Multiple sclerosis
This article needs more Wikipedia's guidelines for medical content, or are excessively dated, are contained in this article. (July 2022) |
Multiple sclerosis | |
---|---|
Other names | Multiple cerebral sclerosis, multiple cerebro-spinal sclerosis, disseminated sclerosis, encephalomyelitis disseminata |
CD68-stained tissue shows several macrophages in the area of a demyelinated lesion caused by MS. | |
Specialty | Neurology |
Symptoms | Variable, including almost any neurological symptom or sign, with autonomic, visual, motor, and sensory problems being the most common.[1] |
Usual onset | Age 20–50[2] |
Duration | Long term[3] |
Causes | Unknown[4] |
Diagnostic method | Based on symptoms and medical tests[5] |
Treatment | Disease-modifying therapies[6]
Physiotherapy[7] Occupational therapy[7] |
Frequency | 0.032% (world) |
Multiple sclerosis (MS) is an
While the cause is unclear, the underlying mechanism is thought to be either
No cure for multiple sclerosis is known.[18] Current treatments are aimed at mitigating inflammation and resulting symptoms from acute flares and prevention of further attacks with disease-modifying medications.[8][19] Physical therapy[7] and occupational therapy,[20] along with patient-centered symptom management, can help with people's ability to function. The long-term outcome is difficult to predict; better outcomes are more often seen in women, those who develop the disease early in life, those with a relapsing course, and those who initially experienced few attacks.[21]
Multiple sclerosis is the most common immune-mediated disorder affecting the central nervous system.[22] Nearly one million people in the United States had MS in 2022,[23] and in 2020, about 2.8 million people were affected globally, with rates varying widely in different regions and among different populations.[24] The disease usually begins between the ages of 20 and 50 and is twice as common in women as in men.[2] MS was first described in 1868 by French neurologist Jean-Martin Charcot.[25]
The name "multiple
Signs and symptoms
As MS lesions can affect any part of the central nervous system, a person with MS can have almost any neurological symptom or sign referable to the central nervous system.
Fatigue[26] is one of the most common symptoms of MS.[27][28] Some 65% of people with MS experience fatigue symptomatology, and of these some 15–40% report fatigue as their most disabling MS symptom.[29]
Autonomic, visual, motor, and sensory problems are also among the most common symptoms.[1]
The specific symptoms are determined by the locations of the lesions within the nervous system, and may include focal
Difficulties thinking and emotional problems such as depression or
Uhthoff's phenomenon, a worsening of symptoms due to exposure to higher-than-usual temperatures, and Lhermitte's sign, an electrical sensation that runs down the back when bending the neck, are particularly characteristic of MS, although may not always be present.[1] Another presenting manifestation that is rare but highly suggestive of a demyelinating process such as MS is bilateral internuclear ophthalmoplegia, where the patient experiences double vision when attempting to move their gaze to the right & left.[38]
Some 60% or more of MS patients find their symptoms, particularly including fatigue,[39] are affected by changes in their body heat.[40][41][42]
Measures of disability
The main measure of disability and severity is the
Disease course
The condition begins in 85% of cases as a clinically isolated syndrome (CIS) over a number of days with 45% having motor or sensory problems, 20% having optic neuritis,[31] and 10% having symptoms related to brainstem dysfunction, while the remaining 25% have more than one of the previous difficulties.[5] The course of symptoms occurs in two main patterns initially: either as episodes of sudden worsening that last a few days to months (called relapses, exacerbations, bouts, attacks, or flare-ups) followed by improvement (85% of cases) or as a gradual worsening over time without periods of recovery (10–15% of cases).[2] A combination of these two patterns may also occur[13] or people may start in a relapsing and remitting course that then becomes progressive later on.[2]
Relapses
Relapses are usually not predictable, occurring without warning.
Prodromal phase
MS may have a
Causes
Multiple sclerosis is an autoimmune disease with a combination of genetic and environmental causes underlying it. Both T-cells and B-cells are involved, although T-cells are often considered to be the driving force of the disease. The causes of the disease are not fully understood. The Epstein-Barr Virus (EBV) has been shown to be directly present in the brain of most cases of multiple sclerosis and the virus is transcriptionally active in the infected cells.[54][55] EBV nuclear antigens are believed to be involved in the pathogenesis of multiple sclerosis, but not all people with MS have signs of EBV infection.[15] Dozens of human peptides have been identified in different cases of the disease, and while some have plausible links to infectious organisms or known environmental factors, others do not.[56]
Immune dysregulation
Failure of both central and peripheral nervous system clearance of autoreactive immune cells is implicated in the development of MS.[15] The thymus is responsible for the immune system's central tolerance, where autoreactive T-cells are killed without being released into circulation. Via a similar mechanism, autoreactive B-cells in the bone marrow are killed. Some autoreactive T-cells & B-cells are able to escape these defense mechanisms, which is where peripheral immune tolerance defenses take action by preventing them from causing disease. However, these additional lines of defense can still fail.[15][19] Further detail on immune dysregulation's role in MS is provided in the pathophysiology section of this article as well as here.
