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| {{Infobox_Disease | | __NOTOC__ |
| | Name = Multiple sclerosis
| | {| class="infobox" style="float:right;" |
| | Image = MRI_of_Multiple_sclerosis.jpg
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| | Caption = [[MRI]] FLAIR sequence showing four bright spots (plaques) where multiple sclerosis has damaged myelin in the brain
| | | [[File:Siren.gif|30px|link=Multiple sclerosis resident survival guide]]|| <br> || <br> |
| | DiseasesDB = 8412
| | | [[Multiple sclerosis resident survival guide|'''Resident'''<br>'''Survival'''<br>'''Guide''']] |
| | ICD10 = {{ICD10|G|35||g|35}}
| | |} |
| | ICD9 = {{ICD9|340}}
| | '''For patient information click [[{{PAGENAME}} (patient information)|here]]''' |
| | ICDO =
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| | OMIM = 126200
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| | MedlinePlus = 000737
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| | eMedicineSubj = neuro
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| | eMedicineTopic = 228
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| | eMedicine_mult = {{eMedicine2|oph|179}} {{eMedicine2|emerg|321}} {{eMedicine2|pmr|82}} {{eMedicine2|radio|461}}
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| | MeshID = D009103
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| }}
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| {{CMG}}
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| {{Editor Help}} | | {{CMG}}; {{AE}} {{Fs}} |
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| '''Multiple sclerosis''' (abbreviated '''[[MS]]''', formerly known as '''disseminated sclerosis''' or '''encephalomyelitis disseminata''') is a [[chronic (medicine)|chronic]], [[Inflammation|inflammatory]], [[demyelinating disease]] that affects the [[Central Nervous System|central nervous system (CNS)]]. Disease onset usually occurs in young adults, is more common in women and the disease has a [[prevalence]] that ranges between 2 and 150 per 100,000 depending on the country or specific population.<ref name="pmid11603614">{{cite journal |author=Rosati G |title=The prevalence of multiple sclerosis in the world: an update |journal=Neurol. Sci. |volume=22 |issue=2 |pages=117–39 |year=2001 |pmid=11603614 |doi=}}</ref> MS was first described in 1868 by [[Jean-Martin Charcot]].
| | {{SK}} Disseminated sclerosis; encephalomyelitis disseminata; Ms; Demyelinating Autoimmune Disease; multipel sclerosis; multiple scelerosis; multipel scelerosis |
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| MS affects the [[neuron]]s in the areas of the [[brain]] and [[spinal cord]] known as the [[white matter]]. These cells carry signals in between the [[grey matter]] areas, where the processing is done, and between these and the rest of the body. More specifically, MS destroys [[oligodendrocyte]]s which are the cells responsible for creating and maintaining a fatty layer, known as the [[myelin]] sheath, which helps the neurons carry electrical [[Signal (biology)|signal]]s. MS results in a thinning or complete loss of myelin and, less frequently, the cutting (transection) of the neuron's extensions or [[axons]]. When the myelin is lost, the neurons can no longer effectively conduct their electrical signals. The name ''multiple sclerosis'' refers to the scars (scleroses - better known as plaques or lesions) in the white matter. Loss of myelin in these lesions causes some of the symptoms that may vary widely depending upon which signals are interrupted. However, more advanced forms of [[MRI|imaging]] are now showing that much of the damage happens outside these regions. A consequence of this course of action is that almost any neurological [[symptom]] can accompany the disease.
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| Multiple sclerosis may take several forms, with new symptoms occurring either in discrete attacks (relapsing forms) or slowly accumulating over time (progressive forms). Most people are first diagnosed with relapsing-remitting MS but develop secondary-progressive MS (SPMS) after a number of years. Between attacks, symptoms may resolve completely, but permanent neurological problems often persist, especially as the disease advances.
| | {{Multiple sclerosis}} |
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| Although much is known about the mechanisms involved in the disease process, the cause remains elusive. The theory with the most adherents is that it results from attacks to the [[nervous system]] by the body's own [[immune system]]. Some believe it is a metabolically dependent disease while others think that it might be caused by a virus such as [[Epstein-Barr virus|Epstein-Barr]]. Still other people believe that its virtual absence from the tropics points to a deficiency of vitamin D during childhood.
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| The disease currently does not have a cure, but several therapies have proven helpful. The aims of treatment are returning function after an attack, preventing new attacks, and preventing disability. As with any treatment, medications have several adverse effects, and many therapies are still under investigation. At the same time different alternative treatments are pursued by many patients, despite the paucity of supporting scientific study.
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| The [[prognosis]], or expected course of the disease, for a person depends on the subtype of the disease; the characteristics of the individual, the initial symptoms; and the degree of disability the person experiences as time advances. However [[life expectancy]] of patients is nearly the same as that of the unaffected population and in many cases a normal life is possible.
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| ==Signs and symptoms==
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| MS can cause a variety of symptoms, including changes in sensation ([[hypoesthesia]]), muscle weakness, abnormal muscle spasms, or difficulty in moving; difficulties with coordination and balance ([[ataxia]]); problems in speech ([[dysarthria]]) or swallowing ([[dysphagia]]), visual problems ([[nystagmus]], [[optic neuritis]], or [[diplopia]]), [[fatigue (medical)|fatigue]] and acute or chronic [[pain and nociception|pain]] syndromes, [[Urinary bladder|bladder]] and [[bowel]] difficulties, [[cognitive]] impairment, or emotional symptomatology (mainly [[clinical depression|depression]]). [[Lhermitte's sign]] is considered a classic MS finding, but it can be seen in several other conditions as well. The main clinical measure of disability progression and severity of the symptoms is the [[Expanded Disability Status Scale]] or EDSS.<ref>{{cite journal |author=Kurtzke JF |title=Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS) |journal=Neurology |volume=33 |issue=11 |pages=1444-52 |year=1983 |pmid=6685237 |doi=}}</ref>
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| The initial attacks are often transient, mild (or asymptomatic), and self-limited. They often do not prompt a health care visit and sometimes are only identified in retrospect once the diagnosis has been made based on further attacks. The most common initial symptoms reported are: changes in [[sensation]] in the arms, legs or face (33%), complete or partial vision loss ([[optic neuritis]]) (16%), weakness (13%), [[diplopia|double vision]] (7%), unsteadiness when walking (5%), and balance problems (3%); but many rare initial symptoms have been reported such as [[aphasia]] or [[psychosis]].<ref>{{cite journal |author=Navarro S, Mondéjar-Marín B, Pedrosa-Guerrero A, Pérez-Molina I, Garrido-Robres J, Alvarez-Tejerina A |title=[Aphasia and parietal syndrome as the presenting symptoms of a demyelinating disease with pseudotumoral lesions] |journal=Rev Neurol |volume=41 |issue=10 |pages=601-3 |year= |pmid=16288423}}</ref><ref>{{cite journal |author=Jongen P |title=Psychiatric onset of multiple sclerosis |journal=J Neurol Sci |volume=245 |issue=1–2 |pages=59–62 |year=2006 |pmid=16631798}}</ref> Fifteen percent of individuals have multiple symptoms when they first seek medical attention.<ref>Paty D, Studney D, Redekop K, Lublin F. ''MS COSTAR: a computerized patient record adapted for clinical research purposes.'' Ann Neurol 1994;36 Suppl:S134-5. PMID 8017875</ref> For some people the initial MS attack is preceded by [[infection]], [[Physical trauma|trauma]], or strenuous physical effort.
