Multiple sclerosis

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Template:DiseaseDisorder infobox Multiple Sclerosis (abbreviated MS, also known as disseminated sclerosis or encephalomyelitis disseminata) is a chronic, inflammatory, demyelinating disease that affects the central nervous system (CNS). MS can cause a variety of symptoms, including changes in sensation, visual problems, muscle weakness, depression, difficulties with coordination and speech, severe fatigue, cognitive impairment, problems with balance, overheating, and pain. MS will cause impaired mobility and disability in more severe cases.

Multiple sclerosis affects neurons, the cells of the brain and spinal cord that carry information, create thought and perception, and allow the brain to control the body. Surrounding and protecting some of these neurons is a fatty layer known as the myelin sheath, which helps neurons carry electrical signals. MS causes gradual destruction of myelin (demyelination) and transection of neuron axons in patches throughout the brain and spinal cord. The name multiple sclerosis refers to the multiple scars (or scleroses) on the myelin sheaths. This scarring causes symptoms which vary widely depending upon which signals are interrupted.

The predominant theory today of the cause of MS is that it results from attacks by an individual's immune system on the nervous system and it is therefore usually categorized as an autoimmune disease. There is a minority view that MS is not an autoimmune disease, but rather a metabolically dependent neurodegenerative disease. Although much is known about how MS causes damage, its exact cause remains unknown.

Multiple sclerosis may take several different forms, with new symptoms occurring either in discrete attacks or slowly accruing over time. Between attacks, symptoms may resolve completely, but permanent neurologic problems often persist, especially as the disease advances. MS currently does not have a cure, though several treatments are available that may slow the appearance of new symptoms.

MS primarily affects adults, with an age of onset typically between 20 and 40 years, and is more common in women than in men.[1][2]

Classification

The course of MS is difficult to predict, as the disease may lie dormant one moment and progress steadily the other. Nevertheless, several subtypes, or patterns of progression, have been described. Subtypes use the course of the disease so far in order to extrapolate the future development of it. The probable prognosis gives a better groundwork for therapeutic decisions. As a standard, the subtypes are relapsing-remitting, secondary progressive, primary progressive and progressive relapsing[3].

Relapsing-remitting

Relapsing-remitting describes the initial course of 85% to 90% of individuals with MS. This subtype is characterized by unpredictable attacks (relapses) followed by periods of months to years of relative quiet (remission) with no new signs of disease activity. Deficits suffered during the attacks may either resolve or may be permanent. When deficits always resolve between attacks, this is referred to as "benign" MS.

Primary progressive

Primary progressive describes the approximately 10% of individuals who never have remission after their initial MS symptoms. Decline occurs continuously without clear attacks. The primary progressive subtype tends to affect people who are older at disease onset.

Secondary progressive

Secondary progressive describes around 80% of those with initial relapsing-remitting MS, who then begin to have neurologic decline between their acute attacks without any definite periods of remission. This decline may include new neurologic symptoms, worsening cognitive function, or other deficits. Secondary progressive is the most common type of MS and causes the greatest amount of disability.

Progressive relapsing

Progressive relapsing describes those individuals who, from the onset of their MS, have a steady neurologic decline but also suffer superimposed attacks; and is the least common of all subtypes

Others

Special cases of the disease with non-standard behavior have also been described although many researchers believe they are different diseases. These cases are sometimes referred to as borderline forms of multiple sclerosis and are Neuromyelitis optica (NMO), Balo concentric sclerosis, Schilder's diffuse sclerosis and Marburg multiple sclerosis[4].

Diagnosis

Multiple sclerosis is difficult to diagnose in its early stages. In fact, definite diagnosis of MS cannot be made until there is evidence of at least two anatomically separate demyelinating events occurring at least thirty days apart.

On the other hand, there are several ways to diagnose MS when it has become more severe, including, medical history and examination, Magnetic resonance imaging, testing of cerebrospinal fluid and optic nerve reactions. Nevertheless, the signs and symptoms of MS can be similar to other medical problems, such as neuromyelitis optica, stroke, brain inflammation, infections such as Lyme disease (which can produce identical MRI lesions and CSF abnormalities[5][6][7][8]), tumors, and other autoimmune problems, such as lupus. Additional testing may be needed to help distinguish MS from these other problems.

