Multiple Sclerosis Genetic Report
SUMMARY: Identification of 233 novel variants associated with multiple sclerosis and the body’s immune response system.
DESCRIPTION: Multiple sclerosis is an autoimmune disease that leads to degeneration of the central nervous system. It’s characterized by damage to the nerves that can lead to problems with vision, movement, and speech. This study analyzed the genetic data of 115,803 individuals of European ancestry and discovered 233 variants that appear to correlate with a risk of developing multiple sclerosis. These variants help explain ~48% of the heritability of multiple sclerosis. Many of these variants are located near genes that are expressed in the brain and play a role in antigen recognition by the immune system. To date, this is the largest genome-wide association analysis of multiple sclerosis and it explains almost half of the genetic contribution to the disease risk.
DID YOU KNOW? Though multiple sclerosis cannot be cured, doctors recommend lowering inflammation levels by maintaining a healthy diet (e.g. mediterranean diet rich in fish, whole grains, fruits, vegetables and olive oil) and exercising regularly. [SOURCE]
SAMPLE RESULTS: Learn more about the Nebula Research Library.
MS-ASSOCIATED VARIANTS: rs1071743, rs3097671, rs2844482, rs4081559, rs10801908, rs11256593, rs9266629, rs438613, rs1800693, rs7454108, rs6670198, rs62420820, rs1738074, rs35540610, rs1323292, rs1077667, rs35486093, rs2150879, rs701006, rs11809700, rs9843355, rs4939490, rs4896153, rs72928038, rs10063294, rs1026916, rs1014486, rs11751659, rs11079784, rs6589706, rs11749040, rs631204, rs4808760, rs12478539, rs58166386, rs7977720, rs34947566, rs1250551, rs114071505, rs28703878, rs3809627, rs140522, rs67111717, rs59655222, rs2364485, rs2331964, rs6990534, rs2327586, rs12925972, rs9610458, rs9591325, rs2248137, rs12365699, rs1177228, rs1076928, rs1087056, rs28834106, rs60600003, rs6032662, rs2546890, rs10951042, rs9878602, rs1465697, rs483180, rs1112718, rs35703946, rs12434551, rs34026809, rs62013236, rs9909593, rs2986736, rs9271366, rs13327021, rs12133753, rs10093, rs61863928, rs2317231, rs12622670, rs983494, rs6533052, rs4796224, rs72922276, rs12722559, rs3135024, rs12147246, rs1801133, rs405343, rs7731626, rs58394161, rs9863496, rs244656, rs1049079, rs6564681, rs6742, rs3737798, rs17724508, rs883871, rs9308424, rs2269434, rs719316, rs2084007, rs6738544, rs7975763, rs34695601, rs735542, rs249677, rs2523500, rs6496663, rs6589939, rs4262739, rs2289746, rs17780048, rs12614091, rs766848979, rs4409785, rs57116599, rs11231749, rs2705616, rs10245867, rs6837324, rs10936602, rs34681760, rs9992763, rs34536443, rs13385171, rs2726479, rs3184504, rs9955954, rs760517, rs5756405, rs1399180, rs9277626, rs10230723, rs17493811, rs7855251, rs6911131, rs17051321, rs7222450, rs2836438, rs10951154, rs2585447, rs3819292, rs2229092, rs10191360, rs4940730, rs12832171, rs11125803, rs73414214, rs13414105, rs11919880, rs13136820, rs354033, rs802730, rs56095240, rs11852059, rs531612, rs6789653, rs7260482, rs6427540, rs6672420, rs9808753, rs12588969, rs4325907, rs11161550, rs11083862, rs6072343, rs10271373, rs4728142, rs2286974, rs8062446, rs2590438, rs9568402, rs12609500, rs72989863, rs12971909, rs4812772, rs61884005, rs962052, rs137955, rs4820955, rs35218683, rs13066789, rs11899404, rs3923387, rs61708525, rs12211604, rs11578655, rs2469434, rs55858457, rs32658, rs1415069, rs1365120, rs17741873, rs9900529, rs3093982, rs10936182
WEEKLY UPDATE: October 6, 2019
Multiple Sclerosis Information
Multiple sclerosis (multiple sclerosis) is an autoimmune, chronic inflammatory neurological disease. It is commonly called “the disease with a thousand faces” due to the fact that symptoms vary widely. In people with MS, the immune system attacks the patient’s myelin sheaths, the electrically insulating outer layer of nerve fibres in the central nervous system (CNS).
