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Multiple Sclerosis (MS) is a chronic inflammatory relapsing or progressive disorder of the central nervous system (CNS) white matter characterized by areas of immune mediated demyelination and axonal injury.


A complex interplay of a number of factors, probably a variable combination, produces the disease. Both hereditary and environmental factors are implicated in etiology. 20% of MS patients have at least one affected relative with a polygenic hereditary predisposition. Many viruses and bacteria are suspected of causing MS, most recently the Epstein-Barr virus, but none have been conclusively proven.

Epidemiology including risk factors and primary prevention

Incidence and prevalence rates vary with geography and ethnicity.1 MS affects 2.5 million people worldwide and nearly one million people in the U.S. alone. It is more common in late adolescence or early adult life with at least a 3:1 ratio of female to male. It is more likely to occur in white populations than in Native Americans, African Americans and Asians. MS is more common in countries with temperate climates and there is a higher rate of prevalence in northern United States and Canada compared to the south. A number of other factors are associated with higher disease rates, such as urban background, higher educational and socioeconomic status, higher latitude, cold humid weather, and meat and dairy food consumption.2,3

The prevalence of MS has increased in recent decades. The incidence of MS has increased, but the course of the disease has become milder, particularly in the 25 years since the first disease-modifying therapies (DMTs) became available.4


There is periventricular infiltration of lymphocytes and macrophages in the brain, brain stem, optic nerves and spinal cord. There is inflammation, intrathecal immunoglobulin G production with oligoclonal bands, antibody producing plasma cell infiltration and disruption of blood brain barrier. The demyelinating lesions are known as plaques which appear as indurated areas and hence the term sclerosis. There is myelin loss, destruction of oligodendrocytes and reactive astrogliosis with relative sparing of the axon cylinder in the demyelinating lesions of the brain and spinal cord. In some cases, axons are also aggressively destroyed. The cortex and the grey matter nuclei are also affected with diffuse injury to the white matter. The grey matter atrophy is associated with physical disability, fatigue, and cognitive impairment in MS. The location of lesions in CNS dictates the type of deficits.5

MS is a complex disease in which the interaction between environmental and genetic factors produces a cascade of events, comprising of activation of the adaptive and innate immune system, blood-brain barrier breakdown, central nervous system demyelination, and axonal and neuronal damage with variable degrees of repair. These events express as potentially reversible focal neurologic symptoms or progressive non-remitting physical and cognitive disability, or both.6

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

The severity of the disease varies widely from patient to patient and is unpredictable. About 20% of patients remain asymptomatic or become only mildly symptomatic after an initial clinical event. Another 20% progress rapidly. Most patients will experience some degree of progression. There are five types of MS; they include

  • Clinically isolated syndrome (CIS) with supportive magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) findings.
  • Relapsing remitting MS (RRMS). 88% of all initial MS diagnoses are RRMS. Patients have isolated relapses when symptoms may appear or resurface, followed by periods with fewer or no symptoms.
  • Secondary progressive MS (SPMS). About 50% of all RRMS patients develop SPMS. This happens gradually within 10 years of initial diagnosis. While patients with SPMS have fewer relapses, their disability worsens and symptoms become more pronounced.7
  • Primary-progressive MS (PPMS). This makes up about 10% of all MS diagnoses. These patients have a steady worsening of symptoms and disability.
  • Progressive-relapsing MS (PRMS). It is characterized by steady worsening of disability with occasional relapses and constitutes about 5% of all MS population.

Specific secondary or associated conditions and complications 8,9

  • Fatigue is one of the most common and debilitating symptoms– 10 Sleep disorders, depression, medications, and heat sensitivity may contribute to fatigue.
  • Many patients lose mobility and risk falls and lose hand function and ability to perform activities of daily living.11
  • Spasticity is one of the primary symptoms of MS. It is usually more severe in the legs and torso.
  • Pain is present in about two-thirds of patients at some point during the course of the disease and 40% are never pain-free.
  • Depression is also found frequently.
  • Cognitive impairments affect attention, memory and executive function.
  • Bowel, bladder and sexual dysfunction are common.12,13
  • Visual and eye movement abnormalities can cause debilitating symptoms.
  • Vestibular dysfunction can be due to benign paroxysmal positional vertigo or due to demyelinating plaques in central vestibular anatomic locations.
  • Speech, breathing, and swallowing dysfunction may be found in patients with advanced progression of disability.

