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Subsections
Multiple Sclerosis

Neurology

Multiple Sclerosis

Background

  1. Definition
    • A chronic inflammatory demyelinating disease
    • It is the most common autoimmune demyelinating inflammatory disease of the CNS
  2. Synopsis
    • Progressive disease which affects the CNS
    • All races affected
    • White northern Europeans have the highest incidence
    • Incidence increases as you move further away from the equator
    • Most commonly, multiple sclerosis begins between the ages of 20 and 40, but it can begin anytime between ages 15 and 60 years.
    • It is somewhat more common among women
    • Multiple sclerosis is uncommon among children
    • Most people with multiple sclerosis have periods of relatively good health (remissions) alternating with periods of worsening symptoms (flare-ups or relapses).
    • Relapses can be mild or debilitating. Recovery during remission is good but often incomplete. Thus, multiple sclerosis worsens slowly over time
    • On average, without treatment, people have about one relapse every 2 years, but frequency varies greatly
    • Average age at diagnosis is 29 years in females, 31 years in males
    • Patterns of MS
      • Relapsing-Remitting MS (RRMS)
        • Initial phase of disease (85% of new onset disease)
        • Characterized by relapsing attacks of neurological disability, followed by partial or complete recovery
        • Relapses (when symptoms worsen) alternate with remissions (when symptoms lessen or do not worsen).
        • Remissions may last months or years.
        • Relapses can occur spontaneously or can be triggered by an infection such as influenza.
        • Caused by the demyelination of neuronal axons
      • Primary Progressive MS (PPMS)
        • Accounts for about 15% of cases
        • Increased axonal injury
        • Less relapse and neuronal symptoms slowly become more progressive
        • Compared to RRMS, it usually begins at a later age
        • Associated with a faster onset of disability
        • Disability accumulates solely by progressive decline
      • Secondary Progressive MS (SPMS)
        • Develops in about 2% of patients with RRMS per year
        • Always begin as RRMS
        • Patients have functional deterioration not associated with acute attacks
        • Acute attacks may or may not continue to occur
        • A higher degree of neurologic disability
        • This pattern begins with relapses alternating with remissions (the relapsing-remission pattern), followed by gradual progression of the disease.
      • Progressive relapsing MS (PRMS)
        • About 5% of MS patients
        • Represents patients with primary progressive disease who later in their course developed relapses
        • Steady deterioration
        • Superimposed acute attacks on the progressive disease
        • Disability caused by incomplete recovery from acute exacerbations as well as by ongoing deterioration
        • The disease progresses gradually, but progression is interrupted by sudden relapses

Pathophysiology

  1. Pathology of Disease
    • Initial trigger possibly linked to viral infection, genetics or environmental factors
    • No specific viral origin has been found
    • However, many viral infections may mimic the immune reaction against neural antigens
      • Lead to injury of oligodendrocytes and the myelin sheath surrounding axons in the CNS
    • Immune attack is by T lymphocytes, B cells, and macrophages
    • Characteristic lesions found in MS
      • Myelin loss
      • Demyelination of oligodendrocytes
      • Astroglial scarring
    • Regions typically affected
      • Periventricular
      • Corpus callosum
      • Centrum semiovale
      • Deep white matter
      • Basal ganglia (to a lesser extent)
  2. Etiology/Risk Factors 1
    • The etiology of MS is unknown
      • Could be a complex interaction between
        • Genetic and environmental factors and
        • The immune system
    • Risk Factors 2, 4, 5, 13, 14
      • Genetic factors
        • HLA-DRB1*1501 haplotype
        • Strongest known genetic risk factor
        • Increases risk by 2-4-fold
        • Not specific and is not essential for the diagnosis of MS
      • Family Hx of MS
        • Among first-degree relatives of patients with MS
          • 20- to 40-fold increased risk of MS
        • Concordance in monozygotic twins is about 25% to 30%
        • Concordance in dizygotic twins only 5%
      • Vaccines like Hep B vaccine
        • Controversial
      • Environmental factors that are implicated
        • Geographic locations
        • Viral infections like
          • EBV
          • Human herpes virus
        • Cigarette smoking also appears to increase the chances of developing multiple sclerosis. The reason is unknown.
        • Obesity
        • Sunlight and UV radiation exposure
        • Low vitamin D level
  3. Epidemiology 1, 3
    • Incidence/Prevalence
      • United States
        • Approximately 400,000 people are affected
      • International
        • Approximately 1.1 million people affected
      • After 1985, the incidence of multiple sclerosis ranged from 1.12 to 6.96 per 100,000 populations among European economic area populations
      • Female to male ratio 2:1
    • Morbidity/Mortality
      • One of the common causes of nontraumatic disability in young adults
      • Mortality primarily due to MS is uncommon
      • Overall, 25 years survival is less than expected

