Multiple sclerosis (MS) is an autoimmune disease of the central nervous system
(CNS). The pathological process involves white-matter inflammation in many scattered areas of the CNS, along with demyelination, oligodendrocyte loss, glial scarring, and eventual axonal destruction. MS may shorten lifespan but with earlier diagnosis and newer treatments, lifespan may be preserved. The most common form of MS is relapsing-remitting, either with complete or incomplete remission. Most patients who have relapsing-remitting MS will transition to secondary progressive MS, characterized by progressive worsening of neurologic function over time. Another form, primary progressive MS, accounts for about 10% of MS cases and is characterized by the progression of neurological disability from the outset. Less common (about 5%) is the progressive-relapsing form of the disease in which progressive disability is apparent from the outset of the condition, although clear exacerbations also occur and are usually followed by partial remission. In a minority of patients, the disease is relatively benign with no or little evidence of accumulating disability between exacerbations.
It remains to be determined whether primary progressive MS has the same pathophysiology as relapsing-remitting disease.
The age of onset is typically the mid-to-late 20s for the relapsing-remitting type and mid-to-late 30s for the primary-progressive type (although the age range is wide). Persons with relapsing-remitting MS can transition to progressive MS anywhere from 10-25 years after disease onset. The age of peak onset is 5 years earlier for women than for men, and women with MS typically outnumber men by 2-3 times. ,
Symptoms and signs of the disease depend upon the part of the central nervous system affected. MRI studies show that most lesions are asymptomatic, although the effect of lesions may be cumulative, and the condition of some patients rapidly deteriorates.
Presenting symptoms can include:
Fatigue and cognitive difficulties may become prominent with time and may correlate with the pathologic progression.
The disease is most common in Western European lineage who live in temperate zones. No exact list of risk factors has been identified for MS. However, the following are relevant:
Genetic susceptibility. There is a relationship between MS and some alleles of the major histocompatibility complex, such as HLA-DRB1 locus, and also with some non-MHC susceptibility genes, including IL7R and ILR2RA, among others. ,
Gender, race, and ethnicity. MS is more common among women than men, and recent studies have shown a sharp rise in prevalence among African Americans in recent decades such that their risk is higher than white Americans. , The condition is also common among Palestinians, Persian Zoroastrians, northern Europeans, individuals living at the northern latitudes of the US or southern latitudes of Canada, New Zealanders, southeastern Australians, and Sardinians, and rare among Chinese and Japanese individuals, African blacks, and certain other ethnic groups.
Geography. Risk depends on place of residence during the prepubertal years, increasing with distance from the equator. However, this finding may represent genetic susceptibility or vitamin D activity. Furthermore, it is thought that MS incidence increases when people shift from a rural area to an urban area. ,
Smoking. Smoking increases risk.
Heredity. Monozygotic twins have a 20%-39% risk when one twin has MS, as compared with non-twin siblings or dizygotic twins, who have a 3%-5% risk. Maternal origin of a hereditary factor is suggested.
There have been some epidemiologic associations between MS and certain infectious agents, including Epstein-Barr virus , Chlamydia pneumoniae, and Varicella zoster virus. , , However, no definitive causal links have been established, and treatments directed at infection have not so far proved helpful. In contrast, some studies have shown that Cytomegalovirus(CMV) infection plays a protective role.
Despite recent questions regarding potential links between MS and the hepatitis B vaccine, the evidence for any such causal link is weak. , For persons who have MS, vaccines are believed to be safe. ,
Two or more clinically distinct episodes of dysfunction of white matter pathways (i.e., separated in space and time) as described above, in a person of the appropriate age, strongly suggest MS. These tracts include the optic nerves, sensory and motor tracts of the spinal cord and brain stem, and those of the cerebellum. Subcortical and periventricular white matter is most commonly involved, although lesions are often silent in these areas.
The diagnosis of MS is based on the 2010 McDonald Criteria, which includes specific clinical and MRI findings to determine the dissemination of lesions in time and space.
Dissemination in space is demonstrated with MRI by one or more T2 lesions in at least two of the typical sites (e.g., periventricular, juxtacortical, infratentorial or spinal cord). This criterion is also met by the development of a further clinical attack that implicates a new central nervous system site.
Dissemination in time is demonstrated with MRI by the simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions or a new T2 and/or gadolinium-enhancing lesion(s) on a follow-up MRI, compared with a prior scan.
Presenting symptoms were listed previously. Some additional symptoms include:
Diagnostic tests can also help confirm a clinical diagnosis:
Brain MRI is the test of choice and may show multiple white-matter lesions. A lesion’s potential to represent an MS plaque corresponds directly to its size and proximity or relationship to the cerebral ventricles. Enhancement of a lesion indicates that it has been active within the past 3 months. Other disease processes such as ischemia and lupus can also cause white-matter lesions. Established MRI criteria are quite accurate in determining patients who are likely to have MS. , MRI may show typical lesions, such as Dawson’s fingers, which are demyelinating plaques in the corpus callosum. Incidental MRI lesions suggesting MS may be found in the absence of clinical involvement (called Radiographically Isolated Syndrome), which may portend progression to MS.
