The initial reason I decided to look at ketones in the treatment of epilepsy, is because of the long history of use and more recently, significant research confirming the benefits of ketosis on seizure control. This is not to suggest that a ketogenic diet is superior to medication for seizure control or that its for everyone. The purpose of this review is to provide interested readers with some background as to the history and development of the ketogenic diet. Furthermore, we’ll be dissecting through the available information and important trials performed over the past 50 years. As a large number of trials (most of low quality) can be found when searching the literature, we’ll be concentrating our efforts on larger, more definitive studies of good quality. We’ll also mention some of the less recognized research to provide the reader with an over-all picture. Please remember that because of the large number of studies published, some might be missed but please don’t panic. References and review papers will be included at the end for those interested in more in-depth analysis.
Let me say right from the start, that although modern literature has addressed many aspects of ketone supplementation in epilepsy, a large number of questions around the diets still remain. The result is that the reader might find that this review leads to more questions then answers. Our intention is not to provide answers to all the unknowns but to stimulate more discussions/research in this area to try to improve our understanding of the origins and management of this complex disease.
EPILEPSY AND SEIZURES. WHAT IS IT?
The following definition can be found on the International League Against Epilepsy webpage; “Seizures and epilepsy are not the same. An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. Epilepsy is a disease characterized by an enduring predisposition to generate epileptic seizures and by the neurobiological, cognitive, psychological, and social consequences of this condition. Translation: a seizure is an event and epilepsy is the disease involving recurrent unprovoked seizures.”
The burden of disease is massive with an estimated 50 million people affected by epilepsy globally. Between 1980 – 2017, an estimated 130 000 deaths globally were attributed to epilepsy (https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)32203-7). Around 30% of patients are considered to have refractory epilepsy. Although definitions differ, this implies that treatment fails to achieve seizure freedom for 12 months or more.
Epilepsy is an extremely complex disease with many causes and clinical patterns (usually diagnosed on EEG – see below). Seizures can occur as a result of epilepsy, but other causes exist as well. For example, encephalitis may present with seizures but not lead to lifelong epilepsy. The mechanisms are complex and poorly understood. Chronic treatment, when deemed necessary, involves the use of one or more drugs which suppress seizure activity in a number of ways.
Human EEG with prominent resting state activity – alpha-rhythm. Left: EEG traces (horizontal – time in seconds; vertical – amplitudes, scale 100 μV). Right: power spectra of shown signals (vertical lines – 10 and 20 Hz, scale is linear). Alpha-rhythm consists of sinusoidal-like waves with frequencies in 8–12 Hz range (11 Hz in this case) more prominent in posterior sites. Alpha range is red at power spectrum graph.
Epileptic spike and wave discharges (seizures) monitored with EEG
As it’s not our intention to provide detailed information regarding epilepsy, I draw the readers attention to an excellent website maintained by the ILAE where they will find extensive information (https://www.ilae.org). We will instead concentrate on the research into nutritional aspects of seizure control.
KETONES AND EPILEPSY – HISTORICAL PERSPECTIVE
A little history never hurt anyone and provides for some interesting insights into the progression and development of the ketogenic diet (KD).
Epilepsy and seizures have been recognized for a long time (although for much of recorded history was considered to reflect some sort of demonic possession of the body). One of the first recorded references to epilepsy can be found in the ancient Greek writings of Hippocrates (On the Sacred Disease). Because of the demon stigma related to epilepsy, many suffers were ostracized from their communities and left to fend for themselves in the wilderness. Ironically, this often led to a decrease in seizure severity and frequency as sufferers were forced to source their own food, leading to inadequate food intake and starvation. https://en.wikipedia.org/wiki/Ketogenic_diet
Epilepsy was also referred to in at least 3 Gospels; Matthew 17:14-18, Mark 9:14-29 and Luke 9:38-42. While all appear to describe some interpretation of the same story, only Matthew refers directly to the disease. The Gospels describe a father who brings his child suffering from epileptic seizures (presumed to be caused by demonic possession) to Jesus for healing. In Mark 9:29, Jesus suggests that praying and fasting was the cure for the child “This kind can come forth by nothing, but by prayer and fasting” This was later depicted in Raphael’s “The transfiguration”.
