NORD gratefully acknowledges Robert P Lisak, MD, FRCP (E), FAAN, FANA, Parker Webber Chair in Neurology, Professor of Neurology, Professor of Immunology/ Microbiology/Biochemistry, Wayne State University School of Medicine; June Halper, MSN, APN-C, MSCN, FAAN, Chief Executive Officer, Consortium of Multiple Sclerosis Centers; and the Multiple Sclerosis Coalition, for their assistance in the preparation of this report.
The symptoms of multiple sclerosis may vary greatly. Some people may have visual impairment (including central visual fields), double vision (diplopia), or involuntary rhythmic movements of the eyes (nystagmus). People with multiple sclerosis may also experience impairment of speech, numbness or tingling sensation in the limbs and difficulty walking.
Dysfunction of the bladder and bowel may also be present along with sexual dysfunction. Multiple sclerosis is rarely fatal; the average life expectancy is 93 percent of that of the general population. In some cases however, changes in mobility make it necessary to use a cane, crutches, or other mobility devises. In a limited number of patients, the disease may result in life-threatening complications.
In order to illustrate by how much symptoms of MS may vary, the National Multiple Sclerosis Society (NMSS) cites a study of 697 persons with MS who experienced the following symptoms in addition to pain, depression and other emotional changes:
Ambulation problems———- 87%
Difficulty moving arms———-41%
Over the past decade it has become common for clinical researchers to classify MS into several types. These types were originally proposed to improve experimental design but are used often at this time as a guide to treatment options. MS is classified as:
Relapsing Remitting MS (RRMS)
This form of MS is characterized by clearly defined acute to subacute attacks with varying degrees of recovery often complete or nearly complete early in the disease course. Between attacks, the disease is stable. About 70-75 85% of initial diagnoses of MS are classified as RRMS. More recently the term “relapsing form of MS” has been used to identify patients with any clinical form of MS that demonstrate a clinical relapse. One could also logically posit that a new T2 lesion or a gadolinium enhancing lesion on MRI scan is the equivalent of a relapse.
Secondary-Progressive MS (SPMS)
SPMS begins as RRMS. SPMS is characterized by progressive disability at a variable rate that may be accompanied by relapses, minor remissions, and plateaus. Of the people with an initial diagnosis of RRMS, 50% or more will develop SPMS within 10 years and 90% within 25 years. It is important to remember that most of these numbers are based on studies preceding the era of disease modifying therapy.
Primary Progressive MS (PPMS)
From onset, PPMS shows steady rates of progression of disability or occasional plateaus and/or minor remissions. We now recognize that a small number of these patients may have superimposed clinical relapses and/or PPMS makes up about 15% of all MS diagnoses.
Clinical Isolated Syndrome (CIS)
Clinical isolated syndrome is the first episode of a neurologic event involving the central nervous system that is typical of multiple sclerosis. The suspicion and likelihood of an episode of CIS being the first attack increases with abnormalities on MRI of the brain and/or spinal cord.
Radiologically Isolated Syndrome (RIS)
Radiologically isolated syndrome is likely the preclinical stage of MS. It is defined as lesions typical of MS on an MRI scan done for a different reason such as headache, head injury or other reasons that are not as a result of symptoms not suggestive or typical of MS. Follow up of many of these individuals frequently demonstrates additional lesions typical of MS and/or a clinical event (CIS) and then RRMS. Some individuals go on to a clinical course of PPMS.
Tumefactive MS is a rare form of MS characterized by a tumor-like lesion and signs and symptoms similar to those of a brain tumor. Symptoms often differ from other types of MS and may include headaches, changes in thinking, confusion, speech problems, seizures, and weakness. Tumefactive MS often but not always develops into RRMS.
Pediatric MS is a rare form of MS. Approximately 3-5% of MS patients is diagnosed in childhood (under 18 years of age). It can be difficult to diagnose MS in young children because the symptoms overlap with many other conditions and the signs and symptoms can be different from adult-onset MS.
The exact cause of multiple sclerosis is not known. Nevertheless, most clinical investigators agree that MS may be the result of an abnormal immunopathologically likely autoimmune in a genetically susceptible person in response to one or more environmental factors.