Spinal MRI may aid diagnosis. Fewer abnormalities are apparent on spinal cord imaging than on imaging of the brain in MS patients. However, this test may satisfy the criterion of dissemination in space when few or no abnormalities are seen above the foramen magnum. In an axial view, lesions are typically located dorsally or laterally and span one vertebral segment or less.
The differential diagnosis of MS includes:
Acute disseminated encephalomyelitis
Systemic lupus erythematosus
Lumbar puncture may show oligoclonal bands, myelin basic protein, or IgG abnormalities in 80%-85% of patients with active MS but these findings are not specific for MS.
Abnormal visual-evoked, somatosensory-evoked, or auditory-evoked potentials may be identified; visual and somatosensory findings are most helpful for diagnostic purposes.
In a patient with a first episode of optic neuritis (clinically isolated syndrome), an MRI showing one or more white-matter lesions larger than 3 mm is associated with a greater than 50% chance of developing MS within 10 years (compared with a 22% chance for those without such lesions). These individuals should have a follow-up MRI every 6-12 months. Overall, 39% of optic neuritis patients have been shown to develop MS within 10 years, and 60% have developed it within 40 years. The presence of oligoclonal bands in the cerebrospinal fluid at the time of initial presentation with optic neuritis also increases the likelihood that patients will develop MS.
The Expanded Disability Status Scale (EDSS) allows a determination of the extent of the disease burden.
Corticosteroids may be used to treat acute attacks. They appear to shorten an attack but do not seem to affect its ultimate outcome. Typical regimens include intravenous methylprednisolone for 3-5 days, followed by an optional short prednisone taper. Oral steroid therapy may be effective; however, a study of patients with optic neuritis suggested that oral treatment may be detrimental. ,
Plasma exchange and human immune globulin infusion , are being investigated in rapidly worsening relapsing-remitting MS and as part of other immune treatment regimens. They are best used during severe relapses unresponsive to corticosteroids.
There are many disease-modifying therapies approved for relapsing-remitting MS that include subcutaneous, intramuscular, intravenous, and oral formulations. They include interferon beta-1a, interferon beta-1b, glatiramer acetate, dimethyl fumarate, fingolimod, teriflunomide, natalizumab, daclizumab, ocrelizumab, and alemtuzumab. Drug choice depends on an individualized risk-benefit assessment for each patient.
Treatment options for progressive disease are limited.,, Immunosuppressive therapies, such as steroids, methotrexate, cyclophosphamide, cladribine, interferon, total lymphoid irradiation, mitoxantrone, and human immune globulin infusion, are possible options. Long-term use is limited by risk of infection and malignancy. Ocrelizumab was approved in 2017 for primary progressive multiple sclerosis.
In addition to the disease-modifying treatments noted above, treatments may also be directed at specific symptoms. , Paroxysmal symptoms, such as spasms, sensory deficits, dysarthria/ataxia, and pain disorders, have shown some response to anticonvulsants such as valproic acid, carbamazepine, and gabapentin. Seizures, while not a common symptom of MS, are more common than in the general population.
Several medications, including benzodiazepines, baclofen, and tizanidine, may reduce muscle spasticity and, especially, painful spasms.
Modafinil or amantadine may help symptoms of fatigue.
Bladder spasticity may be treated with anticholinergic or other bladder antispasmodic medications. In cases of bladder dyssynergia, these medications can cause urinary retention.
Physiotherapy may improve movement, but benefits are usually short-lived.
Cannabis and similar pharmaceutical agents can be used for spasticity and related pain. However, studies have shown inconsistent results.
Statins, normally used to lower cholesterol, and some other emerging treatments may have benefit, but they require further study.
It is important to address comorbid conditions, notably depression, which is present in nearly 50% of patients and as well as anxiety and other complications.
Several dietary factors have emerged in studies on the risk of developing MS or on its progression after diagnosis.
Supplemental Vitamin D. Limited evidence suggests that vitamin D may play a preventive role. In the Nurses’ Health Study I and II, regular use of a vitamin D supplement, typically within a multiple vitamin, resulted in a 40% reduction in MS risk. The effect of vitamin D may be related to an increase in the antiinflammatory cytokine TGF-β and a reduction in Th1 cells that are known to be involved in the progression of autoimmune diseases, including MS.
It is unclear if vitamin D supplementation prevents the progression of MS or decreases disability in MS patients. A prospective study including 181 MS patients showed a negative correlation between serum vitamin D levels and disability scores. Another prospective investigation of 468 MS patients showed that those who had a serum 25 (OH)D concentration ≥ 50 nmol/L had a lower yearly increase in T2 lesion volume and less brain atrophy and disability, compared with those with levels below 50 nmol/L. Vitamin D intakes up to 4,000 IU daily are not likely to cause toxicity. The effects of vitamin D supplementation are the subject of ongoing trials.