Fasting therapy for the treatment of epilepsy was formally adopted in 1911 by the French physician Guelpa. The endocrinologist Rawle Geyelin (1921) was the first to document cognitive improvements in patients adhering to a fasting regimen. Also, in 1921, Wilder (from the Mayo Clinic) and Woodyatt reported that fasting and a low carbohydrate (CHO)/high fat diet were found to increase ketone bodies in normal subjects and perhaps produce neurologic benefits in children. Wilder postulated that while it was not possible to continue starvation indefinitely, a diet with excess fat and low CHO may produce similar effects. Subsequently, in 1925, Peterman (also from the Mayo Clinic) reported a ketone diet which is similar to the modern diet. And in 1928, Barborka reported on the efficacy of KD’s in treating epilepsy in adults and suggested that seizures were completely controlled or improved in 56 of 100 pts.
While extensively utilized during the 1920’s and 30’s, the KD fell out of favour with the advent of the first effective drug treatment for epilepsy, called phenytoin (Dilantin) in 1938. Although much diminished, a number of centres including Johns Hopkins Hospital continued to research and promote the diet, culminating in the textbook by Livingston (1972) in which he reported the outcomes of over 1000 children on KD that he had followed over the prior decades. He reported that 52% had complete control of seizures and 27% demonstrated an improvement. And subsequently, in the late 1990’s, a TV program called Dateline presented the true story of a 2-year-old boy named Charlie who suffered from intractable seizures and was placed on a KD by John Freeman at Johns Hopkins. The child rapidly became seizure free and his father formed the Charlie Foundation with the aim of promoting KD awareness in the general population. In 1997 a film starring Merryl Streep called “First do no harm” was produced and brought the KD concept to mainstream public attention. The final strong evidence supporting the use of KD in epilepsy came from 2 trials in 1998 and 2008 by Freeman and Neal respectively (These will be discussed on more detail later). KD had finally entered mainstream treatment of epilepsy.
Ketogenic diet – so how does it work?
Good question. The answer is – no one really knows. However, there are a lot of theories as we shall see.
Although in-vivo studies (in-vivo means “taking place in living organisms”) have confirmed the anti-convulsant effects of the KD, the actual mechanisms by which KD improves seizure control in patients with epilepsy are poorly understood. This is not surprising as the basic science looking into epilepsy is evolving quickly but is far from complete. We’ll discuss a few but not in detail. (I will provide further references at the end for the interested reader)
Aside – it should be noted that most of the work on ketones (including some of the stuff I’ll be dealing with here) is based on animal research, largely rodents etc. Whether or not the results from animal studies are translatable into humans is controversial and a discussion for another time.
Many theories have been presented as to the mechanism by which KD exerts its anti-epileptic actions. Some early theories focused on concepts of acidosis and dehydration with increasing ketone body (KB) concentration. More recently, interest has turned to the interactions between KB’s and varies neurotransmitters and their receptors including GABA (gamma aminobutyric acid – an inhibitory neurotransmitter) and glutamate (the most abundant excitatory neurotransmitter), changes in neuronal membrane potentials (the electrical gradient across cellular membranes), ion channels, biogenic monoamines (eg. noradrenaline and serotonin) and various neuroprotective properties.
And that’s all I’m going to say about that. Next, lets talk a bit more about the clinically relevant and practical stuff ……
Although KDs contain many different fats (with decrease carbohydrate concentrations) it would appear that the effects are not diet specific. Any diet that increases ketones or reduces blood glucose may have anti-convulsant effects. There is some evidence that fat ratios of > 3:1 and increased caloric restriction improve seizure control but this is based on older rat experiments. The caloric restriction appears to be important in its own right and needs to be considered when designing a KD. For example, if the diet contains too much protein, this can be used by the body (called gluconeogenesis) for synthesis of CHO and may limit the beneficial effects of the KD.
It would also appear that once started on the KD, it takes time to reach maximum effect. Readers may recall that ketones are transported across the blood brain barrier (BBB) by a carrier molecule and it takes time to upregulate this process. As such, maximum effect is usually seen after 1-2 weeks on KD. Once reaching steady state, the percentage of brain to plasma beta-hydroxybutyrate (BHB) remains around 26%. Interestingly, the anti-seizure properties of KD can been seen for some time after ceasing the diet. The reasons for this are not clear. Other interesting observations include the lack of correlation between BHB concentrations and seizure control and the fact that children seem to benefit more than adults (although there is some controversy over this). And lastly, it is not clear whether all KB’s have the same anti-convulsant effects. Animal experiments suggest that acetoacetate (AcAc) or acetone may be more effective then BHB although whether this is the case in humans is not known.
Can glucose restriction alone produce anti-seizure effects?
As has been previously mentioned, caloric restriction on its own may suffice to control seizures. This was originally noted in the early starvation studies and may result from a decrease in cerebral energy supply limiting the ability of neurons to reach the high levels of synaptic activity required for seizures to occur. Glucose concentrations are noted to decrease during KD as well and its thought that this may be responsible for some of the beneficial effects. ATP sensitive potassium channel activity may also be suppressed in low glucose states further suppressing the potential for seizures, however the mechanisms are poorly understood.
