Multiple sclerosis

From Wikipedia, the free encyclopedia

Jump to: navigation, search
Multiple sclerosis
Classification and external resources

Demyelinization by MS. The CD68 colored tissue shows several macrophages in the area of the lesion. Original scale 1:100
ICD-10 G35.
ICD-9 340
OMIM 126200
DiseasesDB 8412
MedlinePlus 000737
eMedicine neuro/228 oph/179 emerg/321 pmr/82 radio/461
MeSH D009103

Multiple sclerosis (abbreviated MS, also known as disseminated sclerosis or encephalomyelitis disseminata) is a disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms.[1] Disease onset usually occurs in young adults, and it is more common in females.[1] It has a prevalence that ranges between 2 and 150 per 100,000.[2] MS was first described in 1868 by Jean-Martin Charcot.[3]

MS affects the ability of nerve cells in the brain and spinal cord to communicate with each other. Nerve cells communicate by sending electrical signals called action potentials down long fibers called axons, which are wrapped in an insulating substance called myelin. In MS, the body's own immune system attacks and damages the myelin. When myelin is lost, the axons can no longer effectively conduct signals.[4] The name multiple sclerosis refers to scars (scleroses—better known as plaques or lesions) in the white matter of the brain and spinal cord, which is mainly composed of myelin.[3] Although much is known about the mechanisms involved in the disease process, the cause remains unknown. Theories include genetics or infections. Different environmental risk factors have also been found.[4][5]

Almost any neurological symptom can appear with the disease, and often progresses to physical and cognitive disability[4] and neuropsychiatric disorder.[6] MS takes several forms, with new symptoms occurring either in discrete attacks (relapsing forms) or slowly accumulating over time (progressive forms).[7] Between attacks, symptoms may go away completely, but permanent neurological problems often occur, especially as the disease advances.[7]

There is no known cure for MS. Treatments attempt to return function after an attack, prevent new attacks, and prevent disability.[4] MS medications can have adverse effects or be poorly tolerated, and many patients pursue alternative treatments, despite the lack of supporting scientific study. The prognosis is difficult to predict; it depends on the subtype of the disease, the individual patient's disease characteristics, the initial symptoms and the degree of disability the person experiences as time advances.[8] Life expectancy of patients is nearly the same as that of the unaffected population.[8]

Contents

[edit] Classification

Progression of MS subtypes

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. They are important not only for prognosis but also for therapeutic decisions. In 1996 the United States National Multiple Sclerosis Society standardized four subtype definitions:[7]

  1. relapsing remitting,
  2. secondary progressive,
  3. primary progressive, and
  4. progressive relapsing.

The relapsing-remitting subtype is characterized by unpredictable relapses followed by periods of months to years of relative quiet (remission) with no new signs of disease activity. Deficits suffered during attacks may either resolve or leave sequelae, the latter being more common as a function of time.[1] This describes the initial course of 85–90% of individuals with MS.[7] When deficits always resolve between attacks, this is sometimes referred to as benign MS.[9] The relapsing-remitting subtype usually begins with a clinically isolated syndrome (CIS). In CIS, a patient has an attack suggestive of demyelination, but does not fulfill the criteria for multiple sclerosis.[1][10] However only 30 to 70% of persons experiencing CIS later develop MS.[10]

Secondary progressive MS describes around 65 % of those with an initial relapsing-remitting MS, who then begin to have progressive neurologic decline between acute attacks without any definite periods of remission.[1][7] Occasional relapses and minor remissions may appear.[7] The median time between disease onset and conversion from relapsing-remitting to secondary progressive MS is 19 years.[11]

The primary progressive subtype describes the approximately 10–15% of individuals who never have remission after their initial MS symptoms.[12] It is characterized by progression of disability from onset, with no, or only occasional and minor, remissions and improvements.[7] The age of onset for the primary progressive subtype is later than for the relapsing-remitting, but similar to mean age of progression between the relapsing-remitting and the secondary progresive. In both cases it is around 40 years of age.[1]

Progressive relapsing MS describes those individuals who, from onset, have a steady neurologic decline but also suffer clear superimposed attacks. This is the least common of all subtypes.[7]

Cases with non-standard behavior have also been described. Sometimes referred to as borderline forms of multiple sclerosis, these include Devic's disease, Balo concentric sclerosis, Schilder's diffuse sclerosis and Marburg multiple sclerosis.[13] There is debate whether these are atypical variants of MS or different diseases.[14] Multiple sclerosis also behaves differently in children, taking them more time to reach the progressive stage.[1] Nevertheless they still reach it at a lower mean age than adults.[1]

[edit] Signs and symptoms

Main article: Multiple sclerosis signs and symptoms
Main symptoms of multiple sclerosis
Nystagmus, characterised by involuntary eye movements, is one of many symptoms that can appear with MS.

The person with MS can suffer almost any neurological symptom or sign, including changes in sensation (hypoesthesia and paraesthesia), muscle weakness, 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, acute or chronic pain, and bladder and bowel difficulties.[1] Cognitive impairment of varying degrees and emotional symptoms of depression or unstable mood are also common.[1] Uhthoff's phenomenon, an exacerbation of extant symptoms due to an exposure to higher than usual ambient temperatures, and lhermitte's sign, an electrical sensation that runs down the back when bending the neck, are particularly characteristic of MS although not specific.[1] The main clinical measure of disability progression and symptom severity is the Expanded Disability Status Scale or EDSS.[15]

Symptoms of MS usually appear in episodic acute periods of worsening (called relapses, exacerbations, bouts, attacks, or "flare-ups"), in a gradually progressive deterioration of neurologic function, or in a combination of both.[7] Multiple sclerosis relapses are often unpredictable, occurring without warning and without obvious inciting factors with a rate rarely above 1 and a half per year.[1] Some attacks, however, are preceded by common triggers. Relapses occur more frequently during spring and summer.[16] Viral infections such as the common cold, influenza, or gastroenteritis increase the risk of relapse.[1] Stress may also trigger an attack.[17] Pregnancy affects the susceptibility to relapse, with a lower relapse rate at each trimester of gestation. During the first few months after delivery, however, the risk of relapse is increased.[1] Overall, pregnancy does not seem to influence long-term disability. Many potential triggers have been examined and found not to influence MS relapse rates. There is no evidence that vaccination and breast feeding,[1] physical trauma,[18] or Uhthoff's phenomenon,[16] are relapse triggers.

[edit] Causes

Most likely MS occurs as a result of some combination of both environmental and genetic factors.[1] Epidemiological studies of MS have provided hints on possible causes for the disease. Theories try to combine the known data into plausible explanations, but none has proved definitive.

[edit] Genetics

HLA region of Chromosome 6. Changes in this area increase the probability of suffering MS.

