Multiple Sclerosis (MS)

What is Multiple Sclerosis (MS)

Multiple sclerosis is a disease of the brain, spinal cord, and optic nerves (central nervous system). It causes the body’s disease-fighting (immune) system to destroy the protective covering (myelin sheath) around nerves in the brain.

When this happens, signals (nerve impulses) going to and from the brain and spinal cord do not get sent properly or may not get sent at all.

4 Interesting Facts of Multiple Sclerosis

  1. Affects central and peripheral nervous systems; causes breakdown in insulating material of neuronal cells (ie, myelin)
  2. May cause tinnitus
  3. Affects other neurologic functions, most frequently vision
  4. Differentiated by MRI examination, which reveals demyelinated lesions
  5. Multiple sclerosis is a chronic and often disabling disease that impairs the central nervous system; it is considered to be immune mediated
  6. Can be relapsing-remitting (85% of patients) or progressive; pace of disease and rate of progression vary
  7. Symptoms vary widely depending on location and severity of lesions; they include numbness or tingling, muscle weakness/spasticity, vision problems, fatigue, impaired balance or coordination, and bladder dysfunction
  8. Diagnosis is based on clinical evidence (supplemented by paraclinical studies) that disease activity consistent with focal demyelination has affected 2 or more areas of the central nervous system and on more than 1 occasion Paraclinical studies used to aid diagnosis and exclude other diagnoses include neuroimaging (MRI), analysis of cerebrospinal fluid, and evoked potential testing
  9. Diagnosis should be made by clinician with expertise in multiple sclerosis
  10. Treatment strategies include: Treatment of acute exacerbations with corticosteroids
  11. Reduction of biologic activity with disease-modifying medications
  12. Symptom management
  13. Rehabilitation and psychosocial support
  14. Disease is not curable Significant variation exists in rate of accumulation of disability; half of patients require mobility assistance within 20 years of diagnosis
  15. Patients with multiple sclerosis live, on average, 7 to 14 years less than general population

There are several types of MS:

  • Relapsing-remitting MS. This is the most common type. This causes sudden attacks of symptoms. After an attack, you may recover completely until the next attack, or some symptoms may remain permanently.
  • Secondary progressive MS. This usually develops after the onset of relapsing-remitting MS. Similar to relapsing-remitting MS, this type also causes sudden attacks of symptoms. Attacks may be less frequent, but symptoms slowly get worse (progress) over time.
  • Primary progressive MS. This causes symptoms that steadily progress over time. This type of MS does not cause sudden attacks of symptoms.

The age of onset of MS varies, but it often develops between 20–40 years of age. MS is a lifelong (chronic) condition. There is no cure, but treatment can help slow down the progression of the disease.

What are the causes?

The cause of this condition is not known.

What increases the risk?

You are more likely to develop this condition if:

  • You are a woman.
  • You have a relative with MS. However, the condition is not passed from parent to child (inherited).
  • You have a lack (deficiency) of vitamin D.
  • You smoke.

MS is more common in the northern United States than in the southern United States.

What are the signs or symptoms?

Relapsing-remitting and secondary progressive MS cause symptoms to occur in episodes or attacks that may last weeks to months. There may be long periods between attacks in which there are almost no symptoms. Primary progressive MS causes symptoms to steadily progress after they develop.

Symptoms of MS vary because of the many different ways it affects the central nervous system. The main symptoms include:

  • Vision problems and eye pain.
  • Numbness.
  • Weakness.
  • Inability to move your arms, hands, feet, or legs (paralysis).
  • Balance problems.
  • Shaking that you cannot control (tremors).
  • Muscle spasms.
  • Problems with thinking (cognitive changes).

MS can also cause symptoms that are associated with the disease, but are not always the direct result of an MS attack. They may include:

  • Inability to control urination or bowel movements (incontinence).
  • Headaches.
  • Fatigue.
  • Inability to tolerate heat.
  • Emotional changes.
  • Depression.
  • Pain.

How is this diagnosed?

This condition is diagnosed based on:

  • Your symptoms.
  • A neurological exam. This involves checking central nervous system function, such as nerve function, reflexes, and coordination.
  • MRIs of the brain and spinal cord.
  • Lab tests, including a lumbar puncture that tests the fluid that surrounds the brain and spinal cord (cerebrospinal fluid).
  • Tests to measure the electrical activity of the brain in response to stimulation (evoked potentials).

How is this treated?

There is no cure for MS, but medicines can help decrease the number and frequency of attacks and help relieve nuisance symptoms. Treatment options may include:

  • Medicines that reduce the frequency of attacks. These medicines may be given by injection, by mouth (orally), or through an IV.
  • Medicines that reduce inflammation (steroids). These may provide short-term relief of symptoms.
  • Medicines to help control pain, depression, fatigue, or incontinence.
  • Vitamin D, if you have a deficiency.
  • Using devices to help you move around (assistive devices), such as braces, a cane, or a walker.
  • Physical therapy to strengthen and stretch your muscles.
  • Occupational therapy to help you with everyday tasks.
  • Alternative or complementary treatments such as exercise, massage, or acupuncture.

Follow these instructions at home:

  • Take over-the-counter and prescription medicines only as told by your health care provider.
  • Do not drive or use heavy machinery while taking prescription pain medicine.
  • Use assistive devices as recommended by your physical therapist or your health care provider.
  • Exercise as directed by your health care provider.
  • Return to your normal activities as told by your health care provider. Ask your health care provider what activities are safe for you.
  • Reach out for support. Share your feelings with friends, family, or a support group.
  • Keep all follow-up visits as told by your health care provider and therapists. This is important.

Seek Additional Information

  • National Multiple Sclerosis

Contact a health care provider if:

  • You feel depressed.
  • You develop new pain or numbness.
  • You have tremors.
  • You have problems with sexual function.

Get help right away if:

  • You develop paralysis.
  • You develop numbness.
  • You have problems with your bladder or bowel function.
  • You develop double vision.
  • You lose vision in one or both eyes.
  • You develop suicidal thoughts.
  • You develop severe confusion.

Pitfalls

  • Many disorders mimic multiple sclerosis
    • Consider possibility of other causes before accepting diagnosis of multiple sclerosis, especially in patients with atypical clinical symptoms
  • Be wary of accepting a historical event as an attack in absence of contemporaneous or current objective evidence providing corroboration
  • Do not diagnose multiple sclerosis on basis of MRI findings alone 
  • Use caution in applying MRI imaging criteria in patients with symptoms atypical for multiple sclerosis and in patients with symptom onset after age 40 years
    • White matter lesions are common in general population with increasing age, particularly in those with conditions known to cause T2 hyperintensities (eg, hypertension, smoking, diabetes, high cholesterol, migraines)
  • Patients with a diagnosis of multiple sclerosis may experience worsening or unmasking/decompensation of preexisting symptoms (pseudoexacerbation) during acute infectious illnesses or during heat exposure
  • Multiple sclerosis is a chronic and often disabling disease that impairs the central nervous system; it is considered to be immune mediated
  • Characterized by multifocal areas of inflammation, demyelination, gliosis (scarring), and neuronal loss
    • Lesions typically develop at different times and in different locations within the central nervous system (referred to as dissemination in time and space)
  • Clinical course is variable, ranging from clinically benign to rapidly progressive and debilitating