Essentials Of Assessment


Depending on site of lesions, patients may give history of sensory symptoms, visual loss or blurring, dysarthria, ataxia, vertigo, tremors, motor weakness, gait disturbances, bowel and bladder symptoms (such as constipation, bladder incontinence, urgency, and frequency) and cognitive disturbance. Symptoms characteristically worsen with heat. These symptoms can occur in “attacks,” (also known as exacerbations or relapses) as in the case of typical relapsing-remitting multiple sclerosis, or as a single “attack” as in clinically isolated syndrome.14

Physical examination

Signs and symptoms depend upon when in the course of the disease patient presents. They may vary from cognitive dysfunction (memory, attention and concentration) to cranial nerve abnormalities (e.g., optic disc swelling or atrophy visual field deficits, internuclear ophthalmoplegia, speech and swallowing deficits), motor and sensory loss, spasticity, and ataxia. A comprehensive systemic examination to delineate depression and other associated symptoms is warranted.

Functional assessment

Impairments in the areas of mobility, activities of daily living (ADLs), bowel and bladder function, dysarthria and dysphagia exist in patients with MS. An assessment by physical, occupational and speech therapists is essential. Cognitive function should be evaluated to assess memory, attention, problem solving, and executive function.

The Functional Assessment of Multiple Sclerosis (FAMS) is a validated self-report health-related quality of life scale can be used for patients with MS. It consists of 44 items in six domains: mobility, emotional well-being, general contentment, thinking/fatigue, family/social well-being and other items.

Laboratory studies

Cerebrospinal fluid for cell count, protein, gamma globulin, and oligoclonal bands is helpful for confirmation of the diagnosis. Blood tests and imaging are needed to exclude other causes of symptoms.


  • MRI is more sensitive and useful than computed tomography (CT). The hallmark findings are multiple lesions in the periventricular regions showing as areas of increased signal intensity of T2 weighted images. Lesions are rounded or ovoid and appear homogenous but may possess a rim of altered signal intensity. Similar lesions are found in the white matter of the spinal cord and brain stem. MRI also has a prognostic value and may correlate with disability. MRI findings are a better barometer of disease activity than clinical evaluations.
  • Positron emission tomography (PET) scan of the brain.

Supplemental assessment tools

Somatosensory evoked potentials (SSEP), visual and auditory evoked potentials are useful to identify subclinical impairments or confirm clinical findings 16

Diagnostic Criteria

The Revised McDonald criteria are utilized to diagnose MS based on patient-reported symptoms, neurologic examination, and diagnostic tests and imaging including MRI14, 17.

It requires the demonstration of dissemination of MS disease characteristics in space and time. Dissemination in space refers to lesions in different areas of the CNS as determined by clinical symptoms and/or MRI. Dissemination in time refers to the development of new lesions over time. Examples include finding gadolinium-enhancing (acute) and non-enhancing (chronic) lesions on the MRI, and/or distinct clinical attacks. The presence of oligoclonal bands in the CSF which measures intrathecal antibodies also supports dissemination in time. The Revised McDonald criteria have a sensitivity of 68% and a specificity of 61%. Mc Ginley and colleagues have published a table of the 2017 Revised Criteria for the Diagnosis of Multiple Sclerosis.17

Early predictions of outcomes10

Factors associated with a better prognosis (slower accumulation of disability, longer time before chronic progression) include:

  • Young age at onset
  • Female gender
  • RRMS course as opposed to PPMS
  • Initial symptoms of sensory impairment or optic neuritis
  • First manifestations affecting only one CNS region
  • High degree of recovery from initial bout
  • Longer interval between first and second relapse
  • Low number of relapses in the first 2 years
  • Less disability at 5 years after onset
  • Fewer MRI lesions18

Baseline to six-month corpus callosum atrophy as measured by cross-sectional area and baseline T2 lesion volume of >= 5 cm3 are predictive of the development of clinically definite MS within 2 years in patients with CIS.19

Over time, more relapses are associated with poorer recovery of neurological function and accelerated brain atrophy on MRI.19,33

