Although no form of complementary and alternative medicine (CAM) has proven beneficial in multiple sclerosis (MS), up to 75 percent of patients use some version of CAM, according to patient surveys by several MS centers. Patients resort to alternative medicine to alleviate fatigue, spasticity, pain, sexual dysfunction, and cognitive changes – symptoms for which there are few effective options. However, there is little objective evidence for CAM therapies. At best, there are suggestive animal studies and small clinical trials, many of which gave either negative or equivocal results.
Given the lack of favorable data, how should neurologists advise patients who are interested in CAM and, more important, what kind of evidence is there to argue for or against it as an option? Neurology Today interviewed several leading experts on CAM in MS to review the evidence and recommendations.
STATE OF THE EVIDENCE
The field of scientific study of CAM in MS is still in its infancy, and even positive evidence for CAM is inconclusive, said Allen C. Bowling, MD, PhD, Medical Director of the Complementary and Alternative Medicine Program at Rocky Mountain MS Center in Englewood, CO, who is also Clinical Associate Professor of Neurology at the University of Colorado Health Sciences Center in Denver.
Perhaps the most well studied form of CAM is dietary modification with polyunsaturated fatty acids, which is still controversial, said Dr. Bowling. Animal models and evidence from human trials suggest that a diet low in saturated fat and high in polyunsaturated fat may benefit patients with MS, but studies have not established this with certainty.
The strongest clinical evidence for polyunsaturated fatty acids supplementation involves people with relapsing-remitting MS who have relatively little disability. In a pooled analysis of three studies of omega-6 polyunsaturated fatty acids that involved a total of 172 patients, use of an omega-6 polyunsaturated fatty acid – that is, linoleic acid – reduced the length and severity of MS attacks (Neurology 1984;34:1441–1445). In that analysis, linoleic acid slowed the progression of disability in people with little or no disability at the start of treatment, whereas this benefit was not observed in those with severe MS and MS of longer duration.
“As with this or any other dietary approach, it is important for the patient to maintain a well-balanced diet to be sure that they are getting all the nutrients they need,” he added.
A moderate “unconventional” approach to diet would include following a diet that is similar to the one recommended by the American Heart Association and the American Cancer Society: whole grain cereals and breads, five daily servings of fruit and vegetables, limited saturated fat intake, fatty fish two to three times a week, and moderate use of salt, sugar, and alcoholic beverages.
Boosting the amount of polyunsaturated fats by supplementation with omega-3 and omega-6 fatty acids is an option worth considering, Dr. Bowling said. If that is done, it is important to supplement with modest doses of vitamin E (in the range of 0.6 to 0.9 IU of vitamin E for each gram of polyunsaturated fat), since a diet that is high in polyunsaturated fats may produce vitamin E deficiency, he noted. It is best to avoid high doses of vitamin E, he emphasized.
Vitamins, minerals, and other supplements, although popular among MS patients, are controversial, explained Dr. Bowling, and may even be harmful depending on the product and the doses used.
Dr. Bowling noted that vitamin D is mildly immunosuppressive, decreasing the production of proinflammatory cytokines and inhibiting lymphocyte proliferation. In one study, vitamin D supplementation reduced symptoms of experimental autoimmune encephalitis (EAE), a mouse model of MS (Proc Natl Acad Sci USA 1996;93:7861–7864).
In mice with mild symptoms of EAE – using a scoring system to assess tremor, spasticity, and weakness – vitamin D halted the progression of disease; whereas in vitamin D-deficient mice, the mean time of onset of EAE was reduced or delayed.
An epidemiologic study published this year suggested that vitamin D may be helpful in decreasing the risk of developing MS (Neurology 2004;62:60–65).
Two cohorts of women were analyzed in the Nurse's Health Study – 92,252 women at a 20-year follow-up and 95,310 women at a 10-year follow-up. Their diet was assessed at baseline and every four years thereafter. A highly significant 40-percent relative risk reduction for developing MS was observed in women who took vitamin D greater than or equal to 400 mg per day compared with women who took no vitamin D.