The exact causes of multiple sclerosis has yet to be determined, despite great research efforts. In multiple sclerosis, many inflammatory centres of demyelination become scattered in the white matter of the brain and spinal cord. This is most likely caused by the attack of the body’s own immune cells on the myelin sheaths of the nerve cell processes. Since the centres of demyelination can occur throughout the entire CNS, multiple sclerosis can cause almost any neurological symptom. Visual disturbances, resulting in reduction of visual acuity are typical and can cause disorders of eye movement (internal nuclear ophthalmoplegia) or complete blindness. However, this is not specific to multiple sclerosis. The severity of the patient’s disabilities is often indicated on a scale, called the Expanded Disability Status Scale (EDSS).
Along with epilepsy, multiple sclerosis is one of the most common neurological diseases in young adults and is of considerable socio-medical importance. There is no cure for the disease, but many interventions can have favourable outcomes. Contrary to popular belief, multiple sclerosis does not necessarily lead to severe disabilities. Even many years after the onset of the disease, the majority of patients remain able to walk.
Causes and development
The cause of multiple sclerosis is unknown, however, there are numerous theories regarding the cause. The available findings indicate that multiple sclerosis is a multifactorial disease involving genetic factors and environmental influences as a trigger for immune-mediated damage.
Multiple Sclerosis Causes
Is MS Genetic?
Multiple sclerosis is not a hereditary disease in the classic sense. As of October 2013, 110 genetic variations have been identified to occur more frequently in multiple sclerosis patients than in the general population. These may contribute to a predisposition to multiple sclerosis. Although each of these variations alone represents only a very low risk of developing multiple sclerosis, together they account for about 20 percent of the genetic components of the disease. Among other things, polymorphisms of genes involved in the interleukin signalling pathway are of scientific interest.
Many of the gene variants found are directly related to the immune system (e.g., the TNFR1 variant rs1800693, the HLA type HLA-DRB1*15:01). Some of them have also been identified as genetic risk factors in autoimmune diseases such as diabetes type 1 or Crohn’s disease.
The risk of disease also depends on ethnicity. Epidemiological studies from the United States indicate that multiple sclerosis occurs less frequently in those with Hispanics and African American descent.
Identical twins of multiple sclerosis patients have a 35% risk of developing the disease, while siblings (about 4%), first-degree relatives (about 3%), second-degree relatives (about 1%) or third-degree relatives (about 0.9%) are significantly less likely to develop multiple sclerosis. The risk in the general population is about 0.1 %.
An examination of three pairs of identical twins, of which only one twin was affected by multiple sclerosis, revealed no differences at the genetic or epigenetic level; there were also no differences in the transcriptome.
One potential cause for the origin of multiple sclerosis is the infection hypothesis. This states that the triggering factor causing the disease was suspected to be a childhood infection with a pathogen that has cross-reactivity with protein components of myelin. However, convincing evidence of a specific pathogen has not yet been provided. Studies on adopted children and stepchildren of multiple sclerosis patients, in whom no increased probability of disease could be proven, speak against the possibility of direct transmission of multiple sclerosis.
Numerous viruses (including Epstein-Barr virus and human herpes virus 6) have been investigated for a possible role in the development of the disease. In fact, children with multiple sclerosis have been shown to have more frequent immune reactions against the Epstein-Barr virus than children without the disease. Bacterial pathogens (including Chlamydia, Spirochaetes, Rickettsia and Streptococcus mutans) have also been linked to the development of multiple sclerosis.
It is suspected that there is a connection between the immune system’s exposure to infectious diseases and a reduced susceptibility to multiple sclerosis. Living with siblings in the first six years of life significantly reduces the risk of developing multiple sclerosis, which is explained by an increased mutual infection of siblings with infectious diseases.
Vitamin D metabolic hypothesis
Diseases that occur less frequently in the equatorial zone are also attempted to be explained by the vitamin D metabolism. In humans, vitamin D is mainly produced in the skin by sunlight. Exposure to the sun in childhood and sufficient vitamin D levels in the blood are believed to reduce the risk of developing multiple sclerosis later on. The low incidence of multiple sclerosis in traditionally living Greenlandic Inuit was explained by their vitamin D-rich diet.