Many researchers suggest that the disorder may represent an abnormal immune reaction directed against the body’s own tissues (autoimmune disorder). In autoimmune disorders, the body’s natural defenses (e.g., antibodies and inflammatory cells including lymphocytes and monocyte/macrophages) against substances that are perceived as foreign (antigens) inappropriately begin to attack healthy tissues, for unknown reasons. According to many researchers, the autoimmune process may be triggered by exposure to particular environmental agents (e.g., certain bacteria or viruses) in individuals with a genetic susceptibility for MS. Other important environmental factors seem to include vitamin D insufficiency, tobacco smoking, Research is concentrating on immune therapies designed to moderate the autoimmune attack without harming normal immune cells.
Some researchers believe that one or more different viruses may play some role in triggering the disease process in individuals with MS. Different viruses have been implicated over many years but the best evidence seems to be an association with Epstein Barr virus (EBV).
Other researchers suggest that a common bacterium may contribute to the development of MS. In one study, the cerebrospinal fluid from all 37 individuals with MS (relapsing-remitting or progressive MS) showed the presence of the bacterium that causes “walking pneumonia” (Chlamydia pneumoniae). In contrast, the study’s control group (i.e., individuals with neurologic diseases other than MS) the bacterium was present in only a small number of cases and few of the control subjects had developed antibodies against the microorganism. There has not been confirmation of these findings and it may represent an epiphenomenon.
Evidence also suggests that individuals with MS may have a genetic susceptibility for the disorder that may be determined by the “cumulative” interaction of several genes (polygenic inheritance); in addition, there may be different genetic abnormalities or mechanisms that result in susceptibility to the disease (heterogeneity). Researchers have implicated several different genes that may be associated with MS. These include certain closely linked genes (major histocompatibility complex [MHC]) that regulate production of the major histocompatibility antigens, a group of proteins that play a role in the immune system. Researchers suggest that the presence of certain genetically determined histocompatibility antigens may play some role in predisposing individuals to MS.
While conducted many years ago, two large studies reported in the New England Journal of Medicine (February 2001) failed to show any evidence of a link between vaccination and multiple sclerosis. There has been no recent evidence to link immunizations to multiple sclerosis.
The number of people with MS has been estimated to be between 300,000 and 500,000 in the US and 2.5 million people worldwide. However, this may be an underestimate because these figures are based on data collected in the 1970’s, prior to the use of MRI for diagnosis. Twice as many females as males are affected. The disorder may appear at any age, although the diagnosis is most often made between 20 and 50 years of age.
Multiple sclerosis is more common in Caucasian Americans than in Americans of African or Asian heritage, although the disease is not rate in African Americans. In a few ethnic societies (Inuits, Bantus and American Indians), multiple sclerosis is rare or absent. This may hint at a genetic link to this disorder. Multiple sclerosis seems to occur more often in the moderate regions (temperate climates).
The diagnosis MS is based on clinical expertise of a board certified neurologist. There are certain criteria observed that have evolved over time from Schumacher, to Poser, to currently McDonald. Clinicians must evaluate the characteristic age of onset, clinical pattern, history, and neurologic findings typical of MS. Criteria also require that changes in the central nervous system must be separated in space and time and not just occur one time only. Ultimately, MS is a clinical diagnosis because, while there are many laboratory tests, there is no one definitive test that firmly establishes the certainty of the disease; therefore, it is important that this diagnosis be made by an MS specialist.
Clinical features that suggest MS include the age of onset which is typically between the ages of 15 and 50 years. The less common presentation is in an older man or woman with gradual development of neurologic problems (progressive form). The more common presentation is with symptoms that are episodic and spontaneously improve (relapsing-remitting). The least common is the diagnosis in children (pediatric MS). This type of MS is becoming more widely recognized in the medical community during recent years.
The clinical profile for MS requires symptomatic disease activity over time (not occurring just once and never again) and confirmed by an objective neurologic examination. The more common symptoms are numbness, strange sensations in the body (paresthesias), pain, motor abnormalities, and visual problems. The course of the disease, once the diagnosis is established, can be categorized into relapsing-remitting (attacks and recovery), secondary progressive (relapsing MS that changes to a worsening form with little or no recovery), primary progressive (gradual worsening with no recovery), or progressive relapsing (worsening with occasional relapses). The establishment of the clinical course of MS takes time and careful monitoring before the classification can be certain.