A meta-analysis looking at CSF and peripheral blood osteopontin (OPN) levels found significantly higher levels of OPN in MS patients versus controls except for the CIS subtype. Progressive subtypes had higher levels than the CIS subtype. RRMS with significantly higher levels than CIS or SPMS patients. Patients with active disease had significantly higher levels than those with stable disease.16


  • Patients should limit their exposure to viral illnesses because infections may trigger relapses. Avoidance of heat and hot weather are important as exposure to heat may cause exacerbation.
  • Given a high risk of falls, it is important to remove environmental hazards.
  • Decreased sun exposure may be a critical factor if vitamin D deficiency. Vitamin D insufficiency has been shown to affect T cell differential and regulation which may affect cellular immune responses. Vitamin D may also affect B cell activation and differentiation, a cell type that may be implicated in the inflammatory cascade in CNS autoimmune disease.20

Social role and social support system

Family and social support can be critical in maintaining a good mental and physical state. Concerns regarding work, environment, quality of life, end-of-life issues, and the impact of the disease on the family are all significant.

Professional issues

Many ethical and legal issues can arise relating to diagnosis, the effects of physical, cognitive and psychological impairments, and aspects of medical management and drug trials. Researchers performing placebo-controlled need to make patients aware of the risk of stopping conventional treatments.21 It has been suggested to limit the selection of patients to those who have declined treatment after appropriate education and counseling or have failed all treatments.21 However, selection bias may then be introduced. Since the rate of MS is much higher in women than men, there is a risk of gender bias.22 Clinical data is much less for men than women.22

Rehabilitation Management and Treatments

Available or current treatment guidelines

The American Academy of Neurology, National MS Society, Consortium of MS Centers, and Paralyzed Veterans of America have all published guidelines for different aspects of MS, including disease-modifying therapies, immunizations, urinary dysfunction, fatigue, and spasticity. Rehabilitation should address maintenance of functional mobility, activities of daily living, leisure and social participation, vocational activities, home adaptations, personal support and quality of life.23,24

At different disease stages

  • Exacerbations/Relapses:
    Rapid evolution of new symptoms or worsening of old symptoms are characterized as exacerbations, relapses, or attacks. If symptoms are mild, such as mild sensory changes or mild fatigue, they may be left to resolve on their own. Severe and functionally limiting exacerbations are treated with high-dose steroids as intravenous infusion daily for three to five days. If no response to steroids, a course of plasma exchange or intravenous immunoglobulin may help. Rest, energy conservation, range of motion and joint protection techniques, and preservation of mobility are important in the acute stage.24
  • Reducing disease activity (prevention of relapses or lesions on imaging): Disease- modifying agents/Disease modifying therapies (DMA/DMT)
    Treatment goals with disease modifying therapies are to maximize neurologic function and decrease disease activity (such as relapses/exacerbations or new lesions on MRI). This may in turn prevent permanent disability. Initiation of treatment unfortunately is often delayed, since many will present to an MS specialist long after their first clinical symptoms. Therapies have the greatest efficacy within the first 5 years after onset of symptoms. Because of its autoimmune nature, targeting the immune system remains a vital component of treatment, however, predisposing the patients to infection. Therefore, immune modulation through antigen-specific therapy has a hopeful, important future. The development of immunomodulatory therapies and disease-modifying agents for MS had significant impact in altering the natural history of the disease. There are more than 20 disease-modifying therapies approved for treating multiple sclerosis. Therapies targeting an antigen, a synthetic form of myelin basic protein, called copolymer I, were successful, for the treatment of relapsing-remitting MS. Patients with RRMS and SPMS are often started on disease modifying therapy with immune modulatory agents: interferon beta-1a or 1b (suppresses T-helper cell response), Glatiramer acetate (alters T-cell activation), Natalizumab (a monoclonal antibody that blocks T-cell migration across blood-brain barrier), Fingolimod (prevents T-cell migration across blood brain barrier) and Mitoxantrone (an immunosuppressive agent that inhibits cell replication). Teriflunomide, cladribine and alemtuzumab reduce T and B-lymphocytes. Dimethyl fumarate decreases inflammatory cytokines. Diroximel fumarate decreases oxidative stress, Siponimod inhibits lymphocytic migration and is the first and only treatment for secondary progressive MS. Ocrelizumab (depletes B cells and is the first treatment for primary progressive MS. Best practices for medication management exist since multiple intravenous and oral disease modifying treatments are available. Determining which subtype of MS an individual has is an important factor in selection of disease modifying therapies. More aggressive forms of MS may be treated with higher efficacy therapies and less aggressive forms with may be treated with moderate of lower efficacy treatments. Natalizumab is reserved for patients who have inadequate response to other MS therapies, and Mitoxantrone for select patients with worsening disease.23,24,26