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| ==Diagnosis== | | == [[Multiple sclerosis overview|Overview]] == |
| Multiple sclerosis is difficult to [[diagnose]] in its early stages. In fact, a definite diagnosis cannot be made until other disease processes (differential diagnoses) have been ruled out and, in the case of relapsing-remitting MS, there is evidence of at least two [[anatomy|anatomically]] separate demyelinating events separated by at least thirty days. In the case of primary progressive, a slow progression of signs and symptoms over at least 6 months is required. | |
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| Historically, different criteria were used and the Schumacher and Poser criteria were both popular. Currently, the [[McDonald criteria]] represent international efforts to standardize the diagnosis of MS using clinical, laboratory and radiologic data.<ref>McDonald WI; Compston A; Edan G; Goodkin D; Hartung HP; Lublin FD; McFarland HF; Paty DW; Polman CH; Reingold SC; Sandberg-Wollheim M; Sibley W; Thompson A; van den Noort S; Weinshenker BY; Wolinsky JS. ''Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis.'' Ann Neurol 2001 Jul;50(1):121-7 PMID 11456302</ref>
| | == [[Multiple sclerosis historical perspective|Historical Perspective]] == |
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| | == [[Multiple sclerosis classification|Classification]] == |
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| * Clinical data alone may be sufficient for a diagnosis of MS. If an individual has suffered two separate episodes of neurologic symptoms characteristic of MS, and the individual also has consistent abnormalities on [[physical examination]], a diagnosis of MS can be made with no further testing. Since some people with MS seek medical attention after only one attack, other testing may hasten the diagnosis and allow earlier initiation of therapy.
| | == [[Multiple sclerosis pathophysiology|Pathophysiology]] == |
| * [[Magnetic resonance imaging]] (MRI) of the brain and spine is often used during the diagnostic process. MRI shows areas of demyelination ([[lesion]]s) as bright spots on the image. A substance, called [[Gadolinium]], can be injected into the spinal column to highlight active plaques and, by elimination, demonstrate the existence of historical lesions not associated with clinical symptoms. This can provide the evidence of chronic disease needed for a definitive diagnosis of MS.
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| * Testing of [[cerebrospinal fluid]] (CSF) can provide evidence of chronic [[inflammation]] of the central nervous system. The CSF is tested for [[oligoclonal band]]s, which are [[immunoglobulin]]s found in 85% to 95% of people with definite MS (but also found in people with other diseases).<ref>Rudick, RA, Whitaker, JN. ''Cerebrospinal fluid tests for multiple sclerosis.'' In Scheinberg, P (Ed). Neurology/neurosurgery update series, Vol. 7, CPEC. Princeton, NJ 1987</ref> Combined with MRI and clinical data, the presence of oligoclonal bands can help make a definite diagnosis of MS. [[Lumbar puncture]] is the procedure used to collect a sample of CSF.
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| * The brain of a person with MS often responds less actively to stimulation of the [[optic nerve]] and [[sensory neuron|sensory nerves]]. These brain responses can be examined using [[visual evoked potential]]s (VEPs) and [[Sensory evoked potentials|somatosensory evoked potentials]] (SEPs). Decreased activity on either test can reveal demyelination which may be otherwise asymptomatic. Along with other data, these exams can help find the widespread nerve involvement required for a definite diagnosis of MS.<ref>Gronseth GS; Ashman EJ. ''Practice parameter: the usefulness of evoked potentials in identifying clinically silent lesions in patients with suspected multiple sclerosis (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology.'' Neurology 2000 May 9;54(9):1720–5. PMID 10802774</ref>
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| Another test, which may become important in the future, is measurement of [[antibody|antibodies]] against myelin [[protein]]s such as [[myelin oligodendrocyte glycoprotein]] (MOG) and [[myelin basic protein]] (MBP). As of 2007, however, there is no established role for these tests in diagnosing MS. [[Optical coherence tomography]] of the [[eye]]'s [[retina]] is also under study<ref>{{cite journal |author=Gordon-Lipkin E, Chodkowski B, Reich DS ''et al'' |year=2007 |month=Oct |title=Retinal nerve fiber layer is associated with brain atrophy in multiple sclerosis. |journal=Neurology |volume=69 |issue=16 |pages=1603-09 |id=PMID 17938370}}</ref>, mainly as a tool to measure response to medication and axonal degeneration<ref>{{cite journal |author=Albrecht P, Fröhlich R, Hartung HP, Kieseier BC, Methner A |title=Optical coherence tomography measures axonal loss in multiple sclerosis independently of optic neuritis |journal=J Neurol |volume=Online |issue= |pages= |year=2007 |pmid=17987252 |doi=10.1007/s00415-007-0538-3}}</ref>.
| | == [[Multiple sclerosis causes|Causes]] == |
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| The signs and symptoms of MS can be similar to other medical problems, such as [[Devic's disease|neuromyelitis optica]], [[stroke]], [[acute disseminated encephalomyelitis|brain inflammation]], [[infection]]s such as [[Lyme disease]] (which can produce identical MRI lesions and CSF abnormalities<ref>Garcia-Monco JC; Miro Jornet J; Fernandez Villar B; Benach JL; Guerrero Espejo A; Berciano JA. ''[Multiple sclerosis or Lyme disease? a diagnosis problem of exclusion]'' Med Clin (Barc) 1990 May 12;94(18):685-8. PMID 2388492</ref><ref>Hansen K; Cruz M; Link H. ''Oligoclonal Borrelia burgdorferi-specific IgG antibodies in cerebrospinal fluid in Lyme neuroborreliosis.'' J Infect Dis 1990 Jun;161(6):1194-202. PMID 2345300</ref><ref>Schluesener HJ; Martin R; Sticht-Groh V. ''Autoimmunity in Lyme disease: molecular cloning of antigens recognized by antibodies in the cerebrospinal fluid.'' Autoimmunity 1989 2(4):323-30. PMID 2491615</ref><ref>Kohler J; Kern U; Kasper J; Rhese-Kupper B; Thoden U. ''Chronic central nervous system involvement in Lyme borreliosis'' Neurology 1988 Jun;38(6):863-7. PMID 3368066</ref>),
| | == [[Multiple sclerosis differential diagnosis|Differentiating Multiple sclerosis from other Diseases]] == |
| [[tumor]]s, and other autoimmune problems, such as [[lupus erythematosus|lupus]]. Additional testing may be needed to help distinguish MS from these other problems.
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| ==== MRI and CT ==== | | == [[Multiple sclerosis epidemiology and demographics|Epidemiology and Demographics]] == |
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| <gallery heights="175" widths="175">
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| Image:Monthly multiple sclerosis MRI.gif|T1-weighted [[Magnetic resonance imaging|MRI]] scans (post-contrast) of same brain slice at monthly intervals. Bright spots indicate active lesions.
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| Image:Multiple Sclerosis2.jpg|Multiple Sclerosis
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| </gallery>
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| </div>
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| ==Disease course and clinical subtypes== | | == [[Multiple sclerosis risk factors|Risk Factors]] == |
| [[Image:Types of MS-2.jpg|thumb|400px|right|Graph representing the different types of multiple sclerosis]] | |
| The course of MS is difficult to predict, and the disease may at times either lie dormant or progress steadily. Several subtypes, or patterns of progression, have been described. Subtypes use the past course of the disease in an attempt to predict the future course. Subtypes are important not only for [[prognosis]] but also for therapeutic decisions. In 1996 the United States [[National Multiple Sclerosis Society]] standardized the following four subtype definitions:<ref>Lublin FD; Reingold SC. ''Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis.'' Neurology 1996 Apr;46(4):907-11. PMID 8780061</ref>
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| ;Relapsing-remitting
| | == [[Multiple sclerosis screening|Screening]] == |
| :Relapsing-remitting describes the initial course of 85% to 90% of individuals with MS. This subtype is characterized by unpredictable attacks ([[relapse]]s) followed by periods of months to years of relative quiet ([[remission (medicine)|remission]]) with no new signs of disease activity. Deficits suffered during the attacks may either resolve or may be permanent. When deficits always resolve between attacks, this is referred to as "[[benign]]" MS.
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| ;Secondary progressive
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| :Secondary progressive describes around 80% of those with initial relapsing-remitting MS, who then begin to have neurologic decline between their acute attacks without any definite periods of remission. This decline may include new neurologic symptoms, worsening [[neurocognitive|cognitive]] function, or other deficits. Secondary progressive is the most common type of MS and causes the greatest amount of [[disability]].
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| ;Primary progressive
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| :Primary progressive describes the approximately 10% of individuals who never have remission after their initial MS symptoms. Decline occurs continuously without clear attacks. The primary progressive subtype tends to affect people who are older at disease onset.
