View source for Multiple sclerosis

{{Infobox_Disease
 | Name           = Multiple sclerosis
 | Image          = MRI_of_Multiple_sclerosis.jpg
 | Caption        = [[MRI]] FLAIR sequence showing four bright spots (plaques) where multiple sclerosis has damaged myelin in the brain
 | DiseasesDB     = 8412
 | ICD10          = {{ICD10|G|35||g|35}}
 | ICD9           = {{ICD9|340}}
 | ICDO           = 
 | OMIM           = 126200
 | MedlinePlus    = 000737
 | eMedicineSubj  = neuro
 | eMedicineTopic = 228
 | eMedicine_mult = {{eMedicine2|oph|179}} {{eMedicine2|emerg|321}} {{eMedicine2|pmr|82}} {{eMedicine2|radio|461}}
 | MeshID         = D009103
}}
{{Neuron map|Myelin sheath of a healthy neuron}}
{{SI}}
{{CMG}}

'''Contributors:'''  [[User:zorkun|Cafer Zorkun]] M.D., PhD.

{{Editor Help}}

==Overview==

'''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]]. 

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.

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. 

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. 

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.

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.

==Epidemiology==

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>

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.

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.

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>

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>

==History==

The French [[neurologist]] [[Jean-Martin Charcot]] (1825&ndash;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>

Prior to Charcot, Robert Hooper (1773&ndash;1835), a British pathologist and practicing [[physician]], Robert Carswell (1793&ndash;1857), a British professor of [[pathology]], and [[Jean Cruveilhier]] (1791&ndash;1873), a French professor of pathologic [[anatomy]], had described and illustrated many of the disease's clinical details.

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]].

There are several historical accounts of people who probably had MS. Saint Lidwina of Schiedam (1380&ndash;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&mdash;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&ndash;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''.

==Pathophysiology==
{{Main|Pathophysiology of multiple sclerosis}}
Although much is known about how multiple sclerosis causes damage, the reasons why multiple sclerosis occurs are not known.

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.

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>

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.

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.

==Causes==

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>
{{cite journal
| author=Peter Behan and Abhijit Chaudhuri
| title=The pathogenesis of multiple sclerosis revisited
| journal=J R Coll Physicians Edinb
| 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>

===Environmental===

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]].

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>

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.

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>

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>

===Genetic===
[[Image:HLA complex1.JPG|thumb|left|upright|HLA region of Chromosome&nbsp;6. Changes in this area increase the probability of suffering MS.]]
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:

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.

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.

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.

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.

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.

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>

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.

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.

==Signs and symptoms== 

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>

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.

===Bladder===

[[Urinary bladder|Bladder]] problems (See also [[urinary system]] and [[urination]]) appear in 70-80% of MS patients and they have an important effect both in [[hygiene]] habits and social activity.<ref>{{cite journal |author=Hennessey A, Robertson NP, Swingler R, Compston DA |title=Urinary, faecal and sexual dysfunction in patients with multiple sclerosis |journal=J. Neurol. |volume=246 |issue=11 |pages=1027-32 |year=1999 |pmid=10631634}}</ref><ref>{{cite journal |author=Burguera-Hernández JA |title=[Urinary alterations in multiple sclerosis] |language=Spanish; Castilian |journal=Revista de neurologia |volume=30 |issue=10 |pages=989-92 |year=2000 |pmid=10919202}}</ref>

However bladder problems are usually related with high levels of [[disability]] and pyramidal signs in lower limbs<ref>{{cite journal |author=Betts CD, D'Mellow MT, Fowler CJ |title=Urinary symptoms and the neurological features of bladder dysfunction in multiple sclerosis |journal=J. Neurol. Neurosurg. Psychiatr. |volume=56 |issue=3 |pages=245-50 |year=1993 |pmid=8459239}}</ref>

The most common problems are an increase of frequency and urgency ([[Urinary incontinence|incontinence]]) but difficulties to begin urination, hesitation, leaking, retention and sensation of incomplete urination also appear. When there is retention secondary [[urinary infection]]s are common.

There are many [[Cerebral cortex|cortical]] and [[subcortical]] structures implicated in [[micturition]].<ref>{{cite journal |author=Nour S, Svarer C, Kristensen JK, Paulson OB, Law I |title=Cerebral activation during micturition in normal men |journal=Brain |volume=123 ( Pt 4) |issue= |pages=781-9 |year=2000 |pmid=10734009}}</ref> Accordingly; MS lesions in different [[central nervous system]] structures can cause these kind of symptoms.

Treatment objectives are aliviation of symptoms of urinary dysfunction, treatment of urinary infections, reduction of complicating factors and preservation of [[kidney|renal]] function.Treatments can be classified in two main subtypes: pharmacological and non pharmacological.

Pharmacological treatments vary greatly depending on the origin or type of dysfunction; however some examples of the medications used are:<ref>{{cite journal |author=Ayuso-Peralta L, de Andrés C |title=[Symptomatic treatment of multiple sclerosis] |language=Spanish; Castilian |journal=Revista de neurologia |volume=35 |issue=12 |pages=1141-53 |year=2002 |pmid=12497297 |doi=}}</ref>
[[alfuzosin]] for retention,<ref>Information from the USA National library of medicine on alfuzosin [http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a604002.html]</ref> 
[[trospium]] and [[flavoxate]] for urgency and incontinency,<ref>Information from the USA National library of medicine on trospium [http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a604037.html]</ref><ref>Information from the USA National library of medicine on flavoxate [http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682706.html] </ref>
or [[desmopressin]] for [[nocturia]].<ref>{{cite journal |author=Bosma R, Wynia K, Havlíková E, De Keyser J, Middel B |title=Efficacy of desmopressin in patients with multiple sclerosis suffering from bladder dysfunction: a meta-analysis |journal=Acta Neurol. Scand. |volume=112 |issue=1 |pages=1-5 |year=2005 |pmid=15932348 |doi=10.1111/j.1600-0404.2005.00431.x}}</ref><ref>Information from the USA National library of medicine on desmopressin [http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682876.html]</ref>

Non pharmacological treatments involve the use of [[pelvic floor]] muscle training, stimulation, [[biofeedback]], [[pessary|pessaries]], bladder retraining, and sometimes intermittent [[urinary catheterization|catheterization]].<ref>Frances M Diro (2006) "Urological Management in Neurological Disease". [http://www.emedicine.com/neuro/topic673.htm]</ref>

===Cognitive===

Cognitive impairments are common. Neuropsychological studies suggest that 40 to 60 percent of patients have cognitive deficits;<ref>{{cite journal |author=Rao S, Leo G, Bernardin L, Unverzagt F |title=Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction |journal=Neurology |volume=41 |issue=5 |pages=685-91 |year=1991 |pmid=2027484}}</ref> with the lowest percentages usually from community-based studies and the highest ones from hospital-based. 

