Multiple Sclerosis

Multiple sclerosis (MS) is an often debilitating (and sometimes fatal) neurological disorder that strikes more than a quarter of a million people in the United States each year (Noonan CW et al 2002). The symptoms of MS often first appear in early adulthood and can include numbness, impaired vision, weakness, loss of balance, and bladder dysfunction. Fatigue is a common early symptom. Depression is more common in people who have MS than in the general population (Patten SB et al 1997). In recent years, scientists have made dramatic advances in understanding and treating this enigmatic disease.

What Is MS?

The term multiple sclerosis refers to the numerous sclerotic lesions, or scars, that form on nerve cells. MS results from progressive damage to the myelin sheathing that insulates and protects nerve cell axons. Axons are the long, thin structures that transmit electrical impulses along the length of individual nerves, before propagating the impulse across a synapse to the next neuron. Like electrical wires, axons are encased in a nonconductive sheathing. In the case of neurons, this insulation consists of a white fatty substance known as myelin.

For reasons that remain a mystery, the immune systems of people who have MS attempt to destroy the body's own myelin. Specifically, a type of white blood cell called a T-cell becomes sensitized against myelin self-antigens. These sensitized T-cells secrete various inflammatory mediators (including tumor necrosis factor, cytokines, and prostaglandins) that eventually strip away myelin and damage supportive cells, thereby incapacitating or destroying the axon (Kidd PM 2001). MS is thus an inflammatory autoimmune demyelinating disease.

Symptoms affecting mobility tend to appear early in the course of MS. They may include sensations of heaviness, weakness, clumsiness, leg dragging, stiffness, and a tendency to drop objects. Sensory symptoms may include numbness, tingling, and electrical sensations. Visual symptoms (such as blurred, double, or foggy vision; eyeball pain; and even blindness) may appear early in the course of the disease. Visual symptoms afflict more than one-third of all people who have MS. If MS affects the nerves that supply the vestibular apparatus in the ears, the person with MS will experience dizziness, nausea, and vomiting. In the later stages of the disease, involvement of the genitourinary tract may result in loss of bladder, sexual, and bowel function (Hartung HP et al 2004; Kidd PM 2001).

Symptoms may come and go for more than 30 years, and the rate of disease progression varies markedly from one person to another. But studies indicate that, in about half of all patients, the disease will inexorably progress towards severe disability or premature death (Kidd PM 2001). The inherent unpredictability of the disease has prompted some scientists to propose that MS is not a single disease at all. Rather, they postulate, it falls within a spectrum of disorders, characterized as inflammatory demyelinating diseases of the central nervous system (Weinshenker BG 1995).

What Causes MS?

While it's unclear exactly what causes MS, researchers have made progress in understanding the underlying chemical reactions that occur during MS. In recent years, nitric oxide has been implicated in the development of MS. In the vascular system, nitric oxide acts as a dilator, expanding arterial walls and lowering blood pressure. In the central nervous system, however, nitric oxide generates free-radical byproducts that contribute to myelin destruction and the loss of nerve function (Smith KJ et al 2002). The picture is complicated, however, by the fact that nitric oxide also has good effects in MS, including modulating the immune system (Smith KJ et al 2002). Studies hoping to manipulate nitric oxide production have yielded mixed results in people who have MS. Research is ongoing.

Researchers have identified a number of factors that are associated with MS. It is unlikely that MS has any single cause. Rather, it appears that a multitude of factors likely work together to trigger and exacerbate the disease. These include:

Genetic disorders. Studies examining the incidence of the disease in the general population, in families, and in twins support a genetic component to MS (Willer CJ et al 2000). However, no single gene has been identified that determines susceptibility to the disease; rather, a number of genes are believed to be involved. About one quarter of all people who have MS have a relative who is also afflicted with the disease

Studies of identical twins show that MS occurs in both twins in about 25 percent to 35 percent of cases. This finding suggests that up to 75 percent of MS must be attributable to nongenetic factors and that the contribution of genetics is actually relatively minor (Willer CJ et al 2000, 2003). It appears that, in addition to genetically predisposing factors, external triggers must be encountered in order for the disease to be initiated. These triggers activate the immune system to identify myelin as a nonself molecule and sets in motion the inflammatory cascade that ultimately ends in destruction of the myelin sheath.

Infectious agents. Various infectious agents have been proposed as triggers for MS. There is significant data that infection is involved in both the initiation of the disease and in damage to the nerves (Steiner I et al 2001). Several organisms have been proposed as potential triggers, including human herpesvirus type 6, Mycoplasma pneumoniae, and the relatively common primitive bacterium Chlamydia pneumoniae, among others. In addition, virtually all people who have MS are infected with the Epstein-Barr virus, which is widespread in the general population. Epstein-Barr virus causes the childhood illness infectious mononucleosis (Alotaibi S et al 2004; Munch M et al 1997). Some researchers believe that a dual infection with a retrovirus and the Epstein-Barr virus may serve as a trigger (Haahr S et al 2000).