After symptoms occur that appear to be MS, findings of the neurologic examination must establish that these changes originate in the brain, spinal cord or both. Neurologic findings cause the first note of suspicion that the problem is MS. Magnetic resonance imaging (MRI) is the major diagnostic laboratory tool that can support the diagnosis. Particular characteristics of imaging findings include multiplicity of lesions (changes in the brain), large diameter, and ovoid shape in particular locations in the brain typical of MS. If the findings are inconclusive, the person might have to undergo a lumbar puncture (spinal tap) to examine the cerebrospinal fluid (spinal fluid contents) to evaluate for immunologic patterns. Spinal fluid provides important complementary information to rule out other conditions related to infections or other diseases as well as to support the diagnosis of MS. Blood tests may be required to exclude other diagnoses.
The Revised McDonald Criteria, published in 2011 by the International Panel on the Diagnosis of Multiple Sclerosis and recently updated (2016), provide specific guidelines for using MRI, VEP and cerebrospinal fluid analysis for diagnosis (see Polman, et al. 2011 in References).
Although multiple sclerosis (MS) has no known prevention or cure, there are treatments available to manage symptoms, alter the course of the disease, and help with exacerbations (relapses or flare-ups). Standard pain medications are not particularly effective for pain in MS, which are of several types including stiffness, spasmodic and neurogenic pain. Antispasmodics are used to treat spasmodic pain and neurogenic pain is usually treated by anticonvulsants and/or antidepressants. Trigeminal neuralgia is treated with anti-convulsants such as carbamezapine, gabapentin, pregabalin, topriamate and phenytoin. Recurrent attacks and relapses (exacerbations) are commonly treated with corticosteroids to reduce the inflammation in the central nervous system that damages the myelin and slows or blocks the transmission of nerve impulses. These drugs do not slow down, inhibit future relapses or stop the progression of this disorder. Physical therapy and exercise programs (especially aquatic or water therapy) are of value in most patients.
The symptoms of MS can be classified as primary (directly due to the disease itself), secondary (due to inadequate management of primary symptoms), and tertiary (those that result from complications of the disease). For example, if a person has bladder problems that are uncontrolled, s/he can have infections and become socially isolated. S/he can stop driving or working due to this uncontrolled problem.
Symptoms of MS can be subtle and mild (numbness, tingling) or severe (inability to walk or move) and can vary from time to time and from person to person. Therefore, treatment must be individualized to each person and dynamic, to address ever-changing problems related to the disease. Frequently people with MS require a team approach to manage their disease along with medications, rehabilitation, counseling, and educational services.
Disease-modifying medications help to reduce the frequency and severity of attacks, reduce the accumulation of damaged or active disease areas (lesions) in the brain and spinal cord, and appear to slow down the progression of disability. It is believed that these drugs are most effective when started early, before the disease progresses further. The following consensus paper by the Multiple Sclerosis Coalition discusses disease-modifying drugs that have been approved by the FDA:
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Lisak, RP and Kira, J-I , “Multiple Sclerosis,” in International Neurology, Lisak, RP, Truong, DD, Carroll, WM, Bhidayasiri, R (eds); Chapter 89; pp351-364, Wiley Blackwell, Oxford, UK, 2016.
Hopkins, SE, Hacohen, Y, Narula, S, Banwell, BL, “Multiple Sclerosis in children”, in International Neurology, Lisak, RP, Truing, DD, Carroll, WM, Bhidayasiri, R (eds), Chapter 90, pp361-364, Wiley Blackwell, Oxford, UK, 2016.
Oh, J, Calabresi, PA. Disease Modifying Therapies in Relapsing Multiple Sclerosis. In: Rae-Grant, Fox & Bethoux Multiple Sclerosis and Related Disorders Clinical Guide to Diagnosis, Medical Management and Rehabilitation. New York: Demos Health, 2013.
