Overall the authors put together an excellent overview of the scientific basis for the beneficial effects of a select number of nutraceuticals utilizing in vitro and some in vivo studies as they relate to concussive brain injuries. Their selection of nutraceuticals for discussion is also to be commended, as these have shown considerable beneficial effects in TBIs and/or other neurological disease models.
In my view, the only weakness of the paper was its discussion of the clinical studies, in which they gave an overall impression of poor or equivocal results for most nutraceuticals. Even though the authors note that many clinical studies suffer from methodological and other study design problems, I think further elaborations on the deficiencies of such studies needs to be discussed.
Unfortunately, a number of the studies they referenced were misquoted or the authors of the papers themselves omitted reported positive results buried within the paper's data. For example, they implied that most studies found no beneficial effects using omega-3 oil (N-3 oil) supplementation in seizure patients. They quote DeGiorgio et al. as finding no benefit using omega-3 oils in patients with chronic epilepsy, when in fact they found a positive trend in reduction in the severity of the seizures, but no reduction in the frequency of seizures. Yuen et al., which they also quote as finding no benefit, in fact found that seizure frequency was significantly reduced for the first 6 weeks of treatment, but then the effect was not sustained.
I have treated a number of seizure patients of varying severity and duration with nutraceutical products, many of whom were on a number of anti-seizure medications, and have had great success in dramatically reducing the need for medications or, in some cases, eliminating the need for medications altogether. To accomplish this goal, one needs to approach the disorder not only from its pathophysiology, but also the patient's reaction to dietary influences. For example, the typical American diet contains large amounts of excitatory food additives, which are known to play a major role in epilepsy. It makes little sense to attempt pharmaceutical treatment of a patient's seizures while they are consuming high doses of the very amino acid driving the seizures. We also know, from large nutritional surveys, that a majority of Americans are deficient in magnesium. Magnesium is essential for modulation of NMDA receptors and low magnesium significantly lowers seizure thresholds.
Considerable evidence shows that seizures, as well as TBIs are a immunoexcitotoxic disorders, with elevations in cytokines, particularly TNF-α, and an increase in calcium-permeable AMPA receptors in the hippocampus and cortex. This has been demonstrated specifically in the case of seizures.[263
] In addition, high sugar intake, especially high fructose corn syrup, increases advanced glycation end products (AGEs), which stimulate RAGE receptors on microglia, again driving brain inflammation and generating high levels of free radicals. Likewise, a high intake of omega-6 oils (N-6 oils), as occurs in the typical Western diet, increases brain inflammation and has been shown to worsen seizures. So we see that merely altering the omega-3 intake is not sufficient to curtail seizures. One must also consider the N-6/N-3 ratio. A high intake of N-6 oils drives out beneficial N-3 oils, greatly increasing brain inflammation. Most studies never look at the participants’ N-6 oil intake.
I find the same problem in their analysis of the studies on vitamin E, C and omega-3 oils in neurodegenerative disease prevention and treatment. If one actually looks at the data within these studies, that is, when the data is actually provided, one sees evidence that is not included in the abstract or the paper's final conclusion. For example, they quote Sasso et al. concerning the Physician Health Study using vitamin C and E as indicating they found no benefit of either supplement in preventing strokes, when in fact that is not exactly what the authors of the study found. Among 754 males having CVD at the baseline there was a 26% reduction in stroke incidence among those taking the vitamin E and C. As with all such studies one of the major problems is compliance. They reported that compliance at 4 years was 78%, but like all such studies compliance is self-reported by the participants.
I was also interested in the type of supplements used in the studies quoted. The only information available was that the authors of these studies used a synthetic form of alpha-tocopherol and ascorbic acid. The doses were quite low—400IU every other day for the vitamin E and 500 mg a day for the vitamin C. Smokers have been shown to have severe depletion of vitamin C and it takes high doses of vitamin C just to return the serum levels to normal. This would mean that to truly test high dose vitamin C one would require much higher doses over an extended time period than were used in this study. The vitamin E in many of these studies would average 200 IU a day, which again, is extremely low and one would not expect a significant effect.
The form of vitamin E is also essential, which the authors of this paper address. Natural vitamin E is normally composed of 4 subtypes, alpha, beta, gamma and delta tocopherols and 4 subtypes of tocotrienols, alpha, beta, gamma and delta. The only anti-inflammatory form of natural vitamin E is the gamma fraction. Alpha-tocopherol is considered a much weaker antioxidant form of vitamin E as compared to natural vitamin E (mixed tocopherols). In some of the quoted studies they used DL-alpha-tocopherol, which has very poor antioxidant function and is poorly absorbed. The supplements used in most of these studies were donated by the manufacturers, and many are cheaply made and of poor quality. High quality supplements containing mixed tocopherols are relatively expensive and as such are rarely used in large population studies.
