High Fat Diet May Prevent Sudden Death in Epilepsy

[dropcap]T[/dropcap]he human brain consists of highly complex circuitry which is wired to elicit a synchronous pattern of electrical signals. This allows for communication between differing regions of the brain. When this electrical activity is disrupted, neurons begin to fire in a hypersynchronous fashion, which can result in a seizure. 

And for nearly half a century, researchers have been struggling to develop a drug that is effective at halting seizure activity in all epilepsy cases. Seizures are highly unpredictable and, if left uncontrolled, can be detrimental. In fact, epilepsy patients are around 24 times more likely to die from unknown reasons than the general population. Poorly controlled seizures can lead to Sudden Unexpected Death in Epilepsy (SUDEP), occurring in 0.66% of people with uncontrolled epilepsy each year. With around one third of epilepsy sufferers being unable to control their seizure activity through anti-seizure drugs, there is high demand for alternative therapeutic options to the drugs currently offered.

Recent research shows that a diet high in fat but low in carbohydrates called the ‘ketogenic diet’ may be beneficial for patients unresponsive to anti-seizure drugs. Prior research demonstrated that the ketogenic diet can reduce seizure frequency by a minimum of 50% in two thirds of untreatable epilepsy patients with 13% of patients amazingly remaining seizure free. The ketogenic diet causes the body to engage in ketosis, an alternate metabolic pathway to glycogenesis and lipogenesis that usually occurs during fasting. Both glycogenesis and lipogenesis use glucose as an energy source, whereas ketosis occurs when there are limited glucose supplies. This causes the body to burn fat and produce molecules called ketones, which are used as an energy source to fuel the heart, muscles and brain. Epilepsy patients on the ketogenic diet often incorporate high fat foods such as avocado, butter, and salmon into their diet. These have been shown to boost the amount of ketones in your body.

Researchers in the U.S produced a mouse model of SUDEP, characterized by the lack of the ion channel Kcna1, a potassium voltage-gated channel. Mutations of these ion channels have been linked with epilepsy in humans and interestingly, familial epilepsy patients with a loss-of-function (LOF) mutation in the KCNA1 gene were susceptible to seizures. The mutation results in a slower inactivation of the potassium channels leading to enhanced excitability and therefore seizure susceptibility. To further understand the role of this LOF mutation, the mouse model developed was trialled on the ketogenic diet. The mice were treated with a dietary ratio of 1 part carbohydrates and proteins, 6.3 parts fat. In fact, these mice showed delays in seizure progression with age, as well as a lifespan increase by 47%, compared with controls. These results were particularly impressive as many unexpected deaths in epilepsy show progressed seizure activity and severity with age, which ultimately result in death. By treating these patients with the ketogenic diet, there is a possibility to delay the disease progression and increase life expectancy.

The Emory research team in Georgia have found that ketones may work to control seizure activity by stabilizing neuronal activity. The anticonvulsant effects of the ketone diet in rats was seen after 3 weeks of being on the diet, which resulted in a change in gene expression. In particular, genes involved in energy metabolism were up-regulated in the hippocampus of rats. Additionally, an increased number of mitochondria were also found in the hippocampus. Mitochondria are the central hub for producing ATP, which is the main source of energy production in the body. This data suggests that the ketone diet increased energy production and enhanced metabolism in the brain via alternative energy stores. The team also found that synaptic transmission in hippocampal slices were resistant to low glucose levels in the ketogenic fed rats. It has been hypothesised that limited glucose can result in activation of potassium channels and thus trigger hyperpolarisation of neurons. Therefore, increased energy stores produced by ketosis could counteract the effects of limited glucose and essentially stabilize neuronal firing.

Early research concerning the mechanism by which the ketogenic diet works suggest that an increase in the inhibitory chemical neurotransmitter, GABA, produces the anticonvulsant effects. In addition, other studies show that there is a decrease in the excitatory neurotransmitter glutamate. A reduction in the build-up of glutamate could prevent the excessive excitement of neurons and therefore reduce the risk of triggering a seizure. It has been hypothesized that the increased energy production by mitochondria results in an increase in the conversion of glutamate to glutamine in astrocytes and therefore reduces glutamate release. This increased metabolism also results in more efficient conversion of glutamine to GABA, therefore resulting in a clearance of excitatory glutamate transmitter and an increase in inhibitory GABA transmitter. However, more research is required to divulge the secrets of the diet’s medical properties.

The ketogenic dietary approach has also been shown to be protective against other neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, ALS (also known as motor neuron disease) and even cancer, albeit in the early stages of research. However, the diet has not been proven to be effective in all cases of untreatable epilepsy and although it is a recognized alternative to drugs, it is not 100% effective. Nevertheless, research into alternative therapies such as the ketogenic diet, the medium-chain triglyceride (MCT) diet and the modified Atkins diet have shown some promising results for people suffering with epilepsy, and will no doubt benefit the lives of many.

References

Brenner, R and Wilcox, K. 2012. Potassium Channelopathies of Epilepsy. Jasper’s Basic Mechanisms of the Epilepsies. 4th Edition.

Bough, KJ et al. 2006. Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. Annals of Neurology. 60 (2), pp. 223–235.

Felton,E et al. 2015. Dietary therapy is the best option for refractory nonsurgical epilepsy. Epilepsia. 56(9), pp. 1325–1329.

Simeone, K et al. 2016. Ketogenic diet treatment increases longevity in Kcna1-null mice, a model of sudden unexpected death in epilepsy. Epilepsia. 57 (8), pp. e178–e182.

Yudkoff, M et al. 2008. Ketosis and Brain Handling of Glutamate, Glutamine and GABA. Epilepsia. 49 (8), pp. 73-75.