MS is not considered a hereditary disease. However, a number of genetic variations have been shown to increase the risk of developing the disease.[19]

The risk of acquiring MS is higher in relatives of a person with the disease than in the general population, especially in the case of siblings, parents, and children.[4] The disease has an overall familial recurrence rate of 20%.[1] In the case of monozygotic twins, concordance occurs only in about 35% of cases, while it goes down to around 5% in the case of siblings and even lower in half-siblings. This indicates susceptibility is partly polygenically driven.[4][1]

Apart from familial studies, specific genes have been linked with MS. Differences in the human leukocyte antigen (HLA) system—a group of genes in chromosome 6 that serves as the major histocompatibility complex (MHC) in humans—increase the probability of suffering MS.[1] The most consistent finding is the association between multiple sclerosis and alleles of the MHC defined as DR15 and DQ6.[1] Other loci have shown a protective effect, such as HLA-C554 and HLA-DRB1*11.[1]

[edit] Environmental factors

Different environmental factors, both of infectious and non infectious origin have been proposed to as risk factors for MS. Although some are partly modifiable, only further research—especially clinical trials—will reveal whether their elimination can help prevent MS.[20]

MS is more common in people who live farther from the equator, although many exceptions exist.[1] Decreased sunlight exposure has been linked with a higher risk of MS.[20] Decreased vitamin D production and intake has been the main biological mechanism used to explain the higher risk among those less exposed to sun.[20][21]

Severe stress may also be a risk factor although evidence is weak.[20] Smoking has also been shown to be an independent risk factor for developing MS.[21] Association with occupational exposures and toxins—mainly solvents—has been evaluated, but no clear conclusions have been reached.[20] Vaccinations were also considered as causal factors for the disease; however, most studies show no association between MS and vaccines.[20] Several other possible risk factors, such as diet and hormone intake, have been investigated; however, more evidence is needed to confirm or refute their relation with the disease.[21]

Gout occurs less than would statistically be expected in people with MS, and low levels of uric acid have been found in MS patients as compared to normal individuals. This led to the theory that uric acid protects against MS, although its exact importance remains unknown.[22]

[edit] Infections

Genetic susceptibility can explain some of the geographic and epidemiological variations in MS incidence, like the high appearance of the disease among some families or the risk decline with genetic distance, but does not account for other phenomena, such as the changes in risk that occur with migration at an early age.[5]

An explanation for this epidemiology finding could be that some kind of infection, produced by a widespread microbe rather than a rare pathogen, is the origin of the disease.[5] Different hypotheses have elaborated on the mechanism by which this may occur. The hygiene hypothesis proposes that exposure to several infectious agents early in life is protective against MS. MS would be an autoimmune reaction triggered in susceptible individuals by multiple infective microorganisms.[1] The prevalence hypothesis proposes that the disease is due to a pathogen more common in regions of high MS prevalence. This pathogen is very common, causing in most individuals an asymptomatic persistent infection. Only in a few cases, and after many years since the original infection, does it bring demyelination.[5][23] The hygiene hypothesis has received more support than the prevalence hypothesis.[5]

Evidence for viruses as a cause includes the presence of oligoclonal bands in the brain and cerebrospinal fluid of most patients, the association of several viruses with human demyelinating encephalomyelitis, and induction of demyelination in animals through viral infection.[24] Human herpes viruses are a candidate group of viruses linked to MS;[25] Varicella zoster virus has been found at high levels in the cerebrospinal fluid of MS patients,[26] but the most reproduced finding is the reduced risk of having the disease in those who have never been infected by the Epstein-Barr virus[5],[27] together with the correlation of its markers with disease activity.[28] This goes against the hygiene hypothesis, since the non-infected have probably experienced a more hygienic upbringing.[5] Other agents that have also been related with MS are human endogenous retroviruses and Chlamydia pneumoniae.[29][30][31]

[edit] Pathophysiology

Main article: Pathophysiology of multiple sclerosis

[edit] Blood-brain barrier breakdown

Demyelination in MS. On Klüver-Barrera myelin staining, decoloration in the area of the lesion can be appreciated (Original scale 1:100).

The blood–brain barrier is a capillary system that should prevent entrance of T cells into the nervous system.[4] The blood–brain barrier is normally not permeable to these types of cells, unless triggered by infection or a virus, which decreases the integrity of the tight junctions forming the barrier.[4] When the blood–brain barrier regains its integrity, usually after infection or virus has cleared, the T cells are trapped inside the brain.[4]

[edit] Autoimmunology

MS is currently believed to be an immune-mediated disorder with an initial trigger, which may have a viral etiology,[4] although this concept has been debated for years and some still oppose it. Damage is believed to be caused by the patient's own immune system. The immune system attacks the nervous system, possibly as a result of exposure to a molecule with a similar structure to one of its own.[4]

Lesions

The name multiple sclerosis refers to the scars (scleroses – better known as plaques or lesions) that form in the nervous system. MS lesions most commonly involve white matter areas close to the ventricles of the cerebellum, brain stem, basal ganglia and spinal cord; and the optic nerve. The function of white matter cells is to carry signals between grey matter areas, where the processing is done, and the rest of the body. The peripheral nervous system is rarely involved.[4]

More specifically, MS destroys oligodendrocytes, the cells responsible for creating and maintaining a fatty layer—known as the myelin sheath—which helps the neurons carry electrical signals.[4] MS results in a thinning or complete loss of myelin and, as the disease advances, the cutting (transection) of the neuron's extensions or axons.[32] When the myelin is lost, a neuron can no longer effectively conduct electrical signals.[4] A repair process, called remyelination, takes place in early phases of the disease, but the oligodendrocytes cannot completely rebuild the cell's myelin sheath.[33] Repeated attacks lead to successively fewer effective remyelinations, until a scar-like plaque is built up around the damaged axons.[33] Four different lesion patterns have been described.[34]

Inflammation

Apart from demyelination, the other pathologic hallmark of the disease is inflammation. According to a strictly immunological explanation of MS, the inflammatory process is caused by T cells, a kind of lymphocyte. Lymphocytes are cells that play an important role in the body's defenses.[4] In MS, T cells gain entry into the brain via the previously described blood–brain barrier. Recent evidence from animal models also point to a role of B cells in addition to T cells in development of the disease.[35][36]

The T cells recognize myelin as foreign and attack it as if it were an invading virus. This triggers inflammatory processes, stimulating other immune cells and soluble factors like cytokines and antibodies. Leaks form in the blood–brain barrier, which in turn cause a number of other damaging effects such as swelling, activation of macrophages, and more activation of cytokines and other destructive proteins.[4]

[edit] Diagnosis

T1-weighted MRI scans (post-contrast) of the same brain slice at monthly intervals. Bright spots indicate active lesions.