Classification

  • Based on phenotype, determined by current and historical data; the disease is a dynamic process and thus phenotype may change over time 
    • Relapsing-remitting multiple sclerosis
      • Disease course characterized by relapses with stable neurologic disability between episodes
      • Characteristics: 
        • Relapse (ie, attack, exacerbation) is defined as a monophasic clinical episode with patient-reported symptoms and objective findings typical of multiple sclerosis 
          • Reflects focal or multifocal inflammatory demyelinating event in the central nervous system
          • Develops acutely or subacutely, with duration of at least 24 hours, with or without recovery, occurring in the absence of fever or infection
        • Substantial or complete resolution occurs over weeks to months; over time, recovery may be less evident
        • Must be distinct episodes separated by interims of a month or more 
      • Most common phenotype, affecting about 85% of patients 
    • Progressive multiple sclerosis
      • Steadily increasing, objectively documented neurologic disability independent of relapses
      • Characteristics:
        • Fluctuations, periods of stability, and superimposed relapses may occur
        • This phenotype is further described as:
          • Primary progressive multiple sclerosis 
            • Characterized by progressive disability from onset of disease
            • No distinct relapses or remissions; occasional plateaus and temporary minor improvements may occur
            • Affects about 15% of patients 
          • Secondary progressive multiple sclerosis 
            • Characterized by a progressive course following an initial relapsing-remitting course; diagnosis is made retrospectively
            • Is a sequela of prolonged relapsing-remitting multiple sclerosis; most patients convert to secondary progressive multiple sclerosis after 20 to 40 years 
            • Greater fixed neurologic disability
    • Clinically isolated syndrome
      • First clinical episode of a disease that shows clinical characteristics of inflammatory demyelination (eg, optic neuritis) and could be multiple sclerosis but does not yet fulfill criteria of dissemination in time 
        • Usually affects optic nerves (20%), brainstem (10%-20%), and spinal cord (40%) 
        • Similar to typical multiple sclerosis relapse, but in a patient not known to have multiple sclerosis 
      • If patient is subsequently diagnosed with multiple sclerosis (based on fulfilled criteria of dissemination in space and time and exclusion of other diagnoses), then the clinically isolated syndrome is retrospectively recognized as the patient’s first attack
      • Coupled with MRI lesions, carries high likelihood for meeting diagnostic criteria for multiple sclerosis
  • Each phenotype is additionally described by specific modifier terminology 
    • Modifiers include:
      • Activity (active versus not active)
        • Determined by occurrence of clinical relapses and/or presence of new (or enlarging) T2- and/or gadolinium-enhancing lesions on MRI over specified time period (preferably at least 1 year) 
      • Progression (with progression versus without progression) 
        • Clinical progression is defined as steadily increasing, objectively documented neurologic dysfunction/disability over a given period (eg, 1 year) without unequivocal recovery; no imaging measures are yet established
    • Modifiers used for each phenotype:
      • Relapsing-remitting multiple sclerosis
        • Disease modifiers: active/not active
      • Progressive multiple sclerosis
        • Disease modifiers of both progressive phenotypes: active/not active; with progression/without progression 
          • Active; with progression (had an attack and is gradually worsening)
          • Active; without progression (eg, had an attack within previous specified time period, such as 1 year)
          • Not active; with progression (eg, not having relapses but walking speed has decreased)
          • Not active; without progression (eg, not having relapses and neurologic disability is stable)
      • Clinically isolated syndrome
        • Modifier: active/not active
          • If course is subsequently clinically active and fulfills multiple sclerosis diagnostic criteria, phenotype becomes relapsing-remitting multiple sclerosis
  • Radiologically isolated syndrome has been identified but is not considered a specific phenotype (imaging signs alone do not fulfill diagnostic criteria of multiple sclerosis) 
    • Defined as MRI findings strongly suggestive of multiple sclerosis in a patient with no neurologic manifestations or other clear-cut explanation 
      • Suspicion raised for multiple sclerosis based on morphology and location of detected lesions
      • With increasing use of MRI, suggestive incidental findings on brain imaging are not uncommon

Clinical Presentation

Presentation and course are highly variable and unpredictable

  • Affects different areas of the central nervous system, simultaneously or sequentially
  • Frequency of episodes and pace of progression (if any) vary
  • Episodes of reversible neurologic deficits may be followed by progressive neurologic deterioration over time

Symptoms must occur as distinct episodes separated by 1 month or more, and last longer than 24 hours per episode 

  • Usually acute or subacute onset within hours or days; hyperacute onset typically suggests another cause 
  • Attacks usually reach maximal deficit within 4 weeks and resolve spontaneously 
    • Typical relapse is symptomatic for about 8 weeks from onset to recovery 

Typical symptoms, by anatomic site:

  • Spinal cord
    • Symptoms of acute onset (over days) with partial transverse myelitis is a common presentation 
      • Hypoesthesia, dysesthesia, paresthesia (eg, numbness; tingling, burning, or pricking sensations)
      • Weakness of limbs (eg, hemiparesis, monoparesis, paraparesis)
      • Sphincter dysfunction (eg, bladder urgency or retention; constipation)
  • Optic nerve
    • Optic neuritis is a common presentation of multiple sclerosis
      • Symptoms include acute onset (over days) of:
        • Blurred vision; dimness or reduced color vision; typically monocular
        • Periorbital pain (mild or moderate) with eye movement
  • Brainstem and cerebellum
    • Diplopia
      • Commonly due to internuclear ophthalmoplegia (conjugate lateral gaze disorder; affected eye with impaired adduction); may also result from sixth cranial nerve palsy
    • Oscillopsia
    • Gait ataxia: impaired coordination and poor balance
    • Vertigo
    • Facial paresis and/or hypoesthesia
    • Intentional/postural tremor
    • Impaired swallowing
  • Cerebral hemisphere
    • Hemiparesis
    • Hemisensory disturbance
  • Other clinical symptoms
    • Uhthoff phenomenon: transient worsening of symptoms when core body temperature increases (eg, hot shower, exercise, summer heat wave); may result from transient conduction block
    • Fatigue
    • Depression
    • Cognitive impairment (eg, memory loss, impaired attention, slowed information processing)
    • Painful spasms and stiffness, primarily in legs
    • Paroxysmal symptoms (occurring for at least 24 hours)
    • Sexual dysfunction

Physical examination

  • Examination may find evidence of neurologic dysfunction, including in asymptomatic locations
    • Neurologic examination may find: 
      • Hyperreflexia, extensor plantar reflexes, impaired rapid alternating movements
      • Ascending paresthesias
      • Loss of vibration sense and proprioception
      • Ataxia
      • Cerebellar tremors of head or trunk; cerebellar dysarthria (eg, scanning speech)
      • Paraparesis
      • Intention tremor, spasticity, and dysarthria
      • Impaired sphincter tone
      • Lhermitte sign: electrical sensation that runs down the spine or limbs with flexion of the neck
        • Characteristic of, but not specific to, multiple sclerosis 
    • Ophthalmic examination may find:
      • Gaze disturbance (impaired adduction of affected eye)
      • Gaze-evoked nystagmus
      • Signs of optic neuritis include:
        • Relative afferent pupillary defect (Marcus Gunn pupil)
          • Pupils respond differently to light stimulus shone in 1 eye at a time (swinging flashlight test)
        • Reduced visual acuity and reduced color vision
        • Funduscopic examination findings may be normal or may show optic disk edema or pallor (papillitis)

Causes and Risk Factors

Causes

  • Cause has not yet been established; considered multifactorial and immune mediated 
    • Believed to involve a combination of genetic susceptibility and environmental exposures
  • Demyelination is the hallmark of pathophysiology
    • Inflammatory autoimmune process attacks the myelinated axons in the central nervous system, destroying the myelin and the axons to varying degrees
    • Results in formation of plaques, the histopathologic hallmark
    • Demyelinating damage can be partially repaired or compensated in early disease; as inflammation and damage continue, neuronal damage accumulates 
      • Typifies relapsing-remitting disease that often transitions to chronic, slow progression of disability

