Epilepsy is a chronic brain disorder that is characterized by recurrent seizures, which are short episodes of involuntary movement that can affect part or all of the body, sometimes accompanied by loss of consciousness and control of bladder or bowel function. Epilepsy is defined as the occurrence of 2 or more unprovoked seizures. A common type of epilepsy affecting 6 in 10 people is idiopathic epilepsy, which means that in over 50% of global cases, the cause of the disease is not identified.

Epilepsy of known cause is called secondary or symptomatic epilepsy. Causes of secondary or symptomatic epilepsy are: brain tumors, stroke, brain infection and severe head injury, congenital abnormalities associated with brain defects, brain damage as a result of prenatal or perinatal injuries, and certain genetic syndromes. About 50–70 million people worldwide suffer from epilepsy. It is estimated that 2.4–4.6 million people worldwide are diagnosed with epilepsy each year.

These global load estimates are falling more on the populations of low- and middle-income countries, where the cumulative estimate of annual incidence of epilepsy is much higher (139 per100,000 people) than in high-income countries (49 per 100,000 people). Regardless of the country’s income, the public health burden of epilepsy carries a high risk of disability, economic loss, social isolation, and premature death. Epilepsy is a serious and costly health problem worldwide and includes estimated indirect and direct costs annually of around EUR 15.5 billion in Europe and USD 15.5 billion in the United States.

In this regard, the World Health Organization has made this a priority, calling for the development of national healthcare plans for the treatment of epilepsy, not only to ensure the availability of effective care, but also to prevent its causes. Almost 80–90% of people diagnosed with epilepsy live in low- and middle-income countries. Recent studies in low-, middle-, and high-income countries have shown that up to 70% of adults and children with epilepsy can be successfully treated with antiepileptic drugs.

Classic Epilepsy Therapy

Classic epilepsy treatment includes pharmacological and surgical therapy or vagus nerve stimulation. Despite these therapies, approximately 30% of patients with epilepsy do not have sufficiently controlled seizures and become resistant to drugs. This is defined as insufficient seizure control, despite optimal therapy using a combination of two or more appropriately selected antiepileptic drugs.

Under these circumstances, adding next antiepileptic drug often does not significantly reduce seizures. Although epilepsy research is ongoing, the mechanisms of this disease have not been completely elucidated and fully effective therapy for all epilepsy patients has not yet been developed. Epilepsy is the highest research priority for many pharmaceutical companies, which makes epilepsy one of the most studied brain disease in the pharmaceutical industry, but despite such tremendous commitment, we are not seeing significant progress in developing new effective drugs.

Patients with drug-resistant epilepsy are addicted to informal care of family and friends as well as healthcare professionals such as social workers, neurologists, and psychologists. Problems associated with drug-resistant epilepsy in children, adolescents, and adults cause repeated hospitalizations of numerous patients. Living with uncontrolled epilepsy has a negative impact on the quality of life of patients with epilepsy and their caregivers.

Ketogenic Diet

A ketogenic diet should be considered for patients who have not responded adequately to therapy with two well-selected and well-dosed antiepileptic drugs. Therefore, neurologists often recommend other therapies, such as diet, including ketogenic diet, to provide patients with better antiepileptic control. The ketogenic diet is a last resort treatment for many children, adolescents, and adults with epilepsy resistant to routine medications.

It should be recognized that, despite the development of new antiepileptic drugs every year, the treatment, as already mentioned, in about one-third of patients with epilepsy is not fully effective. Ketogenic diet treatment is a non-pharmacological therapy used worldwide, especially for children with epilepsy that is difficult to control. Ketogenic diet has been used in patients with difficult-to-treat epilepsy since 1921, with minor changes in recent years.

The ketogenic diet assumes a very high-fat and low-carbohydrate diet, reducing carbohydrate to less as 10% of used energy. This restriction triggers a systemic shift from glucose metabolism toward the metabolism of fatty acids yielding ketone bodies, such as acetoacetate and β-hydroxybutyrate as substrates for energy. The ketogenic diet provides sufficient protein for growth and development.