Multiple sclerosis can be difficult to diagnose since its signs and symptoms may be similar to other medical problems.[1][37] Medical organizations have created diagnostic criteria to ease and standardize the diagnostic process for practicing physicians, specially in the first stages of the disease.[1] Historically, the Schumacher and Poser criteria were both popular.[38] Currently, the McDonald criteria focus on a demonstration with clinical, laboratory and radiologic data of the dissemination of MS lesions in time and space.[1][39][40]

Clinical data alone may be sufficient for a diagnosis of MS if an individual has suffered separate episodes of neurologic symptoms characteristic of MS.[39] Since some people seek medical attention after only one attack, other testing may hasten and ease the diagnosis. The most commonly used diagnostic tools are neuroimaging, analysis of cerebrospinal fluid and evoked potentials. Magnetic resonance imaging of the brain and spine shows areas of demyelination (lesions or plaques). Gadolinium can be administered intravenously as a contrast to highlight active plaques and, by elimination, demonstrate the existence of historical lesions not associated with symptoms at the moment of the evaluation.[39][41]

Testing of cerebrospinal fluid obtained from a lumbar puncture can provide evidence of chronic inflammation of the central nervous system. The cerebrospinal fluid is tested for oligoclonal bands, which are an inflammation marker found in 75–85% of people with MS.[39].[42] Since no known test is perfectly specific to MS, only biopsies or post-mortem examinations can yield an absolutely certain diagnosis.

The nervous system of a person with MS often responds less actively to stimulation of the optic nerve and sensory nerves due to demyelination of such pathways. These brain responses can be examined using visual and sensory evoked potentials.[43]

[edit] Management

Main article: 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 effects. Alternative treatments are pursued by some patients, despite the shortage of supporting, comparable, replicated scientific study.

[edit] Acute attacks

During symptomatic attacks, administration of high doses of intravenous corticosteroids, such as methylprednisolone,[44][45] 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 symptoms, corticosteroid treatments do not appear to have a significant impact on long-term recovery.[46] Potential side effects include osteoporosis[47] and impaired memory, the latter being reversible.[48] Severe attacks which do not respond to corticosteroids might be treated by plasmapheresis.[49]

[edit] Disease-modifying treatments

Disease-modifying treatments are expensive and most of these require frequent (up-to-daily) injections. Others require IV infusions at 1–3 month intervals.

The earliest clinical presentation of relapsing-remitting MS (RRMS) is the clinically isolated syndrome (CIS). Several studies have shown that treatment with interferons during an initial attack can decrease the chance that a patient will develop clinical MS.[50][51][52]

As of 2007, six disease-modifying treatments have been approved by regulatory agencies of different countries for RRMS. Three are interferons: two formulations of interferon beta-1a (trade names Avonex, CinnoVex, ReciGen 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), a non-interferon, non-steroidal immunomodulator. The fifth medication, mitoxantrone, is an immunosuppressant also used in cancer chemotherapy, approved only in the USA and largely for secondary progressive MS. 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 their efficacy rates differ, and studies of their long-term effects are still lacking.[53][54][55][56] Comparisons between immunomodulators (all but mitoxantrone) show that the most effective is natalizumab, both in terms of relapse rate reduction and halting disability progression;[57] it has also been shown to reduce the severity of MS.[58] Mitoxantrone may be the most effective of them all;[59] however, it is generally not considered as a long-term therapy, as its use is limited by severe cardiotoxicity.[60]

The interferons and glatiramer acetate are delivered by frequent injections, varying from once-per-day for glatiramer acetate to once-per-week (but intra-muscular) for Avonex. Natalizumab and mitoxantrone are given by IV infusion at monthly intervals.

Treatment of progressive MS is more difficult than relapsing-remitting MS. Mitoxantrone has shown positive effects in patients with 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.[56] No treatment has been proven to modify the course of primary progressive MS.[61]

As with any medical treatment, these treatments have several adverse effects. One of the most common is irritation at the injection site for glatiramer acetate and the interferon treatments. Over time, a visible dent at the injection site, due to the local destruction of fat tissue, known as lipoatrophy, may develop. Interferons produce symptoms similar to influenza;[62] 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.[54] More dangerous are liver damage from interferons and mitoxantrone,[63][64][65][66][67] the immunosuppressive effects and cardiac toxicity of the latter;[67] and the putative link between natalizumab and some cases of progressive multifocal leukoencephalopathy.[68][69][70]

[edit] Management of the effects of MS

Disease-modifying treatments 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. Management of these deficits is therefore very important. Both drug therapy and neurorehabilitation have shown to ease the burden of some symptoms, though neither influences disease progression.[71] As for any patient with neurologic deficits, a multidisciplinary approach is key to 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.[72] Multidisciplinary rehabilitation programmes increase activity and participation of patients but do not influence impairment level.[73] Additionally for each symptom there are different treatment options. Treatments should therefore be individualized depending both on the patient and the physician. More specifically psychological interventions seem useful in the treatment of depression, while evidence on effectiveness for other uses such as the treatment of cognitive impairments or vocational counseling is less strong.[74][75]

[edit] Alternative treatments

As with most chronic diseases, alternative treatments are pursued by some patients, despite the shortage of supporting, comparable, replicated scientific study. Examples are dietary regimens,[76] herbal medicine, including the use of medical cannabis to help alleviate symptoms,[77][78] and hyperbaric oxygenation.[79] The therapeutic practice of martial arts such as tai chi, relaxation disciplines such as yoga, or general exercise seems to mitigate fatigue, but has no effect on cognitive function.[80]

[edit] Prognosis

Disability-adjusted life year for multiple sclerosis per 100,000 inhabitants in 2002
     no data      less than 13      13–16      16–19      19–22      22–25      25–28      28–31      31–34      34–37      37–40      40–43      more than 43

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, age, and initial symptoms; and the degree of disability the person experiences.[8] The disease evolves and advances over decades, 30 being the mean years to death since onset.[1]

Female sex, relapsing-remitting subtype, optic neuritis or sensory symptoms at onset, few attacks in the initial years and especially early age at onset, are associated with a better course.[8][81]

The life expectancy of people with MS is 5 to 10 years lower to that of unaffected people.[1] Almost 40% of patients reach the seventh decade of life.[81] Nevertheless, two thirds of the deaths in people with MS are directly related to the consequences of the disease.[1] Suicide is also a much more important risk of death than in the the healthy population, while infections and complications are specially hazardous for the more disabled ones.[1]

Although most patients lose the ability to walk prior to death, 90% are still capable of independent walking at 10 years from onset, and 75% at 15 years.[81][82]

[edit] Epidemiology

Ethnic groups such as the Sami have a lower incidence of MS, possibly due to genetic factors.

