Multiple sclerosis

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Multiple sclerosis
Classification and external
resources

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 an autoimmune condition in which the immune system
attacks the central nervous system, leading to demyelination.[1] Disease onset usually
occurs in young adults, and it is more common in women.[2] It has a prevalence that
ranges between 2 and 150 per 100,000.[3] MS was first described in 1868 by Jean-Martin
Charcot.[4]

MS affects the areas of the brain and spinal cord known as the white matter, destroying a
fatty layer called the myelin sheath, which wraps around nerve fibers and electrically
insulates them. When myelin is lost, the axons of neurons can no longer effectively
conduct action potentials.[1] The name multiple sclerosis refers to the scars (scleroses –
better known as plaques or lesions) in the white matter.[4] 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.[5][1]
Almost any neurological symptom can appear with the disease, and often progresses to
physical and cognitive disability.[1] MS takes several forms, with new symptoms
occurring either in discrete attacks (relapsing forms) or slowly accumulating over time
(progressive forms).[6] Between attacks, symptoms may go away completely, but
permanent neurological problems often occur, especially as the disease advances.[6]

There is no known cure for MS. Treatments attempt to return function after an attack,
prevent new attacks, and prevent disability.[1] 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.[7] Life expectancy of
patients is nearly the same as that of the unaffected population.[7]

Contents
[hide]

• 1 Signs and symptoms

• 2 Disease subtypes
• 3 Diagnosis
• 4 Pathophysiology
o 4.1 MS as an autoimmunological disease
o 4.2 Lesions
o 4.3 Inflammation
• 5 Epidemiology
• 6 Causes
o 6.1 Genetic cause
o 6.2 Infectious cause
o 6.3 Non-infectious environmental risk factors
• 7 Treatment
o 7.1 Management of acute attacks
o 7.2 Disease-modifying treatments
o 7.3 Management of the effects of MS
o 7.4 Alternative treatments
• 8 Prognosis
• 9 History
o 9.1 Medical discovery
o 9.2 Historical cases
• 10 Research directions
• 11 See also
• 12 References
• 13 Further reading

• 14 External links
 [edit] Signs and symptoms
Main article: Multiple sclerosis signs and symptoms

Nystagmus, characterised by involuntary eye movements, is one of many symptoms that

can appear with MS

Symptoms of MS usually appear in episodic acute periods of worsening (relapses,

exacerbations, bouts or attacks), in a gradually-progressive deterioration of neurologic
function, or in a combination of both.[6]

The most common presentation of MS is the clinically isolated syndrome (CIS). In CIS, a
patient has an attack suggestive of demyelination, but does not fulfill the criteria for
multiple sclerosis.[8] Only 30 to 70% of persons experiencing CIS later develop MS.[8]
The disease usually presents with sensorial (46% of cases), visual (33%), cerebellar
(30%) and motor (26%) symptoms.[9] Many rare initial symptoms have also been
reported, including aphasia, psychosis and epilepsy.[10][11][12] Patients first seeking medical
attention commonly present with multiple symptoms.[9] The initial signs and symptoms of
MS are often transient, mild, and self-limited. These signs and symptoms often do not
prompt a person to seek medical attention and are sometimes identified only
retrospectively once the diagnosis of MS has been made. Cases of MS are sometimes
incidentally identified during neurological examinations performed for other causes. Such
cases are referred to as subclinical MS.[13][14]

The person with MS can suffer almost any neurological symptom or sign, including
changes in sensation (hypoesthesias and paraesthesias), muscle weakness, muscle
spasms, or difficulty in moving;[15] difficulties with coordination and balance (ataxia);[15]
problems in speech (dysarthria) or swallowing (dysphagia),[16] visual problems
(nystagmus, optic neuritis, or diplopia),[17] fatigue, acute or chronic pain,[18][19] and bladder
and bowel difficulties.[19][20] Cognitive impairment of varying degrees and emotional
symptoms of depression or unstable mood are also common.[21][22] The main clinical
measure of disability progression and symptom severity is the Expanded Disability Status
Scale or EDSS.[23]