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| ;Progressive relapsing
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| :Progressive relapsing describes those individuals who, from the onset of their MS, have a steady neurologic decline but also suffer superimposed attacks; and is the least common of all subtypes
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| Nevertheless the earliest clinical presentation of relapsing-remitting MS (RRMS) is the '''clinically isolated syndrome (CIS)'''. In CIS, there is a subacute attack suggestive of [[demyelination]] but the person does not fullfill the [[McDonald criteria|criteria]] for multiple sclerosis.<ref name="pmid15847841">{{cite journal |author=Miller D, Barkhof F, Montalban X, Thompson A, Filippi M |title=Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis |journal=Lancet neurology |volume=4 |issue=5 |pages=281–8 |year=2005 |pmid=15847841 |doi=10.1016/S1474-4422(05)70071-5}}</ref> Several studies have shown that starting treatment with [[interferon]]s during the initial attack can decrease the chance that a patient will develop MS.<ref>Jacobs LD; Beck RW; Simon JH; Kinkel RP; Brownscheidle CM; Murray TJ; Simonian NA; Slasor PJ; Sandrock AW. ''Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group.'' N Engl J Med 2000 September 28;343(13):898–904. PMID 11006365</ref><ref>Comi G; Filippi M; Barkhof F; Durelli L; Edan G; Fernandez O; Hartung H; Seeldrayers P; Sorensen PS; Rovaris M; Martinelli V; Hommes OR.''Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study.'' Lancet 2001 May 19;357(9268):1576–82. PMID 11377645</ref><ref name="pmid17679016">{{cite journal |author=Kappos L, Freedman MS, Polman CH, ''et al'' |title=Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study |journal=Lancet |volume=370 |issue=9585 |pages=389–97 |year=2007 |pmid=17679016 |doi=10.1016/S0140-6736(07)61194-5}}</ref>
| | == [[Multiple sclerosis natural history, complications and prognosis|Natural History, Complications and Prognosis]] == |
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| Special cases of the disease with non-standard behavior have also been described although many researchers believe they are different diseases. These cases are sometimes referred to as [[borderline forms of multiple sclerosis]] and are [[Devic's disease|Neuromyelitis optica]] (NMO), [[Balo concentric sclerosis]], [[Schilder disease|Schilder's diffuse sclerosis]] and [[Marburg multiple sclerosis]].<ref>Borderline forms of MS, Fontaine, B., Federation de Neurologie, INSERM U546, Groupe Hospitalier, Faculte de Medecine Pitie-Salpetriere, Paris [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=11787357&query_hl=15&itool=pubmed_docsum]</ref>
| | == Diagnosis == |
| | [[Multiple sclerosis diagnostic study of choice|Diagnostic study of choice]] | [[Multiple sclerosis history and symptoms|History and Symptoms]] | [[Multiple sclerosis physical examination|Physical Examination]] | [[Multiple sclerosis laboratory findings|Laboratory Findings]] | [[Multiple sclerosis electrocardiogram|Electrocardiogram]] | [[Multiple sclerosis x ray|X-Ray Findings]] | [[Multiple sclerosis echocardiography or ultrasound|Echocardiography and Ultrasound]] | [[Multiple sclerosis ct scan|CT-Scan Findings]] | [[Multiple sclerosis MRI|MRI Findings]] | [[Multiple sclerosis other imaging findings|Other Imaging Findings]] | [[Multiple sclerosis other diagnostic studies|Other Diagnostic Studies]] |
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| ==Factors triggering a relapse== | | == Treatment == |
| Multiple sclerosis relapses are often unpredictable and can occur without warning with no obvious inciting factors. Some attacks, however, are preceded by common triggers. In general, relapses occur more frequently during spring and summer than during autumn and winter. Infections, such as the [[common cold]], [[influenza]], and [[gastroenteritis]], increase the risk for a relapse.<ref>{{cite journal |author=Confavreux C |title=Infections and the risk of relapse in multiple sclerosis |journal=Brain |volume=125 |issue=Pt 5 |pages=933-4 |year=2002 |pmid=11960883 |doi=}}</ref>
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| [[Stress (medicine)|Emotional]] and physical stress may also trigger an attack,<ref>{{cite journal |author=Buljevac D, Hop WC, Reedeker W, ''et al'' |title=Self reported stressful life events and exacerbations in multiple sclerosis: prospective study |journal=BMJ |volume=327 |issue=7416 |pages=646 |year=2003 |pmid=14500435 |doi=10.1136/bmj.327.7416.646}}</ref><ref>{{cite journal |author=Brown RF, Tennant CC, Sharrock M, Hodgkinson S, Dunn SM, Pollard JD |title=Relationship between stress and relapse in multiple sclerosis: Part I. Important features |journal=Mult. Scler. |volume=12 |issue=4 |pages=453-64 |year=2006 |pmid=16900759 |doi=}}</ref><ref>{{cite journal |author=Brown RF, Tennant CC, Sharrock M, Hodgkinson S, Dunn SM, Pollard JD |title=Relationship between stress and relapse in multiple sclerosis: Part II. Direct and indirect relationships |journal=Mult. Scler. |volume=12 |issue=4 |pages=465-75 |year=2006 |pmid=16900760 |doi=}}</ref> as can severe illness of any kind.
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| Statistically, there is no good evidence that either [[Physical trauma|trauma]] or [[surgery]] trigger relapses.<ref>{{cite journal |author=Martinelli V |title=Trauma, stress and multiple sclerosis |journal=Neurol. Sci. |volume=21 |issue=4 suppl 2 |pages=S849-52 |year=2000 |pmid= 11205361 |doi=}}</ref> People with MS can participate in sports, but they should probably avoid extremely strenuous exertion, such as marathon running. Heat can transiently increase symptoms, which is known as [[Uhthoff's phenomenon]]. This is why some people with MS avoid saunas or even hot showers.
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| However, heat is not an established trigger of relapses.<ref> {{cite journal |author=Tataru N, Vidal C, Decavel P, Berger E, Rumbach L |title=Limited impact of the summer heat wave in France (2003) on hospital admissions and relapses for multiple sclerosis |journal=Neuroepidemiology |volume=27 |issue=1 |pages=28-32 |year=2006 |pmid=16804331 |doi=10.1159/000094233}}</ref>
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| [[Pregnancy]] can directly affect the susceptibility for relapse. The last three months of pregnancy offer a natural protection against relapses. However, during the first few months after delivery, the risk for a relapse is increased 20%–40%. Pregnancy does not seem to influence long-term disability. Children born to mothers with MS are not at increased risk for [[congenital disorder|birth defect]]s or other problems.<ref>{{cite journal |author=Worthington J, Jones R, Crawford M, Forti A |title=Pregnancy and multiple sclerosis--a 3-year prospective study |journal=J. Neurol. |volume=241 |issue=4 |pages=228-33 |year=1994 |pmid=8195822 |doi=}}</ref> | | [[Multiple sclerosis medical therapy|Medical Therapy]] | [[Multiple sclerosis surgery|Surgery]] | [[Multiple sclerosis alternative therapies|Alternative Therapies]] | [[Multiple sclerosis primary prevention|Primary Prevention]] | [[Multiple sclerosis secondary prevention|Secondary Prevention]] | [[Multiple sclerosis tertiary prevention|Tertiary Prevention]] | [[Multiple sclerosis cost-effectiveness of therapy|Cost-effectiveness of Therapy]] | [[Multiple sclerosis future or investigational therapies|Future or Investigational Therapies]] |
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| Many potential triggers have been examined and found not to influence relapse rates in MS. Influenza [[vaccination]] is safe, does not trigger relapses, and can therefore be recommended for people with MS. There is also no evidence that vaccines for [[hepatitis B]], [[varicella]], [[tetanus]], or [[Bacille Calmette-Guerin]] (BCG—immunization for [[tuberculosis]]) increases the risk for relapse.<ref>{{cite journal |author=Confavreux C, Suissa S, Saddier P, Bourdès V, Vukusic S |title=Vaccinations and the risk of relapse in multiple sclerosis. Vaccines in Multiple Sclerosis Study Group |journal=N. Engl. J. Med. |volume=344 |issue=5 |pages=319-26 |year=2001 |pmid=11172162 |doi=}}</ref>
| | == Case Studies == |
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| ==Pathophysiology==
| | [[Multiple sclerosis case study one|Case #1]] |
| {{Main|Pathophysiology of multiple sclerosis}}
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| Although much is known about how multiple sclerosis causes damage, the reasons why multiple sclerosis occurs are not known.