“Vitamin D is an evolving story,” said Dr. Bowling. “On the basis of scientific studies in animal models and epidemiologic studies, a well-designed clinical trial would be appropriate in MS.”
Vitamin D (along with calcium) is also necessary for maintaining bone health, he noted. Since osteoporosis is more common in MS than in the general population, this is another potential benefit for vitamin D in MS, he added. But, he pointed out, this has not been studied specifically in MS and probably will not be, because so many studies in the general population have shown that vitamin D and calcium promote bone health.
Dennis Bourdette, MD, Chairman and Swank Research Professor of Neurology at Oregon Health & Science University (OHSU) and Director of the MS Center of Oregon in Portland, and colleagues received funding from the NIH National Center for Complementary and Alternative Medicine (NCCAM) to study antioxidant therapies in MS. They are interested in antioxidants because oxidative injury is involved in myelin destruction and axonal injury in MS. In the first phase of the study, several antioxidants were screened in mice with EAE.
Starting with an alphabetical list of agents, Dr. Bourdette and colleagues first screened alpha lipoic acid (ALA). “We had spectacular results,” suppressing paralysis associated with EAE in 100 percent of treated animals, he said.
Other antioxidants they screened – high-dose vitamin E and ginkgo biloba – had no effect on EAE, or only a modest effect.
When high-dose ALA was given during the first attack in EAE mice, animals recovered rapidly with no further relapse, while saline treated animals relapsed and continued to deteriorate over the 30-day study period. Based on these findings, Dr. Bourdette and colleagues received another grant from the Department of Veterans Affairs to study the mechanism of action of ALA.
“ALA stands out in the animal model of MS,” he told Neurology Today. “It is worth noting that ALA has been shown in several controlled clinical trials to have a neuroprotective effect for diabetic nephropathy.”
TOLERABILITY OF ALA
Dr. Bourdette and colleagues have completed a phase I dose-finding study of ALA funded by NCCAM. In that trial, 40 patients with mild relapsing-remitting MS – 10 patients in each group – were treated for two weeks; given placebo twice daily; ALA at 60 mg twice daily; ALA at 1200 mg in the morning and placebo in the afternoon; and ALA at 1200 mg twice daily. These were the doses used in the studies of diabetic nephropathy, explained Dr. Bourdette.
ALA was generally well tolerated at the highest dose and has shown an anti-inflammatory effect, although a few patients experienced mild gastrointestinal disturbances and one patient developed a skin rash necessitating withdrawal from the study. Analysis of immunological parameters showed that high-dose ALA decreased the blood levels of MMP-9, an immunological marker that is increased in MS patients, he explained.
A survey of Oregonian patients with MS revealed that about 20 percent were using ALA at doses well below 600 mg per day, Dr. Bourdette said. The study findings are being prepared for publication.
Based on these studies, Dr. Bourdette believes that 600 mg per day is not an adequate dose. This is because blood levels of ALA are undetectable in patients who take less than 600 mg per day, he said.
Dr. Bourdette and colleagues are considering studying an intravenous form of ALA to improve its absorption in a phase II trial. That study will include patients in relapse. Currently, relapsing patients are treated with corticosteroids. “It would be beneficial to find a nonsteroidal treatment for relapse,” he said.
GINKGO BILOBA AND COGNITION
Dr. Bourdette also has funding from the National MS Society for a pilot project on ginkgo biloba (another antioxidant) versus placebo. The study, still in the recruiting phase, is a double-blind, placebo-controlled trial designed to evaluate the effect of ginkgo biloba on cognition in 60 patients with MS.
“Cognition is commonly impaired in MS, and there is currently no therapy for this. There is some evidence that ginkgo biloba improves cognition in patients with Alzheimer disease and in older people,” explained Dr. Bourdette, citing a preliminary study published in 2002 (Neurology 2002;58:A458–A459).