Symptoms

MS starts with prodromal, mild attacks. For some people the initial MS attack is preceded by infection, trauma, or strenuous physical effort.

The most common initial symptoms reported are: pain (70%)[9], changes in sensation in the arms, legs or face (33%), complete or partial vision loss (optic neuritis) (16%), weakness (13%), double vision (7%), unsteadiness when walking (5%), and balance problems (3%); but many rare initial symptoms have been reported such as aphasia or psychosis.[10][11] Fifteen percent of individuals have multiple symptoms when they first seek medical attention.[12]

With time, the symptoms get more severe. Such symptoms include changes in sensation (hypoesthesia), muscle weakness, abnormal muscle spasms, or difficulty to move; difficulties with coordination and balance (ataxia); problems in speech (dysarthria) or swallowing (dysphagia), visual problems (nystagmus, optic neuritis, or diplopia), fatigue and acute or chronic pain syndromes, bladder and bowel difficulties, cognitive impairment, or psychiatric symptoms such as depression.

Optic neuritis
For more information, see: optic neuritis.

Among patients with optic neuritis, 40% will have multiple sclerosis within 10 years.[13] The presence of a brain lesion on MRI at the time of optic neuritic affects prognosis at the risk of multiple sclerosis at 10 years is 56% with a brain lesion and 26% without.[13]

Autonomic dysfunction

"The most common autonomic symptoms in MS are disorders of micturation, impotence, sudomotor and gastrointestinal disturbances, orthostatic intolerance as well as sleep disorders."[14]

Medical history and examination

Clinical data alone may be sufficient for a diagnosis of MS. If an individual has suffered two separate episodes of neurologic symptoms characteristic of MS, and the individual also has consistent abnormalities on physical examination, a diagnosis of MS can be made with no further testing. Since some people with MS seek medical attention after only one attack, other testing may hasten the diagnosis and allow earlier initiation of therapy.

Magnetic resonance imaging

Magnetic resonance imaging (MRI) of the brain and spine is often used to evaluate individuals with suspected MS. MRI shows areas of demyelination as bright lesions on T2-weighted images or FLAIR (fluid attenuated inversion recovery) sequences. Gadolinium contrast is used to demonstrate active plaques on T1-weighted images. Because MRI can reveal lesions which occurred previously but produced no clinical symptoms, it can provide the evidence of chronicity needed for a definite diagnosis of MS.

Cerebrospinal fluid

Testing of cerebrospinal fluid (CSF) can provide evidence of chronic inflammation of the central nervous system. The CSF is tested for oligoclonal bands, which are immunoglobulins found in 85% to 95% of people with definite MS (but also found in people with other diseases).[15] Combined with MRI and clinical data, the presence of oligoclonal bands can help make a definite diagnosis of MS. Lumbar puncture is the procedure used to collect a sample of CSF.

Evoked potentials

The brain of a person with MS often responds less actively to stimulation of the optic nerve and sensory nerves. These brain responses can be examined using visual evoked potentials (VEPs) and somatosensory evoked potentials (SEPs). Decreased activity on either test can reveal demyelination which may be otherwise asymptomatic. Along with other data, these exams can help find the widespread nerve involvement required for a definite diagnosis of MS.[16]

Others

Another test which may become important in the future is measurement of antibodies against myelin proteins such as myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP). As of 2007, however, there is no established role for these tests in diagnosing MS.