Infectious agents
One hypothesis is that infection by a widespread microbe contributes to disease development, and the geographic distribution of this organism influences the
Epstein-Barr herpes virus (EBV) can cause infectious mononucleosis and infects about 95% of adults. In combination with other genetic and environmental factors, there is "compelling epidemiological and mechanistic evidence for a causal role of EBV in multiple sclerosis", though only a small proportion of those infected with EBV later develop MS.[59][16][60][55] A study of individuals in the United States military between 1993 and 2013 (total population greater than 10 million) compared 801 people who developed MS on or after military service to 1,566 matched controls who did not develop MS during this observation period. The study found a 32-fold increased risk of developing MS after infection with EBV. It did not find an increased risk after infection with other viruses, including the similarly transmitted cytomegalovirus. The finding strongly suggests that EBV plays a role in the onset of MS, although EBV alone may be insufficient to cause it.[16][60]
The nuclear antigen of EBV, which is the most consistent marker of EBV infection across all strains,[61] has been identified as a direct source of autoreactivity in the human body. These antigens appear to be more likely to promote autoimmune responses in a person who also has a vitamin D deficiency. The exact nature of this relationship is poorly understood.[62][15]
Genetics
MS is not considered a
Specific
Geography
The prevalence of MS from a geographic standpoint resembles a gradient, with MS being more common in people who live farther from the
MS is more common in regions with northern European populations,[1] so the geographic variation may simply reflect the global distribution of these high-risk populations.[2]
A relationship between season of birth and MS lends support to this idea, with fewer people born in the Northern Hemisphere in November compared to May being affected later in life.[73]
Environmental factors may play a role during childhood, with several studies finding that people who move to a different region of the world before the age of 15 acquire the new region's risk of MS. If migration takes place after age 15, the persons retain the risk of their home country.[1][74] Some evidence indicates that the effect of moving may still apply to people older than 15.[1]
Impact of heat or cold
MS symptoms may increase if body temperature is high or low.[75][76][77] Fatigue is particularly effected.[39][40][41][42][78][79][80][81]
Other
Pathophysiology
Multiple sclerosis is an autoimmune disease, primarily mediated by T-cells.
Immune dysregulation
As briefly detailed in the causes section of this article, MS is currently thought to stem from a failure of the body's immune system to kill off autoreactive T-cells & B-cells.[15] Currently, the T-cell subpopulations that are thought to drive the development of MS are autoreactive CD8+ T-cells, CD4+ helper T-cells, and TH17 cells. These autoreactive T-cells produce substances called cytokines that induce an inflammatory immune response in the CNS, leading to the development of the disease.[15] More recently, however, the role of autoreactive B-cells has been elucidated. Evidence of their contribution to the development of MS is implicated through the presence of oligoclonal IgG bands (antibodies produced by B-cells) in the CSF of patients with MS.[15][19] The presence of these oligoclonal bands has been used as supportive evidence in clinching a diagnosis of MS.[87] As similarly described before, B-cells can also produce cytokines that induce an inflammatory immune response via activation of autoreactive T-cells.[15][88] As such, higher levels of these autoreactive B-cells is associated with increased number of lesions & neurodegeneration as well as worse disability.[15]
Another cell population that is becoming increasingly implicated in MS are microglia. These cells are resident to & keep watch over the CNS, responding to pathogens by shifting between pro- & anti-inflammatory states. Microglia have been shown to be involved in the formation of MS lesions and have been shown to be involved in other diseases that primarily affect the CNS white matter. Although, because of their ability to switch between pro- & anti-inflammatory states, microglia have also been shown to be able to assist in remyelination & subsequent neuron repair.[15] As such, microglia are thought to be participating in both acute & chronic MS lesions, with 40% of phagocytic cells in early active MS lesions being proinflammatory microglia.[15]
Lesions
The name multiple sclerosis refers to the scars (sclerae – better known as plaques or lesions) that form in the nervous system. These lesions most commonly affect the
To be specific, MS involves the loss of
Inflammation
Apart from demyelination, the other sign of the disease is
The attack on myelin starts inflammatory processes, which trigger other immune cells and the release of soluble factors like
Blood–brain barrier
The blood–brain barrier (BBB) is a part of the capillary system that prevents the entry of T cells into the central nervous system. It may become permeable to these types of cells secondary to an infection by a virus or bacteria. After it repairs itself, typically once the infection has cleared, T cells may remain trapped inside the brain.[8][91] Gadolinium cannot cross a normal BBB, so gadolinium-enhanced MRI is used to show BBB breakdowns.[92]
MS fatigue
The pathophysiology and mechanisms causing MS fatigue are not well understood.[93][94][95] MS fatigue can be affected by body heat,[75][77] and this may differentiate MS fatigue from other primary fatigue.[39][40][81] Fatigability (loss of strength) may increase perception of fatigue, but the two measures warrant independent assessment in clinical studies.[96]
Diagnosis
Multiple sclerosis is typically diagnosed based on the presenting signs and symptoms, in combination with supporting medical imaging and laboratory testing.[5] It can be difficult to confirm, especially early on, since the signs and symptoms may be similar to those of other medical problems.[1][97]
McDonald criteria
The McDonald criteria, which focus on clinical, laboratory, and radiologic evidence of lesions at different times and in different areas, is the most commonly used method of diagnosis[98] with the Schumacher and Poser criteria being of mostly historical significance.[99] The McDonald criteria states that patients with multiple sclerosis should have lesions which are disseminated in time (DIT) and disseminated in space (DIS), i.e. lesions which have appeared in different areas in the brain and at different times.[87] Below is an abbreviated outline of the 2017 McDonald Criteria for diagnosis of MS.