Two main measures are used in epidemiological studies: incidence and prevalence. Incidence is the number of new cases per unit of person–time at risk (usually number of new cases per thousand person–years); while prevalence is the total number of cases of the disease in the population at a given time. Prevalence is known to depend not only on incidence, but also on survival rate and migrations of affected people. MS has a prevalence that ranges between 2 and 150 per 100,000 depending on the country or specific population.[2] Studies on populational and geographical patterns of epidemiological measures have been very common in MS,[23] and have led to the proposal of different etiological (causal) theories.[5][23][20][21]

MS usually appears in adults in their thirties but it can also appear in children.[1] The primary progressive subtype is more common in people in their fifties.[12] As with many autoimmune disorders, the disease is more common in women, and the trend may be increasing.[1][83] In children, the sex ratio difference is higher,[1] while in people over fifty, MS affects males and females almost equally.[12]

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.[83][1] Climate, sunlight and intake of vitamin D have been investigated as possible causes of the disease that could explain this latitude gradient.[21] However, there are important exceptions to the north-south pattern and changes in prevalence rates over time;[1] in general, this trend might be disappearing.[83] This indicates that other factors such as environment or genetics have to be taken into account to explain the origin of MS.[1] MS is also more common in regions with northern Europe populations.[1] But even in regions where MS is common, some ethnic groups are at low risk of developing the disease, including the Samis, Turkmen, Amerindians, Canadian Hutterites, Africans, and New Zealand Māori.[20]

Environmental factors during childhood may play an important role in the development of MS later in life. Several studies of migrants show that if migration occurs before the age of 15, the migrant acquires the new region's susceptibility to MS. If migration takes place after age 15, the migrant retains the susceptibility of his home country.[20][1] However, the age–geographical risk for developing multiple sclerosis may span a larger timescale.[1] A relationship between season of birth and MS has also been found which lends support to an association with sunlight and vitamin D. For example fewer people with MS are born in November as compared to May.[84]

[edit] History

[edit] Medical discovery

Detail of drawing from Carswell book depicting MS lesions in the brain stem and spinal cord (1838)

The French neurologist Jean-Martin Charcot (1825–1893) was the first person to recognize multiple sclerosis as a distinct disease in 1868.[85] Summarizing previous reports and adding his own clinical and pathological observations, Charcot called the disease sclerose en plaques. The three signs of MS now known as Charcot's triad 1 are nystagmus, intention tremor, and telegraphic speech, though these are not unique to MS. Charcot also observed cognition changes, describing his patients as having a "marked enfeeblement of the memory" and "conceptions that formed slowly".[3]

Prior to Charcot, Robert Carswell (1793–1857), a British professor of pathology, and Jean Cruveilhier (1791–1873), a French professor of pathologic anatomy, had described and illustrated many of the disease's clinical details, but did not identify it as a separate disease.[86] Specifically, Carswell described the injuries he found as "a remarkable lesion of the spinal cord accompanied with atrophy".[1]

After Charcot's description, Eugène Devic (1858–1930), Jozsef Balo (1895–1979), Paul Ferdinand Schilder (1886–1940), and Otto Marburg (1874–1948) described special cases of the disease. The disease did not receive its current name until 1955.[1] During all the 20th century there was an important development on the theories about the cause and pathogenesis of MS while efficacious treatments began to appear in 1990.[1]

[edit] Historical cases

There are several historical accounts of people who lived before or shortly after the disease was described by Charcot and probably had MS.

A young woman called Halldora, who lived in Iceland around the year 1200, suddenly lost her vision and mobility, but after praying to the saints, recovered them seven days after. Saint Lidwina of Schiedam (1380–1433), a Dutch nun, may be one of the first clearly identifiable MS patients. From the age of 16 until her death at 53, she suffered intermittent pain, weakness of the legs, and vision loss—symptoms typical of MS.[87] Both cases have led to the proposal of a 'Viking gene' hypothesis for the dissemination of the disease.[88]

Augustus Frederick d'Este (1794–1848), son of Prince Augustus Frederick, Duke of Sussex and Lady Augusta Murray and the grandson of George III of the United Kingdom, almost certainly suffered from MS. D'Este left a detailed diary describing his 22 years living with the disease. His diary began in 1822 and ended in 1846, although it remained 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.[89][90]

Another early account of MS was kept by the British diarist W. N. P. Barbellion, nom-de-plume of Bruce Frederick Cummings (1889–1919), who maintained a detailed log of his diagnosis and struggle with MS.[90] His diary was published in 1919 as The Journal of a Disappointed Man.[91]

[edit] Research directions

Main article: Therapies under investigation for multiple sclerosis

[edit] Therapies

Chemical structure of alemtuzumab

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).[92] However, most treatments already in clinical trials involve drugs that are used in other diseases. These are alemtuzumab (trade name Campath),[93] daclizumab (trade name Zenapax),[94] inosine,[95] BG00012,[96] fingolimod,[97] 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 thrombocytopenic purpura which led to the suspension of the therapy.[98]

Other drugs in clinical trials have been designed specifically for MS, such as laquinimod,[99] and Neurovax.[100]

Low dose naltrexone has been prescribed off-label for certain autoimmune disorders, including MS, and there is anecdotal evidence of benefit,[101][102] but only two small clinical trials have been conducted (as on December 2008),[103] one of them being for primary progressive MS.[104]

[edit] Diagnostic methods

New diagnostic and evolution evaluation methods are also being investigated. The measurement of antibodies against myelin proteins 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.[105][106] A test over serum autoantibodies has been proposed to make a safer and more confident diagnosis.[107]

[edit] Evolution prediction

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.[108]

[edit] Chronic cerebrospinal venous insufficiency

Italian investigator Paolo Zamboni has conducted research suggesting that MS is not an autoimmune condition, but a vascular disease, chronic cerebrospinal venous insufficiency, in which the brain's veins are constricted. He theorises that this leads to a buildup of iron in the brain, which causes the symptoms of MS. Subsequently, he performed a surgical procedure to correct what he believes to be venous insufficiency and claims that some patients have shown significant improvement.[109] The surgeries were non controlled and non randomized.[110] The neurology community has been skeptical. Lily Jung, speaking on behalf of the American Academy of Neurology, was cautious. She feels some of the claims in the report are not supported by the data. Jung said. "We would welcome some randomized, controlled, double-blinded studies to look at the issue, but before then would not be encouraging our patients to jump in with both feet to do this procedure, which has significant risks and has not been proven to be safe."[111][110]