    Caution should be used with disease-modifying agents. Common side effects include nausea, diarrhea, abdominal pain, and flushing. However, they can be associated with progressive multifocal leukoencephalopathy (PML), hepatotoxicity, intracranial hemorrhages and life-threatening infections.18
  • Management of secondary symptoms:
    Ongoing management of spasticity, fatigue, pain, dizziness, ataxia/gait impairment, falls, sensory loss, prevention and management of pressure wounds, neurogenic bowel and bladder, sexual dysfunction, and cognitive problems is indicated. Periodic reassessment of function with routine visits should be part of follow-up care.

    Neurogenic bladder in MS can manifest as a failure to store urine, failure to empty, or a combination. Dysfunction can include detrusor overactivity, hypoactivity or detrusor sphincter dyssynergia. Treatment is targeted to the specific bladder dysfunction present (e.g., anticholinergic medications such as oxybutynin for failure to store, alpha antagonist medications such as terazosin for failure to empty).7 Botulinum toxin injections are also utilized to treat detrusor overactivity in MS.8 Bowel dysfunction can be due to either upper or lower motor neuron impairment and can manifest as failure to store or failure to empty. These are treated according to the type of dysfunction.7

    Fatigue may require further workup such as sleep studies, evaluation for urinary tract infection, or reviewing whether medications are causing sedating side effects. Use of orthotics and assistive devices can improve efficiency of gait mechanics and ADL’s. Energy conservation techniques and maintenance of moderate activity may also reduce fatigue. Medications can also be utilized to treat fatigue in MS (e.g., Amantadine, Modafinil).5 Spasticity can elicit pain and can interfere with sleep and function. A variety of treatments for spasticity can be initiated in a step-wise approach.28 Potassium channel blocking agents such as 4 amino pyridines (Dalfampridine) are believed to improve nerve conduction and have been shown to improve strength and gait.11,18
  • Pre-terminal or end-of-life care: comfort care including psychosocial support, and palliative care includes symptom relief: To meet end-of-life care needs, an interdisciplinary coordinated approach is best, with shared models of care.

Coordination of care

Because there is no cure for MS, symptom management is critically important to quality of life. A multimodal and multidisciplinary approach, using disease-modifying agents, and specific treatments for secondary or associated conditions such as spasticity, fatigue, depression, pain, bladder, or bowel problems provides optimal results. Physical and occupational therapies and other support services are also beneficial, along with effective communication and patient education interventions.17

Patient & family education

Patients and caregivers should be educated about medications, and symptom management and resources provided for community support groups. For patients with advanced disease, caregivers need hands-on training in transfer techniques, skin integrity, bowel programs, and urinary collection devices.

Emerging/unique interventions

More recent disease-modifying treatments have similar mechanism of action as earlier treatments, including Cladribine, Diroximel Fumarate, Oxanimod, Ofatumumab, Dimethyl Fumarate, Ponesimod, and Monomethyl fumarate. 24

The development of the enzyme-linked immunosorbent assay (ELISA) for prior to exposure to JC virus is making it possible to identify patients at increased risk for development of PML.23,26

Measurement of treatment outcomes

The Kurtzke Expanded Disability Status Scale (EDSS)15 and the Multiple Sclerosis Functional Composite (MSFC) are two clinically accepted measures of disease severity, progression and of function.16