Cognitive impairment, sometimes referred to as [[brain fog]], is already present in the beginnings of the disease.<ref>{{cite journal |author= |title=Attention impairment in recently diagnosed multiple sclerosis |journal=Eur J Neurol |volume=5 |issue=1 |pages=61-66 |year=1998 |pmid=10210813}}</ref> Even in probable MS (after the first attack but before a second confirmatory one) up to 50% of patients have mild impairment.<ref>{{cite journal |author=Achiron A, Barak Y |title=Cognitive impairment in probable multiple sclerosis |journal=J Neurol Neurosurg Psychiatry |volume=74 |issue=4 |pages=443-6 |year=2003 |pmid=12640060}}</ref>

Some of the most common declines are in recent [[memory]], [[attention]], processing speed, visual-spatial abilities and [[executive functions]].<ref>{{cite journal |author=Bobholz J, Rao S |title=Cognitive dysfunction in multiple sclerosis: a review of recent developments |journal=Curr Opin Neurol |volume=16 |issue=3 |pages=283-8 |year=2003 |pmid=12858063}}</ref> Other cognitive-related symptoms are [[labile affect|emotional instability]], and [[fatigue (physical)|fatigue]], including purely [[neurological fatigue]]. 
The cognitive impairments in MS are usually mild; and only in 5% of patients can we speak of [[dementia]]. Nevertheless they are related with unemployment and reduced social interactions.<ref>{{cite journal |author=Amato M, Ponziani G, Siracusa G, Sorbi S |title=Cognitive dysfunction in early-onset multiple sclerosis: a reappraisal after 10 years |journal=Arch Neurol |volume=58 |issue=10 |pages=1602-6 |year=2001 |pmid=11594918}}</ref> They are also related with driving difficulties.<ref>{{cite journal |author=Shawaryn M, Schultheis M, Garay E, Deluca J |title=Assessing functional status: exploring the relationship between the multiple sclerosis functional composite and driving |journal=Arch Phys Med Rehabil |volume=83 |issue=8 |pages=1123-9 |year=2002 |pmid=12161835}}</ref>

[[Neurocognitive]] testing is important for determining the extent of [[cognitive]] deficits. Neuropsychological stimulation may help to reverse or decrease the cognitive defects although its management relies on lifestyle strategies.Interferons have demonstrated that can help to reduce cognitive limitations in multiple sclerosis.<ref>{{cite journal |author=Montalban X, Rio J |title=Interferons and cognition |journal=J Neurol Sci |volume=245 |issue=1-2 |pages=137-40 |year=2006 |pmid=16626757}}</ref> [[Anticholinesterase]] drugs such as [[donepezil]] commonly used in [[alzheimer disease]]; although not approved yet for multiple sclerosis; have also shown efficacy in different clinical trials.<ref>{{cite journal |author=Christodoulou C, Melville P, Scherl W, Macallister W, Elkins L, Krupp L |title=Effects of donepezil on memory and cognition in multiple sclerosis |journal=J Neurol Sci |volume=245 |issue=1-2 |pages=127-36 |year=2006 |pmid=16626752}}</ref><ref>{{cite journal |author=Porcel J, Montalban X |title=Anticholinesterasics in the treatment of cognitive impairment in multiple sclerosis |journal=J Neurol Sci |volume=245 |issue=1-2 |pages=177-81 |year=2006 |pmid=16674980}}</ref><ref>Information from the USA National library of medicine on donepezil [http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a697032.html]</ref>

===Emotional===

Emotional symptoms are also common and are thought to be both the normal response to having a debilitating disease and the result of damage to specific areas of the cental nervous system that generate and control emotions. 

[[Clinical depression]] is the most common neuropsychiatric condition: lifetime depression prevalence rates of 40-50% and 12 month prevalence rates around 20% have been typically reported for samples of people with MS; these figures are considerably higher than those for the general population or for people with other chronic illnesses.<ref>{{cite journal |author=Sadovnick A, Remick R, Allen J, Swartz E, Yee I, Eisen K, Farquhar R, Hashimoto S, Hooge J, Kastrukoff L, Morrison W, Nelson J, Oger J, Paty D |title=Depression and multiple sclerosis |journal=Neurology |volume=46 |issue=3 |pages=628-32 |year=1996 |pmid=8618657}}</ref><ref>{{cite journal |author=Patten S, Beck C, Williams J, Barbui C, Metz L |title=Major depression in multiple sclerosis: a population-based perspective |journal=Neurology |volume=61 |issue=11 |pages=1524-7 |year=2003 |pmid=14663036}}</ref> Many brain-imaging studies have tried to relate depression to lesions in different brain regions with variable success. On balance the evidence seems to favour an association with neuropathology in the left anterior temporal/parietal regions.<ref>{{cite journal |author=Siegert R, Abernethy D |title=Depression in multiple sclerosis: a review |journal=J. Neurol. Neurosurg. Psychiatr. |volume=76 |issue=4 |pages=469-75 |year=2005 |pmid=15774430}}</ref>

Other feelings such as [[anger]], [[anxiety]], [[frustration]], and hopelessness also appear frequently, and [[suicide]] is a very real threat since 15% of deaths in MS sufferers are due to this cause.<ref>{{cite journal |author=Sadovnick A, Eisen K, Ebers G, Paty D |title=Cause of death in patients attending multiple sclerosis clinics |journal=Neurology |volume=41 |issue=8 |pages=1193-6 |year=1991 |pmid=1866003}}</ref>