Are all fats equal?
Polyunsaturated fatty acids or PUFA’s seem to play a role. Certainly, KD leads to increased concentrations of specific PUFA’s, amino acids and docosahexaenoic acid (an omega-3 fatty acid). PUFA’s have been shown to decrease neuronal excitability in the hippocampus and supplementing KD with PUFA’s provides further seizure control. How this increase in cerebral energy supply improves seizure control is not known. Theoretically, the resulting enhanced activity of the neuronal Na/K ATPase pump may limit hyper-excitability of neuronal cells and increase resistance to seizures.
What about cell signalling?
There is evidence (in rats anyway) that KB may alter neurotransmitter signalling in the brain. Certainly, there appears to be an increase in noradrenaline signalling in brain associated with KB’s. Furthermore, as previously mentioned, effects on GABA might play a role. KD appears to be most effective in seizures induce by GABAnergic antagonists (ie. blocking GABA). KD may increase GABAenrgic activity leading to improved seizure control,
So what exactly is a Ketogenic diet anyway?
I thought we’d introduce the basics of ketogenic diet and the various alternatives now. There will be a more extensive discussion later.
The original KD as described in 1921 by Wilder and Peterman from the Mayo Clinic consisted of;
1g protein per kg body weight (in children), 10-15g CHO per kg and the rest fats. This diet has been modified over the years and is currently divided into several broad approaches. As previously discussed, it’s not clear whether the alternative diets effect the degree of seizure control.
1. Classic 4:1 diet – this consists of 4:1 ratio of fats to protein/CHO.
a. 2 approaches can be used to initiate feed
i. 12-48 hours fasting followed by 4:1 diet
ii. Weekly increase in ketogenic ratio – begin 1:1 and slowly increase to 4:1
b. Supplementation with minerals and vitamins is necessary
2. MAD – modified Atkins diet –this was developed to improve tolerability
a. Consists of 1:1 ratio fat:protein/CHO with 65% fat, 25% protein and 10% CHO
b. Fat encouraged and CHO limited to 10-20g/d in children and 15-20g/d in adults
c. Vitamin and calcium supplementation recommended
d. Likely as effective as classic KD especially if lower CHO used initially
3. LGI - Low-Glycemic Index diet – first reported in 2005
a. Consists of 0.6:1 fat:protein/CHO with 60% fat, 30% protein and 10% CHO
b. Low GI index (GI < 50)
c. Compared with KD – less ketone bodies but better tolerability with similar efficacy
d. No good quality studies
Aside: The Glycemic Index (GI) is a relative ranking of carbohydrate in foods according to how they affect blood glucose levels. Carbohydrates with a low GI value (55 or less) are more slowly digested, absorbed and metabolised and cause a lower and slower rise in blood glucose and, therefore usually, insulin levels.
Ok but what of these side effects I’ve been hearing so much about?
Some side effects are common and occur early such as dehydration, hypoglycaemia, lethargy and GI symptoms. Others are less common and present following prolonged use, including growth retardation (children), loss of weight, nutrient deficiency, decreased bone density, hepatic failure, and immune dysfunction. Freeman has reported a significant rise in mean blood cholesterol to over 250 mg/dl following prolonged intake a of ketogenic diet (reverting to baseline upon ceasing diet). This in turn may be atherogenic, leading to lipid deposition in blood vessels. In addition, there are reports of dilated cardiomyopathy in patients on the ketogenic diet, possibly as a consequence of the toxic effects of elevated plasma free fatty acids. Finally, an increased incidence in nephrolithiasis (kidney stones) in patients on the ketogenic diet as well as increases in serum uric acid secondary have been reported.
The MAD and LGI diets seem to be better tolerated with GI complaints, loss of weight and dyslipidaemia being the main problems with MAD and constipation and vomiting with LGI.
It should be noted that most of the literature relates to side effects in children. Less is known about the long-term side effects in adults.
Well this all sounds great but is there any hard evidence that the KD is beneficial?
In order to answer this question, we’ll have to delve a little into the published studies on the KD. Don’t panic. We’ll keep it as simple as we can, and I’ll try to point out whether the evidence is significant or not.