Environmental toxins. Exposure to chemical toxins, such as organic solvents and pesticides, has been suggested as another possible MS trigger. Similarly, exposure to heavy metals, such as mercury, has been implicated in MS. Mercury is believed to be one of the most toxic of all nonradioactive elements; it is widely known to affect neurological tissue (Mutter J et al 2005). Recently, researchers in the Czech Republic removed mercury-containing amalgam dental fillings from patients who had autoimmune diseases, including MS. On follow-up, the patients who had MS in particular experienced an improvement in their symptoms after the procedure. This suggests that mercury, which is known to leach out of such fillings, may play an adverse role in the disease (Prochazkova J et al 2004). Other studies have also found a possible link between mercury exposure from dental fillings and the incidence of MS. This idea is controversial because there is also data supporting the position that mercury from dental amalgam fillings is not a health threat (Bates MN et al 2004; Siblerud RL et al 1994).

Organic solvents. In the mid 1990s, researchers in Sweden evaluated 13 studies on the connection between solvent exposure and autoimmune disease between 1966 and 1994. Organic solvents include chemicals such as toluene, paint thinner, and acetone, the latter of which is commonly found in nail polish remover. Ten of those studies indicated a significant relationship between organic solvent exposure and MS. All the analyses suggested that exposure to solvents increases a person's relative risk of developing MS (Landtblom AM et al 1996).

More recently, a team of scientists in Norway analyzed the occupational health records of more than 57,000 workers in their country, covering a 16-year period. They concluded that workers (such as painters) who were routinely exposed to organic solvents had a significantly greater incidence of MS than men and women who were not occupationally exposed to solvents. These results were compatible with the hypothesis that organic solvents are a possible risk factor for MS (Riise T et al 2002).

MS and Food Allergies

Allergies to certain foods may also play a role in the development or exacerbation of MS. MS is most prevalent in areas where consumption of wheat gluten and milk are also high. Gluten and milk are common food allergens (Butcher J 1976; Kidd PM 2001). This relationship has not been proven conclusively, but allergies may play some role in the onset or severity of MS. Components of some foods may act as triggers to the immune system, causing it to begin an inappropriate autoimmune response similar to the body's autoimmune response to bacteria and viruses.

Milk has long been suspected to play a role in the development of MS. Researchers in France examined epidemiological data from populations around the world and found a highly significant correlation between consumption of liquid cow's milk and the prevalence of MS. Interestingly, they discovered a weaker correlation between MS and the consumption of butter and cream, and no correlation between MS and cheese consumption (Malosse D et al 1992). While it's been demonstrated that saturated fat, which is relatively high in whole milk products, is harmful to people who have MS, there may be more to the dairy connection than mere fat. One of the proteins in milk mimics a particular protein affiliated with human myelin. This milk protein could easily trigger an autoimmune response to native myelin, triggering an MS episode. Indeed, this immunologic cross-reactivity has been demonstrated in the laboratory in rodents that have MS (Guggenmos J et al 2004; Stefferl A et al 2000).

Apart from specific cross-reactions to food proteins, a majority of patients who have MS reportedly have a variety of digestive system deficits, including poor digestive enzyme production, poor digestion of fats and proteins, and suboptimal absorption of various nutrients, including vitamin B12 (Lauer K et al 1986). Certain bacteria, notably Lactobacillus species, are helpful and necessary symbionts; their presence benefits the digestive process. Along with other beneficial bacteria, they constitute the normal gut microflora. Other microorganisms, such as the fungus Candida albicans , may be characterized as pest organisms capable of upsetting the delicate balance of the normal microflora. At least one researcher has reported that some patients who have MS who were treated for yeast infections—and who subsequently had their gut microflora recolonized with friendly probiotic organisms (such as those present in active yogurt cultures)—experienced significant improvement in their MS symptoms (Kidd PM 2001; Wright JV 1997).

Conventional MS Treatment

Current first-line treatments for MS include a number of drugs designed to influence the immune system to slow or halt inflammation and destruction of myelin or inhibit nitric oxide. Recent years have brought dramatic advances in treatment, but substantial room for improvement remains. None of the drugs available today rise above a partially effective designation. While drug therapies may reduce the severity and frequency of symptoms, a complete cure remains as elusive as ever.

