Multiple Sclerosis

Author(s): K. Rao Poduri, MD, Nathan Odom, MD, Kristen Brusky, DO

Originally published:11/11/2011

Last updated:09/18/2015



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

MS affects 2.5 million people worldwide and 400,000 in the U.S. alone. It is more common in late adolescence or early adult life with at least a 2:1 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.


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.

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:

  1. Clinically isolated syndrome (CIS) with supportive magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) findings.
  2. 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.
  3. 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.
  4. Primary-progressive MS (PPMS). This makes up about 10% of all MS diagnoses. These patients have a steady worsening of symptoms and disability.
  5. 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

  1. Fatigue is one of the most common and debilitating symptoms. Sleep disorders, depression, medications, and heat sensitivity may contribute to fatigue.
  2. Many patients lose mobility and risk falls.
  3. Spasticity is one of the primary symptoms of MS. It is usually more severe in the legs and torso.
  4. Pain is present in about two-thirds of patients at some point during the course of the disease and 40% are never pain-free.
  5. Depression is also found frequently.
  6. Bowel, bladder and sexual dysfunction are common.



Depending on site of lesions, patients may give history of sensory symptoms, visual loss or blurring, dysarthria, ataxia, 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.

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 opthalmoplegia, 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

Deficits 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.

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.


  1. 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.
  2. 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.

Early predictions of outcomes

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

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


  1. 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.
  2. Given a high risk of falls, it is important to remove environmental hazards.

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.


Available or current treatment guidelines

The MS Council for Clinical Practice Guidelines has 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.

At different disease stages

  1. New onset/acute:
    Rapid evolution of new symptoms or worsening of old symptoms characterized as exacerbations are treated with high-dose steroids; 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.
  2. Subacute: Disease- modifying agents:
    Patients with RRMS and SPMS are often started on disease-modifying therapy with immune-modulatory agents such as Interferon beta-1a or 1b (suppress 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). Treatment is typically initiated with a beta interferon agent or glatiramer. Choice is largely based on patient preference and side effect profile. Natalizumab is reserved for patients who have inadequate response to other MS therapies, and Mitoxantrone for select patients with worsening disease.
  3. Chronic/stable:
    Ongoing management of spasticity, fatigue, pain, ataxia/gait impairment, falls, sensory loss, prevention and management of decubiti, 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.
  4. 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 model that provides optimal results is multimodal and multidisciplinary approach, using disease-modifying agents, medications to address spasticity, fatigue, depression, pain, and bladder or bowel problems, physical and occupational therapies and other support services with effective communication and patient education interventions.

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

Functional Independence measure is used to determine the level of a patient’s disability and indicates how much assistance is required for the individual to carry out activities of daily living (ADLs).

The Kurtzke Expanded Disability Status Scale (EDSS) is used to measure the disability status of MS patients. The purpose was to create an objective approach to quantify the level of functioning.

Measurement of Treatment Outcomes

Outcomes should include quantitative functional independence measure (FIM) data, as well as qualitative patient satisfaction and fulfillment with life activities and goals.

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.


Cutting edge concepts and practice

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. Monoclonal antibodies therapy resulted in a clear paradigm shift in MS therapeutics. Their use in early, inflammatory phases could have the potential to prevent or delay disability.

The development of immunomodulatory therapies and disease-modifying agents for MS had significant impact in altering the natural history of the disease. Therapies targeting an antigen, a synthetic form of myelin basic protein, called copolymer I, were successful, for the treatment of relapsing-remitting MS. The possibility of developing an MS vaccine is in the horizon. Therapy to improve nerve conduction with potassium channel blocking agents such as 4 amino pyridines is shown to improve strength and gait.

Current research is directed at three major goals: preventing the development of new demyelinating lesions, protecting demyelinated axons from degeneration, and promoting remyelination. Strategies to reverse the damage to myelin and oligodendrocytes to enhance remyelination are under way. Advances in assistive technology and improved adaptive equipment, with computer devices and powered wheelchairs favorably enhance the impact of the disease on the lives of patients. Regaining quality of life by reducing functional dependence in conjunction with effective prevention of disease relapses must be the goal of future therapeutic approaches.


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. Sustainability of programs to treat and maintain health of the individuals with MS is a major challenge.



National Multiple Sclerosis Society. Epidemiology of MS. Available at Accessed September 6, 2011.

Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000; 343(13):938-52.

Crayton H, Heyman RA, Rossman HS. A multimodal approach to managing the symptoms of multiple sclerosis. Neurology. 2004 Dec 14; 63(11 Suppl 5):S12-8.

Freeman JA. Improving mobility and functional independence in persons with multiple sclerosis. J Neurol. 2001; 248(4):255-59.

Khan F, Turner-Stokes L, Ng L, Kilpatrick T. Multidisciplinary rehabilitation for adults with multiple sclerosis, The Cochrane Library. 2008; Issue 3.

Samkoff LM, Goodman AD. Symptomatic management in multiple sclerosis. Neurol Clin. 2011; 29(2):449-63.

Matsuda PN, Shumway-Cook A, Bamer AM, Johnson SL, Amtmann D, Kraft GH. Falls in multiple sclerosis. PM&R. 2011; 3(7):624-32.

Steinman, L. Antigen-specific therapy of multiple sclerosis: The long-sought magic bullet. 2007;4:661-665

Souza A, Kelleher A, Cooper R, Cooper RA, Iezzoni LI, Collins DM. Multiple sclerosis and mobility-related assistive technology: Systematic review of literature. JRRD. 2010; 47(3):213-224.

D’Amico E, Caserta C, Patti F.Monoclonal antibody therapy in multiple sclerosis: critical appraisal and new perspectives. Expert Rev Neurother. 2015 Mar; 15(3):251-68. doi: 10.1586/14737175.2015.1008458.

Kremer, D; Küry Patrick and Dutta,R: Promoting remyelination in multiple sclerosis: Current drugs and future prospe Mult Scler January 26, 2015 1352458514566419

Original Version of Topic

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

Author Disclosure

K. Rao Poduri, MD
Nothing to Disclose

Nathan Odom, MD
Nothing to Disclose

Kristen Brusky, DO
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