Author(s): Jean L Nickels MD, Sara Z Salim MD and K. Rao Poduri, MD, FAAPMR
Originally published: November 11, 2011 Last updated: July 23, 2020
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DISEASE/DISORDER:

Definition

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.

Etiology

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 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 consumption1.

Patho-anatomy/physiology

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 deficits2.

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 complications3, 4

  1. Fatigue is one of the most common and debilitating symptoms5. Sleep disorders, depression, medications, and heat sensitivity may contribute to fatigue.
  2. Many patients lose mobility and risk falls, and lose hand function and ability to perform activities of daily living6.
  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. Cognitive impairments affect attention, memory and executive function.
  7. Bowel, bladder and sexual dysfunction are common7, 8.
  8. Visual and eye movement abnormalities can cause debilitating symptoms.
  9. Vestibular dysfunction can be due to benign paroxysmal positional vertigo or due to demyelinating plaques in central vestibular anatomic locations.
  10. Speech, breathing, and swallowing dysfunction may be found in patients with advanced progression of disability.

ESSENTIALS OF ASSESSMENT

History

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 syndrome9.

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.

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.

Imaging

  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.

Diagnostic Criteria

The McDonald criteria are utilized to diagnose MS based on patient-reported symptoms, neurologic examination, and diagnostic tests and imaging including MRI9.  The patient’s current clinical presentation is evaluated.  Based on the presentation, a determination is made regarding additional testing needed to fulfill a diagnosis of MS (such as MRI or CSF analysis). 

An attack (also known as an exacerbation or relapse) is a clinical episode which includes patient-reported symptoms and objective findings typical of MS.  These are reflective of a focal inflammatory demyelination occurring in the CNS.  A key to diagnosis with the McDonald criteria is to demonstrate dissemination in space and dissemination in time, meaning findings occurring in different neurologic locations and at different times. 

McDonald Criteria:

  • Two or more clinical “attacks” (relapses) each lasting >24 hours, disseminated in space/time and supported by 2 or more objective neurologic findings (exam findings such as hyperreflexia or by MRI).  This would require no other additional testing to make the diagnosis of MS.
  • Two or more clinical “attacks” (as described above) supported by one objective finding fulfills dissemination in time, but requires additional testing and data to fulfill dissemination in space.
  • One “attack” supported by 2 or more objective findings fulfills dissemination in space but requires additional testing to fulfill dissemination in time
  • One “attack” supported by 1 objective finding, which is suggestive of clinically isolated syndrome, does not fulfill dissemination in space or time and requires additional testing
  • Insidious neurologic presentation, which is suggestive of primary progressive MS, requires one year of disease progression and additional testing

The McDonald criteria have undergone a revision in 2017 (previous revision was in 2010).  In the revised criteria a clinically isolated syndrome no longer requires dissemination in time criteria if oligoclonal bands are found in CSF.  Also, in the revised criteria, asymptomatic lesions have diagnostic value. 

One caveat to the McDonald criteria is that they are not best utilized to differentiate MS from other neurologic conditions, but to identify which patients with clinically isolated syndrome may actually fulfill a diagnosis of MS.  In order to use the McDonald criteria, there should be no fever or infection occurring during attacks and no other leading diagnoses in the differential which better explain the patient’s clinical presentation9.

Early predictions of outcomes10

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

Environmental

  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.

REHABILITATION MANAGEMENT AND TREATMENTS

Available or current treatment guidelines

 American Academy of Neurology, the National MS Society, the 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 life11, 12.

At different disease stages

  1. New onset/acute:
    Rapid evolution of new symptoms or worsening of old symptoms characterized as exacerbations, relapses, or attacks 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.
  2. Subacute: Disease- modifying agents/Disease modifying therapies (DMA/DMT)
    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. 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. Although not changed in years they continue to include: 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. Decision is largely based on provider and patient preference and the side effect profile. Natalizumab is reserved for patients who have inadequate response to other MS therapies, and Mitoxantrone for select patients with worsening disease13, 14.

    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 infections15.
  1. Chronic/stable:
    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 MS8.  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 dysfunction7.

    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 approach16. Potassium channel blocking agents such as 4 amino pyridines (Dalfampridine) are believed to improve nerve conduction and have been shown to improve strength and gait5.
  1. 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 a multimodal and multidisciplinary approach, using disease-modifying agents, and specific treatments for secondary or associated conditions such as spasticity, fatigue, depression, pain, or bladder or bowel problems. Physical and occupational therapies and other support services are also beneficial, along with effective communication and patient education interventions17.

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 include 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 progress MS), and ocrelizumab (depletes B cells and is the first treatment for primary progressive MS). Laquinimod is showing promise for reducing the number of active MRI lesions in Phase II trials13, 14.

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 13, 14.

Measurement of Treatment Outcomes

The Kurtzke Expanded Disability Status Scale (EDSS) 18 is used to measure the disability status of MS patients. The purpose was to create an objective approach to quantify the level of functioning.

Outcomes should include quantitative functional independence measure (FIM) data, as well as qualitative patient satisfaction and fulfillment with life activities and goals. As of October 2019, the IRF-PAI (Inpatient Rehabilitation Facility-Patient Assessment Instrument) has begun to use functional Quality Indicators.

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 satisfaction19.

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/EMERGING AND UNIQUE CONCEPTS AND PRACTICE

Cutting edge concepts and practice

Autologous hemopoietic stem-cell transplantation (aHSCT) is being combined with immunosuppression with chemotherapy and immune-depleting antibodies.  Atkins et.al. followed 24 patients a median of 6.7 years after this treatment. The MS activity-free survival at three years was 69.6% and rate of brain atrophy decreased. Also 35% showed sustained improvements in their expanded Disability Status Scale score. However, there was one fatality. The cost is expensive and recovery time from the process is prolonged20.