Multiple sclerosis relapses are often unpredictable, occurring without warning and
without obvious inciting factors. Some attacks, however, are preceded by common
triggers. Relapses occur more frequently during spring and summer.[24] Infections such as
the common cold, influenza, or gastroenteritis increase the risk of relapse.[25][26] Stress
may also trigger an attack.[27][28][29] Pregnancy may affect susceptibility to relapse, offering
protection during the last trimester, for instance. During the first few months after
delivery, however, the risk of relapse is increased. Overall, pregnancy does not seem to
influence long-term disability.[30] Many potential triggers have been examined and found
not to influence MS relapse rates. There is no evidence that vaccination for influenza,
hepatitis B, varicella, tetanus, or tuberculosis increases risk of relapse.[31] Physical trauma
does not trigger relapses.[32][33] Exposure to higher than usual ambient temperatures can
exacerbate extant symptoms, an effect known as Uhthoff's phenomenon.[34] Uhthoff's
phenomenon is not, however, an established relapse trigger.[24]

[edit] Disease subtypes

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: relapsing remitting,
secondary progressive, primary progressive and progressive relapsing.[6]

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. This
describes the initial course of 85–90% of individuals with MS.[6] When deficits always
resolve between attacks, this is sometimes referred to as benign MS.[35]

Secondary progressive MS describes those with initial relapsing-remitting MS, who then
begin to have progressive neurologic decline between acute attacks without any definite
periods of remission.[6] Occasional relapses and minor remissions may appear.[6] The
median time between disease onset and conversion from relapsing-remitting to secondary
progressive MS is 19 years.[36]

The primary progressive subtype describes the approximately 10–15% of individuals who
never have remission after their initial MS symptoms.[37] It is characterized by
progression of disability from onset, with no, or only occasional and minor, remissions
and improvements.[6] The age of onset for the primary progressive subtype is later than
other subtypes.[37]

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.[6]

Cases with non-standard behavior have also been described. Sometimes referred to as
borderline forms of multiple sclerosis,[38] these include Devic's disease, Balo concentric
sclerosis, Schilder's diffuse sclerosis and Marburg multiple sclerosis.[39][40] There is debate
whether these are atypical variants of MS or different diseases.[41]

[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 many other medical problems.[42] Medical organizations have created diagnostic
criteria to ease and standardize the diagnostic process for practicing physicians.
Historically, the Schumacher and Poser criteria were both popular.[43] Currently, the
McDonald criteria focus on a demonstration with clinical, laboratory and radiologic data
of the dissemination of MS lesions in time and space. A diagnosis cannot be made until
other possible conditions have been ruled out and there is evidence of demyelinating
events separated anatomically and in time.[44]

Clinical data alone may be sufficient for a diagnosis of MS if an individual has suffered
separate episodes of neurologic symptoms characteristic of MS.[44] 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.[44][45] 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.[44][46] 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.[47]

[edit] Pathophysiology
Main article: Pathophysiology of multiple sclerosis
Structure of a typical neuron

Myelin sheath of a healthy neuron

Dendrite
Soma
Axon
Nucleus
Node of
Ranvier
Axon Terminal
Schwann cell
Myelin sheath
Demyelinization in MS. On Klüver-Barrera myelin staining, decoloration in the area of
the lesion can be appreciated (Original scale 1:100).

[edit] MS as an autoimmunological disease

MS is currently believed to be an immune-mediated disorder with an initial trigger, which

may have a viral etiology,[1] 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.[1]

[edit] 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.[1]

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.[1] 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.[48] When
the myelin is lost, a neuron can no longer effectively conduct electrical signals.[1] A repair
process, called remyelination, takes place in early phases of the disease, but the
oligodendrocytes cannot completely rebuild the cell's myelin sheath.[49] Repeated attacks
lead to successively fewer effective remyelinations, until a scar-like plaque is built up
around the damaged axons.[49] Four different lesion patterns have been described.[50]

[edit] 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.[1] In MS, 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.[1] 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.[1] When the blood–brain barrier regains its integrity, usually
after infection or virus has cleared, the T cells are trapped inside the brain.[1] 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.[1]
[edit] Epidemiology

World map showing that risk (incidence) for MS increases with distance from the equator

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.[3] Studies on populational and geographical patterns of
epidemiological measures have been very common in MS,[51] and have led to the proposal
of different etiological (causal) theories.[51][52][5][53]

MS usually appears in adults in their thirties,[2] but it can also appear in children,[54] and
the primary progressive subtype is more common in people in their fifties.[37] As with
many autoimmune disorders, the disease is more common in women, and the trend may
be increasing.[51][55] In children, the sex ratio may reach three females for each male.[54] In
people over fifty, MS affects males and females almost equally.[37]

Ethnic groups such as the Samis have a reduced risk of MS, probably due to genetic
factors.