[edit] See also

[edit] References

  1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap Compston A, Coles A (October 2008). "Multiple sclerosis". Lancet 372 (9648): 1502–17. doi:10.1016/S0140-6736(08)61620-7. PMID 18970977. 
  2. ^ a b Rosati G (April 2001). "The prevalence of multiple sclerosis in the world: an update". Neurol. Sci. 22 (2): 117–39. doi:10.1007/s100720170011. PMID 11603614. 
  3. ^ a b c Charcot, J. (1868). "Histologie de la sclerose en plaques". Gazette des hopitaux, Paris 41: 554–5. 
  4. ^ a b c d e f g h i j k l m n o p Compston A, Coles A (April 2002). "Multiple sclerosis". Lancet 359 (9313): 1221–31. doi:10.1016/S0140-6736(02)08220-X. PMID 11955556. 
  5. ^ a b c d e f g h Ascherio A, Munger KL (April 2007). "Environmental risk factors for multiple sclerosis. Part I: the role of infection". Ann. Neurol. 61 (4): 288–99. doi:10.1002/ana.21117. PMID 17444504. 
  6. ^ Berrios G E & Quemada J I (1990) Andre G. Ombredane and the psychopathology of multiple sclerosis: a conceptual and statistical history. Comprehensive Psychiatry 31: 438–446
  7. ^ a b c d e f g h i Lublin FD, Reingold SC (April 1996). "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 46 (4): 907–11. PMID 8780061. 
  8. ^ a b c d Weinshenker BG (1994). "Natural history of multiple sclerosis". Ann. Neurol. 36 (Suppl): S6–11. doi:10.1002/ana.410360704. PMID 8017890. 
  9. ^ Pittock SJ, Rodriguez M (2008). "Benign multiple sclerosis: a distinct clinical entity with therapeutic implications". Curr. Top. Microbiol. Immunol. 318: 1–17. doi:10.1007/978-3-540-73677-6_1. PMID 18219812. 
  10. ^ a b Miller D, Barkhof F, Montalban X, Thompson A, Filippi M (May 2005). "Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis". Lancet Neurol 4 (5): 281–8. doi:10.1016/S1474-4422(05)70071-5. PMID 15847841. 
  11. ^ Rovaris M, Confavreux C, Furlan R, Kappos L, Comi G, Filippi M (April 2006). "Secondary progressive multiple sclerosis: current knowledge and future challenges". Lancet Neurol 5 (4): 343–54. doi:10.1016/S1474-4422(06)70410-0. PMID 16545751. 
  12. ^ a b c Miller DH, Leary SM (October 2007). "Primary-progressive multiple sclerosis". Lancet Neurol 6 (10): 903–12. doi:10.1016/S1474-4422(07)70243-0. PMID 17884680. 
  13. ^ De Seze J (January 2006). "[Borderlines types of multiple sclerosis]" (in French). Rev. Neurol. (Paris) 162 (1): 137–43. PMID 16446632. 
  14. ^ O'Riordan JI (June 1997). "Central nervous system white matter diseases other than multiple sclerosis". Curr. Opin. Neurol. 10 (3): 211–4. PMID 9229127. 
  15. ^ Kurtzke JF (1983). "Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS)". Neurology 33 (11): 1444–52. PMID 6685237. 
  16. ^ a b Tataru N, Vidal C, Decavel P, Berger E, Rumbach L (2006). "Limited impact of the summer heat wave in France (2003) on hospital admissions and relapses for multiple sclerosis". Neuroepidemiology 27 (1): 28–32. doi:10.1159/000094233. PMID 16804331. 
  17. ^ Heesen C, Mohr DC, Huitinga I, et al. (March 2007). "Stress regulation in multiple sclerosis: current issues and concepts". Mult. Scler. 13 (2): 143–8. doi:10.1177/1352458506070772. PMID 17439878. 
  18. ^ Martinelli V (2000). "Trauma, stress and multiple sclerosis". Neurol. Sci. 21 (4 Suppl 2): S849–52. doi:10.1007/s100720070024. PMID 11205361. http://link.springer-ny.com/link/service/journals/10072/bibs/00214%20Suppl%202/0021S849.htm. 
  19. ^ Dyment DA, Ebers GC, Sadovnick AD (Feb 2004). "Genetics of multiple sclerosis". Lancet Neurol 3 (92): 104–10. doi:10.1016/S1474-4422(03)00663-X. PMID 14747002. 
  20. ^ a b c d e f g h i Marrie RA (December 2004). "Environmental risk factors in multiple sclerosis aetiology". Lancet Neurol 3 (12): 709–18. doi:10.1016/S1474-4422(04)00933-0. PMID 15556803. 
  21. ^ a b c d e Ascherio A, Munger KL (June 2007). "Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors". Ann. Neurol. 61 (6): 504–13. doi:10.1002/ana.21141. PMID 17492755. 
  22. ^ Spitsin S, Koprowski H (2008). "Role of uric acid in multiple sclerosis". Curr. Top. Microbiol. Immunol. 318: 325–42. doi:10.1007/978-3-540-73677-6_13. PMID 18219824. 
  23. ^ a b c Kurtzke JF (October 1993). "Epidemiologic evidence for multiple sclerosis as an infection". Clin. Microbiol. Rev. 6 (4): 382–427. PMID 8269393. PMC 358295. http://cmr.asm.org/cgi/pmidlookup?view=long&pmid=8269393. 
  24. ^ Gilden DH (March 2005). "Infectious causes of multiple sclerosis". Lancet Neurol 4 (3): 195–202. doi:10.1016/S1474-4422(05)01017–3 (inactive 2009-12-24). PMID 15721830. 
  25. ^ Christensen T (June 2007). "Human herpesviruses in MS" (PDF). Int MS J 14 (2): 41–7. PMID 17686342. http://www.msforumonline.net/journal/download/default.aspx?pdf=20071441.pdf. 
  26. ^ Sotelo J, Martínez-Palomo A, Ordoñez G, Pineda B (March 2008). "Varicella-zoster virus in cerebrospinal fluid at relapses of multiple sclerosis". Ann. Neurol. 63 (3): 303–11. doi:10.1002/ana.21316. PMID 18306233. 
  27. ^ Lünemann JD, Kamradt T, Martin R, Münz C (July 2007). "Epstein-barr virus: environmental trigger of multiple sclerosis?". J. Virol. 81 (13): 6777–84. doi:10.1128/JVI.00153-07. PMID 17459939. 
  28. ^ Farrell RA, Antony D, Wall GR, Clark DA, Fisniku L, Swanton J, Khaleeli Z, Schmierer K, Miller DH, Giovannoni G. (May 2009). "Humoral immune response to EBV in multiple sclerosis is associated with disease activity on MRI". Neurology 73 (1): 32–8. doi:10.1212/WNL.0b013e3181aa29fe. PMID 19458321. 
  29. ^ Johnston JB, Silva C, Holden J, Warren KG, Clark AW, Power C (October 2001). "Monocyte activation and differentiation augment human endogenous retrovirus expression: implications for inflammatory brain diseases". Ann. Neurol. 50 (4): 434–42. doi:10.1002/ana.1131. PMID 11601494. 