Low-Saturated-Fat Diet. Several investigations have noted associations between MS prevalence and intakes of energy, fat, and protein. Specifically, higher intake of saturated fat found in foods of animal (not plant) origin, including meat, milk, butter, and eggs, was associated with the prevalence of MS. The incidence of MS is low in Japan and in various African countries, where saturated fat intake was historically very low. , ,
Diets high in saturated fat might be involved in MS in various ways. One explanation suggests that meals high in saturated fat reduce oxygen availability to the CNS, resulting in activation of lysing enzymes in cells that may increase the permeability of the blood-brain barrier to potential toxins. The tendency of saturated fats to elevate blood cholesterol concentrations may also play a role, as suggested by a reduction in MS lesions in patients treated with certain cholesterol-lowering drugs. Saturated fats interfere with the conversion of essential fatty acids to their long-chain derivatives (e.g., arachidonic acid [AA], eicosapentanoic acid [EPA], docosahexanoic acid [DHA]). These derivatives reduce the production of proinflammatory cytokines that play key roles in MS.
Additionally, evidence indicates that during relapse, both low density lipoprotein (LDL) oxidizability and autoantibodies to oxidized LDL are increased. The known proinflammatory effects of oxidized LDL might explain the relationship between saturated fat-induced increases in LDL and MS. A study of 61 participants with relapsing-remitting MS showed that a low-fat, plant-based diet, which excluded meat, fish, dairy products, eggs, and veg etable oils, led to reductions in total and LDL cholesterol levels, BMI, and fasting insulin levels. The intervention also led to a significant reduction in fatigue.
In 1948, neurologist Roy Swank, of the Montreal Neurological Institute, hypothesized that a low-saturated-fat diet would retard the progression of MS and tested this diet in 264 people.
Dairy Avoidance. Epidemiologic studies have repeatedly associated milk and dairy product intake with MS prevalence. Two theories have emerged to explain this association. First, some evidence suggests that an immunologic phenomenon may be involved. MS patients are known to have an enhanced antibody response to myelin oligodendrocyte glycoprotein (MOG). These antibodies have been found to cross-react with the bovine milk protein butyrophilin, a process that would not normally occur due to the development of oral tolerance to this protein early in life. Some have suggested that, when gastrointestinal infections or other factors prevent the development of tolerance to this protein, exposure to butyrophilin early in life may lead to susceptibility to MS. A second theory suggests that dairy calcium may suppress the production of 1,25(OH)2D3, the active hormone form of vitamin D that may be protective against MS, as noted above.
Lipid-Supplemented Diets. Several studies have revealed lower levels of essential fatty acids (e.g., linoleic acid, an omega-6 fatty acid) or long-chain omega-3 fatty acids (e.g., EPA) in red blood cells, adipose tissue, plasma lipids, and CSF of patients with MS. Theoretically, supplementation with linoleic acid might be of benefit not only by preventing deficiency, but also by suppressing the type I immune response that partly characterizes the immune response in MS.
However, clinical trials of omega-6 fatty acid treatment for MS have not yielded convincing results. These studies provided patients with 17-20 grams of sunflower oil per day in capsule form for 24-30 months.
Numerous trials have been conducted in which omega-3 fatty acid supplements (e.g., fish oils, EPA and DHA acid, 6-10 grams per day for 1-2 years) were given to patients with MS, and symptoms were rated on the Disability Status Score (DSS). Both the quality of evidence and the outcome of these studies have been reviewed by the Agency for Healthcare Research and Quality (AHRQ). AHRQ concluded that, although some trials with weaker study designs found a reduction in MS incidence or progression, aggregate data are insufficient to draw conclusions about the effects of omega-3 fats on MS incidence, and evidence regarding the progression of MS is inconsistent and inconclusive. A recent Cochrane Collaboration review concluded that supplementation with polyunsaturated fatty acids does not have a significant effect on the progression of MS or the risk of relapses over two years, and that there is insufficient evidence to assess the harm or benefit of supplementation.
A low saturated fat (< 10 g/d), low cholesterol diet may be tried prospectively. This is most effectively accomplished with a low-fat, vegan diet.
Nutrition consultation will be helpful in implementing this diet and arranging outpatient follow-up.
Avoidance of alcohol.
Physical activity when possible.
Stress reduction exercises, such as yoga and meditation, may be useful.
Although there is no known cure for MS, some clinical studies show that disease progression may be slowed if the saturated fat intake is less than 10 grams daily. Family members can assist the patient in reducing saturated fat and may improve their own health by following a similar diet. Limiting or avoiding animal products (red meat, chicken, fish, eggs, and dairy products) and tropical oils (palm, palm kernel, and coconut) is usually necessary to reach this goal, and a nutritionist can aid in following this diet regimen.