Risk factors and/or associations

Age 
  • Relapsing-remitting multiple sclerosis typically affects young adults (mean age of onset is 30 years)
    • Occasionally presents in childhood or late middle age
  • Primary progressive multiple sclerosis typically presents at an older age (mean age of onset is 40 years)
Sex
  • In relapsing-remitting multiple sclerosis, women are affected about 3 times more often than men 
  • In primary progressive multiple sclerosis, men and women are affected about equally 
Genetics
  • Clusters in families; genetics are known to be linked to development of multiple sclerosis 
    • Overall risk in first-degree relatives is 3% (siblings, 5%; parents, 2%; children, 2%); in second- and third-degree relatives, 1% 
    • There is at least a 25% concordance among monozygotic twins 
  • Susceptibility is polygenic; the allele DRB1*1501 in the HLA system is a principal contributor, accounting for 11% of heritability of the disease 
Ethnicity/race
  • Prevalence varies greatly worldwide 
    • Highest in North America and Europe and lowest in sub-Saharan Africa and East Asia
Other risk factors/associations
  • Most notable risk factors are clinically silent lesions on MRI and cerebrospinal fluid oligoclonal bands 
  • Other risk factors include: 
    • Epstein-Barr virus
    • Low sunlight exposure and vitamin D deficiency
    • Cigarette smoking
    • Obesity
  • Risk of developing multiple sclerosis after occurrence of clinically isolated syndrome: 
    • Based on presence of white matter lesions on MRI
      • Typical lesions present: 80% of patients later develop multiple sclerosis 
      • Normal baseline MRI: 10% to 20% of patients later develop multiple sclerosis 
    • Additional risk factors include: presence of oligoclonal bands in cerebrospinal fluid, younger age at onset of clinically isolated syndrome, and greater number of white matter lesions on baseline MRI
  • Risk of relapse is higher during the weeks around an infectious episode 
  • Clinician with expertise in multiple sclerosis should make the diagnosis 
    • Diagnosis of multiple sclerosis is made on clinical features, with input from imaging and other paraclinical studies where needed 
      • Use current established diagnostic criteria (2017 revised McDonald criteria) 
        • Ascertain that episodes are consistent with focal demyelination and that there is no better explanation for the clinical presentation
        • For a diagnosis of relapsing-remitting multiple sclerosis:
          • Establish that lesions have developed at different times (dissemination in time) and in 2 or more areas of the central nervous system (dissemination in space)
          • In cases of an isolated attack or involvement of a single area of the central nervous system, MRI and/or cerebrospinal fluid–specific oligoclonal bands may sometimes be used to fulfill criteria of dissemination in space and time
        • For diagnosis of primary progressive multiple sclerosis:
          • Establish progressive neurologic deterioration over 1 year, and
          • Confirm that 2 additional criteria are present (based on MRI findings and, in some cases, cerebrospinal fluid–specific oligoclonal bands)
      • Use caution in accepting a historical event as an attack in the absence of contemporaneous or current objective evidence providing corroboration 
  • Obtain brain MRI for every patient in whom the diagnosis is being considered, even those who have met the diagnostic criteria of dissemination in space and time based on clinical criteria 
    • MRI should be performed with and without gadolinium; contrast enhancement with gadolinium supplies additional information regarding activity of disease (inflammation)
  • Use additional studies, including spinal cord MRI, analysis of cerebrospinal fluid, evoked potentials, and laboratory testing of blood, to aid diagnosis and exclude alternative diagnoses
    • Maintain a low threshold for additional testing to help avoid misdiagnosis of multiple sclerosis in the following situations: 
      • Clinical and brain MRI evidence is insufficient to support diagnosis
        • Use of additional imaging and, in some cases, cerebrospinal fluid data facilitates earlier diagnosis of multiple sclerosis; it potentially allows for earlier start of disease-modifying treatment 
      • Initial presentation is other than a typical clinically isolated syndrome (eg, progressive course at onset)
      • Clinical, imaging, or laboratory features are atypical for multiple sclerosis
      • Patient is in a population in which multiple sclerosis is less common (eg, children, older adults, ethnicity/race other than white)
    • Perform spinal cord MRI if brain MRI is nondiagnostic or if presenting symptoms are at level of spinal cord 
      • Consider including cervical cord MRI simultaneously with brain MRI (even without symptoms of transverse myelitis)
      • Include cervical cord at minimum; lesions there are more common and better visualized than lesions in thoracic cord
    • Consider lumbar puncture for examination of cerebrospinal fluid, including cerebrospinal fluid–specific oligoclonal bands
      • Consider when the diagnosis is equivocal (eg, history and MRI findings are not completely typical); not a routine diagnostic test
      • More useful in excluding alternative diagnoses and in supporting diagnosis of primary progressive multiple sclerosis than in diagnosing relapsing-remitting disease 
    • Consider performing tests of evoked potentials (visual, auditory, and somatosensory)
      • May provide additional objective evidence of deficits consistent with multiple sclerosis; useful to identify a clinically silent second lesion 
        • Abnormalities in 1 or more type of evoked potential occur in 80% to 90% of patients with multiple sclerosis 
        • Nonspecific for multiple sclerosis; can be obtained to measure prolonged latency, reflecting the specific effect of demyelination on saltatory conduction 
        • Visual evoked potentials are most commonly used
    • Laboratory testing is unlikely to be helpful in patients with typical multiple sclerosis presentation; no biomarker is specific for multiple sclerosis 
      • May be performed as directed by clinical presentation and concern for other disease processes; laboratory tests to consider include: 
        • CBC
        • Inflammatory markers (eg, erythrocyte sedimentation rate, C-reactive protein level)
        • Liver and renal function tests, glucose level, and calcium level
        • Vitamin B₁₂ level
        • Thyroid function tests
        • Antinuclear antibody titers
        • Syphilis serology
        • HIV serology
        • If lumbar puncture is performed: serum IgG level (to calculate IgG index) 
  • Apply results of clinical and paraclinical data to the 2017 revised McDonald criteria for diagnosis of multiple sclerosis 
    • Specify the provisional disease type (eg, relapsing-remitting, primary progressive, secondary progressive)
Number of clinical attacksNumber of lesions with objective clinical evidenceAdditional data needed for diagnosis of multiple sclerosis
2 or more2 or moreNone*
2 or more1 (as well as clear-cut historical evidence of a previous attack involving a lesion in a distinct anatomic location†)None*
2 or more1Dissemination in space demonstrated either by an additional clinical attack implicating a different site in the central nervous system or by MRI‡
12 or moreDissemination in time demonstrated by an additional clinical attack or by MRI§
or
Demonstration of cerebrospinal fluid–specific oligoclonal bands¶
11Dissemination in space demonstrated either by an additional clinical attack implicating a different site in the central nervous system or by MRI‡
plus
either
Dissemination in time demonstrated by an additional clinical attack or by MRI§
or
Demonstration of cerebrospinal fluid–specific oligoclonal bands¶

Caption: If the 2017 revised McDonald Criteria are fulfilled and there is no better explanation for the clinical presentation, the diagnosis is multiple sclerosis. If multiple sclerosis is suspected by virtue of a clinically isolated syndrome but the 2017 revised McDonald criteria are not completely met, the diagnosis is possible multiple sclerosis. If another diagnosis arises during the evaluation that better explains the clinical presentation, the diagnosis is not multiple sclerosis. *No additional tests are required to demonstrate dissemination in space and time. However, unless MRI is not possible, brain MRI should be obtained in all patients in whom the diagnosis of multiple sclerosis is being considered. In addition, spinal cord MRI or cerebrospinal fluid examination should be considered in patients with insufficient clinical and MRI evidence supporting multiple sclerosis, with a presentation other than a typical clinically isolated syndrome, or with atypical features. If imaging or other tests (eg, cerebrospinal fluid) are undertaken and the results are negative, caution needs to be taken before making a diagnosis of multiple sclerosis, and alternative diagnoses should be considered. †Clinical diagnosis based on objective clinical findings for 2 attacks is most secure. Reasonable historical evidence for 1 past attack, in the absence of documented objective neurologic findings, can include historical events with symptoms and evolution characteristic for a previous inflammatory demyelinating attack; at least 1 attack, however, must be supported by objective findings. In the absence of residual objective evidence, caution is needed. ‡The MRI criteria for dissemination in space are as follows: 1 or more T2-hyperintense lesions that are characteristic of multiple sclerosis in 2 or more of 4 areas of the central nervous system: periventricular, cortical/juxtacortical, infratentorial, and spinal cord. §The MRI criteria for dissemination in time are as follows: simultaneous presence of gadolinium-enhancing and nonenhancing lesions at any time or by a new T2-hyperintense or gadolinium-enhancing lesion on follow-up MRI, with reference to a baseline scan, irrespective of timing of baseline MRI. ¶The presence of cerebrospinal fluid–specific oligoclonal bands does not demonstrate dissemination in time per se but can substitute for the requirement for demonstration of this measure.