  30. ^ Christensen T (May 2006). "The role of EBV in MS pathogenesis" (PDF). Int MS J 13 (2): 52–7. PMID 16635422. http://www.msforumonline.net/journal/download/default.aspx?pdf=20061352.pdf. 
  31. ^ Yao SY, Stratton CW, Mitchell WM, Sriram S (May 2001). "CSF oligoclonal bands in MS include antibodies against Chlamydophila antigens". Neurology 56 (9): 1168–76. PMID 11342681. http://www.neurology.org/cgi/pmidlookup?view=long&pmid=11342681. 
  32. ^ Pascual AM, Martínez-Bisbal MC, Boscá I, et al (July 2007). "Axonal loss is progressive and partly dissociated from lesion load in early multiple sclerosis". Neurology 69 (1): 63–7. doi:10.1212/01.wnl.0000265054.08610.12. PMID 17606882. 
  33. ^ a b Chari DM (2007). "Remyelination in multiple sclerosis". Int. Rev. Neurobiol. 79: 589–620. doi:10.1016/S0074-7742(07)79026-8. PMID 17531860. 
  34. ^ Lucchinetti C, Brück W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H (June 2000). "Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination". Ann. Neurol. 47 (6): 707–17. doi:10.1002/1531-8249(200006)47:6<707::AID-ANA3>3.0.CO;2-Q. PMID 10852536. 
  35. ^ Krishnamoorthy G, Saxena A, Mars LT, Domingues HS, Mentele R, Ben-Nun A, Lassmann H, Dornmair K, Kurschus FC, Liblau RS, Wekerle H (June 2009). "Myelin-specific T cells also recognize neuronal autoantigen in a transgenic mouse model of multiple sclerosis". Nat. Med. 15 (6): 626–32. doi:10.1038/nm.1975. PMID 19483694. Lay summary – Max Planck Society. 
  36. ^ Pöllinger B, Krishnamoorthy G, Berer K, Lassmann H, Bösl MR, Dunn R, Domingues HS, Holz A, Kurschus FC, Wekerle H (June 2009). "Spontaneous relapsing-remitting EAE in the SJL/J mouse: MOG-reactive transgenic T cells recruit endogenous MOG-specific B cells". J. Exp. Med. 206 (6): 1303–16. doi:10.1084/jem.20090299. PMID 19487416. 
  37. ^ Trojano M, Paolicelli D (November 2001). "The differential diagnosis of multiple sclerosis: classification and clinical features of relapsing and progressive neurological syndromes". Neurol. Sci. 22 (Suppl 2): S98–102. doi:10.1007/s100720100044. PMID 11794488. http://link.springer-ny.com/link/service/journals/10072/bibs/122%20Suppl%202000/122%20Suppl%2020S98.htm. 
  38. ^ Poser CM, Brinar VV (June 2004). "Diagnostic criteria for multiple sclerosis: an historical review". Clin Neurol Neurosurg 106 (3): 147–58. doi:10.1016/j.clineuro.2004.02.004. PMID 15177763. 
  39. ^ a b c d McDonald WI, Compston A, Edan G, et al. (July 2001). "Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis". Ann. Neurol. 50 (1): 121–7. doi:10.1002/ana.1032. PMID 11456302. 
  40. ^ Polman CH, Reingold SC, Edan G, et al. (December 2005). "Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria"". Ann. Neurol. 58 (6): 840–6. doi:10.1002/ana.20703. PMID 16283615. 
  41. ^ Rashid W, Miller DH (February 2008). "Recent advances in neuroimaging of multiple sclerosis". Semin Neurol 28 (1): 46–55. doi:10.1055/s-2007-1019127. PMID 18256986. 
  42. ^ Link H, Huang YM (November 2006). "Oligoclonal bands in multiple sclerosis cerebrospinal fluid: an update on methodology and clinical usefulness". J. Neuroimmunol. 180 (1-2): 17–28. doi:10.1016/j.jneuroim.2006.07.006. PMID 16945427. 
  43. ^ Gronseth GS, Ashman EJ (May 2000). "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 54 (9): 1720–5. PMID 10802774. http://www.neurology.org/cgi/pmidlookup?view=long&pmid=10802774. 
  44. ^ Methylprednisolone Oral. US National Library of Medicine (Medline) (2003-04-01). Retrieved on 2007-09-01.
  45. ^ Methylprednisolone Sodium Succinate Injection. US National Library of Medicine (Medline) (2003-04-01). Retrieved on 2007-09-01.
  46. ^ Brusaferri F, Candelise L (2000). "Steroids for multiple sclerosis and optic neuritis: a meta-analysis of randomized controlled clinical trials". J. Neurol. 247 (6): 435–42. doi:10.1007/s004150070172. PMID 10929272. 
  47. ^ Dovio A, Perazzolo L, Osella G, et al (2004). "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". J. Clin. Endocrinol. Metab. 89 (10): 4923–8. doi:10.1210/jc.2004–0164 (inactive 2009-12-24). PMID 15472186. 
  48. ^ Uttner I, Müller S, Zinser C, et al (2005). "Reversible impaired memory induced by pulsed methylprednisolone in patients with MS". Neurology 64 (11): 1971–3. doi:10.1212/01.WNL.0000163804.94163.91. PMID 15955958. 
  49. ^ "Some MS Patients have "Dramatic" Responses to Plasma Exchange". Neurology Reviews.com. March 2000. http://www.neurologyreviews.com/mar00/nr_mar00_MSpatients.html. Retrieved 2009-07-10. 
  50. ^ Jacobs LD, Beck RW, Simon JH, et al. (2000). "Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group". N Engl J Med 343 (13): 898–904. doi:10.1056/NEJM200009283431301. PMID 11006365. 
  51. ^ Comi G, Filippi M, Barkhof F, et al. (2001). "Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study". Lancet 357 (9268): 1576–82. doi:10.1016/S0140-6736(00)04725–5 (inactive 2009-12-24). PMID 11377645. 
  52. ^ Kappos L, Freedman MS, Polman CH, et al. (2007). "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". Lancet 370 (9585): 389–97. doi:10.1016/S0140-6736(07)61194-5. PMID 17679016. 
  53. ^ Ruggieri M, Avolio C, Livrea P, Trojano M (2007). "Glatiramer acetate in multiple sclerosis: a review". CNS Drug Rev 13 (2): 178–91. doi:10.1111/j.1527–3458.2007.00010.x (inactive 2009-12-24). PMID 17627671. 
  54. ^ a b Munari L, Lovati R, Boiko A (2004). "Therapy with glatiramer acetate for multiple sclerosis". Cochrane Database Syst Rev (1): CD004678. doi:10.1002/14651858.CD004678. PMID 14974077. 
  55. ^ Rice GP, Incorvaia B, Munari L, et al (2001). "Interferon in relapsing-remitting multiple sclerosis". Cochrane Database Syst Rev (4): CD002002. doi:10.1002/14651858.CD002002. PMID 11687131. 