===Fatigue===

[[Fatigue (medical)|Fatigue]] is very common and disabling in MS. At the same time it has a close relationship with depressive symptomatology.<ref name="pmid12814166">{{cite journal |author=Bakshi R |title=Fatigue associated with multiple sclerosis: diagnosis, impact and management |journal=Mult. Scler. |volume=9 |issue=3 |pages=219–27 |year=2003 |pmid=12814166 |doi=}}</ref> When depression is reduced fatigue also tends to improve, so patients should be evaluated for depression before other therapeutic approaches are used.<ref name="pmid12883103">{{cite journal |author=Mohr DC, Hart SL, Goldberg A |title=Effects of treatment for depression on fatigue in multiple sclerosis |journal=Psychosomatic medicine |volume=65 |issue=4 |pages=542–7 |year=2003 |pmid=12883103 |doi=}}</ref>. In a similar way other factors like disturbed sleep, chronic pain, poor nutrition, or even some medications can contribute to fatigue; and therefore medical professionals are encouraged to identify and modify them.<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> There are also different medications used to treat fatigue; such as [[amantadine]],<ref name="pmid17253480">{{cite journal |author=Pucci E, Branãs P, D'Amico R, Giuliani G, Solari A, Taus C |title=Amantadine for fatigue in multiple sclerosis |journal=Cochrane database of systematic reviews (Online) |volume= |issue=1 |pages=CD002818 |year=2007 |pmid=17253480 |doi=10.1002/14651858.CD002818.pub2}}</ref><ref> [http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682064.html Amantadine.] US National Library of Medicine (Medline) ([[2003-04-01]]). Retrieved on [[2007-10-07]].</ref> or [[pemoline]];<ref name="pmid1641137">{{cite journal |author=Weinshenker BG, Penman M, Bass B, Ebers GC, Rice GP |title=A double-blind, randomized, crossover trial of pemoline in fatigue associated with multiple sclerosis |journal=Neurology |volume=42 |issue=8 |pages=1468–71 |year=1992 |pmid=1641137 |doi=}}</ref><ref> [http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682313.html Pemoline.] US National Library of Medicine (Medline) ([[2006-01-01]]). Retrieved on [[2007-10-07]].</ref> as well as psichological interventions of energy conservation;<ref name="pmid16193899">{{cite journal |author=Mathiowetz VG, Finlayson ML, Matuska KM, Chen HY, Luo P |title=Randomized controlled trial of an energy conservation course for persons with multiple sclerosis |journal=Mult. Scler. |volume=11 |issue=5 |pages=592–601 |year=2005 |pmid=16193899 |doi=}}</ref><ref name="pmid17302106">{{cite journal |author=Matuska K, Mathiowetz V, Finlayson M |title=Use and perceived effectiveness of energy conservation strategies for managing multiple sclerosis fatigue |journal=The American journal of occupational therapy. : official publication of the American Occupational Therapy Association |volume=61 |issue=1 |pages=62–9 |year=2007 |pmid=17302106 |doi=}}</ref> but the effects of all of them are small. For this reason fatigue is a very difficult symptom to manage.

===Internuclear ophthalmoplegia===

[[Image:Internuclear ophthalmoplegia.jpg|thumb|right|180px|''Schematic demonstrating right internuclear ophthalmoplegia, caused by injury of the right [[medial longitudinal fasciculus]] ]]
{{Main|Internuclear ophthalmoplegia}}

Internuclear ophthalmoplegia is a disorder of conjugate lateral gaze.  The affected eye shows impairment of [[adduction]].  The partner eye diverges from the affected eye during abduction, producing [[diplopia]]; during extreme abduction, compensatory [[nystagmus]] can be seen in the partner eye. Diplopia means double vision while nystagmus is involuntary [[eye movement]] characterized by alternating [[smooth pursuit]] in one direction and a [[saccadic movement]] in the other direction.

Internuclear ophthalmoplegia occurs when MS affects a part of the [[brain stem]] called the [[medial longitudinal fasciculus]], which is responsible for communication between the two eyes by connecting the [[abducens nucleus]] of one side to the [[oculomotor nucleus]] of the opposite side. This results in the failure of the [[medial rectus muscle]] to contract appropriately, so that the eyes do not move equally (called disconjugate gaze).

Different drugs as well as optic compensatory systems and prisms can be used to improve this symptoms.<ref>{{cite journal |author=Leigh RJ, Averbuch-Heller L, Tomsak RL, Remler BF, Yaniglos SS, Dell'Osso LF |title=Treatment of abnormal eye movements that impair vision: strategies based on current concepts of physiology and pharmacology |journal=Ann. Neurol. |volume=36 |issue=2 |pages=129-41 |year=1994 |pmid=8053648}}</ref><ref> {{cite journal |author=Starck M, Albrecht H, Pöllmann W, Straube A, Dieterich M |title=Drug therapy for acquired pendular nystagmus in multiple sclerosis |journal=J. Neurol. |volume=244 |issue=1 |pages=9-16 |year=1997 |pmid=9007739}}</ref><ref>{{cite journal |author=Clanet MG, Brassat D |title=The management of multiple sclerosis patients |journal=Curr. Opin. Neurol. |volume=13 |issue=3 |pages=263-70 |year=2000 |pmid=10871249}}</ref><ref>{{cite journal |author=Menon GJ, Thaller VT |title=Therapeutic external ophthalmoplegia with bilateral retrobulbar botulinum toxin- an effective treatment for acquired nystagmus with oscillopsia |journal=Eye (London, England) |volume=16 |issue=6 |pages=804-6 |year=2002 |pmid=12439689}}</ref>
Surgery can also be used in some cases for this problem.<ref>{{cite journal |author=Jain S, Proudlock F, Constantinescu CS, Gottlob I |title=Combined pharmacologic and surgical approach to acquired nystagmus due to multiple sclerosis |journal=Am. J. Ophthalmol. |volume=134 |issue=5 |pages=780-2 |year=2002 |pmid=12429265}}</ref>

===Mobility restrictions===

Restrictions in [[mobility]] (walking, transfers, bed mobility) are common in individuals suffering from multiple sclerosis. Within 10 years after the onset of MS one-third of patients reach a score of 6 on the [[Expanded Disability Status Scale]] (requiring the use of a unilateral walking aid),and by 30 years the proportion increases to 83%. Within 5 years the Expanded Disability Status Score is 6 in 50% of those with the progressive form of MS.<ref>{{cite journal |author=Weinshenker BG, Bass B, Rice GP, ''et al'' |title=The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability |journal=Brain |volume=112 ( Pt 1) |issue= |pages=133-46 |year=1989 |pmid=2917275 |doi=}}</ref>
 