Areas of function have varied research and clinical measurement tools. Examples include: mobility-Timed 25 ft. Walk (T25-FW), upper extremity-9-Hole PEG test, vision-Impact of Visual Impairment Scale, fatigue-Modified Fatigue Impact Scale, mental health and coping-Multiple Sclerosis Quality of Life Inventory or Multiple Sclerosis Quality of Life 54 (MSQOLI, MSQOL-54, respectively). Bowel and bladder tools include the Bowel Control Scale and the Bladder Control Scale that can be administered in 2-3 minutes but are useful only as screening tools. A number of outcome measurement tools exist for assessing functional levels and impairments in MS, including measurement of pain, social support, perceived impairments, and sexual satisfaction.15 Cognitive treatment outcomes can be measured through a neuropsychological battery of testing before and after treatments. Care much be taken to sort out the effects of fatigue, depression and cognitive functioning on testing. Ostenillo and colleagues summarized studies focused on the correlations between varying cognitive test results with MRI findings and/or patient self-assessment scores.16

Disease-modifying therapy effectiveness can be monitored by assessment of lesions on MRI.17

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

A comprehensive approach involves multiple specialists, including neurology, physiatry, neuropsychiatry, to encompass a biopsychosocial approach to improve and preserve function, fulfillment, and quality of life.

The diagnosis and management of multiple sclerosis are rapidly evolving at this time. Remaining current with the literature base is highly recommended.

Cutting Edge/Emerging and Unique Concepts and Practice

Autologous hemopoietic stem-cell transplantation (aHSCT) is being combined with immunosuppression with chemotherapy and immune-depleting antibodies. In a position statement from the American Society for Blood and Marrow Transplantation reviewing 16 studies and 3 meta-analytic reviews, aHCST was determined to be a safe and effective treatment for active relapsing MS.14,34 However, the cost is expensive and recovery time from the process is prolonged.29

Disease modifying agents to target remyelination are currently being studied. Opicinumab is a monoclonal antibody which blocks LINGO-1 (a cell surface glycoprotein), thus allowing potential for remyelination. High-dose biotin has also shown potential to facilitate remyelination.31 There have been advancements in imaging technology including high resolution spectral domain optical coherence tomography to identify optic neuritis. Advancements in MRI technology include double inversion recovery and phase sensitive inversion recovery, which allow more cortical lesions to be found. Magnetic transfer imaging can determine if damage is present in normal appearing brain tissue. This could be one potential way to distinguish MS from other inflammatory CNS white matter disorders such as acute demyelinating encephalomyelitis (ADEM) and Neuromyelitis optica (NMO). Serum and CSF biomarkers including antibodies (GAGA4 IgM and KIR4.1 potassium channel antibodies), antigen microarrays and microRNA expression profiles may also assist in the diagnosis. These technological advancements require further validation and may in the future be incorporated into diagnostic criteria for MS.32 Advances in assistive technology and improved adaptive equipment, with computer devices and powered wheelchairs favorably enhance the lives of patients. Strategies to address nutrition, in particular Vitamin D and healthy lifestyles are also being explored. Regaining quality of life by reducing functional dependence in conjunction with effective prevention of disease relapses must be the goal of future therapeutic approaches.

There are also ongoing studies to determine whether patients can stop disease- modifying treatments if they are stable and have no evidence of disease reactivation. Initial studies have found that among patients who were able to stop their disease modifying treatments, those above the age of 45 had a lower risk of reactivation of disease compared with those aged 45 or younger.24

Gaps in the Evidence-Based Knowledge

Although immunomodulatory therapies reduce relapse rate and MRI-associated disease activity, they are only partially effective and do not ameliorate irreversible axonal injury, which produces much of the symptomatic burden of MS. Targeted immune modulation and the demonstration of reduced disease burden and progression by objective criteria remains a continual area of research. Disease modifying agents are also not without side effects, including risk for PML and life-threatening infections. This is an important issue in the treatment of MS, which can hopefully be addressed by advancements in technology.32 Sustainability of programs to treat and maintain health of the individuals with MS continues to be a major challenge.


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Original Version of Topic

K. Rao Poduri, MD, Nathan Odom, MD, Kristen Brusky, DO. Multiple Sclerosis. 11/11/2011

Previous Revision(s) of the Topic

K. Rao Poduri, MD, Nathan Odom, MD, Kristen Brusky, DO. Multiple Sclerosis. 9/18/2015

Jean L Nickels MD, Sara Z Salim MD and K. Rao Poduri, MD, FAAPMR

Last updatedJuly 23, 2020

Author Disclosure

K. Rao Poduri, MD
Nothing to Disclose

Jean L Nickels MD
Nothing to Disclose

Sara Z Salim MD
Nothing to Disclose