Overview and Risk Factors
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). The pathological process involves white-matter inflammation in many areas of the CNS, along with demyelination, oligodendrocyte loss, glial scarring, and eventual axonal destruction. MS may shorten life span by 10 or more years, compared with national averages. The disease may present in several ways. The most common form is relapsing-remitting, often with incomplete remission and some accumulating disability. It may be progressive from the outset (primary progressive) or may later become progressive after a period of relapses and remissions (secondarily progressive). However, in a small minority of patients, the disease is benign with no or little evidence of accumulating disability.
It remains to be determined whether primary progressive MS has the same pathophysiology as the more common types.
Typical age of MS onset is 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 large). Persons with relapsing-remitting MS can convert to progressive MS, typically in their early 40s. The age of peak onset is 5 years earlier for women than for men, and women with MS typically outnumber men by 2 to 3 times.1,2
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 in descending order of frequency are:
- Sensory change in extremities.
- Optic neuritis.
- Motor symptoms including weakness, spasm, and paraplegia.
- Diplopia or internuclear ophthalmoplegia.
- Gait difficulties.
- Bladder/bowel dysfunction, vertigo, or pain.
Other vague symptoms, such as fatigue or cognitive difficulty may become prominent with time and may correlate with the pathological progression.
No exact list of risk factors has been identified for MS. However, the following demographic and other factors are relevant:
Race and ethnicity. Risk varies dramatically among racial and ethnic groups. Among affected individuals, whites outnumber blacks by a 9:1 ratio. The condition is particularly common among Palestinians, Parsis, and Sardinians, and rare among Chinese and Japanese individuals, African blacks, and certain other ethnic groups.3
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.
Vitamin D. Supplementation of vitamin D is associated with reduced risk.4,5
Smoking. Smoking increases risk.6
Heredity. Monozygotic twins have a 20% to 39% risk when one twin has MS, as compared with a 3% to 5% risk in nontwin siblings or dizygotic twins.7 Maternal origin of a hereditary factor is suggested.8
Chlamydia pneumonia. This illness is associated with progressive MS.9
Viruses. MS is associated with viruses, especially Epstein Barr virus, but no definitive causal link to any particular virus has been established as yet.10
Vaccines. The role, if any, of vaccines as risk factors for MS has been controversial, and evidence for such a link is weak. For persons who have MS, vaccines are believed to be safe.11,12
Stress. Stressful life events have been found to be associated with exacerbations of MS.13,14
Two or more clinically distinct episodes of CNS dysfunction (ie, separated in space and time) as described above, separated in time and space, in a person of the appropriate age, strongly suggests MS. Diagnostic tests, particularly brain MRI, can be helpful.
Presenting symptoms were listed previously. Additional symptoms include:
- Heat intolerance--elevated body temperatures exacerbate symptoms (Uhthoff's phenomenon).
- Radiating "electric shock" with movement of the neck (Lhermitte's phenomenon).
- Depression and/or cognitive dysfunction.
- Dysarthria, dysphagia, and/or nystagmus.
Diagnostic tests can also be helpful.
Brain MRI is the test of choice and may show multiple white-matter lesions. A lesion's potential to represent MS plaques 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 three months. Other disease processes such as ischemia and lupus can also cause white-matter lesions.
Spinal MRI may aid diagnosis. Only 3% of spinal MRIs were abnormal in patients without MS, whereas spinal lesions usually parallel brain lesions in MS,15,16 although they are usually less visible.
Lumbar puncture may show oligoclonal bands, myelin basic protein, or IgG abnormalities in 80% to 85% of patients with active MS.
Abnormal visual-evoked, somatosensory-evoked, or auditory-evoked potentials may be identified; visual and somatosensory findings are most helpful for diagnostic purposes.
In patients with optic neuritis, an MRI showing one or more white-matter lesions greater than 3 mm predicts the onset of MS within 10 years in 56% of cases, compared with 22% of those without such lesions.17 Overall, 39% of optic neuritis patients were shown to develop MS within 10 years, and 60% developed it in 40 years.18 Oligoclonal bands in the cerebrospinal fluid increase the likelihood that optic neuritis patients will develop MS.
Although there is no known cure for MS, the following treatments are used, with limited efficacy:
Corticosteroids may be used to treat acute attacks. They have not been shown to affect the functional outcome of the exacerbation, but they do hasten any eventual recovery. A typical regimen would include intravenous methylprednisolone for five days, followed by a short course of prednisone taper. It is not clear whether oral prednisone can replace intravenous methylprednisolone, and a study of patients with optic neuritis suggests that oral treatment may be detrimental.19,20
A relapsing-remitting diagnosis warrants the use of interferon or glatiramer acetate. Interferon is available as beta 1b and beta 1a. The drug choice depends on an individualized risk-benefit assessment for each patient. Interferon use is limited by its potential to create neutralizing antibodies, which are thought to decrease efficacy.
No therapy has been proven to affect the course of primary progressive disease although clinical trials are evaluating several immune suppressant medications.