McDonald Criteria

Revised McDonald Criteria
Attacks Lesions Additional requirements
2 or more 2 or more lesions None
2 or more 1 lesion Dissemination in space
1 attack 2 or more lesions Dissemination in time
1 attack 1 lesion
(monosymptomatic)		 Dissemination in space anddissemination in space
1 attack
(progressive)		 one lesion One year of disease progression and two of: 1) positive brain MRI, 2) positive spinal MRI , 2) positve CSF
Adapted from Table 4 of Polman et al.[17]

The McDonald Criteria should be met in order to diagnose multiple sclerosis.[17]

Factors triggering a relapse

Multiple sclerosis relapses are often unpredictable and can occur without warning with no obvious inciting factors. Some attacks, however, are preceded by common triggers. In general, relapses occur more frequently during spring and summer than during autumn and winter. Infections, such as the common cold, influenza, and gastroenteritis, increase the risk for a relapse.[18] Emotional and physical stress may also trigger an attack,[19][20][21] as can severe illness of any kind. Statistically, there is no good evidence that either trauma or surgery trigger relapses. People with MS can participate in sports, but they should probably avoid extremely strenuous exertion, such as marathon running. Heat can transiently increase symptoms, which is known as Uhthoff's phenomenon. This is why some people with MS avoid saunas or even hot showers. However, heat is not an established trigger of relapses.[22]

Pregnancy can directly affect the susceptibility for relapse. The least three months of pregnancy offer a natural protection against relapses. However, during the first few months after delivery, the risk for a relapse is increased 20%–40%. Pregnancy does not seem to influence long-term disability. Children born to mothers with MS are not at increased risk for birth defects or other problems.[23]

Many potential triggers have been examined and found not to influence relapse rates in MS. Influenza vaccination is safe, does not trigger relapses, and can therefore be recommended for people with MS. There is also no evidence that hepatitis B, varicella, tetanus, or Bacille Calmette-Guerin (BCG - immunization for tuberculosis) increases the risk for relapse.[24]

Pathophysiology

For more information, see: Pathophysiology of multiple sclerosis.

Although much is known about how multiple sclerosis causes damage, the reasons why multiple sclerosis occurs are not known.

Multiple sclerosis is a disease in which the myelin (a fatty substance which covers the axons of nerve cells) degenerates. According to the view of most researchers, a special subset of lymphocytes, called T cells, plays a key role in the development of MS.

According to a strictly immunological explanation of MS, the inflammatory processes triggered by the T cells create leaks in the blood-brain barrier (a capilar system that should prevent entrance of T-cells in the nervous system). These leaks, in turn, cause a number of other damaging effects such as swelling, activation of macrophages, and more activation of cytokines and other destructive proteins such as matrix metalloproteinases.

In a person with MS, these lymphocytes recognize myelin as foreign and attack it as if it were an invading virus. That triggers inflammatory processes, stimulating other immune cells and soluble factors like cytokines and antibodies.

It is known that a repair process, called remyelination, takes place in early phases of the disease, but the oligodendrocytes that originally formed a myelin sheath cannot completely rebuild a destroyed myelin sheath. The newly-formed myelin sheaths are thinner and often not as effective as the original ones. Repeated attacks lead to successively fewer effective remyelinations, until a scar-like plaque is built up around the damaged axons, according to four different damage patterns[25]. The central nervous system should be able to recruit oligodendrocyte stem cells capable to turn into mature myelinating oligodendrocytes, but it is suspected that something inhibits stem cells in affected areas.

Also the neuron axons are damaged by the attacks. Often, the brain is able to compensate for some of this damage, due to an ability called neuroplasticity. MS symptoms develop as the cumulative result of multiple lesions in the brain and spinal cord. This is why symptoms can vary greatly between different individuals, depending on where their lesions occur.

Causes

Although many risk factors for multiple sclerosis have been identified, no definitive cause has been found. MS likely occurs as a result of some combination of both environmental and genetic factors. Various theories try to combine the known data into plausible explanations. Although most accept an autoimmune explanation, several theories suggest that MS is an appropriate immune response to an underlying condition. In support of alternative theories is the fact that present therapies have not been as successful as was expected based on the autoimmune theory.[26][27][28]

Environmental

Risk factors believed to contribute to the development of MS are for example viral or bacterial infections, vitamin D deficiency and a lack of exposure of illnesses to the immune system in childhood.

Viral infection

The most popular hypothesis is that a viral infection or retroviral reactivation primes a susceptible immune system for an abnormal reaction later in life. On a molecular level, this might occur if there is a structural similarity between the infectious virus and some component of the central nervous system, leading to eventual confusion in the immune system.