- At least 2 clinical attacks with MRI showing 2 or more lesions characteristic of MS.[87]
- At least 2 clinical attacks with MRI showing 1 lesion characteristic of MS with clear historical evidence of a previous attack involving a lesion at a distinct location in the CNS.[87]
- At least 2 clinical attacks with MRI showing 1 lesion characteristic of MS, with DIT established by an additional clinical attack at a distinct CNS site or by MRI showing an old MS lesion.[87]
- 1 clinical attack with MRI showing at least 2 lesions characteristic of MS, with DIT established by an additional attack, by MRI showing old MS lesion(s), or presence of oligoclonal bands in CSF.[87]
- 1 clinical attack with MRI showing 1 lesion characteristic of MS, with DIS established by an additional attack at a different CNS site or by MRI showing old MS lesion(s), and DIT established by an additional attack, by MRI showing old MS lesion(s), or presence of oligoclonal bands in CSF.[87]
As of 2017[update], no single test (including biopsy) can provide a definitive diagnosis.[100]
MRI
Magnetic resonance imaging (MRI) of the brain and spine may show areas of demyelination (lesions or plaques). Gadolinium can be administered
Central vein signs (CVSs) have been proposed as a good indicator of MS in comparison with other conditions causing white lesions.[103][104][105][106] One small study found fewer CVSs in older and hypertensive people.[107] Further research on CVS as a biomarker for MS is ongoing.[108]
Cerebrospinal fluid (lumbar puncture)
Testing of cerebrospinal fluid obtained from a lumbar puncture can provide evidence of chronic inflammation in the central nervous system. The cerebrospinal fluid is tested for oligoclonal bands of IgG on electrophoresis, which are inflammation markers found in 75–85% of people with MS.[101][109]
Differential diagnosis
Several diseases present similarly to MS.[110][111] Medical professionals use a patient's specific presentation, history, and exam findings to make an individualized differential. Red flags are findings that suggest an alternate diagnosis, although they do not rule out MS. Red flags include a patient younger than 15 or older than 60, less than 24 hours of symptoms, involvement of multiple cranial nerves, involvement of organs outside of the nervous system, and atypical lab and exam findings.[110][111]
In an emergency setting, it is important to rule out a stroke or bleeding in the brain.[111] Intractable vomiting, severe optic neuritis,[31] or bilateral optic neuritis[31] raises suspicion for neuromyelitis optica spectrum disorder (NMOSD).[112] Infectious diseases that may look similar to multiple sclerosis include HIV, Lyme disease, and syphilis. Autoimmune diseases include neurosarcoidosis, lupus, Guillain-Barré syndrome, acute disseminated encephalomyelitis, and Behçet's disease. Psychiatric conditions such as anxiety or conversion disorder may also present in a similar way. Other rare diseases on the differential include CNS lymphoma, congenital leukodystrophies, and anti-MOG-associated myelitis.[110][111]
Types and variants
Several phenotypes (commonly termed "types"), or patterns of progression, have been described. Phenotypes 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 treatment decisions.
The International Advisory Committee on Clinical Trials of MS describes four types of MS (revised in 2013) in what is known as the Lublin classification:[113][114]
- Clinically isolated syndrome (CIS)
- Relapsing-remitting MS (RRMS)
- Primary progressive MS (PPMS)
- Secondary progressive MS (SPMS)
CIS can be characterised as a single lesion seen on MRI which is associated with signs and/or symptoms found in MS. Due to the McDonald criteria, it does not completely fit the criteria to be diagnosed as MS, hence being named "clinically isolated syndrome". CIS can be seen as the first episode of demyelination in the central nervous system. To be classified as CIS, the attack must last at least 24 hours and be caused by inflammation or demyelination of the central nervous system.[1][115] Patients who suffer from CIS may or may not go on to develop MS, but 30 to 70% of persons who experience CIS will later develop MS.[116]
RRMS is characterized by unpredictable relapses followed by periods of months to years of relative quiet (
PPMS occurs in roughly 10–20% of individuals with the disease, with no remission after the initial symptoms.[5][117] It is characterized by progression of disability from onset, with no, or only occasional and minor, remissions and improvements.[13] The usual age of onset for the primary progressive subtype is later than of the relapsing-remitting subtype. It is similar to the age that secondary progressive usually begins in RRMS, around 40 years of age.[1]
SPMS occurs in around 65% of those with initial RRMS, who eventually have progressive neurologic decline between acute attacks without any definite periods of remission.[1][13] Occasional relapses and minor remissions may appear.[13] The most common length of time between disease onset and conversion from RRMS to SPMS is 19 years.[118]
Special courses
Independently of the types published by the MS associations, regulatory agencies such as the FDA often consider special courses, trying to reflect some clinical trials results on their approval documents. Some examples could be "highly active MS" (HAMS),[119] "active secondary MS" (similar to the old progressive-relapsing)[120] and "rapidly progressing PPMS".[121]
Also, deficits always resolving between attacks is sometimes referred to as "benign" MS,[122] although people still build up some degree of disability in the long term.[1] On the other hand, the term malignant multiple sclerosis is used to describe people with MS having reached significant level of disability in a short period.[123]
An international panel has published a standardized definition for the course HAMS.[119]
Variants
Atypical
Management
Although no cure for multiple sclerosis has been found, several therapies have proven helpful. Several effective treatments can decrease the number of attacks and the rate of progression.[23] The primary aims of therapy are returning function after an attack, preventing new attacks, and preventing disability. Starting medications is generally recommended in people after the first attack when more than two lesions are seen on MRI.[126]
The first approved medications used to treat MS were modestly effective, though were poorly tolerated and had many adverse effects.[3] Several treatment options with better safety and tolerability profiles have been introduced,[23] improving the prognosis of MS.