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| Multiple sclerosis is a disease in which the [[myelin]] (a [[lipid|fatty]] substance which covers the [[axon]]s of [[neuron|nerve cells]]) degenerates. According to the view of most researchers, a special subset of [[lymphocyte]]s, called [[T cell]]s, plays a key role in the development of MS.
| | ==Related Chapters== |
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| According to a strictly immunological explanation of MS, the inflammatory process is triggered by the T cells. T cells gain entry into the brain via the [[blood-brain barrier]] (a capillary system that should prevent entrance of T-cells into the nervous system). The blood brain barrier is normally not permeable to these types of cells, unless triggered by either infection or a virus, where the integrity of the [[tight junction]]s forming the blood-brain barrier is decreased. When the blood brain barrier regains its integrity (usually after infection or virus has cleared) the T cells are trapped inside the brain. These [[lymphocyte]]s recognize myelin as foreign and attack it as if it were an invading virus. That triggers [[inflammation|inflammatory]] processes, stimulating other immune cells and soluble factors like [[cytokine]]s and [[antibody|antibodies]]. Leaks form in the [[blood-brain barrier]]. These leaks, in turn, cause a number of other damaging effects such as [[edema|swelling]], activation of [[macrophages]], and more activation of cytokines and other destructive [[protein]]s such as [[matrix metalloproteinase]]s. A deficiency of [[uric acid]] has been implicated in this process.<ref>{{cite journal |author=Rentzos M, Nikolaou C, Anagnostouli M, Rombos A, Tsakanikas K, Economou M, Dimitrakopoulos A, Karouli M, Vassilopoulos D |title=Serum uric acid and multiple sclerosis |journal=Clinical neurology and neurosurgery |volume=108 |issue=6 |pages=527-31 |year=2006 |pmid=16202511}}</ref>
| | * [[MS Bike Tour]]. |
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| It is known that a repair process, called remyelination, takes place in early phases of the disease, but the [[oligodendrocyte]]s that originally formed a [[myelin sheath]] cannot completely rebuild a destroyed myelin sheath. The newly-formed myelin sheaths are thinner and often not as effective as the original ones. Repeated attacks lead to successively fewer effective remyelinations, until a scar-like plaque is built up around the damaged axons, according to [[pathophysiology of multiple sclerosis#Demyelination patterns|four different damage patterns]].<ref>Lucchinetti, C. Bruck, W. Parisi, J. Scherhauer, B. Rodriguez, M. Lassmann, H.''Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination'' Ann Neurol, 2000; 47(6):707-17. PMID 10852536</ref> The central nervous system should be able to recruit oligodendrocyte [[stem cell]]s capable of turning into mature myelinating oligodendrocytes, but it is suspected that something inhibits stem cells in affected areas.
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| The [[axon]]s themselves can also be damaged by the attacks.<ref>{{cite journal |author=Pascual AM, Martínez-Bisbal MC, Boscá I, ''et al'' |title=Axonal loss is progressive and partly dissociated from lesion load in early multiple sclerosis |journal=Neurology |volume=69 |issue=1 |pages=63-7 |year=2007 |pmid=17606882 |doi=10.1212/01.wnl.0000265054.08610.12}}</ref> Often, the brain is able to compensate for some of this damage, due to an ability called [[neuroplasticity]]. MS symptoms develop as the cumulative result of multiple [[lesion]]s in the brain and [[spinal cord]]. This is why symptoms can vary greatly between different individuals, depending on where their lesions occur.
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| ==Causes==
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| Although many risk factors for multiple sclerosis have been identified, no definitive cause has been found. MS likely occurs as a result of some combination of both environmental and [[genetics|genetic]] factors. Various theories try to combine the known data into plausible explanations. Although most accept an [[autoimmune]] explanation, several theories suggest that MS is an appropriate immune response to one or several underlying conditions (the [[etiology]] could be heterogeneous<ref>{{cite journal |author=Lassmann H |title=Experimental models of multiple sclerosis |journal=Rev. Neurol. (Paris) |volume=163 |issue=6-7 |pages=651-5 |year=2007 |pmid=17607184 |doi=}}</ref>). The need for alternative theories is supported by the poor results of present therapies, since autoimmune theory predicted greater success.<ref>
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| {{cite journal
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| | author=Peter Behan and Abhijit Chaudhuri
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| | title=The pathogenesis of multiple sclerosis revisited
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| | journal=J R Coll Physicians Edinb
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| | year=2002 | pages=244–265 | volume=32 | url=http://www.rcpe.ac.uk/publications/articles/journal_32_4/3_pathogenesis_of_MS.pdf}}</ref><ref>{{cite journal |author=Chaudhuri A, Behan P |title=Multiple sclerosis is not an autoimmune disease |journal=Arch. Neurol. |volume=61 |issue=10 |pages=1610–2 |year=2004 |pmid=15477520}}</ref><ref>{{cite journal |author=Altmann D |title=Evaluating the evidence for multiple sclerosis as an autoimmune disease |journal=Arch. Neurol. |volume=62 |issue=4 |pages=688; author reply 688-9 |year=2005 |pmid=15824275}}</ref>
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| ===Environmental===
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| The most popular hypothesis is that a [[virus|viral]] infection or [[retrovirus|retroviral]] reactivation primes a susceptible immune system for an abnormal reaction later in life. On a [[molecule|molecular]] level, this might occur if there is a structural similarity between the infectious virus and some component of the central nervous system, leading to eventual confusion in the [[immune system]].
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| Since MS seems to be more common in people who live farther from the equator, another theory proposes that decreased sunlight exposure<ref>{{cite journal |author=van der Mei IA, Ponsonby AL, Dwyer T, ''et al'' |title=Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case-control study |journal=BMJ |volume=327 |issue=7410 |pages=316 |year=2003 |pmid=12907484 |doi=10.1136/bmj.327.7410.316}}</ref> and possibly decreased [[vitamin D]] production may help cause MS. This theory is bolstered by recent research into the [[biochemistry]] of vitamin D, which has shown that it is an important immune system regulator. A large, 2006 study by the Harvard School of Public Health, reported evidence of a link between Vitamin D deficiency and the onset of multiple sclerosis.<ref>{{cite journal |author=Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A |title=Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis |journal=JAMA |volume=296 |issue=23 |pages=2832-8 |year=2006 |pmid=17179460 |doi=10.1001/jama.296.23.2832}}</ref> Other data comes from a 2007 study which concluded that sun exposure during childhood reduces the risk of suffering MS, while controlling for genetic factors.<ref>[http://www.neurology.org/cgi/content/abstract/69/4/381?etoc Childhood sun exposure influences risk of multiple sclerosis in monozygotic twins.] Talat Islam, MBBS, PhD, W. James Gauderman, PhD, Wendy Cozen, DO, MPH and Thomas M. Mack, MD, MPH. ''Neurology'' 2007;69:381-388 </ref><ref>[http://news.bbc.co.uk/1/hi/health/6906712.stm Sunshine 'protective' against MS]. BBC News, 28 July 2007, 23:40 </ref>
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| Other theories, noting that MS is less common in children with siblings, suggest that less exposure to illness in childhood leads to an immune system which is not primed to fight infection and is thus more likely to attack the body. One explanation for this would be an imbalance between the Th1 type of [[T helper cell|helper T-cells]], which fight infection, and the Th2 type, which are more active in [[allergy]] and more likely to attack the body.