The study included 23 patients with mild MS under age 35 treated with ginkgo biloba at 240 mg per day or placebo for three months. Patients who received daily supplementation with ginkgo biloba had a significantly better performance on several cognitive tests.
Exercise has several physical benefits important for MS patients, including decreased fatigue levels and improved quality of life, Dr. Bowling said. It can help improve overall mood, and also help build bone health in MS patients, but this has not been studied specifically in MS patients, he added.
Conventional exercise programs include those developed by a physical therapist. Unconventional approaches such as yoga and tai-chi have been reported anecdotally to be helpful to MS patients, he said.
A study of 69 patients with MS of varying severity showed that a program of once-weekly yoga classes or once-weekly exercise classes using a stationary bike significantly improved fatigue and quality of life compared with a group of patients assigned to a 6-month waiting list for either intervention. The randomized controlled study was led by Barry S. Oken, MD, OHSU Professor in the Departments of Neurology and Behavioral Neuroscience.
Dr. Oken said no change in cognitive function was observed for any of the three groups: yoga, stationary bicycle exercise, or neither. However, a significant improvement was seen for both yoga and exercise on the “vitality” subscale of the SF-36, a quality-of-life measure that encompasses energy or fatigue, and a fatigue subscale of the Multidimensional Fatigue Inventory.
Sixty-nine patients were randomized in a 1:1:1 ratio to the three groups, and 57 completed the study. The patients had scores of up to 6.0 on the Expanded Disability Status Scale – meaning they could walk with an assistive device – and most were taking disease-modifying therapies – interferon 1-a or interferon 1-b, for example – as well as other CNS-active drugs, among them modafinil and other stimulants, benzodiazepines, antidepressants, or drugs for bladder control.
Dr. Oken pointed out that any of the latter drugs would be considered an exclusion in a trial of Alzheimer disease or other neurological conditions, because they can confound cognition. He suggested that the lack of an effect on cognition with yoga and exercise may be attributable to concomitant use of CNS-active agents.
Dr. Oken noted the yoga study posed several logistical problems and was more time consuming and difficult to conduct than a traditional drug trial. Challenges included scheduling classes at a mutually convenient time for all participants and finding an accessible class site for people with disabilities.
“The issue of blinding was difficult because participants obviously knew which program they were assigned to; some of the assessors were blinded as to which group patients were in,” Dr. Oken noted.
The study design did not allow a thorough assessment of physical benefits of either yoga or stationary bike exercise, however. Flexibility and balance were measured, but more subtle signs of physical improvement were not included. Nevertheless, Dr. Oken said the patients reported that they enjoyed the physical benefits of the intervention, and he believes that exercise or yoga should be part of every MS patient's routine. The exercise program should be tailored to the patient's physical abilities.
“I would recommend planned exercise either on a stationary bike or yoga for MS patients. At this point, we don't know which is better or whether a combination of both would be better. You have to take into account patient preference when recommending a type of exercise,” he said.
Parenthetically, Dr. Oken noted that a survey of 1,500 MS patients conducted in Oregon and other northwest states showed that patients preferred yoga to disease-modifying therapy and felt they got more benefit from yoga.
PROMISING BUT NOT PROVEN
Several other forms of CAM are potentially promising and have limited or anecdotal support for treatment of MS-related symptoms, including massage for relaxation, marijuana, small magnets, cooling garments, and caffeine. These forms of CAM deserve further study, Dr. Bowling said.
One CAM treatment that has garnered overwhelming negative evidence is hyperbaric oxygen treatment, he said. After an initial positive study of hyperbaric oxygen in MS in 1983, seven subsequent studies showed no clear benefit in patients with MS for this expensive treatment.