As with any medical treatment, medications used in the management of MS have several
Initial management of acute flare
During symptomatic attacks, administration of high doses of intravenous corticosteroids, such as methylprednisolone, is the usual therapy,[1] with oral corticosteroids seeming to have a similar efficacy and safety profile.[127] Although effective in the short term for relieving symptoms, corticosteroid treatments do not appear to have a significant impact on long-term recovery.[128][129] The long-term benefit is unclear in optic neuritis as of 2020.[130][31] The consequences of severe attacks that do not respond to corticosteroids might be treatable by plasmapheresis.[1]
Chronic management
Relapsing remitting multiple sclerosis
Multiple
Treatment of CIS with interferons decreases the chance of progressing to clinical MS.[1][136][137] Efficacy of interferons and glatiramer acetate in children has been estimated to be roughly equivalent to that of adults.[138] The role of some newer agents such as fingolimod,[139] teriflunomide, and dimethyl fumarate,[140] is not yet entirely clear.[141] Making firm conclusions about the best treatment is difficult, especially regarding the long‐term benefit and safety of early treatment, given the lack of studies directly comparing disease-modifying therapies or long-term monitoring of patient outcomes.[142]
The relative effectiveness of different treatments is unclear, as most have only been compared to placebo or a small number of other therapies.[143] Direct comparisons of interferons and glatiramer acetate indicate similar effects or only small differences in effects on relapse rate, disease progression, and MRI measures.[144] There is high confidence that natalizumab, cladribine, or alemtuzumab are decreasing relapses over a period of two years for people with RRMS.[145] Natalizumab and interferon beta-1a (Rebif) may reduce relapses compared to both placebo and interferon beta-1a (Avonex) while Interferon beta-1b (Betaseron), glatiramer acetate, and mitoxantrone may also prevent relapses.[143] Evidence on relative effectiveness in reducing disability progression is unclear.[143] There is moderate confidence that a two-year treatment with natalizumab slows disability progression for people with RRMS.[145] All medications are associated with adverse effects that may influence their risk to benefit profiles.[143][145]
Ublituximab was approved for medical use in the United States in December 2022.[146]
Medications
Overview of medications available for MS.[147]
Medication | Compound | Producer | Use | Efficacy (annualized relapse reduction rate) | Annualized relapse rate (ARR) |
---|---|---|---|---|---|
Avonex | Interferon beta-1a | Biogen | Intramuscular | 30% | 0.25 |
Rebif | Interferon beta-1a | Merck Serono | Subcutaneous | 30% | 0.256 |
Extavia | Interferon beta-1b | Bayer Schering
|
Subcutaneous | 30% | 0.256 |
Copaxone | Glatiramer acetate | Teva Pharmaceuticals | Subcutaneous | 30% | 0.3 |
Aubagio | Teriflunomide | Genzyme | Oral | 30% | 0.35 |
Plegridy | Interferon beta-1a | Biogen | Subcutaneous | 30% | 0.12 |
Tecfidera | Dimethyl fumarate | Biogen | Oral | 50% | 0.15 |
Vumerity | Diroximel fumarate | Biogen | Oral | 50% | 0.11-0.15 |
Gilenya | Fingolimod | Oral | 50% | 0.22-0.25 | |
Zeposia | Ozanimod | [ better source needed ]
|
Oral | 0.18-0.24 | |
Kesimpta | Ofatumumab | Subcutaneous | 70% | 0.09-0.14 | |
Mavenclad | Cladribine | Oral | 70% | 0.1-0.14 | |
Lemtrada | Alemtuzumab | Intravenous | 70% | 0.08 | |
Ocrevus | Ocrelizumab | Intravenous | 70% | 0.09 |
Progressive multiple sclerosis
In 2011, mitoxantrone was the first medication approved for secondary progressive MS.[148] In this population, tentative evidence supports mitoxantrone moderately slowing the progression of the disease and decreasing rates of relapses over two years.[149][150]
New approved medications continue to emerge in modern medicine. In March 2017, the FDA approved ocrelizumab as a treatment for primary progressive MS in adults, the first drug to gain that approval,
In 2019, siponimod and cladribine were approved in the United States for the treatment of secondary progressive multiple sclerosis (SPMS).[151] Subsequently, ozanimod was approved in 2020, and ponesimod was approved in 2021, which were both approved for management of CIS, relapsing MS, and SPMS in the U.S., and RRMS in Europe.[156]
Adverse effects
The
Fingolimod may give rise to
Associated symptoms
Both medications and neurorehabilitation have been shown to improve some symptoms, though neither changes the course of the disease.[165] Some symptoms have a good response to medication, such as bladder spasticity, while others are little changed.[1] Equipment such as catheters for neurogenic bladder dysfunction or mobility aids can be helpful in improving functional status.