Diagnostics

  1. New Onset MS
    • Difficult diagnosis to make
    • 20-40-year-old; Female: Male ratio is 2.5:1
    • Suspect if 2 episodes neurologic disturbances from 2 distinct sites in white matter
    • MRI (gadolinium improves sensitivity): multiple discrete areas of demyelinating lesions, esp. periventricular (5% of MS patients with normal MRI)
    • Evoked response testing abnormal in 80%
    • CSF: Oligoclonal bands, or Myelin basic protein
  2. History/ Symptoms and Physical Examination 10, 11, 12
    • Abrupt or insidious onset
    • Paroxysmal attacks
    • May be mild or severe
    • Sometimes asymptomatic, detected only on MRI or at autopsy
    • Neurological symptoms
      • Important: characteristic is exacerbation of Sx induced by exercise, hot meal, or hot bath (unmyelinated nerve conduction greatly slowed when temp increases)
      • Visual
        • Optic neuritis
          • Unilateral visual loss, pain around eye increased pain with eye movement, followed by blurred vision (days), & variable vision loss not lasting for more than 2 weeks
        • Diplopia, Nystagmus
        • INO (internuclear ophthalmoplegia)
          • Slow or incomplete abduction of eye ipsilateral to MLF (medial longitudinal fasciculus) lesion
      • Muscular / Sensory
        • Lhermitte's sign
        • Weakness of legs with difficulty ambulating
        • Ataxia, spasticity, gait disturbance
        • Paresis, hyperreflexia
        • Clonus, positive Babinski
        • Severe fatigue common symptom
      • Other symptoms
        • Urinary dysfunction common
          • Failure to empty or store urine
          • Frequent UTIs
            • Can trigger MS exacerbation
          • Hydronephrosis
          • Pyelonephritis
          • Sepsis
        • Constipation, sexual dysfunction
      • Other lesions produce
        • Ataxia
        • Spasticity
        • Gait disturbance
        • Paresis
        • Hyperreflexia
        • Clonus
        • Positive Babinski
        • Paresthesia
      • Patients may also have
        • Vertigo
        • Epilepsy
        • Sensory loss
        • Falling history
    • Cognitive disturbances including
      • Memory loss
      • Attention deficit
    • Psychiatric symptoms of
      • Depression
      • Anxiety
      • Sleep impairment
  3. Laboratory Evaluation 15
    • Cerebrospinal fluid analysis
      • Oligoclonal banding
        • Has potential prognostic value and is helpful for clinical decision-making
      • IgG index of spinal fluid
    • Cerebrospinal fluid abnormalities in MS include
      • Mild mononuclear cell pleocytosis (> 5cell / µL)
      • Increased intrathecal IgG production (measured by CSF IgG index or oligoclonal banding)
      • Normal or slightly elevated CSF protein
    • MS is unlikely if CSF has
      • Increased neutrophils
      • Pleocytosis of > 75
      • Protein of > 1gm/L
    • Other lab tests according to the DDx
    • Modified Fatigue Impact Scale (MFIS) (Open Calc)
  4. Diagnostic Imaging 16, 17
    • Brain MRI
      • Is extremely sensitive in detecting multiple sclerosis (MS)
      • > 95% of patients with MS have MRI findings
      • Shows multifocal lesions within the brain, brainstem & spinal cord
      • According to the 2010 McDonald criteria dissemination in time (DIT) on MRI include
        • A new onset CNS lesion on Follow-up MRI
          • A T2 and /or gadolinium-enhancing lesion
          • Any time from the baseline MRI
        • Occurrence of non-symptomatic gadolinium-enhancing and non-enhancing lesions at the same time on any occasion
      • MRI
        • Criteria for dissemination in space (DIS) include > 1 T2 lesion at least in 2 of the 4 common MS sites of the CNS