Citation: From Thompson AJ et al: Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 17:162-73, 2018, Table.

Primary progressive multiple sclerosis can be diagnosed in patients with:
1 year of disability progression (retrospectively or prospectively determined) independent of clinical relapse
Plus 2 of the following criteria:
1 or more T2-hyperintense lesions* characteristic of multiple sclerosis in 1 or more of the following brain regions: periventricular, cortical, juxtacortical, or infratentorial
2 or more T2-hyperintense lesions* in the spinal cord
Presence of cerebrospinal fluid–specific oligoclonal bands

Caption: *Unlike with the 2010 McDonald criteria, no distinction between symptomatic and asymptomatic MRI lesions is required.

Citation: From Thompson AJ et al: Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 17:162-73, 2018, Panel 6.

  • Determine appropriate modifiers (ie, whether disease is active or not and progressive or not, based on previous year’s history) 
  • Level of disability can be quantified
    • Functional scales, such as the Expanded Disability Status Scale, may be used to describe initial severity of multiple sclerosis, to detect effectiveness of clinical interventions, and to monitor disease progression 
      • Such scoring is generally for research and exclusively done by a neurologist trained in scoring the particular instrument
      • Expanded Disability Status Scale consists of ordinal rating system ranging from 0 (normal neurologic status) to 10 (death due to multiple sclerosis)
        • Lower scale values (0-4) measure impairments based on neurologic examination
        • Determination of middle range (4-6) is heavily dependent on walking ability
        • Upper range (more than 6) measures handicaps of patients
      • Score does not capture nonmotor components of the disease (notably mood, cognition, and fatigue) 

Imaging

  • MRI
    • Standard diagnostic test in evaluation of suspected multiple sclerosis 
      • Used to demonstrate dissemination of lesions in time and space
      • Contraindications include implanted metals and pacemakers
    • Imaging features in multiple sclerosis
      • Presence of demyelination (lesions, plaques, or both)
        • Brain lesions are typically ovoid, well circumscribed, and oriented perpendicular to the ventricles; they occur in characteristic locations (ie, periventricular, cortical/juxtacortical, infratentorial, spinal cord) 
        • Spinal cord lesins are usually well circumscribed and relatively small, occupying less than 50% of cross-sectional area of cord; they often involve the dorsolateral cord 
      • T2-weighted images may show hyperintensity and more chronic lesions; they show typical lesions, both acute and chronic
      • T1-weighted images may show cerebral atrophy and hypointensity representing areas of axonal death
      • Acute lesions are contrast enhancing, making it possible to distinguish between acute and chronic lesions and prove dissemination in time
        • Gadolinium-enhancing lesions are accepted MRI signs of new inflammation 
        • Consensus statement notes that gadolinium-based contrast agents accumulate in the brain and, although there is no known central nervous system toxicity, these agents should be used judiciously, recognizing that gadolinium continues to play an invaluable role in specific circumstances related to diagnosis and follow-up 
    • MRI criteria for dissemination in space
      • Demonstrated by 1 or more T2-hyperintense lesions (3 mm or more in long axis) in at least 2 of 4 areas of the central nervous system (ie, periventricular, cortical/juxtacortical, infratentorial, spinal cord) 
      • Patients with clinically isolated syndrome meeting these imaging criteria have high risk for multiple sclerosis 
    • MRI criteria for dissemination in time
      • Demonstrated by new T2-hyperintense or gadolinium-enhancing lesion on follow-up MRI, with reference to a baseline scan, irrespective of timing of baseline scan; or 
      • Simultaneous presence of gadolinium-enhancing and nonenhancing lesions at any time
    • Symptomatic and asymptomatic MRI lesions can be considered in determination of dissemination in space or time 
    • MRI alone is not diagnostic, as other conditions can mimic early stages of multiple sclerosis 
      • Caution in patients with symptoms atypical for multiple sclerosis and in patients with symptom onset after age 40 years 
        • White matter lesions are common in general population with increasing age, particularly in those with conditions known to cause T2 hyperintensities (eg, hypertension, smoking, diabetes, high cholesterol, migraines)

Functional testing

  • Evoked potentials testing 
    • Evaluates function of afferent (visual, auditory, and somatosensory) or efferent (motor) pathways of central nervous system
      • Uses computer-averaged measurement of central nervous system electric potentials evoked by repetitive stimulation of selected peripheral nerves or of brain; direct measure of central nervous system physiology
    • May be performed in the absence of typical MRI abnormalities to look for evidence of central demyelination
    • Includes visual evoked potentials, brainstem auditory evoked responses, and somatosensory evoked potentials
      • Visual evoked potentials indicate demyelination in the anterior visual pathways when delays in latencies are present
        • Most commonly used; between 42% and 100% of patients with multiple sclerosis have abnormal visual evoked potentials, some without visual complaints 
      • Brainstem auditory evoked responses evaluate ipsilateral asymptomatic lesions in the auditory pathways
      • Somatosensory evoked potentials indicate demyelination in the correlated pathway of spinal cord or brain when delays in latencies are present
        • Least useful, as tests are time-consuming and results are very nonspecific

Procedures

Lumbar puncture for cerebrospinal fluid analysis
General explanation
  • Insertion of a hollow-bore needle between the vertebral bodies into the subarachnoid space to obtain a specimen of cerebrospinal fluid
    • Patient is either in the lateral recumbent position (preferable if measuring opening pressure) or sitting upright
  • Paired samples of cerebrospinal fluid and serum are necessary to ascertain that the oligoclonal bands are unique to the cerebrospinal fluid
  • To add information to diagnosis, prognosis, and monitoring of multiple sclerosis, evaluation of cerebrospinal fluid for biomarkers can: 
    • Support the inflammatory, demyelinating nature of the underlying condition
      • Evaluate for oligoclonal bands and intrathecal IgG production
        • Ordered along with serum IgG level to calculate IgG index
    • Evaluate alternative diagnoses (eg, detection of anti-AQP4 antibody—IgG against aquaporin 4—for differential diagnosis of neuromyelitis optica)
    • Predict clinically definite multiple sclerosis in patients with clinically isolated syndrome (complementary to MRI)
      • Existence of cerebrospinal fluid oligoclonal bands in patients with clinically isolated syndrome is a risk factor for developing clinically definite multiple sclerosis
    • Monitor disease progression and therapeutic effectiveness
Indication
  • Strongly recommended when clinical, imaging, or laboratory features are atypical of multiple sclerosis, as follows: 
    • Presentation is other than a typical isolated syndrome (eg, progressive course at onset)
    • Patient is in a population in which multiple sclerosis is less common (eg, children, older adults, ethnicity/race other than white)
Contraindications 
  • Uncontrolled coagulopathy
  • Skin infection at site of needle insertion
  • Patient at risk of brain herniation 
    • Best predictors of precipitating herniation (even with normal CT result) include:
      • Deteriorating level of consciousness (particularly to a Glasgow Coma Scale score of 11 or less)
      • Brainstem signs (eg, pupillary changes, abnormal posturing, irregular respirations)
      • Very recent seizure
Complications
  • Post–dural puncture headache
  • Radicular injury
  • Infection (eg, epidural abscess, meningitis, diskitis, vertebral osteomyelitis)
  • Epidural hematoma
  • Cerebral herniation
  • Epidermoid tumor formation
Interpretation of results
  • Positive cerebrospinal fluid results include 2 or more cerebrospinal fluid–specific oligoclonal bands (not present in paired serum sample) and elevated IgG index (more than 0.7) 
    • Confirms the inflammatory, demyelinating nature of the disease
    • Oligoclonal bands 
      • Agarose gel electrophoresis with isoelectric focusing and immunoblotting or immunofixation for IgG is most sensitive method to date 
      • Presence is most solid parameter to support the diagnosis of multiple sclerosis, within clinical context
        • Bands appear in cerebrospinal fluid in about 95% of patients with multiple sclerosis, although they are not exclusive to multiple sclerosis 
      • Cerebrospinal fluid oligoclonal bands are independent predictor for risk of second attack in adult patients with clinically isolated syndrome 
        • Diagnosis of multiple sclerosis can be made by presence of cerebrospinal fluid–specific oligoclonal bands in patients with typical clinically isolated syndrome and clinical or MRI criteria for dissemination in space 
          • Assumes the absence of atypical cerebrospinal fluid findings and no better explanation for the clinical presentation
          • Allows presence of cerebrospinal fluid–specific oligoclonal bands to substitute for requirement of dissemination in time
    • IgG index
      • Provides information about intrathecal synthesis of IgG and may help to better prognosticate the disease course
      • Index value has been associated with higher disease activity
  • Cerebrospinal fluid findings atypical of multiple sclerosis that suggest other diagnoses include: 
    • Elevated protein concentration (more than 100 mg/dL)
    • Pleocytosis with more than 50 cells/mm³
    • Presence of neutrophils, eosinophils, or atypical cells