In addition, two of the known gene variants known to be increased in multiple sclerosis patients are involved in vitamin D metabolism. Several studies suggest that supplementation of vitamin D could reduce the risk of multiple sclerosis. However, a causal connection has not yet been established and it could be a random association.
Role of environmental toxins in multiple sclerosis
There is little evidence for the frequently claimed causal connection of the disease with environmental toxins. One common toxin criticized for being dangerous to humans is silver amalgam dental fillings, which are known to contain low levels of mercury. However, meta-analysis studies did not show a clear connection between amalgam fillings and multiple sclerosis diagnosis.
Role of smoking in multiple sclerosis
Determining whether cigarette smoking puts patients at a higher risk of multiple sclerosis has been researched for years. It has become clear that smoking before the onset of the disease causes an increased risk of multiple sclerosis. A meta-analysis study showed a 1.2 to 1.5-fold increase in the risk of the disease, while a Norwegian study showed an increase in risk by a factor of 1.81.
Smoking also appears to have a negative impact on the development of the first neurological symptoms of multiple schlerosis, also referred to as clinically isolated syndrome (CIS). In 129 CIS patients observed over 36 months, 75% were smokers. Only 51% of non-smokers were diagnosed with multiple sclerosis at a later stage. Further research was carried out on the intermediate effects of cigarette consumption on the progression of the disability. The greatest differences were found between patients who never smoked and those who started very early. Early smokers tend to develop chronic forms of the disease more often and after a shorter period of illness. In addition, the risk of disability progression is significantly increased.
It is not yet known which pathological changes triggered by smoking can influence the development and progression of multiple sclerosis.
Role of overweight in multiple sclerosis
In particular, obesity in childhood seems to be at a higher risk of developing multiple sclerosis in adulthood.
A study of 58 multiple sclerosis patients and 259 healthy control subjects, compared multiple sclerosis patient’s syndromes to that of Flammer syndrome, a disease related to abnormal alteration of blood vessels to stimuli. Six out of fifteen symptoms of Flammer syndrome were more frequently reported by multiple sclerosis patients. These include disturbed thermoregulation, cold hands and/or feet, dizziness, reduced thirst, tendency to perfectionism, and low body mass index.
A causal relationship between vaccination – and here in particular the hepatitis B vaccination – and the occurrence of multiple sclerosis has not been proven. On the contrary, an evaluation of data from insured persons in Bavaria has shown that people with multiple sclerosis were vaccinated less frequently than a comparison group without multiple sclerosis five years before this diagnosis.
Chronic cerebrospinal venous insufficiency
In the 1930s, a hypothesis first emerged that multiple sclerosis was caused by a chronic blood flow disorder in the neck and chest veins. This hypothesis of chronic cerebrospinal venous insufficiency (CCSVI) as the cause of multiple sclerosis could not be confirmed. In the 1980s it was discussed again for a short time, again without reaching clear results.
Since 2008, the hypothesis has again received a great deal of attention due to new studies that report a connection between multiple sclerosis and the occurrence of Doppler sonographically proven venous insufficiency. Through subsequently increased intracranial pressure, this could lead to the typical centres of inflammation. The reactions from experts to this theory initially remained subdued, especially since the results could not be reproduced by other research groups and further studies again raised considerable doubts about the quality of the studies on which this theory is based.
These assessments were supported in 2013 by a study published in the Lancet, which used catheter venography, considered to be the gold standard in the imaging diagnosis of venous stenosis, in addition to the ultrasound examinations of the veins used up to then. In this study, CCSVI was consistently found in two to three percent of the subjects examined – with no differences between multiple sclerosis patients, their siblings and a healthy control group.
Influence of the microbiome
Various studies have shown that the microbiome has an influence on the immune system and on autoimmune diseases. There are intestinal bacteria that dampen the immune system and those that activate it. One publication states that the breakdown products of certain intestinal bacteria are important for the nervous system, however further research is needed.In addition, one study claims to have found an unfavourable composition of the microbiome in people with multiple sclerosis. It suspected that this was the cause of the disease.