A
Non-pharmaceutical
There is some evidence that aquatic therapy is a beneficial intervention.[180]
The spasticity associated with MS can be difficult to manage because of the progressive and fluctuating course of the disease.[181] Although there is no firm conclusion on the efficacy in reducing spasticity, PT interventions can be a safe and beneficial option for patients with multiple sclerosis. Physical therapy including vibration interventions, electrical stimulation, exercise therapy, standing therapy, and radial shock wave therapy (RSWT), were beneficial for limiting spasticity, helping limit excitability, or increasing range of motion.[182]
Alternative treatments
Over 50% of people with MS may use
Prognosis
The availability of treatments that modify the course of multiple sclerosis beginning in the 1990s, known as disease-modifying therapies (DMTs), has improved prognosis. These treatments can reduce relapses and slow progression, but as of 2022 there is no cure.[23][199]
The prognosis of MS depends on the subtype of the disease, and there is considerable individual variation in the progression of the disease.[200] In relapsing MS, the most common subtype, a 2016 cohort study found that after a median of 16.8 years from onset, one in ten needed a walking aid, and almost two in ten transitioned to secondary progressive MS, a form characterized by more progressive decline.[23] With treatments available in the 2020s, relapses can be eliminated or substantially reduced. However, "silent progression" of the disease still occurs.[199][201]
In addition to secondary progressive MS (SPMS), a small proportion of people with MS (10–15%) experience progressive decline from the onset, known as primary progressive MS (PPMS). Most treatments have been approved for use in relapsing MS; there are fewer treatments with lower efficacy for progressive forms of MS.[202][199][23] The prognosis for progressive MS is worse, with faster accumulation of disability, though with considerable individual variation.[202] In untreated PPMS, the median time from onset to requiring a walking aid is estimated as seven years.[23] In SPMS, a 2014 cohort study reported that people required a walking aid after an average of five years from onset of SPMS, and were chair or bed-bound after an average of fifteen years.[203]
After diagnosis of MS, characteristics that predict a worse course are male sex, older age, and greater disability at the time of diagnosis; female sex is associated with a higher relapse rate.[204] As of 2018, no biomarker can accurately predict disease progression in every patient.[200] Spinal cord lesions, abnormalities on MRI, and more brain atrophy are predictive of a worse course, though brain atrophy as a predictor of disease course is experimental and not used in clinical practice as of 2018.[204] Early treatment leads to a better prognosis, but a higher relapse frequency when treated with DMTs is associated with a poorer prognosis.[200][204] A 60-year longitudinal population study conducted in Norway found a 7-year shorter life expectancy in MS compared with the general population and a rise in survival in MS during the observation period. Median life expectancy for RRMS patients was 77.8 years and 71.4 years for PPMS, compared to 81.8 years for the general population. Life expectancy for men was 5 years shorter than for women.[205]
Epidemiology
This section needs to be updated.(July 2022) |
MS is the most common autoimmune disorder of the central nervous system.[22] The latest estimation of the total number of people with MS was 2.8 million globally, with a prevalence of 36 per 100,000 people. Moreover, prevalence varies widely in different regions around the world.[24] In Africa, there are 5 people per 100,000 diagnosed with MS, compared to South East Asia where the prevalence is 9 per 100,000, 112 per 100,000 in the Americas, and 133 per 100,000 in Europe.[206]
Increasing rates of MS may be explained simply by better diagnosis.[2] Studies on populational and geographical patterns have been common[57] and have led to a number of theories about the cause.[17][74][82]
MS usually appears in adults in their late twenties or early thirties but it can rarely start in childhood and after 50 years of age.[2][98] The primary progressive subtype is more common in people in their fifties.[117] Similarly to many autoimmune disorders, the disease is more common in women, and the trend may be increasing.[1][207] As of 2020, globally it is about two times more common in women than in men, and the ratio of women to men with MS is as high as 4:1 in some countries.[208][medical citation needed] In children, it is even more common in females than males,[1] while in people over fifty, it affects males and females almost equally.[117]
History
Medical discovery
The French
Diagnosis history
The first attempt to establish a set of diagnostic criteria was also due to Charcot in 1868. He published what now is known as the "
Diagnosis was based on Charcot triad and clinical observation until Schumacher made the first attempt to standardize criteria in 1965 by introducing some fundamental requirements: Dissemination of the lesions in time (DIT) and space (DIS), and that "signs and symptoms cannot be explained better by another disease process".[212] The DIT and DIS requirement was later inherited by the Poser and McDonald criteria, whose 2017 revision is in use.[212][200]
During the 20th century, theories about the cause and pathogenesis were developed and effective treatments began to appear in the 1990s.[1] Since the beginning of the 21st century, refinements of the concepts have taken place. The 2010 revision of the McDonald criteria allowed for the diagnosis of MS with only one proved lesion (CIS).[213]
In 1996, the US National Multiple Sclerosis Society (NMSS) (Advisory Committee on Clinical Trials) defined the first version of the clinical phenotypes that is in use. In this first version they provided standardized definitions for four MS clinical courses: relapsing-remitting (RR), secondary progressive (SP), primary progressive (PP), and progressive relapsing (PR). In 2010, PR was dropped and CIS was incorporated.[213] Three years later, the 2013 revision of the "phenotypes for the disease course" were forced to consider CIS as one of the phenotypes of MS, making obsolete some expressions like "conversion from CIS to MS".[214] Other organizations have proposed later new clinical phenotypes, like HAMS (Highly Active MS).[215]
Historical cases
There are several historical accounts of people who probably had MS and lived before or shortly after the disease was described by Charcot.