The Freeman study
Up until recently, the evidence supporting the use of KD in epilepsy was limited to individual reports and opinions. The first well designed large study was by Dr John Freeman from John’s Hopkins published in 1998. Freeman and colleagues had the goal of determining the effectiveness and tolerability of the KD in children with refractory epilepsy (Refractory was defined as 2 or more seizures per week on at least two anticonvulsant medication). Children ages 1-16 years of age with a wide range of seizure types were included and fasted prior to starting 4:1 or 3:1 KD diet. 150 consecutive children were included in the study. The results were impressive. After 6 months, 71% remained on diet and 32% had > 90% reduction in seizures. At 1 year, 55% remain on diet and 27% had > 90% reduction in seizures.
Most children who discontinued the diet did so because it was either too restrictive or ineffective. Main side effects included kidney stones (4 children) and vomiting/acidosis (5 children). The authors concluded that the diet was more effective than the new anticonvulsant medications and was tolerated well when effective (Freeman 1998 – see references below).
My take on this:
Although ground breaking, the Freeman study did not compare KD treatment with no treatment (or placebo) and was therefore potentially subject to what is known as bias. The gold standard for this sort of intervention is what is called a randomized controlled study. In other words, two groups are compared, one receiving KD and the other not and the participants are randomly placed in each group. This is thought to limit the potential bias that can occur in non-randomized studies and provide better evidence of efficacy (or not).
The first (and not quite only) RCT
The first of the RCT’s was performed by Elizabeth Neal from the Institute of Child Health in London England. She randomized 145 children (a reasonably small group of pts) between the ages of 2 – 16 with daily seizures and > 2 anti-epileptic medication to receive a KD immediately (intervention group) or after 3 months with no other changes to treatment during this period (control group). 54 pts on KD and 49 in control group completed the study (3 months). At the end, pts on KD 75% patients had a decrease in number of seizures, 38% had > 50% reduction and 7% had > 90% reduction.
Things to note from the study;
wide range of seizure types were included
no pre-starvation
both classical 2:1 to 4:1 diets were include. Patients were also randomized to receive medium chain triglycerides (MCT) as part of the fat component
no difference in efficacy/side effects of classical versus MCT diet. This was demonstrated in another publication in 2009 by Neal
high number of non-starters and withdrawals
main side effects were related to GI tract including vomiting, constipation, lack of energy and hunger
My take on this:
There was both a clinically and statistically significant difference compared to control group. Although a relatively small study, it is the first to provide high level evidence of the efficacy of KD.
Aside – when analysing a study, it’s always important to consider whether the difference in outcomes is clinically as well as statistically significant. Many times, in large studies, results may be statistically significant (based on predetermined statistical outcome measures) but the benefit so small as to be clinically unimportant.
Some general comments about the use of the KD;
traditionally KD was used in treatment of metabolic disorders such as GLUT-1 deficiency syndrome or pyruvate dehydrogenase deficiency. As such, it is also contraindicated in a number of metabolic disorders which may or may not be associated with seizures and it is important to identify these individuals as they should not receive the KD
the relationship between plasma ketone concentration and seizure control is not clear ie. Higher concentrations don’t necessarily improve epilepsy control
doesn’t seem to matter how the diet is initiated; gradually or after starvation, or the exact ratio of fats to protein/CHO. MCT seems to be equally as effective (see below)
most would suggest continuing for at least 3-6 months to receive maximal benefit.
The positive effects seem to continue after ceasing but reasons aren’t clear
What about the MCT diet?
The MCT diet was introduced in 1971. Traditionally the classical diets provide fats in the form of long chain triglycerides (LCT). However, this diet can be very restrictive and unpalatable and as such, is often not tolerated for more than a few weeks. The MCT diet is more ketogenic requiring less fat and therefore less restrictive. It is achieved by adding MCT oil to the KD. MCT yields more ketones per kilocalorie of energy, is absorbed more efficiently and is carried directly to the liver. Other than significant GI symptoms, it is well tolerated and has been demonstrated to have a similar efficacy to the classical diet in terms of seizure control. Often combined with LCT to improve GI tolerability.
Aside - Interestingly, the 2009 paper by Neal on MCT reported BHB concentrations of > 4 mmol/l on average after 12 months. This is impressive as normal post prandial BHB is < 0.1 mmol/l and demonstrates the significant ketogenic potential of the diet.
The Modified Atkins Diet – just a fad? (MAD)
Evidence for the use of MAD is limited to small studies where MAD has had similar efficacy to KD but is more palatable. Only two small RCT’s comparing KD to MAD have been completed. The first by Kim et al (104 children) found similar results comparing the two diets except in children under 2 years of age where KD was more effective. In another small study consisting of 102 children randomized to either MAD or no dietary intervention, there was a significant reduction in seizure reported in MAD group with a mean frequency at 3 months of 59 in MAD vs 96 in control group.
Interestingly, MAD diet appears more effective if CHO component is limited to 10g/d for first 3 months and then increased to 20 g/d.