In multiple sclerosis patients prior to intervention, particularly after the first episode, there appears to be a significant reduction of short-chain fatty acids (for example propionic acid) in the blood and stool. In a new study, these patients were given oral propionate in addition to immunotherapy. This revealed a favourable change in the cell types of the intestinal immune system, which was related to a genetic change in the microbiome. This evidently led to a positive influence on the entire immune system of the patients, who, when treated with additional propionate, showed a milder course of disease overall. This was characteized by reduction in the number of relapses and improvement of the overall clinical picture.
Additionally, the use of antibiotics is considered a risk factor by some researchers due to their role in changing the microbiome.
Neuropathologically, multiple sclerosis is characterised by focal, inflammatory demyelinating lesions in the CNS with varying degrees of axonal loss and reactive gliosis. It is possible that various immunological mechanisms lead to the loss of myelin sheaths. Multiple sclerosis has been histologically defined by Lassmann and collaborators as four different subtypes. This differentiates between patients with a primary immunologically induced demyelination (subtypes I and II) and those with a primary disease of the oligodendroglia cells (subtypes III and IV). It remains unclear whether the expression of the subtypes changes in the course of the progression of the disease. However, the evidence of significant differences in cerebrospinal fluid profile between subtype I compared to subtypes II and III suggests that these are indeed different immunopathogenetic entities.
New imaging methods, such as diffusion tensor imaging, but also neuropathological investigations have for some years now increasingly focused on axonal damage in multiple sclerosis. The mechanisms that lead to this type of damage are not yet fully understood. In the meantime, it has been concluded that damage to axons can occur even when the myelin sheath is still intact. This damage is still reversible in early stages.
Clinical observations have shown that the individual inflammatory demyelinating lesions that cause the relapsing remitting MS neurological disorders are not directly related to the chronic progressive disability. To a far greater extent, gray matter atrophy appears to lead to increasing disability. From autopsies, it is known that the so-called normal appearing white or grey matter shows diffuse pathological changes. In people with MS that have extensive demyelination the grey matter shows a reduced neuronal density of about 20% compared to healthy cortex tissue. The loss of volume in nerve tissue may occur before other multiple sclerosis symptoms and may progress even if the disease improves clinically.
With the new magnetic resonance imaging (MRI) techniques such as Magnetic Resonance Transfer Imaging (MTR), the last doubts have been concluded that neural destruction is not limited to individual lesions of the white matter but occurs diffusely throughout the CNS, including in the grey matter. The disorders that cause the progressive disability in multiple sclerosis are thus not only the result of oligodendrocyte deficiency, but are much more complex.
The first symptoms of multiple sclerosis usually appear between the ages of 15 and 40 and present as a relapse. However, some patients are also slightly younger. While the relapses usually subside completely at the beginning of the disease, neurological deficits are increasingly left behind in the later course of the disease after relapses. At the beginning of the disease, visual and sensory disturbances are frequently observed.
Which symptom develops in an episode depends on the localisation of the active demyelinating focus in the central nervous system: Inflammation in the area of the optic nerve (retrobulbar neuritis) causes visual disturbances, which become noticeable as visual blur or milky haze and can also be accompanied by eye pain (typical initial symptom). Herds of inflammation in the area of sensitive railway systems can cause sensory disorders such as paresthesia, numbness and pain. The hands and legs (feet and lower legs) are often affected.
Pain can also be caused by trigeminal neuralgia, muscle cramps and Lhermitte’s symptom described as an electric shock. The Lhermitte’s symptom is considered typical of multiple sclerosis and may indicate foci in the neck part of the spinal cord.
If the motor system is affected, signs of paralysis in the extremities occur, whereby an abnormal involuntary increase in muscle tone can additionally restrict the patient’s mobility. Herds in the brainstem and cerebellum can lead to disorders of eye movement and vision problems (double vision and nystagmus), swallowing disorders (dysphagia), dizziness, as well as disorders of movement coordination (ataxia) and speech disorders (dysarthria). Charcot’s triad is the complex of symptoms of intention tremor, nystagmus and chanting (choppy) speech that occurs in demyelinating foci in the area of the upper cerebellar pedicle.
A temporal fading of the optic nerve papillae, the presence of paraspasticity and the absence of the abdominal skin reflexes is called Marburg’s triad. If vegetative centres and orbits are affected, disturbances in the control of bladder and bowel function and sexual dysfunction may occur. In the course of the disease, many people with MS experience increased physical and psychological fatigue. This fatigue occurs independently of physical and psychological stress and increases during the day. Like the other symptoms, fatigue can also increase within the framework of the Uhthoff phenomenon, more pronounced emergence of symptoms due to temperature increase. Cognitive and psychological disorders should not be neglected. Affective disorders in particular are frequent. Subcortical dementia can also occur in the late stages.