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.[55] Climate, sunlight and intake of vitamin D have been investigated as
possible causes of the disease that could explain this latitude gradient.[53] However, there
are important exceptions to the north-south pattern such as incidence and prevalance in
the Canary Islands[56] and changes in prevalence rates over time;[57] in general, this trend
might be disappearing.[55] This indicates that other factors such as environment or
genetics have to be taken into account to explain the origin of MS.[57]

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 fifteen, the migrant acquires the new region's susceptibility to MS. If migration
takes place after age fifteen, the migrant retains the susceptibility of his home country.[52]
However, the age–geographical risk for developing multiple sclerosis may span a larger
timescale.[58]

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 Maoris.[52] Scotland appears to have one of the highest rates of MS in
the world.[59]

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

[edit] Genetic cause

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

MS is not considered a hereditary disease. However, genetics may play a role in

determining a person's susceptibility to MS.
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.[1] In the case
of monozygotic twins, concordance occurs only in about 35% of cases, and half-siblings
have a lower risk than full siblings, indicating a polygenic origin.[1][60]

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 in humans—increase the probability of suffering
MS.[61] Two other genes have been shown to be linked to MS. These are the IL2RA and
the IL7RA, subunits of the receptor for interleukin 2 and interleukin 7 respectively.[62][63]
The HLA complex is involved in antigen presentation, which is crucial to the functioning
of the immune system, while mutations in the IL2 and IL7 genes were already known to
be associated with diabetes and other autoimmune conditions, supporting the notion that
MS is an autoimmune disease.[64][61][65] Other studies have linked genes in chromosome 5
with the disease.[66]

[edit] Infectious cause

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, with risk increasing with
age at infection.[5][67][68] 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][51]
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.[69] Human herpesviruses are a candidate group of viruses linked to MS;[70]
Varicella zoster virus has been found at high levels in the cerebrospinal fluid of MS
patients,[71] 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][72] 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.[73][74][75]
[edit] Non-infectious environmental risk factors

Increased sun exposure has been linked with a lower risk of MS.

MS is more common in people who live farther from the equator. Decreased sunlight
exposure has been linked with a higher risk of MS.[52][76][77] Decreased vitamin D
production and intake has been the main biological mechanism used to explain the higher
risk among those less exposed to sun.[52][53][78]

Severe stress may also be a risk factor although evidence is weak;[52] parents who lost a
child unexpectedly were more likely to develop MS than parents who had not.[79]
Smoking has also been shown to be an independent risk factor for developing MS.[80][53]
Association with occupational exposures and toxins—mainly solvents—has been
evaluated, but no clear conclusions have been reached.[52] Vaccinations were also
considered as causal factors for the disease; however, most studies show no association
between MS and vaccines.[52]

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, which can protect against oxidative stress from substances
such as peroxynitrite, protects against MS, although its exact importance remains
unknown.[81][82][83] 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.[53]

Although some of these risk factors, including infection, are partly modifiable, only
further research—especially clinical trials—will reveal whether their elimination can help
prevent MS.[84]

[edit] Treatment
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 paucity of supporting, comparable, replicated
scientific study.