Differential Diagnosis

General

  • Many disorders mimic multiple sclerosis
    • 5% to 10% of patients with initial diagnosis of multiple sclerosis are later found to have a different diagnosis 
  • Atypical features that should alert the clinician to the possibility of alternative diagnoses (red flags) include: 
    • Age older than 60 years or younger than 15 years at onset of disease
    • Symptoms of systemic disease (eg, weight loss, fever, night sweats)
    • Nonspecific neurologic symptoms and/or findings not readily localizable to central nervous system
    • Recurrent symptoms in same location
    • Hyperacute presentation (maximal defect in minutes to hours) or short-lasting symptoms (minutes to hours)
    • Rapidly progressive disease from onset; failure to remit
    • Severe optic neuritis with poor recovery or simultaneous bilateral optic presentation
    • Complete transverse myelitis or longitudinally extensive lesion
    • Encephalopathy (alterations in awareness and coma)
    • Multiple cranial neuropathies
    • Absence of disease above the foramen magnum
  • However, none of these features exclude the diagnosis of multiple sclerosis
    • Consider possibility of other causes before accepting diagnosis of multiple sclerosis, especially in patients with atypical clinical symptoms

Most common

Treatment Goals

  • Limit severity and reduce duration of symptoms during an acute attack
  • Reduce frequency and severity of future attacks and limit accumulation of disability over time
  • Manage symptoms

Admission criteria

  • Severe acute exacerbations of multiple sclerosis (functionally disabling symptoms)
  • Requirement of IV steroid therapy
    • Consider home IV or oral steroids if patient remains independent despite symptoms or has good home support
  • Inability or lack of support to meet medical and social care needs at home

Recommendations for specialist referral

  • Refer all patients in whom multiple sclerosis is suspected to a neurologist 
    • Refer patients with complications to a multiple sclerosis specialist, if available
  • Refer patients with isolated episode of optic neuritis, confirmed by ophthalmologist, to a neurologist for further assessment 
  • Care typically requires a multidisciplinary approach; it may involve any of the following: general practitioner; consultant neurologists; multiple sclerosis nurses; physical and occupational therapists; speech-language pathologists; psychologists; dietitians; social workers; and continence specialists 

Treatment Options

Treatment of acute attacks

  • Treat attacks that affect ability to perform usual tasks with corticosteroids, as early as possible and preferably within 14 days of onset of symptoms 
    • High-dose corticosteroids are the mainstay of treatment for significant, acute symptoms 
    • Can shorten duration and severity of acute exacerbation, but they have no proven effect on long-term disability 
    • Nonspecialists should discuss whether or not to offer steroids with a clinician having expertise in multiple sclerosis; not all relapses require steroid treatment 
    • Potential complications (eg, depression, agitation, worsening of blood glucose control in people with diabetes) should be considered
    • No difference in effectiveness or safety between oral and parenteral therapy 
      • Consider IV therapy when oral steroids have failed or not been tolerated or in patients admitted to hospital for severe relapse 
  • Severely symptomatic patients with symptoms refractory to steroids may benefit from plasmapheresis 

Reduce biologic activity of multiple sclerosis with disease-modifying therapies

  • Use immunomodulating agents that target the inflammatory component of multiple sclerosis; no current therapies directly prevent neurodegeneration or promote repair of myelin or neurons 
    • These drugs can significantly reduce the number of attacks and decrease disease progression, but they cannot eliminate them 
  • Decision to start, switch, or stop disease-modifying therapies is complex and best managed by clinician with expertise in management of multiple sclerosis
    • American Academy of Neurology has published a comprehensive systematic review and a summary of practice guideline recommendations for disease-modifying therapies for adults with multiple sclerosis 
    • European guideline on pharmacologic treatment of multiple sclerosis is also available 
  • Initiation of treatment
    • Multiple Sclerosis Coalition recommends initiation of treatment with an FDA-approved disease-modifying agent as follows: 
      • As soon as possible after a diagnosis of relapsing or primary progressive multiple sclerosis, irrespective of person’s age
      • For patients with a first clinical event and characteristic MRI features suggesting multiple sclerosis in whom other possible causes have been excluded
      • For those with progressive multiple sclerosis who continue to have clinical relapses and/or inflammatory activity
  • Choice of agent depends on multiple factors including disease severity, drug safety profile, patient characteristics/comorbidities, route of administration, and patient and practitioner preference
    • Best managed by a neurologist familiar with prescribing these evolving and potentially toxic agents 
    • FDA-approved disease-modifying drugs include: 
      • Injectable agents: interferons and glatiramer acetate 
      • Infused agents: humanized monoclonal antibodies: alemtuzumab, ocrelizumab, natalizumab; mitoxantrone remains FDA approved but is rarely used
      • Oral agents: dimethyl fumarate, fingolimod, teriflunomide
    • Combination therapy with immunomodulating agents is not routinely recommended
  • Several treatments that are not FDA approved for disease modification in multiple sclerosis have been used off label (eg, cyclophosphamide, cladribine, azathioprine, mycophenolate mofetil, rituximab) 
  • Continue treatment with chosen agent indefinitely or until the following events occur (alternative agent should be considered in these cases): 
    • Suboptimal treatment response
    • Intolerable adverse effects
    • Inadequate adherence to treatment regimen
    • Availability of a more appropriate treatment option

Pharmacologic symptom management 

  • Spasticity: muscle relaxants (eg, baclofen, tizanidine, dantrolene); use of a benzodiazepine (eg, diazepam) can be habit forming and cause drowsiness, but it may be useful for spasticity at night to aid sleep 
  • Bladder urgency: antispasmodics (eg, oxybutynin, tolterodine, solifenacin)
  • Depression and emotional lability: antidepressants (eg, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, bupropion); sedating antidepressants (eg, amitriptyline, trazodone) given at night may be useful for patients with pain or insomnia
  • Erectile dysfunction: phosphodiesterase inhibitors (eg, sildenafil, tadalafil, vardenafil)
  • Fatigue: amantadine, modafinil, and amphetaminelike stimulants (eg, methylphenidate) are commonly used 
  • Painful dysesthesias and paroxysmal dystonic spasms: antiepileptic drugs (eg, gabapentin, pregabalin, carbamazepine) or tricyclic antidepressants (eg, amitriptyline, nortriptyline)

Radiologically isolated syndrome

  • Current recommendations do not support initiation of disease-modifying therapy based on a radiologically isolated syndrome 
  • Follow patients prospectively; about one-third of people with radiologically isolated syndrome are diagnosed with multiple sclerosis within 5 years of presentation 