A Brief History of Ketogenic Diet Treatment and Its Side Effects

In 1998, a multicenter study was conducted in 51 children with drug-resistant epilepsy. Forty-seven % of children remained on a diet for a year. Forty-three % of them were seizure-free, 39% controlled 50–90% of seizures, and 17% did not respond. Adverse reactions associated with the administration of a ketogenic diet were severe dehydration or acidosis, lethargy, somnolence, severe infections, mood swings, vomiting, and constipation.

The reasons for discontinuing treatment were intolerance, difficulties in maintaining a restrictive diet and inadequate seizure control. The authors thought that the decrease in seizures was unlikely to be a placebo effect. In the same year, a group from Johns Hopkins published a study conducted on 150 children aged 1–16 years.

One year after starting the ketogenic diet, 7% were without seizures, 27% of children had a decrease in seizure frequency >90% and 50% a seizure frequency reduction >50%. The authors noted that children which after a ketogenic diet had reduction in seizure frequency >50% during the first three months of treatment resulted in the gradual improvement during prolong therapy, but if no 50% seizure reduction was observed at that time, it was unlikely that improvement would occur in the following months.

Seventy children with drug resistant epilepsy were qualified for a retrospective long-term study at the University of São Paulo to assess the effectiveness and tolerability of the ketogenic diet. Within one year, in 55% of those who remained on the ketogenic diet, 70% had seizure control >75%, 25% had seizure control in the range of 50–75%, and 2.5% had seizure control <50%. The effectiveness of the ketogenic diet was significantly higher in cases of generalized epilepsy than partial epilepsy. About 10% of children discontinued their diet due to distaste, and 3.7% experienced vomiting and nausea.

Possible Anti-Seizure Mechanisms of the Ketogenic Diet

Although the anticonvulsant mechanisms of ketogenic diet are not still completely understood, it is believed that ketone bodies and polyunsaturated fatty acids presumably play a major role in the anticonvulsant effect of ketogenic diet. During ketogenic diet treatment, body energy is generally generated by the oxidation of fatty acids in mitochondria, resulting in the production of large amounts of acetyl-CoA. Accumulation of acetyl-CoA leads to the synthesis of two ketone bodies mainly in the liver, acetoacetate, and β-hydroxybutyrate, which then enter the blood circulation.

Ketone bodies are then used as an alternative source of energy in the brain instead of glucose. After entering the brain, the ketone bodies are transformed into acetyl-CoA and then enter the tricarboxylic acid cycle in the mitochondria of the brain, which ultimately leads to the production of adenosine triphosphate (ATP). Reduction of neuronal excitability is the most important role of GABA in the brain and therefore GABA plays a key role in the initiation and spread of seizure activity in the brain.

It has been observed that ketogenic diet can lead to glutamic acid decarboxylase activation, which induces GABA synthesis. It has also been shown that this diet can alter GABA transaminase activity that inhibits GABA degradation. Increasing energy metabolism through a ketogenic diet can compensate for the metabolic and transient failure of GABAergic inhibition, the lack of which will not prevent the occurrence and spread of seizures.

Ketogenic Diet and Gut Microbiota: Friends or Foes?

Dysbiosis may be involved in the drug-resistant epilepsy mechanism, and restoration of intestinal microbes may be a new therapeutic method in drug-resistant epilepsy. People with drug-resistant epilepsy show altered intestinal microflora. Numerous rare flora increases in patients with drug-resistant epilepsy. Then Hampton suggested that the antiepileptic effect of the ketogenic diet could be attributed to intestinal microbes.

The mechanisms by which the ketogenic diet exerts an anticonvulsant effect are likely to be numerous and may vary in different types of epilepsy. Recent articles describe a new mechanism for ketogenic diet to prevent seizures by changing gut microbiota in animals and humans. To date, very few studies have focused on the role of gut microbiota in the treatment of epilepsy using a ketogenic diet.

Presented very interesting research on gut microbiota-dependent anticonvulsant properties of the ketogenic diet in which two mouse models of refractory epilepsy were used, demonstrating the relationship between the ketogenic diet and gut microbiota to obtain a therapeutic effect. Diet significantly increases the relative abundance of Akkermansia muciniphila, from 2.8% to 36.3% during 4 and 14 days of dietary treatment.

 

Author: Marzena Ułamek-Kozioł, Stanislaw Czuczwar, Sławomir Januszewski, Ryszard Pluta

 

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