In MS a wide range of impairments may exist which can act either alone or in combination to impact directly on a person's balance, function and mobility. Such impairments include [[fatigue (medical)|fatigue]], [[Muscle weakness|weakness]], hypertonicity, low exercise tolerance, impaired balance, [[ataxia]] and [[tremor]].<ref>{{cite journal |author=Freeman JA |title=Improving mobility and functional independence in persons with multiple sclerosis |journal=J. Neurol. |volume=248 |issue=4 |pages=255-9 |year=2001 |pmid=11374088 |doi=}}</ref>

Interventions may be aimed at the level of the impairments that reduce mobility; or at the level of disability. At this second level interventions include provision, education and instruction in use of equipment such as walking aids, wheelchairs,  motorized scooters and car adaptations; and instruction about compensatory strategies to accomplish an activity, (for example,undertaking safe transfers by pivoting in a flexed posture rather than standing up and stepping around)

===Optic neuritis===
{{Main|Optic neuritis}}
Up to 50% of patients with MS will develop an episode of optic neuritis, and 20% of the time optic neuritis is the presenting  sign of MS. The presence of demyelinating white matter lesions on brain [[MRI]] at the time of presentation of optic neuritis is the strongest predictor for developing clinically definite MS. Almost half of the patients with optic neuritis have white matter lesions consistent with multiple sclerosis. 
At five years follow-up, the overall risk of developing MS is 30%, with or without MRI lesions. Patients with a normal MRI still develop MS (16%), but at a lower rate compared to those patients with three or more MRI lesions (51%). From the other perspective, however, almost half (44%) of patients with any demyelinating lesions on MRI at presentation will not have developed MS ten years later. <ref>{{cite journal |author=Beck RW, Trobe JD |title=What we have learned from the Optic Neuritis Treatment Trial |journal=Ophthalmology |volume=102 |issue=10 |pages=1504-8 |year=1995 |pmid=9097798}}</ref><ref>{{cite journal |author= |title=The 5-year risk of MS after optic neuritis: experience of the optic neuritis treatment trial. 1997 |journal=Neurology |volume=57 |issue=12 Suppl 5 |pages=S36-45 |year=2001 |pmid=11902594}}</ref>

Individuals experience rapid onset of [[pain]] in one eye, followed by blurry [[Visual perception|vision]] in part or all of the [[visual field]] of that [[eye]]. [[Inflammation]] of the optic nerve causes loss of vision usually due to the swelling and destruction of the [[myelin]] sheath covering the optic nerve.  

The blurred vision usually resolves within ten weeks, but individuals are often left with less vivid [[color vision]] (especially red) in the affected eye.

Systemic intravenous treatment with corticosteroids, which may quicken the healing of the optic nerve, prevent complete loss of vision, and delay the onset of other symptoms, is often recommended.

===Pain===
[[Pain]] is a common symptom in MS; appearing in 55% of patients at some point of their disease process; specially as time passes.<ref>{{cite journal |author=Stenager E, Knudsen L, Jensen K |title=Acute and chronic pain syndromes in multiple sclerosis. A 5-year follow-up study |journal=Italian journal of neurological sciences |volume=16 |issue=9 |pages=629-32 |year=1995 |pmid=8838789 |doi=}}</ref>
It is strong and debilitating and has a profound effect in the [[quality of life]] and [[mental health]] of the sufferer.<ref>{{cite journal |author=Archibald CJ, McGrath PJ, Ritvo PG, ''et al'' |title=Pain prevalence, severity and impact in a clinic sample of multiple sclerosis patients |journal=Pain |volume=58 |issue=1 |pages=89-93 |year=1994 |pmid=7970843 |doi=}}</ref> 
It usually appears after a lesion to the ascending or descending tracts that control the transmission of painful stimulus. such as the [[anterolateral system]], but many other causes are also possible.<ref>{{cite journal |author=Clanet MG, Brassat D |title=The management of multiple sclerosis patients |journal=Curr. Opin. Neurol. |volume=13 |issue=3 |pages=263-70 |year=2000 |pmid=10871249 |doi=}}</ref>
Most frequent pains reported are [[headache]]s (40%), dysesthetic limb pain (19%), back pain (17%), and painful [[spasm]]s (11%).<ref>{{cite journal |author=Pöllmann W, Feneberg W, Erasmus LP |title=[Pain in multiple sclerosis--a still underestimated problem. The 1 year prevalence of pain syndromes, significance and quality of care of multiple sclerosis inpatients] |language=German |journal=Der Nervenarzt |volume=75 |issue=2 |pages=135-40 |year=2004 |pmid=14770283 |doi=10.1007/s00115-003-1656-5}}</ref>

[[Acute (medical)|Acute]] pain is mainly due to [[optic neuritis]], being [[corticosteroids]] the best treatment available; to [[trigeminal neuralgia]], to [[Lhermitte's sign]] or to [[dysesthesias]].<ref>{{cite journal |author=Kerns RD, Kassirer M, Otis J |title=Pain in multiple sclerosis: a biopsychosocial perspective |journal=Journal of rehabilitation research and development |volume=39 |issue=2 |pages=225-32 |year=2002 |pmid=12051466 |doi=}}</ref> [[Subacute]] pain is usually secondary to the disease and can be consequence of being too much time in the same position, urinary retention, infected skin ulcers and many others. Treatment will depend on cause. [[Chronic (medical)|Chronic]] pain is very common and the harder to treat being its most common cause dysesthesias.