  56. ^ a b Martinelli Boneschi F, Rovaris M, Capra R, Comi G (2005). "Mitoxantrone for multiple sclerosis". Cochrane Database Syst Rev (4): CD002127. doi:10.1002/14651858.CD002127.pub2. PMID 16235298. 
  57. ^ Johnson KP (2007). "Control of multiple sclerosis relapses with immunomodulating agents". J. Neurol. Sci. 256 (Suppl 1): S23–8. doi:10.1016/j.jns.2007.01.060. PMID 17350652. 
  58. ^ Natalizumab reduces MS severity - http://www.abstracts2view.com/aan2008chicago/view.php?nu=AAN08L_P04.169
  59. ^ Gonsette RE (2007). "Compared benefit of approved and experimental immunosuppressive therapeutic approaches in multiple sclerosis". Expert opinion on pharmacotherapy 8 (8): 1103–16. doi:10.1517/14656566.8.8.1103. PMID 17516874. 
  60. ^ Murray TJ (2006). "The cardiac effects of mitoxantrone: do the benefits in multiple sclerosis outweigh the risks?". Expert opinion on drug safety 5 (2): 265–74. doi:10.1517/14740338.5.2.265. PMID 16503747. 
  61. ^ Leary SM, Thompson AJ (2005). "Primary progressive multiple sclerosis: current and future treatment options". CNS drugs 19 (5): 369–76. doi:10.2165/00023210-200519050-00001. PMID 15907149. 
  62. ^ Sládková T, Kostolanský F (2006). "The role of cytokines in the immune response to influenza A virus infection". Acta Virol. 50 (3): 151–62. PMID 17131933. 
  63. ^ Primetherapeutics - serious liver damage per FDA - Primetherapeutics
  64. ^ Betaseron [package insert]. Montville, NJ: Berlex Inc; 2003
  65. ^ Rebif [package insert]. Rockland, MA: Serono Inc; 2005.
  66. ^ Avonex [package insert]. Cambridge, MA: Biogen Inc; 2003
  67. ^ a b Fox EJ (2006). "Management of worsening multiple sclerosis with mitoxantrone: a review". Clinical therapeutics 28 (4): 461–74. doi:10.1016/j.clinthera.2006.04.013. PMID 16750460. 
  68. ^ Kleinschmidt-DeMasters BK, Tyler KL (2005). "Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis". N Engl J Med 353 (4): 369–74. doi:10.1056/NEJMoa051782. PMID 15947079.  Free full text with registration
  69. ^ Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D (2005). "Progressive multifocal leukoencephalopathy in a patient treated with natalizumab". N Engl J Med 353 (4): 375–81. doi:10.1056/NEJMoa051847. PMID 15947078. http://content.nejm.org/cgi/content/abstract/353/4/375. 
  70. ^ "Brain Infections Return for Multiple Sclerosis Drug Tysabri". 2008-08-01. http://blogs.wsj.com/health/2008/08/01/brain-infections-return-for-multiple-sclerosis-drug-tysabri. Retrieved 2008-08-01. 
  71. ^ Kesselring J, Beer S (2005). "Symptomatic therapy and neurorehabilitation in multiple sclerosis". Lancet neurology 4 (10): 643–52. doi:10.1016/S1474-4422(05)70193–9 (inactive 2009-12-24). PMID 16168933. 
  72. ^ The Royal College of Physicians (2004) (PDF). Multiple Sclerosis. National clinical guideline for diagnosis and management in primary and secondary care. Salisbury, Wiltshire: Sarum ColourView Group. 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.
  73. ^ Khan F, Turner-Stokes L, Ng L, Kilpatrick T (2007). "Multidisciplinary rehabilitation for adults with multiple sclerosis". Cochrane Database Syst Rev (2): CD006036. doi:10.1002/14651858.CD006036.pub2. PMID 17443610. 
  74. ^ Khan F, Ng L, Turner-Stokes L (2009). "Effectiveness of vocational rehabilitation intervention on the return to work and employment of persons with multiple sclerosis". Cochrane Database Syst Rev (1): CD007256. doi:10.1002/14651858.CD007256.pub2. PMID 19160331. 
  75. ^ Thomas PW, Thomas S, Hillier C, Galvin K, Baker R (2006). "Psychological interventions for multiple sclerosis". Cochrane Database Syst Rev (1): CD004431. doi:10.1002/14651858.CD004431.pub2. PMID 16437487. 
  76. ^ Farinotti M, Simi S, Di Pietrantonj C, et al. (2007). "Dietary interventions for multiple sclerosis". Cochrane database of systematic reviews (Online) (1): CD004192. doi:10.1002/14651858.CD004192.pub2. PMID 17253500. 
  77. ^ Chong MS, Wolff K, Wise K, Tanton C, Winstock A, Silber E (2006). "Cannabis use in patients with multiple sclerosis". Mult. Scler. 12 (5): 646–51. doi:10.1177/1352458506070947. PMID 17086912. 
  78. ^ Zajicek JP, Sanders HP, Wright DE, Vickery PJ, Ingram WM, Reilly SM, Nunn AJ, Teare LJ, Fox PJ, Thompson AJ (2005). "Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up". J. Neurol. Neurosurg. Psychiatr. 76 (12): 1664–9. doi:10.1136/jnnp.2005.070136. PMID 16291891. 
  79. ^ Bennett M, Heard R (2004). "Hyperbaric oxygen therapy for multiple sclerosis". Cochrane database of systematic reviews (Online) (1): CD003057. doi:10.1002/14651858.CD003057.pub2. PMID 14974004. 
  80. ^ Oken BS, Kishiyama S, Zajdel D, et al. (2004). "Randomized controlled trial of yoga and exercise in multiple sclerosis". Neurology 62 (11): 2058–64. PMID 15184614. 
  81. ^ a b c Phadke JG (May 1987). "Survival pattern and cause of death in patients with multiple sclerosis: results from an epidemiological survey in north east Scotland". J. Neurol. Neurosurg. Psychiatr. 50 (5): 523–31. doi:10.1136/jnnp.50.5.523. PMID 3495637. 
  82. ^ Myhr KM, Riise T, Vedeler C, et al (February 2001). "Disability and prognosis in multiple sclerosis: demographic and clinical variables important for the ability to walk and awarding of disability pension". Mult. Scler. 7 (1): 59–65. PMID 11321195. http://msj.sagepub.com/cgi/pmidlookup?view=long&pmid=11321195. 
  83. ^ a b c Alonso A, Hernán MA (July 2008). "Temporal trends in the incidence of multiple sclerosis: a systematic review". Neurology 71 (2): 129–35. doi:10.1212/01.wnl.0000316802.35974.34. PMID 18606967. 
  84. ^ Kulie T, Groff A, Redmer J, Hounshell J, Schrager S (2009). "Vitamin D: an evidence-based review". J Am Board Fam Med 22 (6): 698–706. doi:10.3122/jabfm.2009.06.090037. PMID 19897699. 