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| Other theories describe MS as an immune response to a chronic infection. The association of MS with the [[Epstein-Barr virus]] suggests a potential viral contribution in at least some individuals.<ref>{{cite journal |author=Levin LI, Munger KL, Rubertone MV, ''et al'' |title=Temporal relationship between elevation of epstein-barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis |journal=JAMA |volume=293 |issue=20 |pages=2496-500 |year=2005 |pmid=15914750 |doi=10.1001/jama.293.20.2496}}</ref> Still others believe that MS may sometimes result from a chronic infection with [[spirochetal]] bacteria, a hypothesis supported by research in which cystic forms were isolated from the cerebrospinal fluid of all MS patients in a small study.<ref>{{cite journal |author=Brorson O, Brorson SH, Henriksen TH, Skogen PR, Schøyen R |title=Association between multiple sclerosis and cystic structures in cerebrospinal fluid |journal=Infection |volume=29 |issue=6 |pages=315-9 |year=2001 |pmid=11787831 |doi=}}</ref> When the cysts were cultured, propagating spirochetes emerged. Another bacterium that has been implicated in MS is ''[[Chlamydophila pneumoniae]]''; it or its DNA has been found in the cerebrospinal fluid of MS patients by several research laboratories, with one study finding that the [[oligoclonal bands]] of 14 of the 17 MS patients studied consisted largely of antibodies to Chlamydophila antigens.<ref>{{cite journal |author=Yao SY, Stratton CW, Mitchell WM, Sriram S |title=CSF oligoclonal bands in MS include antibodies against Chlamydophila antigens |journal=Neurology |volume=56 |issue=9 |pages=1168-76 |year=2001 |pmid=11342681 |doi=}}</ref>
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| Severe stress may also be a factor—a large study in Denmark found that parents who had lost a child unexpectedly were 50% more likely to develop MS than parents who had not.<ref>{{cite journal | author = Li J, Johansen C, Bronnum-Hansen H, Stenager E, Koch-Henriksen N, Olsen J | title = The risk of multiple sclerosis in bereaved parents: A nationwide cohort study in Denmark. | journal = Neurology | volume = 62 | issue = 5 | pages = 726-9 | year = 2004 | pmid = 15007121}}</ref> [[Tobacco smoking|Smoking]] has also been shown to be an independent risk factor for developing MS.<ref>{{cite journal |author=Franklin GM, Nelson L |title=Environmental risk factors in multiple sclerosis: causes, triggers, and patient autonomy |journal=Neurology |volume=61 |issue=8 |pages=1032-4 |year=2003 |pmid=14581658 |doi=}}</ref>
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| ===Genetic===
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| MS is not considered a [[hereditary]] disease. However, increasing scientific evidence suggests that genetics may play a role in determining a person's susceptibility to MS:
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| Some populations, such as the Roma, Inuit, and Bantus, rarely if ever get MS. The indigenous peoples of the Americas and Asians have very low incidence rates.
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| In the population at large, the chance of developing MS is less than a tenth of one percent. However, if one person in a family has MS, that person's first-degree relatives—parents, children, and siblings—have a one to three percent chance of getting the disease.
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| For identical [[twins]], the likelihood that the second twin may develop MS if the first twin does is about 30%. For fraternal twins (who do not inherit an identical set of genes), the likelihood is closer to that for non-twin siblings, or about 4%. This pattern suggests that, while genetic factors clearly help determine the risk of MS, other factors such as environmental effects or random chance are also involved. The actual correlation may be somewhat higher than reported by these numbers as people with MS lesions remain essentially asymptomatic throughout their lives.
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| Further indications that more than one gene is involved in MS susceptibility comes from studies of families in which more than one member has MS. Several research teams found that people with MS inherit certain regions on individual genes more frequently than people without MS. Of particular interest is the [[human leukocyte antigen]] (HLA) or [[major histocompatibility complex]] region on chromosome 6. HLAs are genetically determined proteins that influence the immune system. However, there are other genes in this region which are not related to the immune system.
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| The HLA patterns of MS patients tend to be different from those of people without the disease. Investigations in northern Europe and America have detected three HLAs that are more prevalent in people with MS than in the general population. Studies of American MS patients have shown that people with MS also tend to exhibit these HLAs in combination—that is, they have more than one of the three HLAs—more frequently than the rest of the population. Furthermore, there is evidence that different combinations of the HLAs may correspond to variations in disease severity and progression.
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| A large study examining 334,923 [[single nucleotide polymorphism]]s (small variations in [[gene]]s) in 931 families showed that apart from HLA-DRA there were two genes in which polymorphisms strongly predicted MS; these were the ''[[IL-2 receptor|IL2RA]]'' (a subunit of the [[Receptor (biochemistry)|receptor]] for [[interleukin 2]]) and the ''[[IL-7 receptor|IL7RA]]'' (''idem'' for [[interleukin 7]]) genes. Mutations in these genes were already known to be associated with [[diabetes mellitus type 1]] and other autoimmune conditions; the findings circumstantially support the notion that MS is an autoimmune disease.<ref>{{cite journal |author= |title=Risk Alleles for Multiple Sclerosis Identified by a Genomewide Study |journal=N Engl J Med |volume= |issue= |pages= |year=2007 |pmid=17660530 |doi=10.1056/NEJMoa073493}}</ref>
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| Studies of families with multiple cases of MS and research comparing proteins expressed in humans with MS to those of mice with EAE suggest that another area related to MS susceptibility may be located on chromosome 5. Other regions on chromosomes 2, 3, 7, 11, 17, 19, and X have also been identified as possibly containing genes involved in the development of MS.
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| These studies strengthen the theory that MS is the result of a number of factors rather than a single gene or other agent. Development of MS is likely to be influenced by the interactions of a number of genes, each of which (individually) has only a modest effect. Additional studies are needed to specifically pinpoint which genes are involved, determine their function, and learn how each gene's interactions with other genes and with the environment make an individual susceptible to MS.
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| ==Treatment==
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| {{main|treatment of multiple sclerosis}}
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| Although there is no known cure for multiple sclerosis, several therapies have proven helpful.
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| The primary aims of therapy are returning function after an attack, preventing new attacks, and preventing disability. As with any medical treatment, medications used in the management of MS have several [[adverse effect (medicine)|adverse effects]], and many possible therapies are still under investigation. At the same time different [[Alternative medicine|alternative treatments]] are pursued by many patients, despite the paucity of supporting, comparable, replicated scientific study.
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| ===Management of acute attacks===
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| During symptomatic attacks administration of high doses of [[intravenous therapy|intravenous]] [[corticosteroid]]s, such as [[methylprednisolone]],<ref> [http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682795.html Methylprednisolone Oral.] US National Library of Medicine (Medline) ([[2003-04-01]]). Retrieved on [[2007-09-01]].</ref><ref>[http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a601157.html Methylprednisolone Sodium Succinate Injection.] US National Library of Medicine (Medline) ([[2003-04-01]]). Retrieved on [[2007-09-01]].</ref> is the routine therapy for acute relapses.The aim of this kind of treatment is to end the attack sooner and leave fewer lasting deficits in the patient. Although generally effective in the short term for relieving [[symptom]]s, corticosteroid treatments do not appear to have a significant impact on long-term recovery.<ref>{{cite journal |author=Brusaferri F, Candelise L |title=Steroids for multiple sclerosis and optic neuritis: a meta-analysis of randomized controlled clinical trials |journal=J. Neurol. |volume=247 |issue=6 |pages=435–42 |year=2000 |pmid=10929272 |doi=}}</ref> Potential side effects include osteoporosis<ref>{{cite journal |author=Dovio A, Perazzolo L, Osella G, ''et al'' |title=Immediate fall of bone formation and transient increase of bone resorption in the course of high-dose, short-term glucocorticoid therapy in young patients with multiple sclerosis |journal=J. Clin. Endocrinol. Metab. |volume=89 |issue=10 |pages=4923–8 |year=2004 |pmid=15472186 |doi=10.1210/jc.2004-0164}}</ref> and impaired memory, being the latter reversible<ref>{{cite journal |author=Uttner I, Müller S, Zinser C, ''et al'' |title=Reversible impaired memory induced by pulsed methylprednisolone in patients with MS |journal=Neurology |volume=64 |issue=11 |pages=1971–3 |year=2005 |pmid=15955958 |doi=10.1212/01.WNL.0000163804.94163.91}}</ref>
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| ===Disease modifying treatments===
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| [[Image:Injection 23.JPG|right|thumb|Disease-modifying treatments are expensive and require frequent injections.]]