[edit] Management of acute attacks

During symptomatic attacks, administration of high doses of intravenous corticosteroids,

such as methylprednisolone,[85][86] 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.[87] Potential
side effects include osteoporosis[88] and impaired memory, the latter being reversible.[89]

[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.[90][91][92]

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 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
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.[93][94][95][96] Comparisons between immunomodulators (all but mitoxantrone) show
that the most effective is natalizumab, both in terms of relapse rate reduction and halting
disability progression;[97] it has also been shown to reduce the severity of MS.[98]
Mitoxantrone may be the most effective of them all;[99] however, it is generally not
considered as a long-term therapy, as its use is limited by severe cardiotoxicity.[100]
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.[96] No treatment has been
proven to modify the course of primary progressive MS.[101]

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;[102] 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.[94] More dangerous are liver damage from
interferons and mitoxantrone,[103][104][105][106][107] the immunosuppressive effects and cardiac
toxicity of the latter;[107] and the putative link between natalizumab and some cases of
progressive multifocal leukoencephalopathy.[108][109][110]

[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.[111] 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.[112] Similarly, for each symptom there are different treatment options. Treatments
should therefore be individualized depending both on the patient and the physician.

[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,[113] herbal medicine, including the use of medical cannabis to help
alleviate symptoms,[114][115] and hyperbaric oxygenation.[116] The therapeutic practice of
martial arts such as tai chi, relaxation disciplines such as yoga, or general exercise seems
to mitigate fatigue and improve quality of life.[117]

[edit] 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, age, and initial
symptoms; and the degree of disability the person experiences.[7] Female sex, relapsing-
remitting subtype, optic neuritis or sensory symptoms at onset, few attacks in the initial
years and specially early age at onset, are associated with a better course.[7][118]

The life expectancy of people with MS, at least for earlier years, is nearly the same as
that of unaffected people.[7] Almost 40% of patients reach the seventh decade of life.[118]
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, a percentage much
higher than in the healthy population.[7][119]

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.[118][120]

[edit] History
[edit] Medical discovery

Detail of drawing from Carswell book depicting multiple sclerosis 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. 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".[4]
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.[121]

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.

[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.[122]
Both cases have led to the proposal of a 'viking gene' hypothesis for the dissemination of
the disease.[123]

Augustus Frederick d'Este (1794–1848), an illegitimate grandson of King George III of

Great Britain, almost certainly suffered from MS. D'Este left a detailed diary describing
his 22 years living with the disease. 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.[124][125]

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.[125] His diary was published in 1919 as The Journal of a
Disappointed Man.[126]

[edit] Research directions

Main article: Therapies under investigation for multiple sclerosis
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).[127] However, most treatments already in clinical trials
involve drugs that are used in other diseases. These are alemtuzumab (trade name
Campath),[128] daclizumab (trade name Zenapax),[129] inosine[130], BG00012[131], 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.[132] Other drugs in clinical trials have been designed
specifically for MS, such as fingolimod,[133] laquinimod,[134] and Neurovax.[135]

Low dose naltrexone has been prescribed off-label for certain autoimmune disorders,
including MS, and there is anecdotal evidence of benefit,[136][137] but only a small clinical
trial for the primary progressive variety has been published.[138]

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.[139][140] 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.[141]