Vitamin D deficiency

Since MS seems to be more common in people who live farther from the equator, another theory proposes that decreased sunlight exposure[29] and possibly decreased vitamin D production may help cause MS. This theory is bolstered by recent research into the biochemistry of vitamin D, which has shown that it is an important immune system regulator. Indeed, recent studies strongly indicate that Vitamin D deficiency is associated with the onset of multiple sclerosis.[30]

Lack of exposure

Other theories, noting that MS is less common in children with siblings, suggest that less exposure to illness in childhood leads to an immune system which is not primed to fight infection and is thus more likely to attack the body. One explanation for this would be an imbalance between the Th1 type of helper T-cells, which fight infection, and the Th2 type, which are more active in allergy and more likely to attack the body.

Chronic infection

Other theories describe MS as an immune response to a chronic infection, as with viral infections described above, but that the infection remains and has a more direct effect on the development of MS. The association of MS with the Epstein-Barr virus suggests a potential viral contribution in at least some individuals.[31] Still others believe that MS may sometimes result from a chronic infection with spirochetal bacteria, a hypothesis supported by research in which cystic forms were isolated from the cerebrospinal fluid of all MS patients in a small study.[32] When the cysts were cultured, propagating spirochetes emerged. Another bacterium that has been implicated in MS is Chlamydophila pneumoniae; it or its DNA has been found in the cerebrospinal fluid of MS patients by several research laboratories, with one study finding that the oligoclonal bands of 14 of the 17 MS patients studied consisted largely of antibodies to Chlamydophila antigens.[33]

Others

Severe stress may also be a factor — a large study in Denmark found that parents who had lost a child unexpectedly were 50% more likely to develop MS than parents who had not.[34] Smoking has also been shown to be an independent risk factor for developing MS[35]. Furthermore, a deficiency of uric acid has been implicated in the immunological development of MS[36].

Genetic

MS is not considered a hereditary disease. However, increasing scientific evidence suggests that genetics may play a role in determining a person's susceptibility to MS:

Some populations, such as the Roma, Inuit, and Bantus, rarely if ever get MS. The indigenous peoples of the Americas and Asians have very low incidence rates.

In the population at large, the chance of developing MS is less than a tenth of one percent. However, if one person in a family has MS, that person's first-degree relatives—parents, children, and siblings—have a one to three percent chance of getting the disease.

For identical twins, the concordance, that the second twin may develop MS if the first twin does, is about 30%. For fraternal twins, on the other hand, who do not inherit identical gene pools, the likelihood is closer to that for non-twin siblings, or about 4%. Anyhow, the fact that the rate for identical twins both developing MS is significantly less than 100% suggests that the disease is not entirely genetically controlled. Some (but definitely not all) of this effect may be due to shared exposure to something in the environment, or to the fact that some people with MS lesions remain essentially asymptomatic throughout their lives.

Further indications that more than one gene is involved in MS susceptibility comes from studies of families in which more than one member has MS. Several research teams found that people with MS inherit certain regions on individual genes more frequently than people without MS. Of particular interest is the human leukocyte antigen (HLA) region on chromosome 6. HLAs are genetically determined proteins that influence the immune system. However, there are other genes in this region which are not related to the immune system.

The HLA patterns of MS patients tend to be different from those of people without the disease. Investigations in northern Europe and America have detected three HLAs that are more prevalent in people with MS than in the general population. Studies of American MS patients have shown that people with MS also tend to exhibit these HLAs in combination—that is, they have more than one of the three HLAs—more frequently than the rest of the population. Furthermore, there is evidence that different combinations of the HLAs may correspond to variations in disease severity and progression.

Studies of families with multiple cases of MS and research comparing proteins expressed in humans with MS to those of mice with Experimental autoimmune encephalomyelitis suggest that another area related to MS susceptibility may be located on chromosome 5. Other regions on chromosomes 2, 3, 7, 11, 17, 19, and X have also been identified as possibly containing genes involved in the development of MS.

These studies strengthen the theory that MS is the result of a number of factors rather than a single gene or other agent. In other words, development of MS is likely to be influenced by the interactions of a number of genes, each of which (individually) has only a modest effect. However, additional studies are needed to specifically pinpoint which genes are involved, determine their function, and learn how each gene's interactions with other genes and with the environment make an individual susceptible to MS.