Drug therapy

  • Corticosteroids 
    • Mainstay of treatment during acute attacks
    • Methylprednisolone
      • National treatment guidelines recommend higher doses of methylprednisolone (IV or PO) than the manufacturer recommends
      • Guideline dosing recommendations
        • Methylprednisolone Sodium Succinate Solution for injection; Adults: 1000 mg IV daily for 3 to 5 days. 
          • Oral methylprednisolone or dexamethasone (in equivalent dosages) may be substituted for the IV portion of therapy. 
        • Prednisone Oral tablet; Adults: 1250 mg PO daily for 3 to 5 days. 
          • Dosing is determined by converting the effective methylprednisolone dose to prednisone dose; each 4 mg of methylprednisolone is equivalent to 5 mg of prednisone. 
          • Bioavailability after 1250 mg of oral prednisone is similar to that after 1 g of IV methylprednisolone. 
    • Prednisone (for taper)
      • For optional oral taper after IV methylprednisolone
        • Prednisone Oral tablet; Adults: initiate therapy at 60 to 80 mg/day PO and gradually taper over 2 weeks. 
  • Immunomodulating agents
    • Injectable
      • Interferon beta-1a 
        • For the treatment of remitting-relapsing forms of multiple sclerosis; to slow physical disability and to decrease the frequency of clinical exacerbations
          • Intramuscular dosage (Avonex)
            • Interferon Beta-1a (Hamster) Solution for injection; Adults: 30 mcg (6 million international units) IM once per week is the target dose. To reduce the incidence and severity of flu-like symptoms, initiate with 7.5 mcg IM once (week 1), with subsequent increases of 7.5 mcg each week until the recommended dose of 30 mcg/week is achieved (week 4).
          • Subcutaneous dosage (Rebif)
            • Interferon Beta-1a (Hamster) Solution for injection; Adults: 22 or 44 mcg subcutaneously 3 times weekly is the target dose. Titrate to the full dose over 4-weeks using the titration pack. If the goal dose is 22 mcg: Administer 4.4 mcg subcutaneously 3 times weekly (weeks 1 and 2); then 11 mcg 3 times weekly (weeks 3 and 4); then full dose therapy beginning week 5. If the goal dose is 44 mcg: Administer 8.8 mcg subcutaneously 3 times weekly (weeks 1 and 2); then 22 mcg 3 times weekly (weeks 3 and 4); then full-dose therapy beginning week 5.
      • Interferon beta-1b 
        • For relapsing-remitting forms of multiple sclerosis
          • Interferon Beta-1b (E. coli) Solution for injection; Adults: 250 mcg subcutaneously every other day. To achieve the dose, incremental dose titration every 2 weeks is recommended (62.5 mcg subcutaneously every other day during weeks 1 and 2, 125 mcg subcutaneously every other day during weeks 3 and 4, 187.5 mcg subcutaneously every other day during weeks 5 and 6).
      • Pegylated interferon
        • For the treatment of relapsing forms of multiple sclerosis
          • Peginterferon Beta-1a Solution for injection; Adults: Initially, give 63 mcg subcutaneously once on day 1 of therapy. On day 15, give 94 mcg subcutaneously once. On day 29, give 125 mcg subcutaneously once. Thereafter, continue with 125 mcg subcutaneously every 14 days.
      • Glatiramer acetate 
        • For the treatment of relapsing forms of multiple sclerosis
          • Subcutaneous dosage (20 mg/mL solution)
            • Glatiramer Acetate Solution for injection; Adults: 20 mg subcutaneous once daily. Glatiramer 20 mg/mL and 40 mg/mL solutions for injection are NOT interchangeable.
          • Subcutaneous dosage (40 mg/mL solution)
            • Glatiramer Acetate Solution for injection; Adults: 40 mg subcutaneous 3 times per week. Minimum interval between doses = 48 hours. Glatiramer 20 mg/mL and 40 mg/mL solutions for injection are NOT interchangeable.
    • Infused agents
      • Alemtuzumab 
        • For the treatment of relapsing forms of multiple sclerosis
          • Because of its safety profile, its use is generally reserved for those with inadequate response to 2 or more prior therapies 
          • Alemtuzumab (Hamster) Solution for injection [Multiple Sclerosis]; Adults: Regimen consists of 2 treatment courses as follows: 12 mg IV infusion over 4 hours daily on 5 consecutive days (total dose of 60 mg) for a first treatment course. Follow 12 months later with 12 mg IV infusion over 4 hours daily for 3 consecutive days (total dose of 36 mg) for a second treatment course. Subsequent treatment courses of 12 mg IV daily for 3 consecutive days may be given at least 12 months after the last dose of any prior treatment course.
      • Ocrelizumab 
        • For the treatment of relapsing or primary progressive forms of multiple sclerosis
          • Ocrelizumab Solution for injection; Adults: 300 mg IV infusion as a single dose, followed by a second 300 mg IV infusion 2 weeks later. Subsequent infusions of 600 mg IV are administered every 6 months. The first 600 mg dose is due 6 months after infusion 1 of the initial dose. Infusion rate modifications are necessary if infusion reactions occur, and depend on reaction severity. After completion of each infusion, monitor the patient for at least 1 hour.
      • Natalizumab 
        • For the treatment of relapsing forms of multiple sclerosis
          • Natalizumab (Murine) Solution for injection; Adults: 300 mg IV infusion every 4 weeks. Natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML); consider the benefits and risk of treatment prior to initiating or continuing treatment.
      • Mitoxantrone
        • For the treatment of secondary progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis
          • Rarely used, owing to severe adverse effects; avoid prescribing unless potential therapeutic benefits outweigh risks 
        • Mitoxantrone Hydrochloride Solution for injection; Adults: 12 mg/m2 IV every 3 months.
          • Potentially fatal congestive heart failure may occur during therapy with mitoxantrone for months to years after completion of therapy. Risk increases with cumulative dosing; maximum cumulative lifetime dose of mitoxantrone: 140 mg/m². 
    • Oral agents
      • Dimethyl fumarate 
        • For the treatment of relapsing forms of multiple sclerosis
          • Dimethyl fumarate Oral capsule, gastro-resistant; Adults: 120 mg PO twice daily for 7 days, then 240 mg PO twice daily. May temporarily reduce dose to 120 mg PO twice daily if not tolerated. Resume recommended dose of 240 mg PO twice daily within 4 weeks. If maintenance dose cannot be tolerated, consider discontinuation of therapy.
      • Fingolimod 
        • For the treatment of relapsing forms of multiple sclerosis
          • Fingolimod Oral capsule; Adults: 0.5 mg PO once daily.
      • Teriflunomide 
        • For the treatment of relapsing forms of multiple sclerosis
          • Teriflunomide Oral tablet; Adults: 7 mg or 14 mg PO once daily.
      • Siponimod
        • For the treatment of relapsing forms of multiple sclerosis
        • Before initiation of therapy, test for for CYP2C9 variants to determine CYP2C9 genotype. 
          • Siponimod Oral tablet; Adults: Give 0.25 mg PO once on days 1 and 2, 0.5 mg PO (two 0.25 mg tablets) once on day 3, and 0.75 mg PO (three 0.25 mg tablets) once on day 4. Begin maintenance dose of 1 mg PO once daily on day 5. First dose monitoring is recommended in patients with bradycardia (heart rate less than 55 beats per minute), first or second degree (Mobitz type 1) AV block, or a history of myocardial infarction or heart failure. If 1 titration is missed for more than 24 hours, reinitiate with day 1 of the titration regimen. If maintenance treatment is interrupted for 4 or more consecutive days, reinitiate treatment with the titration regimen and complete first dose monitoring when needed.
        • For patients with *1/*1, *1/*2, or *2/*2 CYP2C9 genotypes
          • Siponimod Oral tablet; Adults: Give 0.25 mg PO once on days 1 and 2, 0.5 mg PO (two 0.25 mg tablets) once on day 3, 0.75 mg PO (three 0.25 mg tablets) once on day 4, and 1.25 mg PO (five 0.25 mg tablets) once on day 5. Begin maintenance dose of 2 mg PO once daily on day 6. First dose monitoring is recommended in patients with bradycardia (heart rate less than 55 beats per minute), first or second degree (Mobitz type 1) AV block, or a history of myocardial infarction or heart failure. If 1 titration is missed for more than 24 hours, reinitiate with day 1 of the titration regimen. If maintenance treatment is interrupted for 4 or more consecutive days, reinitiate treatment with the titration regimen and complete first dose monitoring when needed.
        • For patients with *1/*3 or *2/*3 CYP2C9 genotypes