MAD in adults will be reviewed later
LGIT – does it work?
Few studies around, mainly observational in nature. Reports of up to 50% patients have a > 90% reduction in seizures but very controversial with limited data. Kim et al reported on 36 pts with a range of seizure types. They noted that 56% had a > 50% reduction in seizures although none became seizure free. They suggested that while LGIT may be a useful alternative to KD in patients unable to tolerate the restrictive diet, KD is likely more effective.
KD in adults- is an adult just a large child?
So, it seems that the KD in children is an effective means of improving seizure control, but what about adults. Are they just large children physiologically and do they respond in a similar fashion?
The evidence for the use of KD in adults with epilepsy is much less rigorous then in children. Furthermore, there is some evidence that adults are more resistant to becoming ketotic although this may not be the case.
In 2015 Ye et al produce a meta-analysis (a statistical procedure for combining data from multiple studies in order to draw outcome conclusions) where they combined 12 studies and evaluated data from 270 pts. 168 pts were on KD, 87 on MAD and 15 on MCT. They found a combined efficacy of 42% and compliance of 45%. They noted that KD seemed more effective then MAD, but that MAD was better tolerated.
Payne et al in 2011 produced another review where they examined case reports and case series. They concluded that KD and its variants may be effective in approximately 50% of adolescents and adults with drug resistant epilepsy. However, the publications were generally small and of poor quality so making definite recommendations was difficult. Also, tolerability of diet was a problem.
In 2014 another review into published papers by Klein found that in studies they reviewed, 32% KD and 29% MAD had a > 50% reduction in seizures while only 9% KD and 5% MAD had > 90%. Although the benefits persist long term, they did not outlast the treatment. Overall compliance was poor. The most serious side effect was an increase in cholesterol, but this appears to reverse on ceasing diet.
The bottom line for KD in adults is that although there may be some benefit, better studies are necessary before firm recommendations can be made.
Status epilepticus (adults and children) – a brain emergency!
Status epilepticus (SE) is defined as (definitions may vary depending on publication) ‘prolonged seizures lasting longer than 5 mins (although some say 30 mins) or recurrent seizures without return to baseline between seizures’. SE is considered a medical emergency and can result in death or severe neurological damage if not dealt with in a timely manner. Management varies but may require patients to be heavily sedated and placed on a mechanical ventilator while anti-epileptic medication is administered. However, a small percentage of patients will not respond to standard therapies and alternative solutions have been sought including the use of ketones.
As you can imagine, the number of cases of refractory SE given KD is very limited. In adults, a review of 14 cases reported varying degrees of success. In the biggest case series of 10 patients with SE for a median length of 21.5 days and requiring a median of 7 antiepileptic medications, 90% pts achieved ketosis and all seizures ceased in these patients within 3 days.
Another small study of 15 patients received a KD for SE. Seizures ceased within 1 week in 73% patients. Overall, 67% patients were alive at 6 months. Again, the main side effect was hyperlipidaemia.
In children, Arya (2011) reported on 14 children with refractory SE who received KD. On average, the KD was administered after 13 days of seizures. EEG seizure resolution was achieved within 7 days in 71% patients. After 3 months, 4 patients remained seizure free and 3 had decreased seizure frequency.
Recently (Jan 2020), a consensus statement was published dealing with the use of parenteral (intravenous) ketogenic nutrition (KD-PN) strategies to induce ketosis in patients with SE. The statement referred to 35 case reports of patients treated with KD-PN who may have benefited and provides some recommendations for safe and effective use of this formulation based on expert opinions. This is a new and developing area so watch this space.
Summary and alternative sources of ketosis
It seems clear that the KD and its variants have a role to play in the management of epilepsy. Certainly, studies have demonstrated a clinical benefit following the initiation of the KD in patients with refractory epilepsy and it suggests that in the right setting and under proper supervision, the KD can be successfully administered. Also, it is evident that tolerability and side effects are the main barriers to more universal uptake of the technique.
As such, scientists are experimenting with a number of options for inducing ketosis. Dietary supplements such as Ketocal can be administered to supplement ketones. Other ketogenic formulations include ketone salts or ketone esters. Ketone esters (R,S-1,3-butanediol) have been researched since the 1950’s and may provide a more acceptable means of generating ketosis. A number of formulations are available including KetoneAid and HVMN ketone ester and are currently marketed as exercise supplements. At present no intravenous formulation exists, largely due to the significant cost of production.
I will go into more detail of the various options and ketogenic diets in subsequent sections.
For those of you interested, below is a table comparing the various diets – more to follow
REFERENCES
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