Therapies

For more information, see: Therapies for multiple sclerosis.


There is no known definitive cure for multiple sclerosis. However, several types of therapy have proven to be helpful. Different therapies are used for patients experiencing acute attacks, for patients who have the relapsing-remitting subtype, for patients who have the progressive subtypes, for patients without a diagnosis of MS who have a demyelinating event, and for managing the various consequences of MS attacks. Treatment is aimed at returning function after an attack, preventing new attacks, and preventing disability.

Various disease-modifying treatments have been approved by the USA's Food and Drug Administration (FDA); as well as in other countries; for multiple sclerosis. More treatments are being studied and undergoing the approval process.

These are medications derived from human cytokines which help regulate the immune system. Betaseron has been approved by the FDA for relapsing forms of secondary progressive MS.
Interferon beta-1a: (trade names Avonex , Rebif and CinnoVex [Biogereric/biosimolar form of Avonex])
beta-1b: (trade name Betaseron [in Europe and Japan Betaferon]).
A synthetic medication made of four amino acids that are found in myelin. This drug stimulates T cells in the body's immune system to change from harmful, pro-inflammatory agents to beneficial, anti-inflammatory agents that work to reduce inflammation at lesion sites.
This medication is effective, but is limited by cardiac toxicity. Novantrone has been approved by the USA's FDA for secondary progressive, progressive-relapsing, and worsening relapsing-remitting MS.
This medication is effective and safe alone but in combination with other immunotherapies can lead to PML.


Relapsing-remitting symptomatic attacks can be treated. Patients are typically given high doses of intravenous corticosteroids, such as methylprednisolone, to end the attack sooner and leave fewer lasting deficits.

Currently, however, there are no approved treatments for primary progressive multiple sclerosis, though several medications are being studied.

Prognosis

The prognosis (the expected future course of the disease) for a person with multiple sclerosis depends on the individual's age, initial symptoms, the degree of disability the person experiences but also sex and race. The life expectancy of people with MS is now nearly the same as that of unaffected people. This is due mainly to improved methods of limiting disability, such as physical therapy, Occupational Therapy and speech therapy, along with more successful treatment of common complications of disability, such as pneumonia and urinary tract infections.[37] 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.[38]

Currently there are no clinically established laboratory investigations available that can predict prognosis or response to treatment. However, several promising approaches have been proposed. These include measurement of the two antibodies anti-myelin oligodendrocyte glycoprotein and anti-myelin basic protein, and measurement of TRAIL (TNF-related apoptosis-inducing ligand).[39]

Age

The earlier in life MS occurs, the slower disability progresses. Individuals who are older than fifty when diagnosed are more likely to experience a chronic progressive course, with more rapid progression of disability. Those diagnosed before age 35 have the best prognosis. Females generally have a better prognosis than males. Although individuals of African descent tend to develop MS less frequently, they are often older at the time of onset and may have a worse prognosis.

Initial symptoms

Initial MS symptoms of visual loss or sensory problems, such as numbness or tingling, are markers for a relatively good prognosis, whereas difficulty walking and weakness are markers for a relatively poor prognosis. Better outcomes are also associated with the presence of only a single symptom at onset, the rapid development of initial symptoms, and the rapid regression of initial symptoms, since it is an indication that the disease is of the relapsing-remitting subtype. This has a slower decline in function than other subtypes. For instance, supportive equipment (such as a wheelchair or standing frame) is often needed first after twenty years. This means that many individuals with MS will never need a wheelchair. In individuals with progressive subtypes of MS, particularly the primary progressive subtype, on the other hand, supportive equipment is often needed after only about six to seven years. There is also more cognitive impairment in the progressive forms than in the relapsing-remitting course.

Degree of disability

The degree of disability varies among individuals with MS. In general, one of three individuals will still be able to work after 15–20 years. Fifteen percent of people diagnosed with MS never have a second relapse, and these people have minimal or no disability after ten years.[40] The degree of disability after five years correlates well with the degree of disability after fifteen years. This means that two-thirds of people with MS with low disability after five years will not get much worse during the next ten years. It should be noted that most of these outcomes were observed before the use of medications such as interferon, which can delay disease progression for several years.