Secondarily progressive disease can be treated with immunosuppressants, such as methotrexate, cyclosporine, azathioprine, cyclophosphamide, interferon, and steroids. Long-term use of immunosuppressants may be limited by the increased risks of infections or malignancy.
Mitoxantrone is approved by the U.S. Food and Drug Administration (FDA) for the treatment of secondarily progressive MS and appears to be beneficial in slowing progression. However, its potential for cardiac toxicity limits the total lifetime dose and requires vigilant cardiac monitoring.
Paroxysmal symptoms, such as spasms, sensory deficits, dysarthria/ataxia, and pain disorders, have shown some response to anticonvulsants, such as valproic acid, carbamezepine, and gabapentin. Seizures, while not a common symptom of MS, are more common than in the general population.
Several medications, including benzodiazepines, baclofen or tizanidine, may reduce muscle spasticity and, especially, painful spasms.
Modafinil or amantidine may help symptoms of fatigue.
Bladder spasticity may be treated with anticholinergic or other bladder antispasmodic medications. In cases of bladder dysynergia, these medications can cause urinary retention.
Physiotherapy may improve movement, but benefits are usually short-lived.
Other symptoms of the disease, including pain, depression, and fatigue, can be treated by symptom-specific therapy.
Interferon beta 1a has shown some benefit with regard to preserving cognitive function in patients with relapsing-remitting MS.21
Statins, normally used to lower cholesterol, may have benefit in MS, but human studies are needed.
Cannabis and similar pharmaceutical agents have shown inconsistent results.
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.5 The effect of vitamin D may be related to an increase in the anti-inflammatory cytokine TGF-β and a reduction in Th1 cells that are known to be involved in the progression of autoimmune diseases, including MS.22
Low Saturated Fat Diet
Several investigations testing the impact of diet in MS etiology have noted a higher prevalence of MS in correlation with greater intakes of energy, fat, and protein.23 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.23 The incidence of MS is low in Japan and in various African countries, where saturated fat intake is typically very low.24-26
There are several ways in which diets high in saturated fat might be involved in MS. 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.27 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.28 Saturated fats interfere with the conversion of essential fatty acids to their long-chain derivatives (eg, arachidonic acid [AA], eicosapentanoic acid [EPA], docosahexanoic acid [DHA]).24 In turn, these derivatives influence the production of pro-inflammatory cytokines29 that play key roles in MS.24
Additionally, evidence indicates that during relapse, both low density lipoprotein (LDL) oxidizability and autoantibodies to oxidized LDL are increased.30 The known pro-inflammatory effects of oxidized LDL31 might explain the relationship between saturated fat-induced increases in LDL and MS. The reduced amount of LDL that would be expected in the blood of patients on diets very low in saturated fat might explain the benefit of such a diet in MS.
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.27 His experimental diet restricted total and saturated fat intake, the latter to no more than 15 grams per day. It excluded dairy products that were more than 1% fat and fattier cuts of meat. The diet also included 15 grams of vegetable oils and 5 grams of cod liver oil daily, and patients could use an additional 5 grams of vegetable oils, as long as fat intake did not exceed 40 grams per day (not counting the small amounts of fat naturally present in cereal grains, fruits, and vegetables). He noted in a longitudinal study over 50 years that patients following this regimen strictly (ie, those who consumed no more than 30 grams of fat per day) experienced substantial decreases in MS exacerbation, lower mortality rates, and better functional capacity, compared with individuals whose fat intakes were higher.32 Although this study has been criticized for selection bias and a lack of controls, blinding, and randomization, the reported results are impressive. Diets that are low in total and saturated fat have additional benefits, including their potential to control obesity (which is a frequent finding in individuals with MS) and to reduce cardiovascular mortality.23
Epidemiological studies have repeatedly associated milk and dairy product intake with MS prevalence. Two theories have emerged to attempt 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).33 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 oral tolerance, 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)2D3,34 the active hormone form of vitamin D that may be protective against MS, as noted above.
Several studies have revealed lower levels of essential fatty acids (eg, linoleic acid, an omega-6 fatty acid) or long-chain omega-3 fatty acids (eg, EPA) in red blood cells, adipose tissue, plasma lipids, and CSF of patients with MS.23 Theoretically, supplementation with linoleic acid might be of benefit not only by preventing deficiency, but also by suppressing the Type I immune response35 that partly characterizes the immune response in MS.36
However, clinical trials of omega-6 fatty acid treatment for MS have not yielded convincing results. These studies provided patients with 17 to 20 grams of sunflower oil per day in capsule form for 24 to 30 months.
Numerous trials have been conducted in which omega-3 fatty acid supplements (eg, fish oils, EPA and DHA acid, 6 to 10 grams per day for 1 to 2 years) were given to patients with MS, and symptoms rated on the Disability Status Score (DSS). Both the quality of evidence and outcome of these studies have been reviewed by the Agency for Healthcare Research and Quality (AHRQ).37 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.37 The benefit, if any, of therapy for MS with fatty acid supplements remains to be proven.
A low saturated fat (<10 g/day), 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.
Stress reduction exercises, such as yoga, meditation, or other activities may be useful.
What to Tell the Family
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.
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