[edit] See also

• List of multiple sclerosis organizations

[edit] References
1. ^ a b c d e f g h i j k l m n o p q Compston A, Coles A (April 2002). "Multiple sclerosis".
Lancet 359 (9313): 1221–31. doi:10.1016/S0140-6736(02)08220-X. PMID
11955556.
2. ^ a b Debouverie M, Pittion-Vouyovitch S, Louis S, Guillemin F (July 2008).
"Natural history of multiple sclerosis in a population-based cohort". Eur. J.
Neurol.. doi:10.1111/j.1468-1331.2008.02241.x. PMID 18637953.
3. ^ a b Rosati G (April 2001). "The prevalence of multiple sclerosis in the world: an
update". Neurol. Sci. 22 (2): 117–39. PMID 11603614.
4. ^ a b c Charcot, J. Histologie de la sclerose en plaques. Gazette des hopitaux, Paris,
1868; 41: 554–555.
5. ^ a b c d e f g h i 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. ^ 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.
7. ^ a b c d e f Weinshenker BG (1994). "Natural history of multiple sclerosis". Ann.
Neurol. 36 Suppl: S6–11. PMID 8017890.
8. ^ 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.
9. ^ a b Santos EC, Yokota M, Dias NF (September 2007). "[Multiple sclerosis: study
of patients with relapsing-remitting form registered at Minas Gerais Secretary of
State for Health]" (in Portuguese). Arq Neuropsiquiatr 65 (3B): 885–8. PMID
17952303.
10. ^ Navarro S, Mondéjar-Marín B, Pedrosa-Guerrero A, Pérez-Molina I, Garrido-
Robres JA, Alvarez-Tejerina A (2005). "[Aphasia and parietal syndrome as the
presenting symptoms of a demyelinating disease with pseudotumoral lesions]" (in
Spanish; Castilian). Rev Neurol 41 (10): 601–3. PMID 16288423.
11. ^ Jongen PJ (June 2006). "Psychiatric onset of multiple sclerosis". J. Neurol. Sci.
245 (1-2): 59–62. doi:10.1016/j.jns.2005.09.014. PMID 16631798.
12. ^ Yetimalar Y, Seçil Y, Inceoglu AK, Eren S, Başoğlu M (July 2008). "Unusual
primary manifestations of multiple sclerosis". N. Z. Med. J. 121 (1277): 47–59.
PMID 18677330.
13. ^ Hakiki B, Goretti B, Portaccio E, Zipoli V, Amato MP (August 2008).
"'Subclinical MS': follow-up of four cases". Eur. J. Neurol. 15 (8): 858–61.
doi:10.1111/j.1468-1331.2008.02155.x. PMID 18507677.
14. ^ Lebrun C, Bensa C, Debouverie M, et al (February 2008). "Unexpected
multiple sclerosis: follow-up of 30 patients with magnetic resonance imaging and
clinical conversion profile". J. Neurol. Neurosurg. Psychiatr. 79 (2): 195–8.
doi:10.1136/jnnp.2006.108274. PMID 18202208.
15. ^ a b Freeman JA (April 2001). "Improving mobility and functional independence
in persons with multiple sclerosis". J. Neurol. 248 (4): 255–9. PMID 11374088.
16. ^ Merson RM, Rolnick MI (August 1998). "Speech-language pathology and
dysphagia in multiple sclerosis". Phys Med Rehabil Clin N Am 9 (3): 631–41.
PMID 9894114.
17. ^ Kaur P, Bennett JL (2007). "Optic neuritis and the neuro-ophthalmology of
multiple sclerosis". Int. Rev. Neurobiol. 79: 633–63. doi:10.1016/S0074-
7742(07)79028-1. PMID 17531862.
18. ^ Pöllmann W, Feneberg W (2008). "Current management of pain associated with
multiple sclerosis". CNS Drugs 22 (4): 291–324. PMID 18336059.
19. ^ a b Henze T (August 2005). "Managing specific symptoms in people with
multiple sclerosis" (PDF). Int MS J 12 (2): 60–8. PMID 16417816.
20. ^ Andrews KL, Husmann DA (December 1997). "Bladder dysfunction and
management in multiple sclerosis". Mayo Clin. Proc. 72 (12): 1176–83. PMID
9413302.
21. ^ Bobholz JA, Rao SM (June 2003). "Cognitive dysfunction in multiple sclerosis:
a review of recent developments". Curr. Opin. Neurol. 16 (3): 283–8.
doi:10.1097/01.wco.0000073928.19076.84. PMID 12858063.
22. ^ de Seze J, Zephir H, Hautecoeur P, Mackowiak A, Cabaret M, Vermersch P
(November 2006). "Pathologic laughing and intractable hiccups can occur early in
multiple sclerosis". Neurology 67 (9): 1684–6.
doi:10.1212/01.wnl.0000242625.75753.69. PMID 17101907.