          • Periventricular, Infratentorial, Juxtacortical, Spinal cord
        • Sagittal view (View image)
        • Axial view (View image)
    • Evoked potentials
      • Not specific to MS
      • A significant delay in a specific EP component is a suggestive sign of demyelination
      • Assess various afferent and efferent pathways
        • Visual evoked response
        • Brainstem auditory evoked response
        • Somatosensory evoked potentials
  5. Diagnostic Criteria 17
    • The diagnostic criterion for MS is McDonald criteria and it uses
      • Clinical characteristics
      • Laboratory tests
        • MRI of brain and spinal cord
        • CSF analysis
        • Evoked potentials
      • Used to assign diagnostic confidence as follows
        • MS given if diagnostic criteria fulfilled
        • Possible MS given if the criteria are not completely met
        • Not MS given if the criteria are not fully explored or not met
      • The 2010 revised criteria put emphasis on disease dissemination both in space and time
    • The 2010 McDonald criteria for MS
      • Two or more attacks; objective clinical evidence of two or more lesions
      • Two or more attacks; objective clinical evidence of one lesion
        • Dissemination in space, demonstrated by MRI OR
        • Two or more detected lesions consistent with MS PLUS positive CSF
        • Await further clinical attack implicating a different site
      • One attack; objective clinical evidence of two or more lesions
        • Dissemination in time, demonstrated by MRI or second attack
      • One attack; objective clinical evidence of one lesion (mono symptomatic presentation, clinical isolated syndrome)
        • Dissemination in space, demonstrated by, MRI, OR two or more MRI detected lesions consistent with MS plus positive CSF AND
        • Dissemination in time, demonstrated by MRI or second clinical attack
      • Insidious neurological progression suggestive of MS
        • One year of disease progression (retrospectively or prospectively determined) AND
        • Two of the following
        • Positive brain MRI (nine T2 lesions or four or more T2 lesions with positive VEP)
        • Positive spinal cord MRI (two focal T2 lesions)
        • Positive CSF
    • 2017 Revised McDonald Criteria 24
      • The following changes were made:
        • In patients with a typical clinically isolated syndrome and clinical or MRI demonstration of dissemination in space, the presence of CSF-specific oligoclonal bands allows a diagnosis of MS
        • Symptomatic lesions can be used to demonstrate dissemination in space or time in patients with the following
          • Supratentorial involvement
          • Infratentorial involvement
          • Spinal cord syndrome
        • Cortical lesions, in addition to juxtacortical lesions, can be used to fulfill MRI criteria for dissemination in space
          • Care is needed to distinguish neuroimaging artifacts from cortical lesions
      • Research to further refine the McDonald Criteria is needed and includes
        • Focus on optic nerve involvement
        • Validation in diverse populations
        • Incorporation of advanced imaging, neurophysiological and body fluid markers
  6. Differential Diagnosis
    • Key DDx 18
      • Acute disseminated encephalomyelitis (ADEM)
      • Neuromyelitis Optica
      • Idiopathic transverse myelitis
      • Optic neuritis (ON) from other causes
        • Inflammatory ON like SLE, sarcoidosis
        • Infectious ON like syphilis, lyme disease and viral causes
        • Ischemic ON
        • Hereditary ON
    • Extensive DDx