Nondrug and supportive care

  • Education and supportive care 
    • Educate patients and caregivers on multiple sclerosis disease process, treatment, and symptom management
    • Offer information about support groups
  • Rehabilitation 
    • Various modalities are available to aid with maximizing functionality and quality of life
    • Often involves multidisciplinary team (eg, general practitioner; consultant neurologists; multiple sclerosis nurses; physical and occupational therapists; speech-language pathologists; psychologists; dietitians; social workers; continence specialists); team members do the following:
      • Improve physical impairments (eg, spasticity, weakness, fatigue, swallowing or speech impairments)
      • Provide adaptive equipment and devices (eg, walkers, wheelchairs)
      • Teach skills to enhance vocational capabilities
      • Provide counseling to reduce patient stress, anxiety, and depression and to aid in adjusting to challenges of living with multiple sclerosis
  • Complementary/alternative/integrative medicine
    • Many patients with multiple sclerosis (33%-80%) use complementary health approaches to relieve symptoms and/or reduce relapses 
      • Clinicians should ask patients about such use, because some therapies may have interactions with other medications, especially disease-modifying agents 
      • There is no definitive evidence that any dietary supplement is effective to reduce relapses or symptoms of multiple sclerosis; some practices may ease some symptoms
    • Modalities include:
      • Natural products and supplements
        • Cannabis and derivatives 
          • Cannabinoids (eg, oral cannabis extract, tetrahydrocannabinol, cannabidiol, nabiximols) are not FDA approved for multiple sclerosis 
            • Oral cannabis extract
              • Effective for reducing patient-reported symptoms of spasticity and pain 
            • Tetrahydrocannabinol (plant-derived or synthetic)
              • Probably effective for reducing patient-reported symptoms of spasticity and pain 
            • Nabiximols (Sativex)
              • An oromucosal cannabinoid spray containing a tetrahydrocannabinol-cannabidiol mixture
              • Probably effective for improving subjective spasticity symptoms, pain, and urinary frequency 
          • Commonly reported adverse effects include dizziness, drowsiness, difficulty concentrating, and memory disturbance
          • Smoked cannabis has insufficient evidence to determine its safety or effectiveness for treating multiple sclerosis symptoms 
        • Vitamin D
          • A 2010 Cochrane review based on a single randomized clinical trial found insufficient evidence to support use of vitamin D for multiple sclerosis 
          • More recent review suggests moderate vitamin D supplementation (2000-4000 units/day) in all types of multiple sclerosis; mechanism of action of vitamin D in multiple sclerosis appears to be immunomodulatory 
        • ω-3 fatty acids
          • Probably ineffective for reducing multiple sclerosis–associated relapse, disability, or MRI lesions, or for improving fatigue or quality of life 
          • National Institute for Health and Care Excellence guideline recommends not offering ω-3 or ω-6 fatty acid compounds to treat multiple sclerosis; there is no evidence that they affect relapse frequency or progression 
        • Ginkgo biloba
          • Ineffective for improving cognition in patients with multiple sclerosis; possibly effective for fatigue 
        • Bee venom
          • Based on limited studies, appears to have no effect on multiple sclerosis symptoms or relapses; may have serious adverse effects, including anaphylaxis, which limit utility 
      • Mind and body practices
        • Yoga 
          • Limited data; some evidence for positive short-term effects on fatigue and mood, but not on outcomes such as mobility or cognitive function 
        • Magnet therapy
          • Probably effective for reducing fatigue and probably ineffective for reducing depression 
        • Reflexology
          • Reflexology is possibly effective for reducing multiple sclerosis–associated paresthesia 
  • Advise patients on modifiable risk factors
    • Regular exercise: may have beneficial effects on multiple sclerosis and does not have any harmful effects 
    • Vaccinations 
      • Flu vaccinations may be recommended on an individualized basis 
      • Live vaccinations may be contraindicated in people with multiple sclerosis who are being treated with disease-modifying therapies 
    • Smoking cessation: smoking may increase the progression of disability 
      • Evidence-based strategies include nicotine replacement products, pharmacotherapy (eg, bupropion, varenicline), and counseling
        • High-quality evidence indicates that a combination of pharmacotherapy and high-intensity behavioral treatment is more effective than high-intensity behavioral treatment alone 
        • Moderate evidence indicates that nicotine replacement therapy combined with psychosocial support increases abstinence from smoking and reduces mortality 
        • Some evidence indicates that high-intensity behavioral treatment is more effective than low-intensity or usual care 
      • Nicotine replacement therapy may also be supplemented with agents shown to mitigate the effects of withdrawal; a combination of nicotine replacement plus sustained-release bupropion is recommended 
      • Withdrawal agents may also be used instead of nicotine replacement therapy when it is contraindicated; varenicline and sustained-release bupropion are first line choices
PharmacotherapyOdds ratio of success
Combination nicotine patch (longer than 14 weeks) plus ad lib nicotine gum or spray3.6
Varenicline 2 mg/day3.1
Nicotine patch plus bupropion SR2.5
Nicotine patch plus nortriptyline2.3
Nicotine nasal spray2.3
High-dose (greater than 25 mg) nicotine patch2.3
Nicotine patch plus inhaler2.2
Nicotine gum2.2
Varenicline 1 mg/day2.1
Nicotine inhaler2.1
Bupropion SR2
Nicotine patch plus second-generation antidepressant (paroxetine, venlafaxine)2
Regular dose nicotine patch used for either 6 to 14 weeks or for longer than 14 weeks1.9

Citation: Data from Clinical Practice Guideline Treating Tobacco Use and Dependence 2008 Update Panel, Liaisons, and Staff: A clinical practice guideline for treating tobacco use and dependence: 2008 update. A U.S. Public Health Service report. Am J Prev Med. 35(2):158-76, 2008.

Comorbidities

  • Epidemiologic knowledge of comorbidities in multiple sclerosis is inconsistent in the literature 
    • Comorbidities with the highest incidence (based on meta-analyses of population-based studies) include hypertension, stroke, and cancers
    • Top prevalent comorbidities (based on meta-analysis) include depression, anxiety, hypertension, hyperlipidemia, and chronic lung disease
    • Noncoincidental relationships between disorders (if any) are difficult to establish
  • Acute infectious illnesses
    • Patients with a diagnosis of multiple sclerosis may experience worsening or unmasking/decompensation of preexisting symptoms (pseudoexacerbation) during acute infectious illnesses or during heat exposure

