Abstracts and Commentary
Synopsis: Vitamin E had no significant effects in slowing disease progression, and no significant side effects in the patient population were encountered. Patients who regularly take vitamin E have a 60% reduced risk of getting ALS.
Sources: Ascherio E, et al. Vitamin E Intake and Risk of Amyotrophic Lateral Sclerosis. Ann Neurol. 2005;57:104-110; Gerlach M, et al. High Dose Vitamin E Therapy in Amyotrophic Lateral Sclerosis As Add-on Therapy to Riluzole: Results of a Placebo-Controlled Double-Blind Study. J Neural Transm. 2004; Miller E, et al. Meta-Analysis: High Dosage Vitamin E Supplementation May Increase All-Cause Mortality. Ann Intern Med. 2004;142:1-11.
There have been several recent articles which have enhanced the controversies overtaking vitamin E supplements. A recent meta-analysis suggested that high dosage vitamin E supplementation may increase all-cause mortality, meaning death from any cause. This was a meta-analysis of 135,967 participants in 19 clinical trials. Of these, 9 tested vitamin E alone and 10 tested vitamin E combined with other vitamins and minerals. Ascherio et al obtained the data by abstracting the study reports. They assert that patients taking high dosage vitamin E, which they defined as 400 international units daily, had an increased risk of all-cause mortality of 39 per 10,000 persons. For low dosage vitamin E trials, the risk difference was -16 per 10,000 persons. Interestingly, only 2 of these studies were in patients with neurologic diseases. In both, the Alzheimer’s disease collaborative study of high dose vitamin E in symptomatic patients with Alzheimer’s disease, as well as in the DATATOP study in Parkinson’s disease, which both used a dose of 2000 units daily, there was actually a reduction in overall mortality, meaning death from any cause. Nevertheless, when Ascherio and colleagues plot a dose response relationship, DATATOP was said to have an all-cause mortality risk difference of 0.02.
Most of the studies were done in patients with either cardiovascular disease, a history of large bowel adenoma, or early age related cataracts.
More recently, a study examined whether patients who regularly used supplements of the anti-oxidants vitamins E and C have a lower risk of developing ALS than non users. This study was an outgrowth of a large study sponsored by the American Cancer Society. Gerlach et al recruited volunteers in 50 states. A total of 957,740 individuals 30 years of age or older participated. These individuals had information on vitamin use collected at the time of recruitment in 1982. The patients were found, then followed up, for ALS deaths determined from death certificates from 1989-1998. This was done via linkage with a national death index. They documented 525 deaths from ALS. They found that regular use of vitamin E supplements, which was defined as using vitamin E more than 15 times per month, had a markedly reduced incidence of developing ALS. The age and smoking adjusted risk was 0.99 among occasional users, 0.59 in regular users for less than 10 years, and 0.38 for regular users for 10 years or more, as compared with non users of vitamin E. Therefore in users for more than 10 years, there could be roughly a 60% reduction in the risk of dying of ALS. There was no significant association found for use of vitamin C or multi-vitamins. Adjustment for other vitamins such as vitamin A also did not alter the results. Further adjustment for education, level of physical activity, alcohol consumption, servings of fruits and vegetables and high fiber cereals, and use of estrogen replacement therapy did not materially change the result.
A recent controlled, clinical trial examined the effects of vitamin E supplements in patients with diagnosed ALS. One hundred and sixty patients were recruited in 6 German centers that had either probable or definite ALS, and the disease duration of less than 5 years. They were all treated with Riluzole. They were randomly assigned to receive either vitamin E (5000 mg/d) or placebo for 18 months. The primary outcome variable was survival. A number of secondary outcome measurements were also examined. Looking at the primary end point, no significant difference between the placebo and treatment groups could be detected. The functional assessment showed a marginal trend in favor of vitamin E, without reaching significance. Gerlach and colleagues concluded that they had no significant effects in slowing disease progression. However, they did not encounter any significant side effects in the patient population.
These 3 studies all address the use of vitamin E both in a general population, as well as in patients who have ALS. The first study is a meta-analysis, which suggested that taking high dosages of more than 400 units of vitamin E per day may increase or cause mortality. The conclusions of this study however are questionable. It was based on a meta-analysis, and these types of studies are known to have significant flaws. The results of subsequent trials have frequently not verified conclusions reached in meta-analysis studies. In particular, the 2 studies examining neurologic patients actually showed a reduced all-cause mortality in patients with both Alzheimer’s disease and Parkinson’s disease who are taking high doses of vitamin E supplements. We recently re-analyzed the DATATOP data, as well as a continuing follow up, and found that there was no increased all mortality risk in these patients. The results of the meta-analysis above may be confounded by its being a study in largely confined patients with coronary artery disease, cancer, or cataracts. The degree of the overall increase in all-cause mortality was extremely small, being 39 per 10,000 persons or 0.39%. The ability to detect such a small change could very well be largely due to chance. The confidence interval which they found was between 3-74 per 10,000 persons.
The second study is of significant interest. It is carried out by a group at the Harvard School of Public Health, which had earlier found that there is an increased incidence of ALS in servicemen participating in a number of different wars, starting with WWII. Gerlach and colleagues now found that patients using regular vitamin E supplementation for more than 10 years have up to a 60% reduction in the incidence of ALS. This finding could be happenstance and merely reflect greater usage of a number of vitamins, improved diet, or improved physical activity. This, however, does not appear to be the case. All of these were controlled, and none of these other factors showed any association with the reduction of risk of ALS.
Interestingly, the findings are similar to those seen with a number of other neurodegenerative diseases. It appears that taking vitamin E may reduce one’s risk of developing neurodegenerative diseases associated with oxidative stress such as ALS, Parkinson’s disease, and Alzheimer’s disease. The evidence, however, that treatment with vitamin E will have any beneficial effect in these illnesses once they’ve been diagnosed, is much more limited. Vitamin E was unsuccessful in the DATATOP trial in Parkinson’s disease. A more recent trial in patients with mild cognitive impairment did not show any efficacy of vitamin E supplements. In the German trial noted above, vitamin E supplementation at high levels also did not show any benefit in symptomatic ALS patients. The overall data is therefore much more consistent with a preventative effect, rather than a therapeutic effect, once patients become symptomatic. — M. Flint Beal
Dr. Beal, Professor and Chairman; Department of Neurology; Cornell University Medical College New York, NY, is Editor of Neurology Alert.