23. ^ Kurtzke JF (1983). "Rating neurologic impairment in multiple sclerosis: an
expanded disability status scale (EDSS)". Neurology 33 (11): 1444–52. PMID
6685237.
24. ^ 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.
25. ^ Confavreux C (May 2002). "Infections and the risk of relapse in multiple
sclerosis". Brain 125 (Pt 5): 933–4. PMID 11960883.
26. ^ Buljevac D, Flach HZ, Hop WC, et al (May 2002). "Prospective study on the
relationship between infections and multiple sclerosis exacerbations". Brain 125
(Pt 5): 952–60. PMID 11960885.
27. ^ Buljevac D, Hop WC, Reedeker W, et al (September 2003). "Self reported
stressful life events and exacerbations in multiple sclerosis: prospective study".
BMJ 327 (7416): 646. doi:10.1136/bmj.327.7416.646. PMID 14500435.
28. ^ Brown RF, Tennant CC, Sharrock M, Hodgkinson S, Dunn SM, Pollard JD
(August 2006). "Relationship between stress and relapse in multiple sclerosis:
Part I. Important features". Mult. Scler. 12 (4): 453–64. PMID 16900759.
29. ^ Brown RF, Tennant CC, Sharrock M, Hodgkinson S, Dunn SM, Pollard JD
(August 2006). "Relationship between stress and relapse in multiple sclerosis:
Part II. Direct and indirect relationships". Mult. Scler. 12 (4): 465–75. PMID
16900760.
30. ^ Worthington J, Jones R, Crawford M, Forti A (February 1994). "Pregnancy and
multiple sclerosis--a 3-year prospective study". J. Neurol. 241 (4): 228–33. PMID
8195822.
31. ^ Confavreux C, Suissa S, Saddier P, Bourdès V, Vukusic S (February 2001).
"Vaccinations and the risk of relapse in multiple sclerosis. Vaccines in Multiple
Sclerosis Study Group". N. Engl. J. Med. 344 (5): 319–26. PMID 11172162.
32. ^ Martinelli V (2000). "Trauma, stress and multiple sclerosis". Neurol. Sci. 21 (4
Suppl 2): S849–52. PMID 11205361.
33. ^ Sibley WA, Bamford CR, Clark K, Smith MS, Laguna JF (July 1991). "A
prospective study of physical trauma and multiple sclerosis". J. Neurol.
Neurosurg. Psychiatr. 54 (7): 584–9. PMID 1895121.
34. ^ Smith KJ, McDonald WI (October 1999). "The pathophysiology of multiple
sclerosis: the mechanisms underlying the production of symptoms and the natural
history of the disease". Philos. Trans. R. Soc. Lond., B, Biol. Sci. 354 (1390):
1649–73. doi:10.1098/rstb.1999.0510. PMID 10603618.
35. ^ Pittock SJ, Rodriguez M (2008). "Benign multiple sclerosis: a distinct clinical
entity with therapeutic implications". Curr. Top. Microbiol. Immunol. 318: 1–17.
PMID 18219812.
36. ^ 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.
37. ^ a b c d 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.
38. ^ Fontaine B (September 2001). "[Borderline forms of multiple sclerosis]" (in
French). Rev. Neurol. (Paris) 157 (8-9 Pt 2): 929–34. PMID 11787357.
39. ^ Capello E, Mancardi GL (November 2004). "Marburg type and Balò's
concentric sclerosis: rare and acute variants of multiple sclerosis". Neurol. Sci. 25
Suppl 4: S361–3. PMID 15727234.
40. ^ Hainfellner JA, Schmidbauer M, Schmutzhard E, Maier H, Budka H (December
1992). "Devic's neuromyelitis optica and Schilder's myelinoclastic diffuse
sclerosis". J. Neurol. Neurosurg. Psychiatr. 55 (12): 1194–6. PMID 1343820.
41. ^ O'Riordan JI (June 1997). "Central nervous system white matter diseases other
than multiple sclerosis". Curr. Opin. Neurol. 10 (3): 211–4. PMID 9229127.
42. ^ 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. PMID 11794488.
43. ^ 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.
44. ^ 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. PMID
11456302.
45. ^ 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.
46. ^ 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.
47. ^ 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.
48. ^ 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.
49. ^ 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.
50. ^ 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. PMID 10852536.