Epidemiology

The incidence of MS differs geographically, between races, sex and between family members where there is a genetic higher risk of developing MS.

However, advances in the study of related diseases have shown that some cases formerly considered MS are not MS at all. In fact, all the studies before 2004 can be affected by the impossibility to distinguish MS and neuromyelitis optica, NMO, reliably before this date. The error can be important in some areas, and is considered to be 30% in Japan.[41]

Geographically

In northern Europe, continental North America, and Australasia, about one of every 1000 citizens suffers from multiple sclerosis, whereas in the Arabian peninsula, Asia, and continental South America, the frequency is much lower. In sub-Saharan Africa, MS is extremely rare. With important exceptions, there is a north-to-south gradient in the northern hemisphere and a south-to-north gradient in the southern hemisphere, with MS being much less common in people living near the equator.[42] Climate, diet, geomagnetism, toxins, sunlight exposure, genetic factors, and infectious diseases have all been discussed as possible reasons for these regional differences. Environmental factors during childhood may play an important role in the development of MS later in life. This idea is based on several studies of migrants showing that if migration occurs before the age of fifteen, the migrant acquires the new region's susceptibility to MS. If migration takes place after age fifteen, the migrant keeps the susceptibility of his home country.[43]

Race

MS occurs mainly in Caucasians. It is twentyfold lower in the Inuit people of Canada than in other Canadians living in the same region. It is also rare in the Native American tribes of North America, Australian Aborigines and the Māori of New Zealand. Scotland appears to have the highest rate of MS in the world [44]. The reasons for this are unknown. These few examples point out that both genetic and environmental factors play determine the development of MS.

Sex

As observed in many autoimmune disorders, MS is more common in females than males; the mean sex ratio is about two females for every male. In children (who rarely develop MS) the sex ratio may reach three females for each male. In people over age fifty, MS affects males and females equally. Onset of symptoms usually occurs between fifteen to forty years of age, rarely before age fifteen or after age sixty.

Family members

As previously discussed, there is a genetic component to MS. On average one of every 25 siblings of individuals with MS will also develop MS. On the other hand, almost half of the identical twins of MS-affected individuals will develop MS, but only one of twenty fraternal twins. Nevertheless, that the risk is higher for fraternal twins than for average siblings, even if the children share the same amount of genetic material in both cases, indicates that environmental factors also play a role. In the perspective of parent-child, if one parent is affected by MS, each child has a risk of only about one in forty of developing MS later in life.[45]

History

The French neurologist Jean-Martin Charcot (1825–93) was the first person to recognize multiple sclerosis as a distinct, separate disease in 1868. Summarizing previous reports and adding his own important clinical and pathological observations, Charcot called the disease sclerose en plaques. The three signs of MS now known as Charcot's triad are dysarthria (problems with speech), ataxia (problems with coordination), and tremor. Charcot also observed cognition changes in MS since he described his patients as having a "marked enfeeblement of the memory" and "with conceptions that formed slowly".[46]

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

After this, several people, such as Eugène Devic (1858–1930), Jozsef Balo (1895–1979), Paul Ferdinand Schilder (1886–1940), and Otto Marburg (1874–1948) found special cases of the disease that some authors consider different diseases and now are called the borderline forms of multiple sclerosis.

Historically, different criteria of diagnosis were also used. The Schumacher criteria and Poser criteria were both popular.