Special populations

  • Pediatric population
    • Onset is most frequently in adolescence; it is rare before age 10 years 
    • Age of onset ratio of girls to boys is 0.8:1 in children younger than 6 years; it increases to 1.6:1 in those aged 6 to 10 years and reaches 2:1 to 3:1 in adolescents (similar to ratio in adults) 
    • More than 97% of children and adolescents experience a relapsing-remitting disease course 
    • Symptoms are similar to those of adults with relapsing-remitting multiple sclerosis 
      • First attack of pediatric multiple sclerosis is typically monofocal
      • About 15% to 20% of pediatric patients, most younger than 11 years, present with encephalopathy and multifocal neurologic deficits 
        • These deficits may be difficult to distinguish from features of acute disseminated encephalomyelitis
    • Criteria for pediatric multiple sclerosis can be met by any of the following: 
      • 2 or more nonencephalopathic (ie, unlike acute disseminated encephalomyelitis) clinical events of the central nervous system with presumed inflammatory cause, separated by more than 30 days and involving more than 1 area of the central nervous system
      • 1 nonencephalopathic episode typical of multiple sclerosis, which is associated with MRI findings consistent with 2010 revised McDonald criteria for dissemination in space and in which a follow-up MRI shows at least 1 new enhancing or nonenhancing lesion consistent with criteria for dissemination in time
      • 1 attack of acute disseminated encephalomyelitis followed by a nonencephalopathic clinical event, 3 or more months after symptom onset, that is associated with new MRI lesions that fulfill 2010 revised McDonald criteria for dissemination in space 
      • A first, single, acute event that does not meet criteria for acute disseminated encephalomyelitis and whose MRI findings are consistent with the 2010 revised McDonald criteria for dissemination in space and dissemination in time (applies only to children aged 12 years or older)
    • Relapses have higher annualized rate and are often more severe than in adult population 
      • However, children typically recover completely or nearly completely from initial attack
    • Acute exacerbations can be treated with corticosteroids
      • Usual treatment is pulse methylprednisolone at a dosage of 20 to 30 mg/kg IV per day (maximum 1000 mg per day) for 3 to 5 days 
    • First line treatment options include off-label use of injectable agents (eg, glatiramer acetate, interferon beta), which have similar efficacy
    • Fingolimod is currently the only FDA-approved disease-modifying therapy for use in children 
  • Pregnancy
    • Relapse rates may reduce during pregnancy, but may increase 3 to 6 months after childbirth before returning to prepregnancy rates 
      • Pregnancy is associated with a 70% reduction in relapse rates in the third trimester 
      • Best predictor of postpartum relapse is prepregnancy incidence of active relapsing 
    • Pregnancy does not increase risk of progression of disease 
    • Medication use during pregnancy 
      • Treat acute exacerbations in pregnancy with IV methylprednisolone
        • Typically several days of 1 g methylprednisolone IV daily without oral taper 
        • An association of first trimester steroid exposure with cleft lip and palate abnormalities is controversial, but many obstetricians hold that short-term steroids can be used safely in all trimesters 
          • If relapse occurs during pregnancy, there is no contraindication to conventional short-term corticosteroids 
      • Family planning should be discussed early in treatment decision process to optimize medication choices
        • Some medications require several months of cessation before any attempt to conceive (ie, washout period)
          • Approximately 5 maximal half-lives, based on exponential decay 
      • Disease-modifying therapies are not recommended for use in pregnancy 
        • No such therapy is FDA approved for use in pregnancy 
        • Several observational studies, including pregnancy registries, have looked to identify potential risks of disease-modifying therapy during pregnancy and breastfeeding
          • Increasing evidence supports that glatiramer acetate and interferon beta may be continued safely during conception and pregnancy in a woman with very active disease 
          • Use of disease-modifying therapy during pregnancy should be carefully discussed and evaluated, limited in use, and used at minimum effective doses for as brief a time as possible 
            • There are no clear guidelines on use in pregnancy
  • Breastfeeding
    • Exclusive breastfeeding may be associated with decreased multiple sclerosis disease activity 
    • Disease-modifying therapies are currently not recommended for use while breastfeeding 
      • No such therapy is FDA approved for use while breastfeeding
      • Risks and benefits of postponing resumption of treatment should be discussed, especially in women with active relapsing disease before pregnancy 
        • While there are no set guidelines, glatiramer acetate and interferon beta are probably compatible with breastfeeding 

Monitoring

  • All patients with multiple sclerosis should have an annual comprehensive review of all aspects of their care by a clinician with expertise in multiple sclerosis and its complications 
  • Many factors determine frequency of follow-up visits, including: 
    • Disease course and severity of multiple sclerosis symptoms
    • Need for monitoring of disease-modifying therapies, which may be variable, based on agents used
      • Evaluate for medication adherence, adverse effects, tolerability, safety, and effectiveness of therapy either annually or according to medication-specific recommendations 
    • Rehabilitation requirements
    • Individual medical and social needs
  • MRI follow-up (most sensitive available tool for monitoring inflammatory disease activity in multiple sclerosis)
    • Imaging follow-up frequency varies depending on patient’s clinical course 
      • Clinically isolated syndrome and/or suspected multiple sclerosis to look for new lesions (evidence of dissemination in time)
        • 6 to 12 months for high-risk clinically isolated syndrome (2 or more characteristic lesions on brain MRI) 
        • 12 to 24 months for low-risk clinically isolated syndrome (normal brain MRI findings) and/or uncertain clinical syndrome with suspicious MRI features (eg, radiologically isolated syndrome) 
      • Established diagnosis of multiple sclerosis
        • No recent imaging available (eg, transfer to new clinic)
        • Postpartum (to establish new baseline)
        • Before starting or switching disease-modifying therapy
        • Approximately 6 to 12 months after switching disease-modifying therapy (to establish new baseline) 
        • Every 1 to 2 years while on disease-modifying therapy (to assess subclinical disease activity) (but every 2-3 years if clinically stable) 
        • After unexpected clinical deterioration or upon reassessment of original diagnosis
          • Routine spinal cord follow-up is not required unless syndrome is predominantly recurrent transverse myelitis
      • Need for surveillance (using surveillance protocol) for progressive multifocal leukoencephalopathy, a subacute demyelinating disease of white matter caused by reactivation of JC virus infection
        • Some disease-modifying medications can place patients at greater risk for developing progressive multifocal leukoencephalopathy (eg, natalizumab)
          • Every 12 months for patients negative for serum JC virus antibody 
          • Every 3 to 6 months for patients positive for serum JC virus antibody and with 18 or more months on natalizumab 

Complications

  • Pneumonia due to weakening of breathing muscles or due to aspiration (from dysphagia) (Related: Aspiration pneumonia)
  • Osteoporosis
  • Psychosocial: depression, suicide, and divorce rates are higher than in healthy population 
  • Urinary tract infections secondary to bladder dysfunction (Related: Urinary tract infection in adults)
  • Pressure injury from immobility

Prognosis

  • Multiple sclerosis is a chronic and often disabling disease that is not yet curable
  • Development of chronic progressive disability
    • Significant variation exists in severity of exacerbations and rate of accumulation of disability, but the following themes are known:
      • Most patients are unemployed within 15 years of diagnosis 
      • Half of patients require mobility assistance within 20 years of diagnosis 
      • Half of patients eventually develop substantial cognitive deficits 
  • Patients with multiple sclerosis have a reduction in life expectancy of 7 to 14 years compared with general population 
    • At least half die from causes directly related to multiple sclerosis 
    • Primary progressive disease and older age at onset are associated with shorter survival

Prevention

  • Several modifiable environmental and lifestyle risk factors exist; controlling them may reduce the risk of developing multiple sclerosis, especially in people with family history of the disease. Thus counsel as follows: 
    • Avoid cigarette smoking
    • Avoid vitamin D deficiency (primarily by eating healthfully and, if necessary, with supplementation) 
    • Avoid obesity

If you ever feel like you may hurt yourself or others, or have thoughts about taking your own life, get help right away. You can go to your nearest emergency department or call:

  • Your local emergency services (911 in the U.S.).
  • A suicide crisis helpline, such as the National Suicide Prevention Lifeline at 1-800-273-8255. This is open 24 hours a day.

Summary

  • Multiple sclerosis (MS) is a disease of the central nervous system that causes the body’s immune system to destroy the protective covering (myelin sheath) around nerves in the brain.
  • There are 3 types of MS: relapsing-remitting, secondary progressive, and primary progressive. Relapsing-remitting and secondary progressive MS cause symptoms to occur in episodes or attacks that may last weeks to months. Primary progressive MS causes symptoms to steadily progress after they develop.
  • There is no cure for MS, but medicines can help decrease the number and frequency of attacks and help relieve nuisance symptoms. Treatment may also include physical or occupational therapy.
  • If you develop numbness, paralysis, vision problems, or other neurological symptoms, get help right away.

Sources

Lublin FD et al: Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 83(3):278-86, 2014 Reference

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