The drugs usually used to treat MS flare-ups are corticosteroids such as prednisone. These drugs are often prescribed for short periods to alleviate the main symptoms of MS. Studies have shown that the corticosteroids inhibit creation of nitric oxide in the central nervous system (Lieb K et al 2003) in addition to their other, well-known, anti-inflammatory effects such as reduction of cytokine formation and immune cell function. They should not be used for long-term therapy, however, because of their many side effects, including increased risk of infection, weight gain, fatigue, diabetes, osteoporosis, personality changes (including psychosis), and ulcers. Also, while corticosteroids may reduce the symptoms of the disease, they have no effect on its progression.

The US Food and Drug Administration has approved the immune system–modulating drugs interferon ß-1b, interferon ß-1a, and glatiramer acetate for the first-line treatment of relapsing forms of MS (Miller DH et al 2003; Noseworthy JH 1998). Additional cutting-edge treatments include humanized monoclonal antibodies such as daclizumab and alemtuzumab; oral immunomodulators such as sirolimus; cholesterol-lowering statins; estrogens; neuroprotective agents such as NMDA antagonists; the phosphodiesterase inhibitor ibudilast; and sodium-channel blockers, among others (Chofflon M 2005; Farrell R et al 2005; Feng J et al 2004; Miller DH et al 2003; Murdoch D et al 2005; Polman CH et al 2003).

Some of these drugs have been used in combination to reasonably good effect (Vollmer TL et al 2004). Although immunoglobulin G is not considered first-line therapy, some clinicians use it to treat symptoms of MS (Sorensen PS et al 2002). Monoclonal antibodies, such as natalizumab, constitute a new generation of immunosuppressants that act on immune-cell surface ligands. Ligands are the portions of molecules responsible for binding with other molecules, as in the interaction between an antibody and its antigen. The monoclonal antibodies offer relatively focused immunosuppressive actions, and somewhat better safety profiles, compared to conventional immunosuppressants (Chofflon M 2005). Both the monoclonal antibodies and immunoglobulin treatments are very expensive and, because they are human proteins, there is a risk of serious allergic reaction.

Many of the medications have serious side effects, so the benefits must be considered along with the risks before treatment. Mitoxantrone is a broad-spectrum immunosuppressant primarily used as a cancer chemotherapy agent. It is occasionally prescribed to treat MS, especially in cases of progressive disease. But its side effects—which include possible heart damage and potential induction of leukemia—render it less than ideal, especially for long-term use. Pentoxifylline is another drug that offered promise initially, but results from subsequent clinical studies have been disappointing (Prieto JM et al 2001).

Vitamin D Deficiency: An MS Risk Factor

Vitamin D is emerging as a far more important immune system component than was previously appreciated. Long known to play a key role in the regulation of calcium and in the formation and maintenance of healthy bones, vitamin D is now known to influence cell differentiation, function, and survival (Montero-Odasso M et al 2005). In fact, the most bioactive form of vitamin D acts as a hormone in the body, and receptors for it have been discovered in a wide range of tissues.

Vitamin D may also be involved in preventing MS. This was originally inferred from epidemiological data. Scientists noted that MS is more prevalent in people living at higher latitudes (in either the Northern or Southern hemispheres) where sunlight is weaker, particularly in winter. The most bioactive form of vitamin D is generated in the body through a biosynthetic process that begins with, and is dependent on, exposure of the bare skin to sunlight.

In 2004, scientists from the Harvard School of Public Health published the results of two long-term studies on women's health and nutrition. Researchers looked at dietary and supplemental intake of vitamin D as it related to the incidence of MS. Gleaned from the Nurses' Health Study (more than 92,000 women followed from 1980 to 2000) and the Nurses' Health Study II (more than 95,000 women followed from 1991 to 2001), the data support a protective effect for vitamin D against MS, especially for women who consume more than 400 international units (IU) daily of vitamin D from supplements, but not from food sources (Munger KL et al 2004).

Scientists now believe that vitamin D (commonly depleted in people who have MS) may play a crucial role in preventing the disease (Ponsonby AL et al 2005a; Wingerchuk DM et al 2005). Low vitamin D levels are also an emerging risk factor for other diseases and disorders such as type 1 diabetes, heart disease, and rheumatoid arthritis (Holick MF 2005; Merlino LA et al 2004; Munger KL et al 2004; Ponsonby AL et al 2002; Ponsonby AL et al 2005b).

The optimal level of vitamin D varies, but many experts agree that supplemental vitamin D is required, even up to 1000 IU daily (Holick MF 2005). By contrast, a whole-body exposure to peak summer sun will rapidly cause the release of up to 20,000 IU into the circulation (Hollis BW 2005). Other experts suggest that anyone with a blood level of less than 80 nanomoles per liter (nmol/L) of circulating 25-hydroxyvitamin D is at risk of a vitamin D deficiency (Hanley DA et al 2005; Hollis BW 2005).