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| The earliest clinical presentation of relapsing-remitting MS (RRMS) is the clinically isolated syndrome (CIS). Several studies have shown that treatment with [[interferon]]s during an initial attack can decrease the chance that a patient will develop MS.<ref>{{cite journal |author=Jacobs LD, Beck RW, Simon JH, ''et al.'' |title=Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group |journal=[[New England Journal of Medicine|N Engl J Med]] |volume=343 |issue=13 |pages=898–904 |year=2000 |pmid=11006365 |doi=}}</ref><ref>{{cite journal |author=Comi G, Filippi M, Barkhof F, ''et al.'' |title=Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study |journal=[[Lancet (journal)|Lancet]] |volume=357 |issue=9268 |pages=1576–82 |year=2001 |pmid=11377645 |doi=}}</ref><ref name="pmid17679016">{{cite journal |author=Kappos L, Freedman MS, Polman CH, ''et al.'' |title=Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study |journal=Lancet |volume=370 |issue=9585 |pages=389–97 |year=2007 |pmid=17679016 |doi=10.1016/S0140-6736(07)61194-5}}</ref>
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| As of 2007, six disease-modifying treatments have been approved by regulatory agencies of different countries for relapsing-remitting MS. Three are [[interferon]]s: two formulations of [[interferon beta-1a]] (trade names ''Avonex'' and ''Rebif'') and one of [[interferon beta-1b]] (U.S. trade name ''Betaseron'', in Europe and Japan ''Betaferon''). A fourth medication is [[glatiramer acetate]] (''Copaxone''). The fifth medication, [[mitoxantrone]], is an [[immunosuppressant]] also used in [[chemotherapy|cancer chemotherapy]]. Finally, the sixth is [[natalizumab]] (marketed as ''Tysabri''). All six medications are modestly effective at decreasing the number of attacks and slowing progression to disability, although they differ in their efficacy rate and studies of their long-term effects are still lacking.<ref name="pmid17627671">{{cite journal |author=Ruggieri M, Avolio C, Livrea P, Trojano M |title=Glatiramer acetate in multiple sclerosis: a review |journal=CNS Drug Rev |volume=13 |issue=2 |pages=178–91 |year=2007 |pmid=17627671 |doi=10.1111/j.1527-3458.2007.00010.x}}</ref><ref name="pmid14974077">{{cite journal |author=Munari L, Lovati R, Boiko A |title=Therapy with glatiramer acetate for multiple sclerosis |journal=Cochrane Database Syst Rev |volume= |issue=1 |pages=CD004678 |year=2004 |pmid=14974077 |doi=10.1002/14651858.CD004678}}</ref><ref name="pmid11687131">{{cite journal |author=Rice GP, Incorvaia B, Munari L, ''et al'' |title=Interferon in relapsing-remitting multiple sclerosis |journal=Cochrane Database Syst Rev |volume= |issue=4 |pages=CD002002 |year=2001 |pmid=11687131 |doi=}}</ref><ref name="pmid16235298">{{cite journal |author=Martinelli Boneschi F, Rovaris M, Capra R, Comi G |title=Mitoxantrone for multiple sclerosis |journal=Cochrane Database Syst Rev |volume= |issue=4 |pages=CD002127 |year=2005 |pmid=16235298 |doi=10.1002/14651858.CD002127.pub2}}</ref> Comparisons between immunomodulators (all but mitoxantrone) show that the most effective is natalizumab.<ref name="pmid17350652">{{cite journal |author=Johnson KP |title=Control of multiple sclerosis relapses with immunomodulating agents |journal=J. Neurol. Sci. |volume=256 Suppl 1 |issue= |pages=S23–8 |year=2007 |pmid=17350652 |doi=10.1016/j.jns.2007.01.060}}</ref>
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| Mitoxantrone is probably the most effective of them all;<ref>{{cite journal |author=Gonsette RE |title=Compared benefit of approved and experimental immunosuppressive therapeutic approaches in multiple sclerosis |journal=Expert opinion on pharmacotherapy |volume=8 |issue=8 |pages=1103–16 |year=2007 |pmid=17516874 |doi=10.1517/14656566.8.8.1103}}</ref> however, its use is limited by severe [[cardiotoxicity]].<ref name="pmid16503747">{{cite journal |author=Murray TJ |title=The cardiac effects of mitoxantrone: do the benefits in multiple sclerosis outweigh the risks? |journal=Expert opinion on drug safety |volume=5 |issue=2 |pages=265–74 |year=2006 |pmid=16503747 |doi=10.1517/14740338.5.2.265}}</ref>
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| Treatment of progressive MS is more difficult than relapsing-remitting MS. [[Mitoxantrone]] has shown positive effects in patients with a secondary progressive and progressive relapsing courses. It is moderately effective in reducing the progression of the disease and the frequency of relapses in patients in short-term follow-up.<ref name="pmid16235298">{{cite journal |author=Martinelli Boneschi F, Rovaris M, Capra R, Comi G |title=Mitoxantrone for multiple sclerosis |journal=Cochrane database of systematic reviews (Online) |volume= |issue=4 |pages=CD002127 |year=2005 |pmid=16235298 |doi=10.1002/14651858.CD002127.pub2}}</ref> On the other hand no treatment has been proven to modify the course of primary progresive MS.<ref name="pmid15907149">{{cite journal |author=Leary SM, Thompson AJ |title=Primary progressive multiple sclerosis: current and future treatment options |journal=CNS drugs |volume=19 |issue=5 |pages=369–76 |year=2005 |pmid=15907149 |doi=}}</ref>
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| As with any medical treatment, these treatments have several adverse effects. One of the most common is irritation at the injection site. Interferons also produce symtoms similar to [[influenza]]; <ref name="pmid17131933">{{cite journal |author=Sládková T, Kostolanský F |title=The role of cytokines in the immune response to influenza A virus infection |journal=Acta Virol. |volume=50 |issue=3 |pages=151–62 |year=2006 |pmid=17131933 |doi=}}</ref> while some patients taking glatiramer experience a post-injection reaction manifested by flushing, chest tightness, heart palpitations, breathlessness, and anxiety, which usually lasts less than thirty minutes.<ref name="pmid14974077">{{cite journal |author=Munari L, Lovati R, Boiko A |title=Therapy with glatiramer acetate for multiple sclerosis |journal=Cochrane database of systematic reviews (Online) |volume= |issue=1 |pages=CD004678 |year=2004 |pmid=14974077 |doi=10.1002/14651858.CD004678}}</ref>. More dangerous are [[hepatotoxicity|liver damage]] of interferons and mitoxantrone,<ref>Betaseron [package insert]. Montville, NJ: Berlex Inc; 2003</ref><ref>Rebif [package insert]. Rockland, MA: Serono Inc; 2005.</ref><ref>Avonex [package insert]. Cambridge, MA: Biogen Inc; 2003</ref> <ref name="pmid16750460">{{cite journal |author=Fox EJ |title=Management of worsening multiple sclerosis with mitoxantrone: a review |journal=Clinical therapeutics |volume=28 |issue=4 |pages=461–74 |year=2006 |pmid=16750460 |doi=10.1016/j.clinthera.2006.04.013}}</ref> the immunosuppressive effects and [[cardiotoxicity|cardiac toxicity]] of the latter; <ref name="pmid16750460">{{cite journal |author=Fox EJ |title=Management of worsening multiple sclerosis with mitoxantrone: a review |journal=Clinical therapeutics |volume=28 |issue=4 |pages=461–74 |year=2006 |pmid=16750460 |doi=10.1016/j.clinthera.2006.04.013}}</ref> or the relation between natalizumab and some cases of [[progressive multifocal leukoencephalopathy]] in patients who had taken it in combination with interferons.<ref>{{cite journal |author=Kleinschmidt-DeMasters BK, Tyler KL |title=Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis |journal=[[New England Journal of Medicine|N Engl J Med]] |volume=353 |issue=4 |pages=369–74 |year=2005 |pmid=15947079 |doi=10.1056/NEJMoa051782}} [http://content.nejm.org/cgi/content/abstract/353/4/369 Free full text with registration]</ref><ref>{{cite journal |author=Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D |title=Progressive multifocal leukoencephalopathy in a patient treated with natalizumab |journal=N Engl J Med |volume=353 |issue=4 |pages=375–81 |year=2005 |pmid=15947078 |doi=10.1056/NEJMoa051847}} [http://content.nejm.org/cgi/content/abstract/353/4/375 Free full text with registration]</ref>
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| === Management of the effects of MS ===
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| Disease-modifying treatments only reduce the progression rate of the disease but do not stop it. As multiple sclerosis progresses, the symptomatology tends to increase. The disease is associated with a variety of symptoms and functional deficits that result in a range of progressive impairments and [[Disability|handicap]]. Management of these deficits is therefore very important. Both drug therapy and [[neurorehabilitation]] have shown to ease the burden of some symptoms, even though neither influence disease progression.<ref name="pmid16168933">{{cite journal |author=Kesselring J, Beer S |title=Symptomatic therapy and neurorehabilitation in multiple sclerosis |journal=Lancet neurology |volume=4 |issue=10 |pages=643–52 |year=2005 |pmid=16168933 |doi=10.1016/S1474-4422(05)70193-9}}</ref>
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| As for any patient with neurologic deficits, a multidisciplinary approach is key to limiting and overcoming disability; however there are particular difficulties in specifying a ‘core team’ because people with MS may need help from almost any health profession or service at some point.<ref name="isbn = 1 86016 182 0">{{cite book | last = The Royal College of Physicians |title = Multiple Sclerosis. National clinical guideline for diagnosis and management in primary and secondary care | publisher = Sarum ColourView Group | date = 2004 | location = Salisbury, Wiltshire | isbn = 1 86016 182 0 }}[http://www.rcplondon.ac.uk/pubs/books/MS/MSfulldocument.pdf Free full text] ([[2004-08-13]]). Retrieved on [[2007-10-01]].</ref> Similarly for each symptom there are different treatment options. Treatments should therefore be individualized depending both on the patient and the physician
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| ===Therapies under investigation===
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| {{main|therapies under investigation for multiple sclerosis}}
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| Scientists continue their extensive efforts to create new and better therapies for MS. There are a number of treatments under investigation that may curtail attacks or improve function. Some of these treatments involve the combination of drugs that are already in use for multiple sclerosis, such as the combination of [[mitoxantrone]] and [[glatiramer acetate]] (''Copaxone'').<ref> [http://www.mxga-mstrial.co.uk United Kingdom early Mitoxantrone Copaxone trial.] Onyx Healthcare ([[2006-01-01]]). Retrieved on [[2007-09-02]].</ref> However most treatments already in clinical trials involve drugs that are used in other diseases or medications that have been designed specifically for MS. Finally, there are also many basic investigations that try to understand better the disease and in the future may help to find new treatments.