====Trigeminal neuralgia====
[[Trigeminal neuralgia]] or "tic douloureux", is a disorder of the [[trigeminal nerve]] that causes episodes of intense pain in the [[eye]]s, [[lip]]s, [[nose]], [[scalp]], [[forehead]], and [[jaw]]. It affects 1 to 2% of MS patients during their disease.<ref>{{cite journal |author=Brisman R |title=Trigeminal neuralgia and multiple sclerosis |journal=Arch. Neurol. |volume=44 |issue=4 |pages=379-81 |year=1987 |pmid=3493757 |doi=}}</ref><ref>{{cite journal |author=Bayer DB, Stenger TG |title=Trigeminal neuralgia: an overview |journal=Oral Surg. Oral Med. Oral Pathol. |volume=48 |issue=5 |pages=393-9 |year=1979 |pmid=226915 |doi=}}</ref>
The episodes of pain occur paroxysmally, or suddenly; and the patients describe it as trigger area on the face, so sensitive that touching or even air currents can bring an episode of pain. 
Usually it's  successfully treated with anticonvulsants such as 
[[carbamazepine]]<ref>Information from the USA National library of medicine on carbamazepine [http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682237.html]</ref> 
or [[phenytoin]]<ref>Information from the USA National library of medicine on phenytoin [http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682022.html]</ref>
but others such as [[gabapentin]]<ref>Information from the USA National library of medicine on gabapentin [http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a694007.html]</ref> can be used.
<ref>{{cite journal |author=Solaro C, Messmer Uccelli M, Uccelli A, Leandri M, Mancardi GL |title=Low-dose gabapentin combined with either lamotrigine or carbamazepine can be useful therapies for trigeminal neuralgia in multiple sclerosis |journal=Eur. Neurol. |volume=44 |issue=1 |pages=45-8 |year=2000 |pmid=10894995 |doi=}}</ref> 
When drugs are not effective enough surgery may be recommended. Further damage to the nerve  to prevent the transmission of pain (Rhyzotomy) has proven its efficacy;<ref>{{cite journal |author=Kondziolka D, Lunsford LD, Bissonette DJ |title=Long-term results after glycerol rhizotomy for multiple sclerosis-related trigeminal neuralgia |journal=The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques |volume=21 |issue=2 |pages=137-40 |year=1994 |pmid=8087740 |doi=}}</ref> 
however the beneficial effects and risks in multiple sclerosis patients of those procedures that consist in relieving the pressure on the nerve are still under discussion.<ref>{{cite journal |author=Athanasiou TC, Patel NK, Renowden SA, Coakham HB |title=Some patients with multiple sclerosis have neurovascular compression causing their trigeminal neuralgia and can be treated effectively with MVD: report of five cases |journal=British journal of neurosurgery |volume=19 |issue=6 |pages=463-8 |year=2005 |pmid=16574557 |doi=10.1080/02688690500495067}}</ref><ref>{{cite journal |author=Eldridge PR, Sinha AK, Javadpour M, Littlechild P, Varma TR |title=Microvascular decompression for trigeminal neuralgia in patients with multiple sclerosis |journal=Stereotactic and functional neurosurgery |volume=81 |issue=1-4 |pages=57-64 |year=2003 |pmid=14742965 |doi=10.1159/000075105}}</ref>

====Lhermitte's sign====
[[Lhermitte's sign]] is an electrical sensation that runs down the back and into the limbs, and is produced by bending the [[neck]] forward. The sign suggests a lesion of the dorsal columns of the [[cervical]] cord or of the caudal [[Medulla oblongata|medulla]]; correlating significantly with cervical [[MRI]] abnormalities.<ref> {{cite journal |author=Gutrecht JA, Zamani AA, Slagado ED |title=Anatomic-radiologic basis of Lhermitte's sign in multiple sclerosis |journal=Arch. Neurol. |volume=50 |issue=8 |pages=849-51 |year=1993 |pmid=8352672 |doi=}}</ref>
Between 25 and 40% of MS patients report having Lhermitte's sign during the course of their illness.
<ref>{{cite journal |author=Al-Araji AH, Oger J |title=Reappraisal of Lhermitte's sign in multiple sclerosis |journal=Mult. Scler. |volume=11 |issue=4 |pages=398-402 |year=2005 |pmid=16042221 |doi=}}</ref><ref>{{cite journal |author=Sandyk R, Dann LC |title=Resolution of Lhermitte's sign in multiple sclerosis by treatment with weak electromagnetic fields |journal=Int. J. Neurosci. |volume=81 |issue=3-4 |pages=215-24 |year=1995 |pmid=7628912 |doi=}}</ref><ref>{{cite journal |author=Kanchandani R, Howe JG |title=Lhermitte's sign in multiple sclerosis: a clinical survey and review of the literature |journal=J. Neurol. Neurosurg. Psychiatr. |volume=45 |issue=4 |pages=308-12 |year=1982 |pmid=7077340 |doi=}}</ref>
 
====Dysesthesias====
[[Dysesthesias]] are  disagreeable sensations produced by ordinary [[Stimulus (physiology)|stimuli]]. The abnormal sensations are often described as painful feelings such as burning, wetness, itching, electric shock or pins and needles; and are caused by lesions of the peripheral or central sensory pathways. Both Lhermitte's sign and painful dysesthesias usually respond well to treatment with [[carbamazepine]], [[clonazepam]] or [[amitriptyline]].
<ref>Information from the USA National library of medicine on clonazepam[http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682279.html]</ref><ref>Information from the USA National library of medicine on amitriptyline[http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682388.html]</ref><ref>{{cite journal |author=Moulin DE, Foley KM, Ebers GC |title=Pain syndromes in multiple sclerosis |journal=Neurology |volume=38 |issue=12 |pages=1830-4 |year=1988 |pmid=2973568 |doi=}}</ref>

===Sexual===
[[Sexual dysfunction]] (SD) is one of many symptoms affecting persons with a diagnosis of [[multiple sclerosis]] (MS) and other neurological disease.  SD in men encompasses both erectile and ejaculatory disorder.  The prevalence of SD in men with MS ranges from 75 to 91% (O'Leary et al., 2007).  [[Erectile dysfunction]] appears to be the most common form of SD documented in MS. SD may be due to alteration of the ejaculatory
reflexe which may be affected by neurological conditions such as MS <ref>O'Leary, M., Heyman, R., Erickson, J., Chancellor, M.B.: Premature ejaculation and MS: A Review, Consortium of MS Centers,  http://www.mscare.org, June 2007</ref>