Dietary supplements should be used with caution, continued Dr. Bowling, because many of these stimulate the immune system, an unwanted effect in MS. The long list of dietary products that are theoretically harmful due to possible immune stimulation include Chinese herbs, echinacea, garlic, ginseng, zinc, and selenium. Other dietary supplements carry potential risks in MS due to side effects, possible worsening of MS-related symptoms, and potential interactions with MS medications, he said. A detailed MS-relevant review of dietary supplements is covered in a book by Dr. Bowling and Thomas Stewart, JD, PA, MS (See box, “Resources on CAM and MS”).
DISCUSSION WITH PATIENTS
So what does the current state of evidence bode for advising patients? Although there is only modest evidence in support of some forms of CAM, Dr. Bowling and others believe neurologists should familiarize themselves with evidence reported up to this point.
“Most physicians are not comfortable about using treatments that have not been validated in randomized controlled trials,” Dr. Bowling said, “but patients want to learn about these therapies.”
“I believe in listening to patients,” Dr. Bowling continued. “Therapies that make patients feel better are worthy of study as long as they are safe and have a scientific rationale. CAM may be particularly beneficial in the realm of symptom management.”
Dr. Bourdette stressed that discussion of CAM with patients does not imply an endorsement of these therapies. In fact, after discussing these options with patients who are using several forms of CAM, he found they often stop using ones that could be harmful or have limited supporting evidence.
Patricia K. Coyle, MD, a neurologist who is not involved in studies of CAM, agreed that there needs to be open communication between patients and neurologists about CAM therapies they are using. Dr. Coyle, Professor of Neurology and Acting Chair of the Department of Neurology at the State University of New York at Stony Brook and Director of the Stony Brook MS Comprehensive Center, said neurologists should be concerned about patients who opt for an unproven CAM therapy instead of a recommended course of treatment with a validated disease-modifying agent.
“I have actually had patients who choose to undergo bee sting therapy or a procaine patch as a substitute for immunomodulatory therapy,” she said.
Dr. Coyle noted that there is a strong placebo effect in MS that can come into play when patients anecdotally report that a form of CAM is effective. “These reports need to be taken with a strong grain of salt,” she said. It is important to study those forms of CAM for which there is some evidence of effectiveness, she emphasized. “The efforts of the NCCAM in studying and validating alternative therapies should be applauded,” she said.
What types of CAM deserve further study? Said Dr. Bourdette: “We need to focus on the most often used therapies and the ones reported by patients to be of benefit. We also need to study agents based on a scientific rationale derived from our knowledge about MS, and to study agents where preclinical data on animal models suggest benefit.”
ARTICLE IN BRIEF
- ✓ Although many MS patients report that they use various versions of complementary or alternative medicine (CAM) to relieve disease symptoms, there is little objective evidence for CAM therapies.
- ✓ Several neurologists who study CAM say there is some scientific rationale for follow-up studies on the use of certain antioxidants and forms of exercise.
RESOURCES FOR UNDERSTANDING CAM AND MS
There is a lot of misinformation in books, on the Internet, in health food stores, and from vendors of different products. Below are a number of reliable sources for neurologists who wish to become more educated about CAM.
- Jellin JM, Gregory, PJ, Batz F, et.al. Pharmacist's Letter/Prescriber's Letter Natural Medicines Comprehensive Database, 4th ed. Stockton, CA: Therapeutic Research Faculty, 2002.
CAM and MS
- Bowling AC, Stewart TM. Dietary Supplements and Multiple Sclerosis: A Health Professional's Guide. New York: Demos Publishing, 2004.
- Bowling AC, Stewart TM. Current complementary and alternative therapies for multiple sclerosis. Curr Treat Options Neurol 2003;5:55–68.
- Oken BS, Ed. Complementary Therapies in Neurology: An Evidence-Based Approach. New York: The Parthenon Publishing Group, 2004.
- Yadav V, Bourdette D. Complementary and alternative treatments in multiple sclerosis. In: Multiple Sclerosis Therapeutics, 2nd Edition. Rudick RA, Cohen T, Ed. London: Martin Dunitz, 2002.