  85. ^ Berrios G.E. and Quemada J I (1995) Multiple Sclerosis. In Berrios G.E. and Porter R (eds) The History of Clinical Psychiatry. London, Athlone Press, pp174–192
  86. ^ Compston A (October 1988). "The 150th anniversary of the first depiction of the lesions of multiple sclerosis". J. Neurol. Neurosurg. Psychiatr. 51 (10): 1249–52. doi:10.1136/jnnp.51.10.1249. PMID 3066846. 
  87. ^ Medaer R (September 1979). "Does the history of multiple sclerosis go back as far as the 14th century?". Acta Neurol. Scand. 60 (3): 189–92. doi:10.1111/j.1600-0447.1979.tb08970.x. PMID 390966. 
  88. ^ Holmøy T (2006). "A Norse contribution to the history of neurological diseases". Eur. Neurol. 55 (1): 57–8. doi:10.1159/000091431. PMID 16479124. 
  89. ^ Firth, D (1948). The Case of August D`Esté. Cambridge: Cambridge University Press. 
  90. ^ a b Pearce JM (2005). "Historical descriptions of multiple sclerosis". Eur. Neurol. 54 (1): 49–53. doi:10.1159/000087387. PMID 16103678. 
  91. ^ Barbellion, Wilhelm Nero Pilate (1919). The Journal of a Disappointed Man. New York: George H. Doran. 
  92. ^ United Kingdom early Mitoxantrone Copaxone trial. Onyx Healthcare (2006-01-01). Retrieved on 2007-09-02.
  93. ^ 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.
  94. ^ Daclizumab. PDL Biopharma (2006-01-01). Retrieved on 2007-09-02.
  95. ^ Treatment of Multiple Sclerosis Using Over the Counter Inosine. ClinicalTrials.gov (2006-03-16). Retrieved on 2007-09-02.
  96. ^ Efficacy and Safety of BG00012 in Relapsing-Remitting Multiple Sclerosis. ClinicalTrials.gov (2007-09-01). Retrieved on 2007-11-12.
  97. ^ Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis. ClinicalTrials.gov (2006-02-09). Retrieved on 2007-09-02.
  98. ^ The CAMMS223 Trial Investigators (2008). "Alemtuzumab vs. Interferon Beta-1a in Early Multiple Sclerosis". N Engl J Med 359 (17): 1786–1801. doi:10.1056/NEJMoa0802670. PMID 18946064. 
  99. ^ Polman C, Barkhof F, Sandberg-Wollheim M, Linde A, Nordle O, Nederman T (2005). "Treatment with laquinimod reduces development of active MRI lesions in relapsing MS". Neurology 64 (6): 987–91. doi:10.1212/01.WNL.0000154520.48391.69 (inactive 2009-04-04). PMID 15781813. 
  100. ^ Darlington CL (2005). "Technology evaluation: NeuroVax, Immune Response Corp". Curr. Opin. Mol. Ther. 7 (6): 598–603. PMID 16370383. 
  101. ^ Agrawal YP (2005). "Low dose naltrexone therapy in multiple sclerosis". Med. Hypotheses 64 (4): 721–4. doi:10.1016/j.mehy.2004.09.024. PMID 15694688. 
  102. ^ search of clinicaltrials.gov data-base for Low dose naltrexone Multiple Sclerosis
  103. ^ 2007 clinical trial using LDN
  104. ^ 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 (2008). "A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis.". Multiple Sclerosis 14 (8): 1076–83. doi:10.1177/1352458508095828. PMID 18728058. 
  105. ^ Albrecht P, Fröhlich R, Hartung HP, Kieseier BC, Methner A (2007). "Optical coherence tomography measures axonal loss in multiple sclerosis independently of optic neuritis". J Neurol Online (11): 1595. doi:10.1007/s00415-007-0538-3. PMID 17987252. 
  106. ^ Gordon-Lipkin E, Chodkowski B, Reich DS et al (October 2007). "Retinal nerve fiber layer is associated with brain atrophy in multiple sclerosis". Neurology 69 (16): 1603–09. doi:10.1212/01.wnl.0000295995.46586.ae. PMID 17938370. 
  107. ^ Quintana FJ, Farez MF, Viglietta V, Iglesias AH, Merbl Y, Izquierdo G, Lucas M, Basso AS, Khoury SJ, Lucchinetti CF, Cohen IR, Weiner HL. (December 2008). "Antigen microarrays identify unique serum autoantibody signatures in clinical and pathologic subtypes of multiple sclerosis". Proceeding of the National Academy of Sciences 105 (48): 18889–94. doi:10.1073/pnas.0806310105. PMID 19028871. PMC 2596207. http://www.pnas.org/content/105/48/18889.full.pdf+html. 
  108. ^ Thangarajh M, Gomez-Rial J, Hedström AK, et al (August 2008). "Lipid-specific immunoglobulin M in CSF predicts adverse long-term outcome in multiple sclerosis". Mult. Scler. 14 (9): 1208. doi:10.1177/1352458508095729. PMID 18755821. 
  109. ^ Zamboni, P; Galeotti, R; Menegatti, E; Malagoni, AM; Tacconi, G; Dall’Ara, S; Bartolomei, I; Salvi, F (2009). "Chronic Cerebrospinal venous insufficiency in patients with multiple sclerosis". Journal of Neurology, Neurosurgery and Psychiatry (BMJ Publishing Group) 80 (4): 392–399. doi:10.1136/jnnp.2008.157164. ISSN 1468-330X. http://jnnp.bmj.com/content/80/4/392.full. Retrieved 21 December 2009. 
  110. ^ a b "Angioplasty for MS? Italian surgeon’s claims prompt media circus, but Canadian doctors are skeptical". Medical Post. http://www.canadianhealthcarenetwork.ca/physicians/clinical/angioplasty-for-ms-5996. Retrieved Dec 16, 2009. 
  111. ^ MS Resource Centre http://www.msrc.co.uk/index.cfm?CFID=2797780&CFTOKEN=19383080

[edit] Further reading

[edit] External links

v • d • e
Multiple sclerosis and other demyelinating diseases of CNS (G35-G37, 340-341)
Signs and symptoms
Diagnosis and evolution following
Investigation
Treatment
Borderline forms
Other
v • d • e
Pathology of the nervous system, primarily CNS (G04–G47, 323–349)
Inflammation
Both/either
Brain/
encephalopathy
Episodic/
paroxysmal
Other
Spinal cord/
myelopathy
Both/either
central nervous system navs: anat/physio/dev, noncongen/congen/neoplasia, symptoms+signs/eponymous, proc
v • d • e
Immune disorders: hypersensitivity and autoimmune diseases
Type I/allergy/atopy
(IgE)
Foreign
Autoimmune
none
Type II/ADCC
(IgM, IgG)
Foreign
Autoimmune
Type III
(Immune complex)
Foreign
Autoimmune
Type IV/cell-mediated
(T-cells)
Foreign
Autoimmune
Unknown/
multiple
Foreign
Autoimmune
lymphocyte navs: cells/physio, immunodeficiency/immunoproliferative immunoglobulin/neoplasia, proc

Retrieved from "http://en.wikipedia.org/wiki/Multiple_sclerosis"