===Spasticity===

[[Spasticity]] is characterised by increased stiffness and slowness in [[Limb (anatomy)|limb]] movement, the development of certain postures, an association with weakness of voluntary [[muscle]] power, and with involuntary and sometimes painful [[spasm]]s of limbs.<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> A physiotherapist can help to reduce spasticity and avoid the development of [[contracture]]s with techniques such as passive stretching.<ref name="pmid10871810">{{cite journal |author=Cardini RG, Crippa AC, Cattaneo D |title=Update on multiple sclerosis rehabilitation |journal=J. Neurovirol. |volume=6 Suppl 2 |issue= |pages=S179–85 |year=2000 |pmid=10871810 |doi=}}</ref> There is evidence, albeit limited, of the clinical effectiveness of [[baclofen]],<ref>; [http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682530.html Baclofen oral.] US National Library of Medicine (Medline) ([[2003-04-01]]). Retrieved on [[2007-10-17]].</ref> [[dantrolene]],<ref> [http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682576.html Dantrolene oral.] US National Library of Medicine (Medline) ([[2003-04-01]]). Retrieved on [[2007-10-17]].</ref> [[diazepam]],<ref> [http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682047.html Diazepam.] US National Library of Medicine (Medline) ([[2005-07-01]]). Retrieved on [[2007-10-17]].</ref> and [[tizanidine]].<ref> [http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a601121.html Tizanidine.] US National Library of Medicine (Medline) ([[2005-07-01]]). Retrieved on [[2007-10-17]].</ref><ref name="pmid14636486">{{cite journal |author=Beard S, Hunn A, Wight J |title=Treatments for spasticity and pain in multiple sclerosis: a systematic review |journal=Health technology assessment (Winchester, England) |volume=7 |issue=40 |pages=iii, ix–x, 1–111 |year=2003 |pmid=14636486 |doi=}}</ref><ref name="pmid12166503">{{cite journal |author=Paisley S, Beard S, Hunn A, Wight J |title=Clinical effectiveness of oral treatments for spasticity in multiple sclerosis: a systematic review |journal=Mult. Scler. |volume=8 |issue=4 |pages=319–29 |year=2002 |pmid=12166503 |doi=}}</ref> In the most complicated cases [[intrathecal]] injections of baclofen can be used.<ref name="pmid8529173">{{cite journal |author=Becker WJ, Harris CJ, Long ML, Ablett DP, Klein GM, DeForge DA |title=Long-term intrathecal baclofen therapy in patients with intractable spasticity |journal=The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques |volume=22 |issue=3 |pages=208–17 |year=1995 |pmid=8529173 |doi=}}</ref> There are also [[palliative]] measures like [[casting]]s, [[splint (medical)|splints]] or customised seatings.<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>

===Transverse myelitis===
{{Main|Transverse myelitis}}

Some MS patients develop rapid onset of [[paresthesia|numbness]], weakness, [[bowel]] or [[Urinary bladder|bladder]] dysfunction, and/or loss of [[motor neuron|muscle]] function, typically in the lower half of the body. This is the result of MS attacking the [[spinal cord]]. The symptoms and signs depend upon the level of the spinal cord involved and the extent of the involvement.

Prognosis for complete recovery is generally poor. Recovery from transverse myelitis usually begins between weeks 2 and 12 following onset and may continue for up to 2 years in some patients and as many as 80% of individuals with transverse myelitis are left with lasting disabilities.

Treatment is usually symptomatic only, corticosteroids being used with limited success.

===Tremor and ataxia===
 {{Main|Tremor}}
[[Tremor]] is an unintentional, somewhat rhythmic, muscle movement involving to-and-fro movements (oscillations) of one or more parts of the body.  It is the most common of all involuntary movements and can affect the hands, arms, head, face, vocal cords, trunk, and legs. 

[[Ataxia]] is an unsteady and clumsy motion of the limbs or torso due to a failure of the gross coordination of muscle movements. People with ataxia experience a failure of muscle control in their arms and legs, resulting in a lack of balance and coordination or a disturbance of [[Gait (human)|gait]].

Tremor and ataxia are frequent in MS. They present in 25 to 60% of patients. They can be very disabling and embarrassing, and are difficult to manage.<ref>{{cite journal |author=Koch M, Mostert J, Heersema D, De Keyser J |title=Tremor in multiple sclerosis |journal=J. Neurol. |volume=254 |issue=2 |pages=133-45 |year=2007 |pmid=17318714 |doi=10.1007/s00415-006-0296-7}}</ref> The origin of tremor in MS is difficult to precise but it can be due to a mixture of different factors such as damage to the [[cerebellar]] connections, weakness, [[spasticity]], etc.

In the treatment of tremor many medications have been proposed; however their efficacy is very limited. Medications that have been reported to provide some relief are [[isoniazid]],<ref>{{cite journal |author=Bozek CB, Kastrukoff LF, Wright JM, Perry TL, Larsen TA |title=A controlled trial of isoniazid therapy for action tremor in multiple sclerosis |journal=J. Neurol. |volume=234 |issue=1 |pages=36-9 |year=1987 |pmid=3546605 |doi=}}</ref><ref>{{cite journal |author=Duquette P, Pleines J, du Souich P |title=Isoniazid for tremor in multiple sclerosis: a controlled trial |journal=Neurology |volume=35 |issue=12 |pages=1772-5 |year=1985 |pmid=3906430 |doi=}}</ref><ref>{{cite journal |author=Hallett M, Lindsey JW, Adelstein BD, Riley PO |title=Controlled trial of isoniazid therapy for severe postural cerebellar tremor in multiple sclerosis |journal=Neurology |volume=35 |issue=9 |pages=1374-7 |year=1985 |pmid=3895037 |doi=}}</ref><ref>Information from the USA National library of medicine on Isoniazid
[http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682401.html]</ref> [[carbamazepine]],<ref>Information from the USA National library of medicine on carbamazepine [http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682237.html]</ref> [[propranolol]];<ref>{{cite journal |author=Koller WC |title=Pharmacologic trials in the treatment of cerebellar tremor |journal=Arch. Neurol. |volume=41 |issue=3 |pages=280-1 |year=1984 |pmid=6365047 |doi=}}</ref><ref>{{cite journal |author=Sechi GP, Zuddas M, Piredda M, Agnetti V, Sau G, Piras ML, Tanca S, Rosati G |title=Treatment of cerebellar tremors with carbamazepine: a controlled trial with long-term follow-up |journal=Neurology |volume=39 |issue=8 |pages=1113-5 |year=1989 |pmid=2668787 |doi=}}</ref><ref>Information from the USA National library of medicine on propanolol [http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682607.html]</ref> and gluthetimide,<ref>{{cite journal |author=Aisen ML, Holzer M, Rosen M, Dietz M, McDowell F |title=Glutethimide treatment of disabling action tremor in patients with multiple sclerosis and traumatic brain injury |journal=Arch. Neurol. |volume=48 |issue=5 |pages=513-5 |year=1991 |pmid=2021365 |doi=}}</ref> but published evidence of effectiveness is very limited.<ref>{{cite journal |author=Mills RJ, Yap L, Young CA |title=Treatment for ataxia in multiple sclerosis |journal=Cochrane database of systematic reviews (Online) |volume= |issue=1 |pages=CD005029 |year=2007 |pmid=17253537 |doi=10.1002/14651858.CD005029.pub2}}</ref>