Famous people with MS

There are several historical accounts of people who probably had MS. Saint Lidwina of Schiedam (1380–1433), a Dutch nun, may be one of the first identifiable MS patients. From the age of sixteen until her death at age 53, she suffered intermittent pain, weakness of the legs, and vision loss—symptoms typical of MS. Almost a hundred years before there is a story from Iceland of a young woman called Halla. This girl suddenly lost her vision and capacity to talk; but after praying to the saints recovered them seven days after.[47] Augustus Frederick d'Este (1794–1848), an illegitimate grandson of King George III of Great Britain, almost certainly suffered from MS. D'Este left a detailed diary describing his 22 years living with the disease. He began his diary in 1822 and it had its last entry in 1846 (only to remain unknown until 1948). His symptoms began at age 28 with a sudden transient visual loss after the funeral of a friend. During the course of his disease he developed weakness of the legs, clumsiness of the hands, numbness, dizziness, bladder disturbances, and erectile dysfunction. In 1844, he began to use a wheelchair. Despite his illness, he kept an optimistic view of life.[48] Another early account of MS was kept by the British diarist W. N. P. Barbellion, who maintained a detailed log of his diagnosis and struggle with MS. His diary was published in 1919 as The Journal of a Disappointed Man.

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  24. ↑ Confavreux C, Suissa S, Saddier P, Bourdès V, Vukusic S (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. [e]
  25. ↑ Lucchinetti, C. Bruck, W. Parisi, J. Scherhauer, B. Rodriguez, M. Lassmann, H.Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination Ann Neurol, 2000; 47(6):707-17. PMID 10852536
  26. ↑ Peter Behan and Abhijit Chaudhuri (2002). "The pathogenesis of multiple sclerosis revisited". J R Coll Physicians Edinb 32: 244–265.
  27. ↑ Chaudhuri A, Behan P (2004). "Multiple sclerosis is not an autoimmune disease". Arch. Neurol. 61 (10): 1610–2. PMID 15477520.
  28. ↑ Altmann D (2005). "Evaluating the evidence for multiple sclerosis as an autoimmune disease". Arch. Neurol. 62 (4): 688; author reply 688-9. PMID 15824275.
  29. ↑ van der Mei IA, Ponsonby AL, Dwyer T, et al (2003). "Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case-control study". BMJ 327 (7410): 316. DOI:10.1136/bmj.327.7410.316. PMID 12907484. Research Blogging.
  30. ↑ Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A (2006). "Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis". JAMA 296 (23): 2832-8. DOI:10.1001/jama.296.23.2832. PMID 17179460. Research Blogging.
  31. ↑ Levin LI, Munger KL, Rubertone MV, et al (2005). "Temporal relationship between elevation of epstein-barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis". JAMA 293 (20): 2496-500. DOI:10.1001/jama.293.20.2496. PMID 15914750. Research Blogging.
  32. ↑ Brorson O, Brorson SH, Henriksen TH, Skogen PR, Schøyen R (2001). "Association between multiple sclerosis and cystic structures in cerebrospinal fluid". Infection 29 (6): 315-9. PMID 11787831. [e]
  33. ↑ Yao SY, Stratton CW, Mitchell WM, Sriram S (2001). "CSF oligoclonal bands in MS include antibodies against Chlamydophila antigens". Neurology 56 (9): 1168-76. PMID 11342681. [e]
  34. ↑ Li J, Johansen C, Bronnum-Hansen H, Stenager E, Koch-Henriksen N, Olsen J (2004). "The risk of multiple sclerosis in bereaved parents: A nationwide cohort study in Denmark.". Neurology 62 (5): 726-9. PMID 15007121.
  35. ↑ Franklin GM, Nelson L (2003). "Environmental risk factors in multiple sclerosis: causes, triggers, and patient autonomy". Neurology 61 (8): 1032-4. PMID 14581658. [e]
  36. ↑ Rentzos M, Nikolaou C, Anagnostouli M, Rombos A, Tsakanikas K, Economou M, Dimitrakopoulos A, Karouli M, Vassilopoulos D (2006). "Serum uric acid and multiple sclerosis". Clinical neurology and neurosurgery 108 (6): 527-31. PMID 16202511.
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  39. ↑ Berger T, Rubner P, Schautzer F, Egg R, Ulmer H, Mayringer I, Dilitz E, Deisenhammer F, Reindl M. Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event. N Engl J Med. 2003 Jul 10;349(2):139-45. PMID 12853586
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  48. ↑ Firth, D (1948). The Case of August D`Esté. Cambridge: Cambridge University Press. 


Organizations

For more information, see: Multiple Sclerosis organizations.
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