A young woman called Halldora who lived in
Research
Epstein-Barr virus
As of 2022, the pathogenesis of MS as it relates to Epstein-Barr virus (EBV) is actively investigated, as are disease-modifying therapies; understanding of how risk factors combine with EBV to initiate MS is sought. Whether EBV is the only cause of MS might be better understood if an EBV vaccine is developed and shown to prevent MS as well.[16]
Even though a variety of studies showed the connection between an EBV infection and a later development of multiple sclerosis, the mechanisms behind this correlation are not completely clear, and several theories have been proposed to explain the relationship between the two diseases. It is thought that the involvement of EBV-infected
Human endogenous retroviruses
Two members of the human endogenous retroviruses-W (
Medications
Medications that influence voltage-gated sodium ion channels are under investigation as a potential neuroprotective strategy because of hypothesized role of sodium in the pathological process leading to axonal injury and accumulating disability. There is insufficient evidence of an effect of sodium channel blockers for people with MS.[229]
Pathogenesis
MS is a clinically defined entity with several atypical presentations. Some auto-antibodies have been found in atypical MS cases, giving birth to separate disease families and restricting the previously wider concept of MS.
A third kind of auto-antibodies is accepted. They are several
In addition to the significance of auto-antibodies in MS, four different patterns of demyelination have been reported, opening the door to consider MS as a
Disease biomarkers
Since disease progression is the result of degeneration of neurons, the roles of proteins showing loss of nerve tissue such as
Improvement in neuroimaging techniques such as
COVID-19
The hospitalization rate was found to be higher among individuals with MS and COVID-19 infection, at 10%, while the pooled infection rate is estimated at 4%. The pooled prevalence of death in hospitalized individuals with MS is estimated as 4%.[238]
Other emerging theories
One emerging hypothesis, referred to as the hygiene hypothesis, suggests that early-life exposure to infectious agents helps to develop the immune system and reduces susceptibility to allergies and autoimmune disorders. The hygiene hypothesis has been linked with MS and microbiome hypotheses.[239]
It has also been proposed that certain bacteria found in the gut use molecular mimicry to infiltrate the brain via the
In 2024, scientists shared research on their findings of ancient migration to northern Europe from the Yamnaya area of culture, tracing DNA, MS gene variants dating back around 5,000 years.[244][245] The original gene protected ancient cattle herders from animal diseases, but modern lifestyles, diets and better hygiene, have allowed the gene to develop, resulting in the higher risk of MS today.[246]
See also
References
- ^ S2CID 195686659.
- ^ PMID 19932200.
- ^ a b c d "NINDS Multiple Sclerosis Information Page". National Institute of Neurological Disorders and Stroke. 19 November 2015. Archived from the original on 13 February 2016. Retrieved 6 March 2016.
- ^ S2CID 21058811.
- ^ from the original on 5 October 2021. Retrieved 28 December 2023.
- S2CID 233325057.
- ^ S2CID 86669723.
- ^ S2CID 14207583.
- ISBN 978-1-4377-0434-1.
- ^ S2CID 231624230.
- PMID 25254633.
- S2CID 3499974.
- ^ S2CID 40213123.
- PMID 22379455.
- ^ S2CID 251375096.
- ^ S2CID 251152784.
- ^ S2CID 7682774.
- ^ "NINDS Multiple Sclerosis Information Page". National Institute of Neurological Disorders and Stroke. 19 November 2015. Archived from the original on 13 February 2016. Retrieved 6 March 2016.
- ^ S2CID 232019589.
- S2CID 220436640.
- S2CID 7140070.
- ^ S2CID 2772656.
- ^ S2CID 232019589.
- ^ S2CID 249188137.
- ^ PMID 18782501. Archived from the original(PDF) on 30 March 2019. Retrieved 21 October 2010.