Therapeutics

  1. Acute Exacerbations 10, 19
    • Methylprednisolone 250 mg IV q6hr (or 1000 mg IV qD) for 3 days, followed by prednisone 1 mg/kg qD for 2 wk, then 20 mg qD for 1 wk (same Rx for optic neuritis)
    • ACTH 80 U in 500 mL D5W q6hr for 3 days if not responsive to steroids; followed by 40 U IM BID for 1 wk, then taper off over 3 wk
  2. Disease-Modifying Therapies 5, 10, 20, 21, 22
    • Interferons (for frequent relapses & prophylaxis)
      • Beta 1a (Avonex)
        • 30 mcg once/wk
        • Monitor: Hgb, WBC, Plt, LFTs
      • Beta 1a (Rebif)
        • Weeks 1-2: 8.8 mcg subQ 3 x/wk (at least 48 hr apart)
        • Weeks 3-4: 22 mcg subQ 3 x/wk
        • Weeks 5+: 44 mcg subQ 3 x/wk
        • Administration: abdomen (except waistline), thigh, arm, buttocks
        • Monitor: Hgb, WBC, Plt, LFTs
      • Beta 1b
        • Start at 0.0625 mg subQ qOD, THEN
        • Incr over 6 wk to 0.25 mg subQ qOD
        • Administration
        • Reconstitute with 1.2 mL of 0.54% NaCl diluent (provided)
        • Rotate injection site
        • Monitor: Hgb, WBC, Plts, LFTs
    • Glatiramer acetate (Copaxone) 20 mg subQ qD
      • Relapses & prophylaxis
    • Natalizumab 300 mg IV q4wk
      • Dilute in 100 ml 0.9% NaCl and infuse over 1 hour
      • Reduces the number of relapses and increases the patients' quality-adjusted life years (QALYs)
    • Fingolimod 0.5 mg PO qD
      • May take with or without food
    • Mitoxantrone HCL (Novantrone)
      • 12 mg/m² short IV (5-15 min) infusion q3 months only for a maximum of 2-3 years
      • Because of toxicity reserved for patients not responding to other drugs
      • Indicated for SPMS, RPMS and worsening RRM
    • Teriflunomide (Aubagio)
      • 7 mg - 14 mg PO qD
    • Alemtuzumab
      • Received FDA approval in 2014 for treatment of patients with relapsing forms of MS
      • Reserved for patients who have failed one or two more drugs indicated for MS
      • Administered by IV infusion over 4 hours for 2 treatment courses
        • First course: 12 mg qD on 5 consecutive days
        • Second course: 12 mg qD on 3 consecutive days 12 months after first course
    • Ocrelizumab
  3. Further Management (symptomatic relief) 22
    • Antispasticity Agents
      • Baclofen 5-10 mg PO qD initially
        • Titrate to 30-140 mg in divided doses
      • Clonazepam 3 mg PO qD maximum with MS
        • Dose limited by sedating effect
      • Tizanidine 2-36 mg qD PO in divided doses
      • Gabapentin 300 -3600 mg qD PO divided tid
      • Extract of Cannabis (CE)
        • Rate of relief from muscle stiffness after 12 weeks of therapy with cannabinoids almost twice as high with CE than with placebo
    • Bladder Antispasmodics
    • Antiparkinson
    • Selective Serotonin Reuptake Inhibitors
    • Tricyclic Antidepressants
      • Nortriptyline 10-150 mg PO qhs; affects neuropathic pain at low doses, at high doses has antidepressant effect
  4. Long-Term Care
    • Evaluate neurologic impairment with the Expanded Disability Status score (EDSS)
      • Score of > 5.5 is associated with occupational disability and gait impairment
    • Encourage a healthy lifestyle
      • Exercise (mainly swimming)
      • Balanced nutrition
      • Positive outlook
    • Look for infection precipitants
      • May have pyelonephritis without any clinical findings except bacteriuria
      • Treat UTIs aggressively
      • Post-void residual should be < 100 mL or < 20% of voided volume, if not clean, intermittent catheterization is necessary
      • Prevent infection in high residual volume
      • Do urodynamic testing for bladder dysfunction 10
    • Aggressively lower body temp in any febrile illness or hyperthermia
    • Chronic progressive disease
    • Amantadine or SSRIs may help fatigue
    • Baclofen or diazepam for spasticity
    • Weakness
    • Carbamazepine, phenytoin, or TCAs for pain and dysesthesias
    • Cognitive problems
    • Sexual dysfunction
    • GI complaints
      • High fiber diet, fluid and laxatives as needed for constipation
      • Reduce dietary fiber in fecal incontinence

Follow-Up

  1. Admit for workup
    • If diagnosis is unclear
    • For severe symptoms
    • Suspected pyelonephritis
  2. D/C stable patient home with early neuro follow up

Prognosis

  1. MS is associated with high variability of disease progression
  2. Slow progression in most adults
  3. Some of the good clinical prognostic signs include
    • Female sex
    • Young age of onset
    • Optic neuritis or isolated sensory symptoms at onset
    • Long interval between initial and second relapse
    • No more than two relapses in the first year
    • No accumulation of disability after five years of disease evolution
    • Normal or near normal MRI at onset
  4. Clinical Sx/Sx linked to unfavorable outcomes include
    • A progressive course
    • Action tremor
    • Pyramidal symptoms
    • Truncal ataxia

Prevention

  1. MS is non-preventable
  2. Disease-modifying therapy has improved disease progression
  3. Long-term prognosis has improved recently

Evidence-Based Content

  1. Are dietary interventions effective in the treatment of multiple sclerosis?

References

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  3. Alcalde-Cabero E, Almazan-Isla J, Garcia-Merino A, de Sa J, de Pedro-Cuesta J. Incidence of multiple sclerosis among European Economic Area populations, 1985-2009: the framework for monitoring. BMC neurology. 2013; 13:58.
  4. Shahbazi M, Roshandel D, Ebadi H, et al. High frequency of the IL-2 -330 T/HLA-DRB1*1501 haplotype in patients with multiple sclerosis. Clinical immunology. 2010;137(1):134-138.
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Contributor(s)

  1. Gogineni, Anil K., MD
  2. Hernandez, James, DO
  3. Oggu, Rajgopal R., MD
  4. Tom, Jubil, MD

Updated/Reviewed: July 2021