Vitamin D and Calcitriol's Benefits

In addition to reducing the risk of developing MS, supplemental vitamin D may also provide relief for those actively afflicted with the disease, at least in part by inhibiting nitric oxide, according to animal studies (Garcion E et al 2003). A small clinical trial conducted at the Mayo Clinic was designed to assess the safety and tolerability of daily use for a year of calcitriol, a prescription drug form of vitamin D. Patients who enrolled in the trial were diagnosed with relapsing-remitting MS. Patients received an equivalent of 2.5 micrograms per day (mcg/day) of calcitriol (about 100 IU/day), while their dietary calcium was restricted to 800 milligrams per day (mg/day). Researchers concluded that oral calcitriol is safe and well tolerated by patients with MS who comply with dietary recommendations (Wingerchuk DM et al 2005).

Scientists have also discovered that vitamin D effectively blocks development of MS in animals. When the biologically active, hormone form of vitamin D was administered to animals in a laboratory, the disorder was prevented. Conversely, a deficiency of vitamin D tended to increase the animals' susceptibility to the induced disease. When animals were given vitamin D after developing the disease, progression of symptoms was blocked. When vitamin D supplementation was withdrawn, the disease resumed (Cantorna MT et al 1996, 2000). Numerous laboratories have replicated and expanded upon these findings, prompting one researcher to declare: “Prevention of MS by modifying an important environmental factor (sunlight exposure and vitamin D level) offers a practical and cost-effective way to reduce the burden of the disease in future generations” (Chaudhuri A 2005).

Hormone Imbalances and MS

In recent years, researchers have made great progress understanding how hormone status affects autoimmune disorders, including MS. Numerous studies have observed that MS is more common in women, and that the disease course is affected by the normal ebb and flow of steroid hormones during a woman's monthly menstrual cycle (Pozzilli C et al 1999). Interestingly, it is also well known that pregnancy tends to neutralize the disease course, or even positively affect it, enabling women who have MS to bear children safely (Hughes MD 2004).

These findings point to the important role of steroid hormones in influencing the course of the disease. This theory makes even more sense considering that sex steroid hormones such as estrogen, testosterone, progesterone, and dehydroepiandrosterone (DHEA) are known to have immunomodulatory effects. Hoping to better understand the role of hormones in MS, a number of researchers have conducted studies. Their findings include:

• In a study on rats, researchers found that animals given progesterone alone experienced greater motor defects and inflammation than rats treated with estrogen. The negative effects of progesterone were negated when estrogen was added (Hoffman GE et al 2001).
• Administering estrogen (including estriol and beta-estriol) along with progesterone was shown to inhibit production of nitric oxide in central nervous system cells. This effect was enhanced when the levels of estrogen and progesterone were maintained at levels found during late pregnancy (Drew PD et al 2000).
• Estriol treatment significantly reduced disease severity in animals with MS, while treatment with progesterone had no effect. Administering estriol until treatment levels reached levels consistent with those in late pregnancy completely ameliorated the disease (Kim S et al 1999).
• During a human study that examined the presence of MS lesions by magnetic resonance imaging (MRI), patients with high estradiol and low progesterone levels had more lesions that those who had low levels of both hormones, while patients with a high estrogen to progesterone ratio had a significantly greater number of active lesions than patients who had a low ratio (Bansil S et al 1999).

Obviously, these studies point to a conflict in our understanding of the role hormones play in MS. Animal studies have tended to show progesterone as neutral, while estrogen seems to have a protective effect. In people, however, a high ratio of estrogen to progesterone was associated with more MS lesions. Accordingly, there is a great deal of debate among researchers about the possible role of hormones in MS therapy. Some studies (aimed at maintaining levels of estrogen to progesterone that are consistent with late pregnancy) have argued in favor of treating women with MS with bioidentical hormone replacement therapy. Other studies note that pregnant women who have MS tend to experience a rebound of their disease the first 3 months after delivery (El-Etr M et al 2005). According to a recent review, more studies are needed to determine the exact relationship between MS and hormonal imbalances (Trenova AG et al 2004).

DHEA also deserves attention in people of both sexes who have MS. DHEA is a steroid hormone. Altered levels of DHEA have been associated with various autoimmune diseases and their symptoms, including MS (Calabrese VP et al 1990). One study found that people with MS have relatively lower DHEA levels compared to healthy control subjects and that, at least in animals, DHEA therapy reduces T-cell proliferation, secretion of pro-inflammatory chemicals, and nitric oxide synthesis (Du C et al 2001; Offner H et al 2002; Ramsaransing GS et al 2005). Similarly, researchers have found that people with MS have a higher ratio of cortisol (the body's main stress hormone) to DHEA than do healthy control subjects, although this is probably a symptom of the disease rather than a causal factor (Kumpfel T et al 1999).