I have found that many clinical researchers seem to know little about free radical and lipid peroxidation chemistry and even less about naturally occurring antioxidants. As a result, many of these papers are seriously flawed. For example, the vitamin antioxidants in general are excellent in neutralizing a number of reactive oxygen species, but have little activity against lipid peroxidation products (acrolein and 4-hydroxynonenal) and reactive nitrogen species (RNS).[264
] As a result, one would not expect a study, which used one or even two antioxidant vitamins to have much impact on diseases associated with high levels of RNS and lipid peroxidation products. For example, in chronic traumatic encephalopathy, TBI, strokes and the major neurodegenerative disorders one sees very high levels of reactive nitrogen species (peroxynitrite) and 4 hydroxynonenal/acrolein, which many consider to be the major damaging radicals.[261
I have also found that many of those doing these clinical studies do not understand the functional particulars of the antioxidant network. In biological systems, we see an array of antioxidant systems, which interact to not only protect against a wide variety of reactive species, but also to prevent oxidation of the antioxidant molecules themselves. For instance, in a condition where one sees very high levels of oxidative stress, as for example, in Alzheimer's disease, supplementing with a single vitamin such as vitamin E will not only have little chance of success, but can potentially make things worse. This is because the vitamin E is eventually oxidized itself, and becomes a free radical.[262
] The same occurs with the carotenoids and vitamin C. The flavonoids and the thiols (R-lipoid acid) play a major role in protecting the antioxidant vitamins from oxidation. The lesson is, one cannot treat nutraceuticals the same way one treats pharmaceuticals—they are not drugs. There is considerable essential synergism between many nutraceuticals and one must keep in mind that they function as a network.
One must also keep in mind that for over 20 years clinical trial studies suggested that a higher intake of omega-3 oils had no real impact on cardiovascular mortality. Today, most cardiologists accept that it has a tremendous beneficial effect. One problem in the early studies was the fact they were not using a true placebo to compare results. Placebos are supposed to be inert physiologically. Many of these negative studies used olive oil as a placebo, which also has beneficial cardiovascular effects, making the studies invalid. Many placebos used in clinical research today are also not inert. As pointed out by critics, in a great number of clinical trials the placebo is not even named, making it impossible to evaluate the reliability of the study. In many of the clinical studies quoted by the authors, the papers never consider the effect of different intakes of flavonoid-containing foods on the outcome. If, for example, more people in the placebo group were eating a high flavonoid diet it will reduce the observed effect of the supplement in question. We have seen this bias in a great number of cancer-diet population studies.
This paper clearly demonstrates the beneficial effects of a number of nutraceuticals in animal models of human disease. One of the major puzzles is why do these substances work so well in animal models but not in clinical studies. Besides the factors discussed above, one must consider species differences in metabolism, absorption and tissue bioavailability and differences in the clinical aspects of the animal models. For example, many animal models will develop the pathological picture of human Alzheimer's disease, but not the clinical aspects—that is, the actual dementia. Yet, when animal models utilizing many different species are showing the same beneficial effects, they cannot be ignored. In addition, the animal's diet is carefully controlled in the study of disease models, but not in human trials, despite attempts to do so.
A number of clinical studies have shown that hospitalized patients have a high incidence of nutritional impairment, either as a full-blown clinical deficiency or subclinical deficiency at the time of admission and that in ICU patients this deficiency increases significantly during the hospital stay. A number of studies have also shown that nutritional supplementation during hospitalization reduces complications and length of the hospital stay. This cannot be ignored. The review by the authors did not include a number of clinical studies that did show a significant impact of using selected nutraceuticals on neurological disease prevention and outcomes.
Finally, we must face the growing recognition that sponsoring industries, primarily pharmaceutical manufacturers, are instilling a bias in a number of high impact clinical studies so as to favor company interest. It is recognized by both clinicians and pharmaceutical executives that clinical trials are powerful tools that can shape the practice of medicine. Increasingly, these companies have witnessed an encroachment on their profits by the use of nutraceutical by an increasing percentage of the population. By using biased clinical trials to lessen interest in the use of these nutraceutical, they can avoid a loss of profits. While an increasing number of the major clinical journals have disclosure policies, few actually contain printed conflict disclosures in conjunction with the published article. In most cases disclosure is voluntary.
Overall, this study has been excellently presented and clearly shows the potential benefits of nutraceuticals in the prevention and treatment of neurological disorders. I feel that all practicing neurosurgeons and neurologists should read and study this important paper.