One means of quantifying the patient’s impairments is the use of the Expanded Disability Status Scale (EDSS). This scale is used to classify the current severity of the patient’s disabilities, with prior determination of the impairments in seven neurological systems. When the entire course of the disease is considered, it is fatigue, bladder dysfunction and motor system disorders such as paralysis and spasticity that often have the greatest impact on the life of the affected person.
Multiple sclerosis diagnostics
Before the era of imaging techniques, the diagnosis of multiple sclerosis was mainly based on the clinical assessment of symptoms and medical history. Today, the diagnosis is made according to uniform diagnostic criteria of multiple sclerosis. The most recent version of the McDonald criteria, revised in 2010, serves as the basis for diagnosis.
Clinical diagnosis criteria
The main clinical criterion for the diagnosis of multiple sclerosis remains the evidence of a spatial and temporal spread (dissemination) of inflammatory foci. Spatial dissemination refers to the presence of centres of inflammation at more than one location in the central nervous system. Temporal dissemination means that in the course of the disease new foci are added which can lead to clinical symptoms. If neither the patient’s medical history nor the neurological examination reveal symptoms for foci detectable in imaging, these are referred to as clinically silent lesions.
Although spatial and temporal dissemination of disease foci is typical of multiple sclerosis, it can also be caused by other diseases. Therefore, the diagnostic criteria explicitly emphasise that a diagnosis of multiple sclerosis should not be made if the symptoms and pathological findings can be better explained by another disease.
Imaging for multiple sclerosis
The images of the brain and spinal cord obtained by magnetic resonance imaging (MRI) can show inflamed and scarred tissue areas. With the aid of a contrast medium containing gadolinium, such as gadopentetate dimeglumine or gadoteric acid, acute disease foci can be detected, since in their area, in contrast to intact tissue, the blood-brain barrier is permeable to contrast medium. Typical for multiple sclerosis are periventricular (around the lateral ventricles) inflammatory foci in the medullary bed of the brain and so-called beam foci.
The MRI examination can contribute significantly to the diagnosis. According to the McDonald criteria, a diagnosis can be made without MRI imaging (in the case of two attacks and objectifiable functional deficits in at least two neurological systems), but in many patients with a first clinical event, MRI is necessary for early diagnosis. With the MRI examination, both the spatial and temporal dissemination of the inflammatory foci in the brain and spinal cord can be detected.
The McDonald criteria specify exactly how many centres of inflammation must be detectable in which region of the CNS in order to be able to speak of a positive MRI result with regard to spatial dissemination. After the last revision of the McDonald criteria, the detection of temporal dissemination by means of MRI is now also possible with a single MRI, provided that fresh and old lesions that meet certain additional criteria can be detected at the same time. The diagnosis of multiple sclerosis is usually not made solely on the basis of imaging findings.
Laboratory tests for multiple sclerosis
Pathological findings in the cerebrospinal fluid are found in over 95% of patients. For this reason, a lumbar puncture, involving the collection of a sample of cerebrospinal fluid, is recommended if a disease is suspected. In 50 % of the patients there is a slight increase of lymphocytic cells in the cerebrospinal fluid. An intrathecal antibody synthesis, also known as antibody production in the cerebrospinal fluid, identified via detection of oligoclonal bands (OKB), indicates the presence of antibodies in the cerebrospinal fluid. This is a hallmark of a chronic inflammatory process in the central nervous system, and is detectable in more than 95 % of the multiple sclerosis patients.
The exact sensitivity of the test, however, depends on the investigating laboratory. An intrathecal synthesis of antibodies against measles, rubella and varicella zoster virus (MRZ reaction) is found in 89 % of patients.
A so-called ‘bi- or trispecific reaction’ (i.e. an intrathecal synthesis of antibodies against at least two of the three pathogens mentioned), is found in about 67 % of adult multiple sclerosis patients. A positive probability ratio of 25.1 was reported for the bi- or trispecific MRI reaction (i.e. a positive result increases the pre-test odds for the diagnosis of multiple sclerosis by the mentioned factor) specificity is reported to be 97.5 %.