* Charcot J (1868). "Histologie de la sclerose en plaques". Gazette des Hopitaux, Paris. 41: 554–5. - ^ "TikTok - Make Your Day". www.tiktok.com.
- ^ "Fatigue". Letchworth Garden City, United Kingdom: Multiple Sclerosis Trust.
- PMID 35716477.
- PMID 37602098.
- Webmd. Archivedfrom the original on 30 September 2016. Retrieved 7 October 2016.
- ^ S2CID 252564095.
- PMID 30482317.
- PMID 28367411.
- PMID 32350648– via PubMed.
- PMID 31214113.
- PMID 30303036.
- S2CID 221744328.
- PMID 37123672.
- ^ a b c "Hot and bothered: how heat makes MS symptoms worse". Letchworth Garden City, United Kingdom: Multiple Sclerosis Trust.
- ^ PMID 30377640.
- ^ a b "Heat Sensitivity".
- ^ a b "Temperature sensitivity". Letchworth Garden City, United Kingdom: Multiple Sclerosis Trust.
- PMID 6685237.
- S2CID 6763447.
- S2CID 31529508.
- PMID 28185158.
- ^ S2CID 20870484.
- S2CID 8262595.
- PMID 11172162.
- PMID 37669073.
- S2CID 2376078.
- PMID 34155379.
- S2CID 204887642.
- PMID 17984305.
- ^ PMID 29394264.
- PMID 33828551.
- ^ PMID 8269393.
- PMID 15721830.
- PMID 35931816.
- ^ of 13 April 2022.
- PMID 15148332.
- PMID 32435244.
- S2CID 16707321.
- PMID 26858593.
- PMID 22041658.
- S2CID 207051545.
- ^ PMID 21247752.
- PMID 31604244.
- ^ PMID 18606967.
- ^ S2CID 862001.
- ^ PMID 19932200.
- S2CID 34895995.
- PMID 19897699.
- ^ S2CID 175786.
- ^ a b "Heat and cold sensitivity in multiple sclerosis: A patient-centred perspective on triggers, symptoms, and thermal resilience practices - Multiple Sclerosis and Related Disorders".
- PMID 20671034.
- ^ PMID 30459034– via ScienceDirect.
- ^ Staff B (11 August 2014). "Higher Body Temperature in RRMS Patients Could Cause Increased Fatigue". multiplesclerosisnewstoday.com.
- PMID 24561056.
- ^ "(PDF) Elevated body temperature is linked to fatigue in an Italian sample of relapsing–remitting multiple sclerosis patients".
- ^ PMID 35963205.
- ^ S2CID 36999504.
- PMID 29970406.
- PMID 31576507.
- PMID 18219824.
- S2CID 174806511.
- ^ S2CID 206164600.
- PMID 34899715.
- ^ PMID 17531860.
- S2CID 2993523.
- PMID 33381913.
- PMID 23088946.
- PMID 30683707.)
{{cite journal}}
: CS1 maint: overridden setting (link - PMID 33961198.)
{{cite journal}}
: CS1 maint: overridden setting (link - PMID 27146427.
- PMID 28789787.
- S2CID 3057096.
- ^ ISBN 978-92-4-156375-8.
- S2CID 23452341.
- .
- ^ S2CID 13870943.
- S2CID 260317568.
- PMID 31424490.
- ^ Bernitsas E (February 2020). "The Central Vein Sign". Practical Neurology. Archived from the original on 5 October 2021. Retrieved 5 October 2021.
- PMID 33260401.
- .
- (PDF) from the original on 15 July 2021. Retrieved 5 October 2021.
- ^ Chapman M (16 June 2020). "$7.2M NIH Grant Supports Study of MS Diagnostic Biomarker". BioNews Services. Archived from the original on 5 October 2021. Retrieved 5 October 2021.
- S2CID 22724352.
- ^ OCLC 1282172709.
- ^ PMID 35977131.
- S2CID 173991777.
- PMID 24871874.
- PMID 32471886.
- ^ "Clinically Isolated Syndrome (CIS)". National MS Society. Retrieved 4 October 2023.
- S2CID 36401666.
- ^ S2CID 31389841.
- S2CID 39503553.
- ^ PMID 32636933.
- ^ "Novartis receives FDA approval for Mayzent® (siponimod), the first oral drug to treat secondary progressive MS with active disease". Novartis.com. Archived from the original on 20 November 2020. Retrieved 12 November 2021.
- PMID 15651294.
- PMID 18219812.
- ISBN 978-0-521-85234-0.
- S2CID 21212935.
- PMID 30893099.
- PMID 29686116.
- PMID 23235634.
- PMID 11034713.
- from the original on 10 February 2023. Retrieved 5 October 2021.
- PMID 31740484.
- ^ PMID 27003123.
- ^ PMID 11687131.
- PMID 22082979.
- S2CID 16929304.
- PMID 22284996.
- S2CID 362182.
- PMID 18425915.
- S2CID 20323687.
- ^ PMID 27091121.
- ^ PMID 25900414.
- ^ S2CID 206160178.
- PMID 28440858.
- ^ (PDF) from the original on 5 October 2021. Retrieved 5 October 2021.
- PMID 27880972.
- ^ PMID 38174776.