[[Physical therapy]] is not indicated as a treatment for tremor or ataxia; however, the use of different [[Orthotics|orthese]] devices can help. An example is the use of wrist bandages with weights, which can be useful to increase the [[inertia]] of movement and therefore reduce tremor.<ref>{{cite journal |author=Aisen ML, Arnold A, Baiges I, Maxwell S, Rosen M |title=The effect of mechanical damping loads on disabling action tremor |journal=Neurology |volume=43 |issue=7 |pages=1346-50 |year=1993 |pmid=8327136 |doi=}}</ref> Daily use objects have also to be adapted so they are easier to grab and use. 

If all these measures fail some patients are candidates for [[thalamus]] [[surgery]]. This kind of surgery can be both a [[thalamotomy]] or the implantation of a [[thalamic stimulator]]. Complications are frequent (30% in thalamotomy and 10% in deep brain stimulation) and include a worsening of ataxia, [[dysarthria]] and [[hemiparesis]]. 

Thalamotomy is a more efficacious surgical treatment for intractable MS tremor, however the higher incidence of persistent neurological deficits in patients receiving lesional surgery supports the use of deep brain stimulation as the preferred surgical strategy.<ref>{{cite journal |author=Bittar RG, Hyam J, Nandi D, Wang S, Liu X, Joint C, Bain PG, Gregory R, Stein J, Aziz TZ |title=Thalamotomy versus thalamic stimulation for multiple sclerosis tremor |journal=Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia |volume=12 |issue=6 |pages=638-42 |year=2005 |pmid=16098758 |doi=10.1016/j.jocn.2004.09.008}}</ref>

==Diagnosis==
[[Image:Optokinetic nystagmus.gif|thumb|left|[[Pathologic nystagmus|Nystagmus]], characterised by involuntary eye movements, is one of many symptoms that can appear with MS]]
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.

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>

* 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.
* [[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.
* 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.
* 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>

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>.

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>),
[[tumor]]s, and other autoimmune problems, such as [[lupus erythematosus|lupus]]. Additional testing may be needed to help distinguish MS from these other problems.

==== MRI====

<gallery>
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.
Image:Multiple Sclerosis2.jpg|Multiple Sclerosis
</gallery>

'''Patient #1'''

[http://www.radswiki.net Images courtesy of RadsWiki]

<gallery perRow="3">
Image:Multiple-sclerosis-001.jpg|Multiple sclerosis
Image:Multiple-sclerosis-002.jpg|Multiple sclerosis
Image:Multiple-sclerosis-003.jpg|Multiple sclerosis
Image:Multiple-sclerosis-004.jpg|Multiple sclerosis
Image:Multiple-sclerosis-005.jpg|Multiple sclerosis
Image:Multiple-sclerosis-006.jpg|Multiple sclerosis
</gallery>


'''Patient #2: Contrast enchancement of several lesions indicates active disease'''

[http://www.radswiki.net Images courtesy of RadsWiki]

<gallery>
Image:Active-multiple-sclerosis-001.jpg
Image:Active-multiple-sclerosis-002.jpg
Image:Active-multiple-sclerosis-004.jpg
Image:Active-multiple-sclerosis-003.jpg|GAD enhanced T1
</gallery>

==Disease course and clinical subtypes==
[[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>

;Relapsing-remitting
: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.
;Secondary progressive
: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]].
;Primary progressive
: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.
;Progressive relapsing
: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

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>

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>

==Factors triggering a relapse==
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>
[[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.
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.
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>

[[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%&ndash;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>

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>

==Treatment==
{{main|treatment of multiple sclerosis}}

Although there is no known cure for multiple sclerosis, several therapies have proven helpful.
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.

===Management of acute attacks===
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>

===Disease modifying treatments===
[[Image:Injection 23.JPG|right|thumb|Disease-modifying treatments are expensive and require frequent injections.]]
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 |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>

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> 
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> 

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>

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>

=== Management of the effects of MS ===
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> 
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

===Therapies under investigation===
{{main|therapies under investigation for multiple sclerosis}}

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.

===Alternative treatments===
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>
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>

==Prognosis==
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>

*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.
*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.
*The degree of disability varies among individuals with MS.  In general, one of three individuals will still be able to work after 15&ndash;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.

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>

==Research directions==
{{Main|Therapies under investigation for multiple sclerosis}}
A number of treatments that may curtail attacks or improve function are under investigation. Some of these treatments involve the combination of drugs that are already in use for multiple sclerosis, such as the joint administration 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. These are [[alemtuzumab]] (trade name ''Campath''),<ref> [http://www.genzyme.com/corp/media/GENZ%20PR-050207.asp Genzyme and Bayer HealthCare Announce Detailed Interim Two-Year Alemtuzumab in Multiple Sclerosis Data Presented at AAN.] Genzyme (2007-02-01). Retrieved on 2007-09-02.</ref> [[daclizumab]] (trade name ''Zenapax''),<ref> [http://www.pdl.com/index.cfm?navId=49 Daclizumab.] PDL Biopharma  (2006-01-01). Retrieved on 2007-09-02.</ref> [[inosine]],<ref> [http://www.clinicaltrials.gov/ct/show/NCT00067327 Treatment of Multiple Sclerosis Using Over the Counter Inosine.] ClinicalTrials.gov (2006-03-16). Retrieved on 2007-09-02.</ref> BG00012,<ref>[http://www.clinicaltrials.gov/ct2/show/NCT00420212?term=biogen&recr=Open&rank=12 Efficacy and Safety of BG00012 in Relapsing-Remitting Multiple Sclerosis.] ClinicalTrials.gov (2007-09-01). Retrieved on 2007-11-12.</ref> [[fingolimod]],<ref> [http://www.clinicaltrials.gov/ct/show/NCT00289978 Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis.] ClinicalTrials.gov (2006-02-09). Retrieved on 2007-09-02.</ref> and teriflunomide, the active metabolite of the [[DMARD]] [[leflunomide]]. Alemtuzumab performed better than interferon beta-1a in relapsing-remitting MS reducing disability, imaging abnormalities and frequence of relapses, at the cost of increased [[autoimmunity]] problems. These included three cases of [[immune thrombocytopenic purpura|thrombocytopenic purpura]] which led to the suspension of the therapy.<ref name="pmid1234567">{{cite journal |author=The CAMMS223 Trial Investigators |title=Alemtuzumab vs. Interferon Beta-1a in Early Multiple Sclerosis |journal=N Engl J Med |volume=359 |issue=17 |pages=1786–1801 |year=2008 |pmid=18946064 |doi= |url=}}</ref>