The application of anodal transcranial direct current stimulation to the contralateral primary motor cortex has been shown to improve corticospinal excitability, however the study stops short of determining if this improves function or the duration of the effect21.

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 MS22. Current research is also directed at preventing the development of new demyelinating lesions, protecting demyelinated axons from degeneration, and promoting remyelination23. 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. 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.

GAPS IN THE EVIDENCE-BASED KNOWLEDGE

Gaps in the evidence-based knowledge

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 technology22.  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. Sustainability of programs to treat and maintain health of the individuals with MS continues to be a major challenge.

REFERENCES

  1. National Multiple Sclerosis Society. Epidemiology of MS. Available at http://www.nationalmssociety.org. Accessed March 12, 2020.
  2. Grigoriadis N, van Pesch V; ParadigMS Group. A basic overview of multiple sclerosis immunopathology. Eur J Neurol. 2015 Oct;22 Suppl 2:3-13
  3. Samkoff LM, Goodman AD. Symptomatic management in multiple sclerosis. Neurol Clin. 2011; 29(2):449-63.
  4. Matsuda PN, Shumway-Cook A, Bamer AM, Johnson SL, Amtmann D, Kraft GH. Falls in multiple sclerosis. PM&R. 2011; 3(7):624-32.
  5. Jensen HB, Ravnborg M, Dalgas U, and Stenager E. 4-Aminopyridine for symptomatic treatment of multiple sclerosis: a systematic review. Ther Adv Neurol Disord. 2014 Mar; 7(2): 97–113
  6. 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.
  7. Yang CC. Bladder Management in Multiple Sclerosis. Phys Med Rehabil Clin N Am. 2013 Nov; 24(4):673-86.
  8. Goessaert AS, Everaert KC. Onabotulinum toxin A for the treatment of neurogenic detrusor overactivity due to spinal cord injury or multiple sclerosis. Expert Rev Neurother. 2012 Jul; 12 (7):763-75.
  9. Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G,et.al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018 Feb; 17(2):162-173.
  10. Swanton, S, Kryshani F, Miller D. (2016) Early prognosis of multiple sclerosis. D.S. Goodin (Ed.) Multiple Sclerosis and Related Disorders: Handbook of Clinical Neurology, Vol.122, 3rd series (pp. 371-391). Amsterdam, The Netherlands. Elsevier B. V.
  11. American Academy of Neurology. Guidelines. Multiple sclerosis. Available at https://www.aan.com/Guidelines/home/ByTopic?topicId=18. Accessed May 9, 2020.
  12. The Consortium of Multiple Sclerosis Centers. Practice Guidelines. Available at https://www.mscare.org/page/practice_guidelines. Accessed May 9, 2020.
  13. American Academy of Neurology. Practice Guideline Systematic Review Summary: Disease-Modifiying Therapies for Adults with Multiple Sclerosis (April 2018). Available at https://www.aan.com/Guidelines/home/GuidelineDetail/899. Accessed May 9, 2020.
  14. Rae-Grant, A, Day GS, Marrie RA, Rabinstein A, et.al. Practice guideline recommendations summary: disease-modifying therapies for adults with multiple sclerosis. Neurology 2018; 90 (17).
  15. Disease Modifying Agents for Multiple Sclerosis. National MS Society.  http://www.nationalmssociety.org/nationalmssociety/media/msnationalfiles/brochures/brochure-the-ms-disease-modifying-medications.pdf. Updated April, 2020.
  16. Otero-Romero S, Sastre-Garriga J, Comi G, Hartung HP, Soelberg Sørensen P, Thompson AJ, Vermersch P, Gold R, Montalban X. Pharmacological management of spasticity in multiple sclerosis: Systematic review and consensus paper. Mult Scler. 2016 Oct; 22(11):1386-1396.
  17. Toosy A, Ciccarelli O, Thompson A. (2016) Symptomatic treatment and management of multiple sclerosis. D.S. Goodin (Ed.) Multiple Sclerosis and Related Disorders: Handbook of Clinical Neurology, Vol.122, 3rd series (pp. 513-562). Amsterdam, The Netherlands. Elsevier B. V.
  18. Kurtzke JF. Rating Neurologic Impairment in Multiple Sclerosis an Expanded Disability Status Scale (EDSS). Neurology. 1983, 33: 1444
  19. National MS Society. Clinical Study Measures. Available at https://www.nationalmssociety.org/For-Professionals/Researchers/Resources-for-Researchers/Clinical-Study-Measures. Accessed May 9, 2020.
  20. Atkin HL, Bowman M, Allan, D, Anstee G, et.al. Immunoablation and autologous haematopoietic stem-cell transplantation for aggressive multiple sclerosis: a multi-centre single-group phase 2 trial. Lancet 2016; 188: S76-85. 
  21. Cupyers K, Leenus DJF, Van Wijmeersch B, Thijs H, et.al. Anodal tDCS increased corticospinal output and projections strength in multiple sclerosis. Neuroscience Letters 2013; 554: 151-155.
  22. Ntranos A, Lublin F. Diagnostic Criteria, Classification and Treatment Goals in Multiple Sclerosis: The Chronicles of Time and Space. Curr Neurol Neurosci Rep. 2016 Oct; 16(10):90.
  23. Kremer, D; Küry Patrick and Dutta, R: Promoting remyelination in multiple sclerosis: current drugs and future prospects. Mult Scler. 2015 Apr; 21(5):541-9.

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

Author Disclosure

Jean L Nickels MD
Nothing to Disclose

Sara Z Salim MD
Nothing to Disclose

K. Rao Poduri, MD, FAAPMR
Nothing to Disclose