The findings listed here (lymphocytic pleocytosis, OKB, MRZ response) are considered typical for multiple sclerosis, but do not in themselves prove the presence of multiple sclerosis.
Multiple sclerosis treatment
Multiple sclerosis is not yet curable. The goal of all multiple sclerosis treatment measures is to maintain the independence of the patient in everyday life and to ensure the best attainable quality of life. The existing therapeutic options can be divided into relapse therapy, immunomodulating long-term therapy and the treatment of symptomatic complaints. One focus is also on the prevention of complications of multiple sclerosis which can occur, for example, as a result of the patient’s immobility.
Achieving these therapeutic goals requires good cooperation between the patient, nursing staff, the patient’s environment, neurologists, family doctor, physiotherapists, occupational therapists and representatives of other disciplines. The selection of therapeutic measures always takes into account the individual case of the patient.
Pulse therapy is used as a multiple sclerosis treatment in cases of functional impairment in the patient. For purely sensitive relapses, pulse therapy is usually not necessary. The administration of high-dose therapeutic glucocorticoids, which have an anti-inflammatory effect, can initiate and accelerate the regression of symptoms during an episode. Among other things, they reduce the permeability of the blood-brain barrier, so that fewer white blood cells can migrate into the focus of inflammation in the CNS. To date, there is still no study-supported evidence that therapeutic glucocorticoids have a positive effect on the long-term course of the disease.
Intravenous therapy with 1000 mg methylprednisolone over three (to five) days is usual. Common side effects of glucocorticoid therapy are sleep disturbances and mood swings. Since glucocorticoid administration is only for a short period of time, there are no side effects typical of long-term glucocorticoid therapy (e.g. Cushing’s syndrome).
If the second pulse therapy does not have a satisfactory effect either, plasmapheresis can be considered to end an acute attack. This process involves removing the plasma from the patients blood, treating it and returning it to the patient. The use of plasmapheresis is mainly considered in the case of relapses that severely impair the patient’s function (e.g. paralysis). Plasmapheresis can improve the symptoms in about 40% of patients. Its implementation is reserved for specialized centers, since possible complications are cardiovascular disorders and infections, which in rare cases can take a serious course.
The terms immune modulation and immune suppression are not always clearly defined in the literature. In general, these therapies are aimed at either activating or suppressing the immune system. Immunomodulating therapies that do not have an immunosuppressive effect are beta interferons and glatiramer acetate. Immunomodulating therapies which have an immunosuppressive effect are alemtuzumab, cladribine, fingolimod, dimethyl fumarate, natalizumab and teriflunomide (see also Leflunomide).
Classical immunosuppressive drugs such as azathioprine, cyclophosphamide, methotrexate and mitoxantrone can be used as reserve therapy in multiple sclerosis. The aim of long-term therapy with these substances is to prevent new neurological deficits and to delay the worsening of existing deficits. On a pathophysiological level, the active substances used are intended to prevent axonal damage by attenuating the inflammatory reaction in the CNS. The immunosuppressants achieve this by inhibiting the proliferation of white blood cells. The principles of action of immunomodulating substances are not fully understood. The monoclonal antibody Natalizumab was specifically developed as an active substance to prevent the migration of white blood cells into the CNS.
Drugs that have an immunosuppressive effect can increase the risk of infections (in rare cases also serious infections such as PML and opportunistic infections) and cancer. This has not been shown for multiple sclerosis therapies that are not immunosuppressive. In general, the various multiple sclerosis drugs also differ in their safety profile, especially when used during pregnancy.
As multiple sclerosis progresses, many symptoms can lead to a reduction in quality of life. The respective dysfunctions and their extent are differently pronounced in each patient. Particularly frequent and restrictive are walking difficulties, spasticity, pain, bladder dysfunction, speech and swallowing disorders, faster mental and physical fatigue and depressive disorders. In addition to lifestyle changes, physiotherapeutic, speech therapy, occupational therapy, psychotherapy, medication and surgery are suitable for treating these symptoms. Of particular importance is the prophylaxis of serious complications such as aspiration pneumonia, pulmonary embolism, thrombosis, osteoporosis, decubital ulcers, joint contractures, urinary tract infections and desiccosis (dehydration). These complications are partly responsible for the reduced life expectancy of multiple sclerosis patients compared to the general population.