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In the 1992 film, Lorenzo’s Oil, we see the story of Augusto and Michaela Odone, who defied the medical opinions of the time and sought out a treatment for their son Lorenzo’s adrenoleukodystrophy. The notion that a diet could affect a severe neurological disorder was met with skepticism, but the loving parents persisted and finally found what they were looking for.

It is a compelling story, but the reality is more complex. After a few decades of research, we are still left with uncertainty. The diet does prevent the build up of very long chain fatty acids (VLCFA) in the blood, but not in the brain. The evidence does suggest that if the diet is started in asymptomatic individuals with X-linked ALD (but not other disorders) it may delay progression to symptoms. However, once symptoms have started it does not alter the progression of the disease.

We are still at the stage where reviews conclude:

In conclusion, although additional controlled, large, and long-lasting studies are needed to confirm it, Lorenzo’s oil could be effective in preventing neurological manifestations in asymptomatic patients with X-ALD.

Ironically, Lorenzo had significant clinical progression prior to having the special oil (a combination of a 4:1 mix of oleic acid and erucic acid) added to his diet. So while the evidence shows the oil might work in asymptomatic patients, it also shows that it does not work in patients like Lorenzo.

Keto diet for seizures and migraines

Another dietary intervention claimed to be effective for neurological disorders is the ketogenic diet, and again the story is complicated and the evidence short of definitive.

Prior to modern medical treatment, all sorts of interventions were used for patients with epilepsy. Dietary restrictions go back to 500 BCE. The ketogenic diet specifically became popular in the 1920s, but then was largely replaced by modern antiepileptic drugs. In the last 20 years, however, it has seen a resurgence in popularity. So with almost a century of use, where does the evidence stand?

A ketogenic diet is essentially one that is low enough in carbohydrates that the brain becomes starved of glucose. This triggers the production of ketones, which is an alternate fuel source. This results in a host of metabolic changes. It is therefore plausible that there is a real physiological effect from such an extreme diet. But this cuts both ways – there is also the potential for negative effects.

At this point we are still not sure what the potential mechanism is. The production of ketones has been shown to affect the activity of neurotransmitters, which is a plausible mechanism. It also alters antioxidant activity and inflammation in the brain. There are countless studies showing effects on various physiological markers, but nothing tying a specific mechanism to any apparent clinical effect.

The clinical evidence, after almost a century of use, is surprisingly unclear. A 2018 Cochrane review of the ketogenic diet for refractory epilepsy concludes:

The RCTs discussed in this review show promising results for the use of KDs in epilepsy. However, the limited number of studies, small sample sizes and the limited studies in adults, resulted in a low to very low overall quality of evidence.

Most reviews are still concluding that more and better studies are needed. Why is this? Part of the problem is that these studies are hard to do. Subjects need to be placed on an extreme diet, something which is hard to blind and has overall poor compliance. Studies also need to be long term, at least a year if not longer. This is because the effect may take time to occur, may not last, and side effects may start to appear over time.

Studies are plagued by a high drop-out rate, often for lack of benefit. This hugely biases the outcome of studies. But in addition, the high drop-out occurs in clinical practice as well. When a doctor places their own patients on the diet, those who see an apparent benefit are more likely to stick with it. This is a setup for confirmation bias, which might explain why many clinicians are more confident in the treatment than the clinical studies warrant.

I should also point out that the evidence supports effectiveness in children with refractory epilepsy, but not in adults. The reason for this difference is unknown, but it is plausibly due to the different causes of epilepsy between childhood and adult onset.

The side effects of a ketogenic diet are also non-trivial, including gastrointestinal symptoms, increased cholesterol, and long term cardiovascular effects. However, there haven’t been enough long-term studies to really know what the risks are.

So if we do a risk-benefit analysis for the ketogenic diet in childhood refractory epilepsy the result is complex and plagued by unknowns. The diet itself it difficult to adhere to and can have a significant negative impact on quality of life, with significant side effects and some unknown long term risks. There seems to be a benefit in terms of reduction in seizure frequency for some patients, but we still need better quality studies to confirm this.

Because, however, refractory epilepsy is a severe problem that can have a devastating effect on quality of life, many clinicians think it is worth a trial in appropriate patients (the risk is high, but the potential benefit is also high). But clearly the time is ripe for a definitive high quality clinical trial to reduce the uncertainty about this century-old treatment.

What about the ketogenic diet for migraines? Everything I said above about plausibility and side effects applies. The clinical evidence for efficacy is even more preliminary. It consists mainly of case reports and open-label case series. There are no high quality double-blind studies.

The risk-benefit for migraines, in my opinion, is not worth it. What this means is that I would not recommend this intervention outside of an approved clinical trial. I also have concerns about the long-term effects of a ketogenic diet, which have not been adequately studied. Migraines, like seizures, are a chronic condition. We may need to treat patients for decades. That is a major life commitment for an intervention like the ketogenic diet.

There is evidence that milder diets, like the modified Atkin’s diet (MAD) has similar efficacy to the keto diet with fewer side effects and better compliance. This is good, but equivalency to a questionable intervention does not resolve the question of efficacy, and arguably shows a lack of a dose-response effect which could reduce confidence in the treatment.

Further, there are newer migraine interventions coming online, like the recent CGRP antagonists, which are showing great efficacy. I would not recommend the diet until after seeing a headache specialist and exploring all of the established treatments.

The story of dietary interventions for neurological disorders is an instructive one. First, we cannot be dismissive of interventions that seem implausible at first. Similarly, the pop-culture aspect of an intervention, like the keto diet, is not an argument in its favor, but should not cause serious scientists to dismiss it either.

Even more importantly, the controversy over the keto diet shows how important rigorous clinical trials are. We can debate endlessly about the potential risks and benefits of the keto diet, with patients stuck in the middle trying to decide if they should turn their life upside down with an extreme diet, but one that might dramatically improve their lives. The stakes are pretty high for patients.

Unfortunately, the “just try it” approach does not work. It may seem counterintuitive, but the vagaries of chance and the systematic deception of cognitive biases means that unblinded trials are not likely to produce a definitive answer, even for an individual. That last thing you want is for a patient to be convinced that an expensive, difficult, or risky intervention works because of placebo effects, when in fact it is not really helping them. Then they are trapped with a very costly placebo.

We need to know with a higher degree of confidence what the risks and benefits of this intervention are. That requires high quality clinical trials.

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Posted by Steven Novella

Founder and currently Executive Editor of Science-Based Medicine Steven Novella, MD is an academic clinical neurologist at the Yale University School of Medicine. He is also the host and producer of the popular weekly science podcast, The Skeptics’ Guide to the Universe, and the author of the NeuroLogicaBlog, a daily blog that covers news and issues in neuroscience, but also general science, scientific skepticism, philosophy of science, critical thinking, and the intersection of science with the media and society. Dr. Novella also has produced two courses with The Great Courses, and published a book on critical thinking - also called The Skeptics Guide to the Universe.