- ^ "TG Therapeutics Announces FDA Approval of Briumvi (ublituximab-xiiy)" (Press release). TG Therapeutics. 28 December 2022. Archived from the original on 28 December 2022. Retrieved 29 December 2022 – via GlobeNewswire.
- ^ "MS Decisions aid". Letchworth Garden City, United Kingdom: Multiple Sclerosis Trust. 3 December 2023. Retrieved 3 December 2023.
- ISBN 978-1-4557-0738-6.
- ^ PMID 23728638.
- PMID 20439849.
- ^ PMID 31598138.
- ^ Winslow R (28 March 2017). "After 40-year odyssey, first drug for aggressive MS wins FDA approval". STAT. Archived from the original on 1 April 2017.
- ^ a b "Ocrevus- ocrelizumab injection". DailyMed. 13 December 2019. Archived from the original on 27 June 2020. Retrieved 26 March 2020.
- ^ "BLA Approval Letter" (PDF). FDA. 28 March 2017. Archived (PDF) from the original on 2 April 2017.
- PMID 35583174.
- ISBN 978-3-031-13498-2.
- ^ from the original on 24 January 2021. Retrieved 5 September 2019.
- PMID 17131933.
- PMID 20464733.
- S2CID 12529733.
- S2CID 25910077.
- S2CID 46326042.
- ^ "Biogen Idec's TECFIDERA™ (Dimethyl Fumarate) Approved in US as a First-Line Oral Treatment for Multiple Sclerosis" (Press release). Biogen Idec. 27 March 2013. Archived from the original on 12 May 2013. Retrieved 4 June 2013.
- ^ "NDA 204063 – FDA Approved Labeling Text" (PDF). US Food and Drug Agency. 27 March 2013. Archived (PDF) from the original on 4 October 2013. Retrieved 5 April 2013.
"NDA Approval" (PDF). US Food and Drug Agency. 27 March 2013. Archived (PDF) from the original on 4 October 2013. Retrieved 5 April 2013. - S2CID 28253186.
- PMID 17443610.
- PMID 30317542.
- (PDF) from the original on 4 August 2020. Retrieved 24 September 2019.
- (PDF) from the original on 28 April 2022. Retrieved 5 October 2021.
- PMID 30637728.
- PMID 26358158.
- PMID 17482708.
- PMID 15674920.
- PMID 16437487.
- PMID 24515630.
- PMID 31637711.
- PMID 31778221.
- PMID 27772557.
- PMID 30567012.
- PMID 28215060.
- S2CID 207497395.
- S2CID 44156766.
- ^ PMID 16420779.
- PMID 19222053.
- PMID 32428983.
- PMID 21965673.
- PMID 23257784.
the available evidence substantiates neither clinically significant benefit nor harm from vitamin D in the treatment of patients with MS
- S2CID 34692470.
- PMID 30646241.
- PMID 14974004.
- ^ Adams T (23 May 2010). "Gut instinct: the miracle of the parasitic hookworm". The Observer. Archived from the original on 24 October 2014.
- PMID 24438384.
- PMID 30246874.
- S2CID 225049079.
- PMID 31547410.
- PMID 26327679.
- PMID 32761325.
- PMID 35510826.
- ^ S2CID 249438715.
- ^ S2CID 6103857.
- PMID 32682869.
- ^ S2CID 174808956.
- (EDSS) 6.0 is equivalent to requiring a walking aid, and EDSS 8.0 equivalent to chair or bedbound
- ^ S2CID 4313310.
- PMID 28365589.
- ^ "Atlas of MS" (PDF). Multiple Sclerosis International Federation. September 2020.
- PMID 18606967.
- PMID 33174475.
- ^ PMID 3066846.
- PMID 10603616.
- S2CID 8342303.
- ^ PMID 24424194.
- ^ PMID 21387374.
- PMID 24871874.
- PMID 32636933.
- S2CID 221422840.
- PMID 16479124.
- ^ Firth D (1948). The Case of August D'Esté. Cambridge: Cambridge University Press.
- ^ PMID 16103678.
- ISBN 0-7012-1906-8.
- PMID 28167994.
- PMID 31862243.
- PMID 16606758.
- S2CID 205099904.
- PMID 35073561.
- PMID 28207850.
- S2CID 247750447.
- PMID 36518758.
- PMID 26486929.
- ^ .
- PMID 30582947.
- PMID 23917093.
- PMID 23516409.
- (PDF) from the original on 24 January 2021. Retrieved 19 September 2020.
- (PDF) from the original on 22 September 2017. Retrieved 19 September 2020.
- ^ PMID 22159052.
- PMID 31803127.
- PMID 34100130.
- PMID 31734400.
- PMID 21527855.
- PMID 415110.
- PMID 29358320.
- ISBN 978-0-429-12860-8.
- ISSN 0190-8286. Retrieved 11 January 2024.
- ^ Roxby P (10 January 2024). "Scientists crack mystery of how MS gene spread". BBC News. Retrieved 11 January 2024.
- ^ "Novel Study Suggests that MS was Brought to Northern Europe 5,000 Years Ago". National MS Society. 10 January 2024.