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| ===Alternative treatments===
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| Different alternative treatments are pursued by many patients, despite the paucity of supporting, comparable, replicated scientific study. Examples are [[Diet (nutrition)|dietary]] regimens,<ref name="pmid17253500">{{cite journal |author=Farinotti M, Simi S, Di Pietrantonj C, ''et al.'' |title=Dietary interventions for multiple sclerosis |journal=Cochrane database of systematic reviews (Online) |volume= |issue=1 |pages=CD004192 |year=2007 |pmid=17253500 |doi=10.1002/14651858.CD004192.pub2}}</ref>, [[herbal medicine]], including the use of [[marijuana]] to help alleviate symptoms,<ref>{{cite journal |author=Chong MS, Wolff K, Wise K, Tanton C, Winstock A, Silber E |title=Cannabis use in patients with multiple sclerosis |journal=Mult. Scler. |volume=12 |issue=5 |pages=646–51 |year=2006 |pmid=17086912 |doi=}}</ref><ref>{{cite journal |author=Zajicek JP, Sanders HP, Wright DE, Vickery PJ, Ingram WM, Reilly SM, Nunn AJ, Teare LJ, Fox PJ, Thompson AJ |title=Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up |journal=J. Neurol. Neurosurg. Psychiatr. |volume=76 |issue=12 |pages=1664–9 |year=2005 |pmid=16291891 |doi=10.1136/jnnp.2005.070136}}</ref> or [[hyperbaric oxygenation]].<ref name="pmid14974004">{{cite journal |author=Bennett M, Heard R |title=Hyperbaric oxygen therapy for multiple sclerosis |journal=Cochrane database of systematic reviews (Online) |volume= |issue=1 |pages=CD003057 |year=2004 |pmid=14974004 |doi=10.1002/14651858.CD003057.pub2}}</ref>
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| On the other hand the [[Martial arts therapy|therapeutic practice of martial arts]] such as tai chi, relaxation disciplines such as yoga, or general exercise, seem to mitigate fatigue and improve quality of life.<ref name="pmid15184614">{{cite journal |author=Oken BS, Kishiyama S, Zajdel D, ''et al.'' |title=Randomized controlled trial of yoga and exercise in multiple sclerosis |journal=Neurology |volume=62 |issue=11 |pages=2058–64 |year=2004 |pmid=15184614 |doi=}}</ref>
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| ==Prognosis==
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| The [[prognosis]] (the expected future course of the disease) for a person with multiple sclerosis depends on the subtype of the disease; the individual's sex, race, age, and initial symptoms; and the degree of disability the person experiences. The [[life expectancy]] of people with MS is now nearly the same as that of unaffected people. This is due mainly to improved methods of limiting disability, such as [[physical therapy]], [[occupational therapy]] and [[speech therapy]], along with more successful treatment of common complications of disability, such as [[pneumonia]] and [[urinary tract infection]]s.<ref>Weinshenker BG. ''Natural history of multiple sclerosis.'' Ann Neurol 1994;36 Suppl:S6–11. PMID 8017890</ref> Nevertheless half of the deaths in people with MS are directly related to the consequences of the disease, while 15% more are due to suicide.<ref>{{cite journal |author=Stern M |title=Aging with multiple sclerosis |journal=Physical medicine and rehabilitation clinics of North America |volume=16 |issue=1 |pages=219-34 |year=2005 |pmid=15561552}}</ref>
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| *Individuals with progressive subtypes of MS, particularly the primary progressive subtype, have a more rapid decline in function. In the primary progressive subtype, supportive equipment (such as a [[wheelchair]] or [[standing frame]]) is often needed after six to seven years. However, when the initial disease course is the relapsing-remitting subtype, the average time until such equipment is needed is twenty years. This means that many individuals with MS will never need a wheelchair. There is also more cognitive impairment in the progressive forms than in the relapsing-remitting course. | |
| *The earlier in life MS occurs, the slower [[disability]] progresses. Individuals who are older than fifty when diagnosed are more likely to experience a chronic progressive course, with more rapid progression of disability. Those diagnosed before age 35 have the best prognosis. Females generally have a better prognosis than males. Although individuals of African descent tend to develop MS less frequently, they are often older at the time of onset and may have a worse prognosis.
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| *Initial MS symptoms of visual loss or sensory problems, such as [[numbness]] or [[tingling]], are markers for a relatively good [[prognosis]], whereas [[gait disturbance|difficulty walking]] and [[weakness (medical)|weakness]] are markers for a relatively poor prognosis. Better outcomes are also associated with the presence of only a single symptom at onset, the rapid development of initial symptoms, and the rapid regression of initial symptoms.
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| *The degree of disability varies among individuals with MS. In general, one of three individuals will still be able to work after 15–20 years. Fifteen percent of people diagnosed with MS never have a second relapse, and these people have minimal or no disability after ten years.<ref>Pittock SJ; McClelland RL; Mayr WT; Jorgensen NW; Weinshenker BG; Noseworthy J; Rodriguez M. ''Clinical implications of benign multiple sclerosis: a 20-year population-based follow-up study'' Ann Neurol 2004 Aug;56(2):303-6. PMID 15293286</ref> The degree of disability after five years correlates well with the degree of disability after fifteen years. This means that two-thirds of people with MS with low disability after five years will not get much worse during the next ten years. It should be noted that most of these outcomes were observed before the use of medications such as interferon, which can delay disease progression for several years.