Other drugs in clinical trials have been designed specifically for MS, such as [[laquinimod]],<ref name="pmid15781813">{{cite journal |author=Polman C, Barkhof F, Sandberg-Wollheim M, Linde A, Nordle O, Nederman T |title=Treatment with laquinimod reduces development of active MRI lesions in relapsing MS |journal=Neurology |volume=64 |issue=6 |pages=987–91 |year=2005 |pmid=15781813 |doi=10.1212/01.WNL.0000154520.48391.69}}</ref> and ''[[Neurovax]]''.<ref>{{cite journal |author=Darlington CL |title=Technology evaluation: NeuroVax, Immune Response Corp |journal=Curr. Opin. Mol. Ther. |volume=7 |issue=6 |pages=598–603 |year=2005 |pmid=16370383 |doi=}}</ref>

[[Low dose naltrexone]] has been prescribed off-label for certain autoimmune disorders, including MS, and there is anecdotal evidence of benefit,<ref>{{cite journal |author=Agrawal YP |title=Low dose naltrexone therapy in multiple sclerosis |journal=Med. Hypotheses |volume=64 |issue=4 |pages=721–4 |year=2005 |pmid=15694688 |doi=10.1016/j.mehy.2004.09.024 |url=}}</ref><ref>[http://clinicaltrials.gov/ct2/results?term=Low+dose+naltrexone+Multiple+Sclerosis search of clinicaltrials.gov data-base for Low dose naltrexone Multiple Sclerosis]</ref> but only two small clinical trials have been conducted (as on December 2008), one in San Francisco, USA,<ref>[http://clinicaltrials.gov/ct2/show/NCT00501696?term=Low+dose+naltrexone+Multiple+Sclerosis&rank=1 2007 clinical trial using LDN]</ref> the other for the primary progressive variety in Milan, Italy.<ref name="pmid18728058">{{cite journal |author=Gironi M, Martinelli-Boneschi F, Sacerdote P, Solaro C, Zaffaroni M, Cavarretta R, Moiola L, Bucello S, Radaelli M, Pilato V, Rodegher M, Cursi M, Franchi S, Martinelli V, Nemni R, Comi G, Martino G |title=A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis. |journal=Multiple Sclerosis |volume=14 |issue=8 |pages=1076–83 |year=2008 |pmid=18728058 |doi=}}</ref>

New diagnostic and evolution evaluation methods are also being investigated. The measurement of [[antibody|antibodies]] against myelin [[protein]]s such as [[myelin oligodendrocyte glycoprotein]] and [[myelin basic protein]] could be useful for diagnosis. [[Optical coherence tomography]] of the eye's [[retina]] could be used as a measure of response to medication, axonal degeneration and brain atrophy.<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 = 1595|year=2007 |pmid=17987252 |doi=10.1007/s00415-007-0538-3}}</ref><ref>{{cite journal |author=Gordon-Lipkin E, Chodkowski B, Reich DS ''et al'' |year=2007 |month=October |title=Retinal nerve fiber layer is associated with brain atrophy in multiple sclerosis |journal=Neurology |volume=69 |issue=16 |pages=1603–09 |pmid=17938370 | doi = 10.1212/01.wnl.0000295995.46586.ae <!--Retrieved from CrossRef by DOI bot-->}}</ref> Currently there are no clinically established laboratory investigations available that can predict prognosis.  However, several promising approaches have been proposed, such as the measurement of a [[lipid]]-specific [[immunoglobulin M]] as predictor of long-term outcomes.<ref name="pmid18755821">{{cite journal
|author=Thangarajh M, Gomez-Rial J, Hedström AK, ''et al''
|title=Lipid-specific immunoglobulin M in CSF predicts adverse long-term outcome in multiple sclerosis
|journal=Mult. Scler.
|volume=
|issue=
|pages=
|year=2008
|month=August
|pmid=18755821
|doi=10.1177/1352458508095729
|url=
}}</ref>

==Additional Images==

<gallery perRow="3">
Image:MS Demyelinisation KB 10x.jpg|Demyelinization in MS. On Klüver-Barrera myelin staining, decoloration in the area of the lesion can be appreciated (Original scale 1:100).
Image:Symptoms of multiple sclerosis.png|Main symptoms of multiple sclerosis.
Image:MS Risk.jpg|World map showing that risk for MS increases with greater distance from the equator
Image:Carswell-Multiple Sclerosis2.jpg|Detail of drawing from Carswell book depicting multiple sclerosis lesions in the [[brain stem]] and [[spinal cord]] (1838)
Image:Alemtuzumab Fab 1CE1.png|thumb|left|upright|Chemical structure of [[alemtuzumab]].
</gallery>

==References==
{{reflist|2}}

==See also==
* MS fundraisers include the [[MS Challenge Walk]], MS Walk and [[MS Bike Tour]].
* [[List of multiple sclerosis organizations]]

==Further reading==
* [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.
* [http://www.mult-sclerosis.org/chooseglossary.html Multiple Sclerosis Encyclopedia]

==External links==
* {{dmoz|Health/Conditions_and_Diseases/Neurological_Disorders/Demyelinating_Diseases/Multiple_Sclerosis/}}
* [http://www.atlasofms.org/ Database for analysis and comparison of global data on the epidemiology of MS]
* [http://clinicaltrials.gov/search/term=Multiple+Sclerosis NIH listing of clinical trials related to MS]
* [http://www.cochrane.org/reviews/en/topics/79.html Abstract index] of the [[Cochrane Library]]

{{Multiple sclerosis}}
{{Diseases of the nervous system}}
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