Cross AH, Naismith RT. Established and novel disease-modifying treatments in multiple sclerosis. J Intern Med. 2014;275(4):350-363. https://www.ncbi.nlm.nih.gov/pubmed/24444048
Fragoso YD, Adoni T, Anacleto A, et al. Recommendations on diagnosis and treatment of depression in patients with multiple sclerosis. Pract Neurol. 2014;14(4):206-209. https://www.ncbi.nlm.nih.gov/pubmed/24501169
Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83(3):278-286. https://www.ncbi.nlm.nih.gov/pubmed/24871874
Achiron A, Chapman J, Magalashvili D, et al. Modeling of cognitive impairment by disease duration in multiple sclerosis: a cross-sectional study. PloS One. 2013;8(8):e71058. https://www.ncbi.nlm.nih.gov/pubmed/23936485
Menon S, Shirani A, Zhao Y, et al. Characterising aggressive multiple sclerosis. J Neurol Neurosurg Psychiatry. 2013;84(11):1192-1198. https://www.ncbi.nlm.nih.gov/pubmed/23744892
Giesser BS. Diagnosis of multiple sclerosis. Neurol Clin. 2011;29(2):381-388. https://www.ncbi.nlm.nih.gov/pubmed/21439447
Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria. Ann Neurol. 2011 Feb; 69(2):292–302. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084507/
Sormani MP, Li DK, Bruzzi P, et al. Combined MRI lesions and relapses as a surrogate for disability in multiple sclerosis. Neurology. 2011;77(18):1684-1690. https://www.ncbi.nlm.nih.gov/pubmed/21975200
Tarrants M, Oleen-Burkey M, Castelli-Haley J, Lage MJ. The impact of comorbid depression on adherence to therapy for multiple sclerosis. Mult Scler Int. 2011;2011:271321. https://www.hindawi.com/journals/msi/2011/271321/
Gold R, Wolinsky JS, Amato MP, Comi G. Evolving expectations around early management of multiple sclerosis. Ther Adv Neurol Disord. 2010;3(6):351-367. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3002639/
Patti F. Optimizing the benefit of multiple sclerosis therapy: the importance of treatment adherence. Patient Prefer Adherence. 2010;4:1-9. https://www.ncbi.nlm.nih.gov/pubmed/20165593
Langdon D, Benedict R, Wicklein EM, Fredrikson S. Report of Cognitive Difficulties by Clinically Isolated Syndrome Patients and Careers: The Multiple Sclerosis Neuropsychological Questionnaire Data from the CogniCIS Baseline Cohort; Abstract P406. Dusseldorf: 25th Congress of the European Committee for the Treatment and Research in Multiple Sclerosis (ECTRIMS); 2009.
Tremlett H, Yousefi M, Devonshire V, Rieckmann P, Zhao Y, UBC Neurologists. Impact of multiple sclerosis relapses on progression diminishes with time. Neurology. 2009;73(20):1616-1623. https://www.ncbi.nlm.nih.gov/pubmed/19890070
Amato MP, Goretti B, Ghezzi A, et al. Cognitive and psychosocial features of childhood and juvenile MS. Neurology. 2008;70(20):1891-1897. https://www.ncbi.nlm.nih.gov/pubmed/18474844
Kalb R. The emotional and psychological impact of multiple sclerosis relapses. J Neurol Sci. 2007;256 Suppl 1:S29-S33. https://www.ncbi.nlm.nih.gov/pubmed/17350045
The Use of Disease-Modifying Therapies in Multiple Sclerosis: Principles and Current Evidence. Consensus Paper by the Multiple Sclerosis Coalition. Updated July 2016. Available at: http://c.ymcdn.com/sites/www.mscare.org/resource/collection/A0711E7F-0EFA-43B2-AEB9-96ABB9D8F4E6/DMT_Consensus_MS_Coalition092016.pdf Accessed February 28, 2017.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Multiple Sclerosis, Susceptibility to; MS. Entry No: 126200. Last Edited 10/07/2016. Available at: http://omim.org/entry/126200 Accessed February 23, 2017.
Common Questions.Multiple Sclerosis Foundation. Reviewed: November 2016. Available at: https://msfocus.org/Get-Educated/Common-Questions. Accessed February 23, 2017.
Tumefactive multiple sclerosis. Genetic and Rare Diseases Information Center. Last updated: 5/18/2016. https://rarediseases.info.nih.gov/diseases/5885/tumefactive-multiple-sclerosis. Accessed February 23, 2017.
Schreiner TL. Pediatric Multiple Sclerosis. Medscape. Updated: Dec 03, 2015. http://emedicine.medscape.com/article/2091406-overview. Accessed February 23, 2017.
The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.
The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.
National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100