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| Currently there are no clinically established laboratory investigations available that can predict prognosis or response to treatment. However, several promising approaches have been proposed. These include measurement of the two [[antibody|antibodies]] [[myelin oligodendrocyte glycoprotein|anti-myelin oligodendrocyte glycoprotein]] and [[myelin basic protein|anti-myelin basic protein]], and measurement of TRAIL ([[TNF]]-related [[apoptosis]]-inducing [[ligand]]).<ref>Berger T, Rubner P, Schautzer F, Egg R, Ulmer H, Mayringer I, Dilitz E, Deisenhammer F, Reindl M. ''Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event.'' N Engl J Med. 2003 Jul 10;349(2):139-45. PMID 12853586</ref>
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| ==Epidemiology==
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| [[Image:MS Risk.jpg|thumb|450px|right|World map showing that risk for MS increases with greater distance from the equator]]
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| In northern Europe, continental North America, and Australasia, about one of every 1000 citizens suffers from multiple sclerosis, whereas in the [rabian peninsula, Asia, and continental South America, the frequency is much lower. In sub-Saharan Africa, MS is extremely rare. With important exceptions, there is a north-to-south gradient in the northern hemisphere and a south-to-north gradient in the southern hemisphere, with MS being much less common in people living near the equator.<ref>[http://www.fedem.org/revista/n16/kurtzkeing.htm Epidemiology and multiple sclerosis. a personal review]</ref> [[Climate]], [[diet (nutrition)|diet]], geomagnetism, [[toxin]]s, [[sunlight]] exposure, genetic factors, and [[infectious disease]]s have all been discussed as possible reasons for these regional differences. Environmental factors during childhood may play an important role in the development of MS later in life. This idea is based on several studies of migrants showing that if migration occurs before the age of fifteen, the migrant acquires the new region's susceptibility to MS. If migration takes place after age fifteen, the migrant keeps the susceptibility of his home country.<ref>Marrie, RA. ''Environmental risk factors in multiple sclerosis aetiology.'' Lancet Neurol. 2004 Dec;3(12):709-18. Review. PMID 15556803</ref> However other works suggest that the age/geographical risk for developing multiple sclerosis spans a larger timescale than just the first 15 years of life.<ref name="pmid10775541">{{cite journal |author=Hammond SR, English DR, McLeod JG |title=The age-range of risk of developing multiple sclerosis: evidence from a migrant population in Australia |journal=Brain |volume=123 ( Pt 5) |issue= |pages=968–74 |year=2000 |pmid=10775541 |doi=}}</ref>
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| MS occurs mainly in Caucasians. It is twentyfold lower in the Inuit people of Canada than in other Canadians living in the same region. It is also rare in the Native American tribes of North America, Australian Aborigines and the Māori of New Zealand. Scotland appears to have the highest rate of MS in the world.<ref> {{cite journal |author=Rothwell PM, Charlton D |title=High incidence and prevalence of multiple sclerosis in south east Scotland: evidence of a genetic predisposition |journal=J. Neurol. Neurosurg. Psychiatr. |volume=64 |issue=6 |pages=730-5 |year=1998 |pmid=9647300 |doi=}}</ref> The reasons for this are unknown. These few examples point out that either genetic background or lifestyle and cultural factors play an important role in the development of MS.
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| As observed in many autoimmune disorders, MS is more common in females than males; the mean sex [[ratio]] is about two females for every male. In children (who rarely develop MS) the sex ratio may reach three females for each male. In people over age fifty, MS affects males and females equally. Onset of symptoms usually occurs between fifteen to forty years of age, rarely before age fifteen or after age sixty.
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| As previously discussed, there is a genetic component to MS. On average one of every 25 siblings of individuals with MS will also develop MS. Almost half of the [[identical twin]]s of MS-affected individuals will develop MS, but only one of twenty fraternal twins. If one parent is affected by MS, each child has a risk of only about one in forty of developing MS later in life.<ref>Sadovnick, AD, Ebers, GC, Dyment, DA, Risch, NJ. ''Evidence for genetic basis of multiple sclerosis. The Canadian Collaborative Study Group.'' Lancet 1996; 347:1728. PMID 8656905</ref>
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| Finally, it is important to remark that advances in the study of related diseases have shown that some cases formerly considered MS are not MS at all. In fact, all the studies before 2004 can be affected by the impossibility to distinguish MS and [[Devic's disease|''Devic's disease'' (NMO)]] reliably before this date. The error can be important in some areas, and is considered to be 30% in Japan.<ref>{{cite journal |author=Weinshenker B |title=Western vs optic-spinal MS: two diseases, one treatment? |journal=Neurology |volume=64 |issue=4 |pages=594-5 |year=2005 |pmid=15728277}}</ref>
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| ==History==
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| The French [[neurologist]] [[Jean-Martin Charcot]] (1825–93) was the first person to recognize multiple sclerosis as a distinct, separate [[disease]] in 1868. Summarizing previous reports and adding his own important clinical and pathological observations, Charcot called the disease ''sclerose en plaques''. The three signs of MS now known as [[Charcot's triad]] are [[dysarthria]] (problems with speech), [[ataxia]] (problems with coordination), and [[tremor]]. Charcot also observed cognition changes in MS since he described his patients as having a "marked enfeeblement of the memory" and "with conceptions that formed slowly".<ref>Charcot, J. ''Histologie de la sclerose en plaques.'' Gazette des hopitaux, Paris, 1868; 41: 554–555.</ref>
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| Prior to Charcot, Robert Hooper (1773–1835), a British pathologist and practicing [[physician]], Robert Carswell (1793–1857), a British professor of [[pathology]], and [[Jean Cruveilhier]] (1791–1873), a French professor of pathologic [[anatomy]], had described and illustrated many of the disease's clinical details.
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| After this, several people, such as [[Eugène Devic]] (1858–1930), Jozsef Balo (1895–1979), [[Paul Ferdinand Schilder]] (1886–1940), and [[Otto Marburg]] (1874–1948) found special cases of the disease that some authors consider different diseases and now are called the [[borderline forms of multiple sclerosis]].
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| There are several historical accounts of people who probably had MS. Saint Lidwina of Schiedam (1380–1433), a Dutch nun, may be one of the first identifiable MS patients. From the age of sixteen until her death at age 53, she suffered intermittent pain, weakness of the legs, and vision loss—symptoms typical of MS. Almost a hundred years before there is a story from Iceland of a young woman called Halla. This girl suddenly lost her vision and capacity to talk; but after praying to the saints recovered them seven days after.<ref>{{cite journal |author=Poser C |title=The dissemination of multiple sclerosis: a Viking saga? A historical essay |journal=Ann. Neurol. |volume=36 Suppl 2 |issue= |pages=S231-43 |year=1994 |pmid=7998792}}</ref> Augustus Frederick d'Este (1794–1848), an illegitimate grandson of King George III of Great Britain, almost certainly suffered from MS. D'Este left a detailed diary describing his 22 years living with the disease. He began his diary in 1822 and it had its last entry in 1846 (only to remain unknown until 1948). His symptoms began at age 28 with a sudden transient visual loss after the funeral of a friend. During the course of his disease he developed weakness of the legs, clumsiness of the hands, numbness, dizziness, bladder disturbances, and [[erectile dysfunction]]. In 1844, he began to use a [[wheelchair]]. Despite his illness, he kept an optimistic view of life.<ref>{{cite book |last= Firth|first=D |title= The Case of August D`Esté|year=1948 |publisher=Cambridge University Press |location=Cambridge}}</ref> Another early account of MS was kept by the British diarist W. N. P. Barbellion, who maintained a detailed log of his diagnosis and struggle with MS. His diary was published in 1919 as ''The Journal of a Disappointed Man''.
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| ==See also==
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| * MS fundraisers include the [[MS Challenge Walk]], MS Walk and [[MS Bike Tour]].
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| * [[List of multiple sclerosis organizations]] | | * [[List of multiple sclerosis organizations]] |
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| ==References==
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| {{reflist|2}}
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| ==Further reading==
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| * [http://bmj.bmjjournals.com/cgi/content/full/330/7496/885 The patient's journey: multiple sclerosis] Langgartner M, Langgartner I, Drlicek M. ''The patient's journey: multiple sclerosis.'' [[British Medical Journal|BMJ]]. 2005 Apr 16;330(7496):885-8. PMID 15831874.
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| * [http://www.mult-sclerosis.org/chooseglossary.html Multiple Sclerosis Encyclopedia]
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| ==External links==
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| * {{dmoz|Health/Conditions_and_Diseases/Neurological_Disorders/Demyelinating_Diseases/Multiple_Sclerosis/}}
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| * [http://www.atlasofms.org/ Database for analysis and comparison of global data on the epidemiology of MS]
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| * [http://clinicaltrials.gov/search/term=Multiple+Sclerosis NIH listing of clinical trials related to MS]
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| * [http://www.cochrane.org/reviews/en/topics/79.html Abstract index] of the [[Cochrane Library]]
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| {{Multiple sclerosis}}
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