edan G, Miller D, Clanet M, et al. 1997. J Neurol Neurosurg Psychiatry. 62:112 abstract
  21. Polman CH, O'Connor PW, havrdova E, et al. 2006. NEJM. 354(9):899] abstract
  22. Ascherio A, Munger KL, Lennette ET, et al. 2001. JAMA. 286(24):3083 abstract
  23. Comi G, Pulizzi A, Rovaris M, et al. 2008. Lancet. 371(9630):2085 abstract
  24. Kappos L, Freedman MS, Polman CH, et al. 2007. Lancet. 370(9585):389 abstract
  25. Hauser SL, Waubant E, Arnold DL, et al. 2008. NEJM. 358(7):676 abstract
  26. Hommes OR, Sorensen PS, Fazekas F, et al. 2004. Lancet. 364(944):1149
  27. Yousry TA, Habil DM, Major EO, et al. 2006. NEJM. 354(9):924 abstract
  28. Confavreux C, hutchinson M, Hours MM, et al. 1998. NEJM. 339(5):285 abstract
  29. Levin LI, Munger KL, Ruberstone MV, et al. 2005. JAMA. 293(20):2496 abstract
  30. Brex PA, Ciccarelli O, O'Riordan JI, et al. 2002. NEJM. 346(3):158 abstract
  31. Chang A, Tourtellotte WW, Rudick R, Trapp BD. 2002. 346(3):165 abstract
  32. Rudick RA. 1998. JAMA. 280(16):1432 (Case Discussion) abstract
  33. Study Group on Interferon ß1b in Secondary Progressive MS. 1998. Lancet. 352(9139):1491
  34. PRISMS Study Group. 1998. Lancet. 352(9139):1498 abstract
  35. Goodkin DE. 1998. Lancet. 352(9139):1486 abstract
  36. Kappos L, Moeri D, Radue EW, et al. 1999. Lancet. 353:964 abstract
  37. Whiting P, Harbord R, Main C, et al. 2006. Brit Med J. 332(7546):875 abstract
  38. Coles AJ, Wing M, Smith S, et al. 1999. Lancet. 354(9191):1691 abstract
  39. Jacobs LD, Beck RW, Simon JH, et al. 2000. NEJM. 343(13):898 abstract
  40. Noseworthy JH, Lucchinetti C, Rodriguez M, Weishenker BG. 2000. NEJM. 343(13):938 abstract
  41. Confavreux C, Vukusic S, Moreau T, Adeleine P. 2000. NEJM. 343(20):1430 abstract
  42. Confavreux C, Suissa S, Saddier P, et al. 2001. NEJM. 344(5):319 abstract
  43. Ascherio A, Zhang SM, Hernan MA, et al. 2001. NEJM. 344(5):327 abstract
  44. Durelli L, Verdun E, Barbero P, et al. 2002. Lancet. 359(9316):1453 abstract
  45. Hartung HP, Gonsette R, Konig N, et al. 2002. Lancet. 360(9350):2018 abstract
  46. Miller DH, Khan OA, Sheremata WA, et al. 2003. NEJM. 348(1):15 abstract
  47. Sorensen PS, Ross C, Clemmesen KM, et al. 2003. Lancet. 362(9381):1185
  48. Zajicek J, Fox P, Sanders H, et al. 2003. Lancet. 362(9395):1517 abstract
  49. Alotaibi S, Kennedy J, Tellier R, et al. 2004. JAMA. 291(15):1875 abstract
  50. Miller NR and Newman NJ. 2004. Lancet. 364(9450):2045 abstract
  51. Natalizumab. 2005. Med Let. 47(1202):13 abstract
  52. Van Assche G, Van Ranst M, Sciot R, et al. 2005. NEJM. 353(4):362 abstract
  53. Kleinschmidt-DeMasters BK and Tyler KL. 2005. NEJM. 353(4):369 abstract
  54. Langer-Gould A, Atlas SW, Green AJ, et al. 2005. NEJM. 353(4):375 abstract
  55. Keegan M, Konig F, McClelland R, et al. 2005. Lancet. 366(9485):579 abstract
  56. Massberg S and von Andrian UH. 2006. NEJM. 355(11):1089
  57. Kappos L, Antel J, Comi G, et al. 2006. NEJM. 355(11):1124 abstract