51. ^ a b c d Kurtzke JF (October 1993). "Epidemiologic evidence for multiple sclerosis
as an infection". Clin. Microbiol. Rev. 6 (4): 382–427. PMID 8269393.
PMC:358295.
52. ^ a b c d e f g h 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.
53. ^ 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.
54. ^ a b Brissaud O, Palin K, Chateil JF, Pedespan JM (September 2001). "Multiple
sclerosis: pathogenesis and manifestations in children" (in French). Arch Pediatr
8 (9): 969–78. PMID 11582940.
55. ^ 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.
56. ^ Aladro Y, Alemany MJ, Pérez-Vieitez MC, et al (2005). "Prevalence and
incidence of multiple sclerosis in Las Palmas, Canary Islands, Spain".
Neuroepidemiology 24 (1-2): 70–5. doi:10.1159/000081052. PMID 15459512.
57. ^ a b Pugliatti M, Sotgiu S, Solinas G, Castiglia P, Rosati G (April 2001).
"Multiple sclerosis prevalence among Sardinians: further evidence against the
latitude gradient theory". Neurol. Sci. 22 (2): 163–5. PMID 11603620.
58. ^ Hammond SR, English DR, McLeod JG (May 2000). "The age-range of risk of
developing multiple sclerosis: evidence from a migrant population in Australia".
Brain 123 (Pt 5): 968–74. PMID 10775541.
59. ^ Rothwell PM, Charlton D (1998). "High incidence and prevalence of multiple
sclerosis in south east Scotland: evidence of a genetic predisposition". J. Neurol.
Neurosurg. Psychiatr. 64 (6): 730–5. PMID 9647300.
60. ^ Sadovnick AD, Ebers GC, Dyment DA, Risch NJ (June 1996). "Evidence for
genetic basis of multiple sclerosis. The Canadian Collaborative Study Group".
Lancet 347 (9017): 1728–30. PMID 8656905.
61. ^ a b Svejgaard A (June 2008). "The immunogenetics of multiple sclerosis".
Immunogenetics 60 (6): 275–86. doi:10.1007/s00251-008-0295-1. PMID
18461312.
62. ^ Hafler DA, Compston A, Sawcer S, et al (August 2007). "Risk alleles for
multiple sclerosis identified by a genomewide study". N. Engl. J. Med. 357 (9):
851–62. doi:10.1056/NEJMoa073493. PMID 17660530.
63. ^ Weber F, Fontaine B, Cournu-Rebeix I, et al (April 2008). "IL2RA and IL7RA
genes confer susceptibility for multiple sclerosis in two independent European
populations". Genes Immun. 9 (3): 259–63. doi:10.1038/gene.2008.14. PMID
18354419.
64. ^ Anaya JM, Gómez L, Castiblanco J (2006). "Is there a common genetic basis
for autoimmune diseases?". Clin. Dev. Immunol. 13 (2-4): 185–95.
doi:10.1080/17402520600876762. PMID 17162361.
65. ^ Spolski R, Kashyap M, Robinson C, Yu Z, Leonard WJ (September 2008). "IL-
21 signaling is critical for the development of type I diabetes in the NOD mouse".
Proc. Natl. Acad. Sci. U.S.A.. doi:10.1073/pnas.0804358105. PMID 18779574.
66. ^ Palacios R, Aguirrezabal I, Fernandez-Diez B, Brieva L, Villoslada P (October
2005). "Chromosome 5 and multiple sclerosis". J. Neuroimmunol. 167 (1-2): 1–3.
doi:10.1016/j.jneuroim.2005.06.023. PMID 16099057.
67. ^ Leibowitz U, Antonovsky A, Medalie JM, Smith HA, Halpern L, Alter M
(February 1966). "Epidemiological study of multiple sclerosis in Israel. II.
Multiple sclerosis and level of sanitation". J. Neurol. Neurosurg. Psychiatr. 29 (1):
60–8. PMID 5910580.
68. ^ Fleming J, Fabry Z (February 2007). "The hygiene hypothesis and multiple
sclerosis". Ann. Neurol. 61 (2): 85–9. doi:10.1002/ana.21092. PMID 17315205.
69. ^ Gilden DH (March 2005). "Infectious causes of multiple sclerosis". Lancet
Neurol 4 (3): 195–202. doi:10.1016/S1474-4422(05)01017-3. PMID 15721830.
70. ^ Christensen T (June 2007). "Human herpesviruses in MS" (PDF). Int MS J 14
(2): 41–7. PMID 17686342.
71. ^ 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.
72. ^ 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.
73. ^ 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. PMID 11601494.
74. ^ Christensen T (May 2006). "The role of EBV in MS pathogenesis" (PDF). Int
MS J 13 (2): 52–7. PMID 16635422.