Epilepsy is a neurological disease affecting approximately 50 million people worldwide. It is characterized by recurrent seizures, which may manifest as involuntary movements (of a body part or the whole body), sometimes with loss of consciousness and loss of control of bowel or bladder function. Seizures are the result of excessive electrical discharges in a group of brain cells. These discharges can originate in different parts of the brain.
Epilepsy occurs mainly during childhood and old age and can express itself in different ways:
- focal seizures (arising in a specific part of the brain);
- myoclonic seizures (involuntary jerks of the limbs);
- atonic crises (sudden loss of postural tone with possible falls to the ground);
- absence seizures (momentary interruptions of consciousness);
- convulsive seizures.
Epilepsy is one of the oldest recognized conditions in the world, with written records dating back to 4000 BC. Fear, misunderstanding, discrimination, and social stigma have surrounded epilepsy for centuries. Individuals with epilepsy often experience discrimination, social isolation, and may experience difficulties finding employment or when at school.
Despite being an old recognized disease, efforts to manage it are still all directed at seizure control alone. Up to 70% of individuals with epilepsy can control seizures with currently available antiepileptic drugs. The remaining 30% do not respond to any drug therapy. For them, research is moving forward to discover new drugs. To treat epilepsy, there are not only drugs, but also curative and palliative surgery. And innovative therapies, such as gene therapies, are being investigated.
Surgery
Epilepsy surgery is the most effective strategy for seizure control in people with drug-resistant focal epilepsy, often also improving other aspects, such as behaviour, cognitive abilities, and quality of life. The Epilepsy Surgery Committee of LICE, the Italian League Against Epilepsy, has published the Diagnostic-Therapeutic Pathways (PDT) outlining the techniques and methodologies of pre-surgical study and surgical treatment of epilepsy.
Currently, there are three surgical approaches to treat drug-resistant epilepsies:
- ablations;
- disconnections;
- neuromodulation.
“Curative” surgery (ablations and disconnections) aims to stop seizures, while “palliative” surgery (neuromodulation) tends to reduce the severity and frequency of seizures by limiting or preventing the propagation of the electrical discharge, and to decrease neuronal excitability. The decision on which technique to use depends on the individual case and the physician’s assessment.
Curative surgery techniques are:
- individualized resection;
- standardized resection;
- individualized disconnection;
- extra-temporal surgery.
“Palliative” surgery
When curative surgery is not possible, neuromodulation may be used. Here are the main techniques (some old, some new):
- callosotomy;
- multiple subpial transections;
- vagal nerve stimulation (VNS);
- transcutaneous VNS (tVNS);
- deep brain stimulation (DBS);
- reactive neurostimulation (RNS) is approved so far only in the United States, it can monitor electrical changes in cortical activity and give small pulses to the brain to interrupt a seizure;
- trigeminal nerve stimulation (TNS);
- transcranial direct current stimulation (tDCS);
- transcranial magnetic stimulation (TMS).
Drug treatments research
The first approach to the treatment of epilepsy is based on the use of drugs called ‘antiepileptics’ which, however, are limited to symptom control (seizures) and do not affect the onset of the disease. Until 1990 only a few drugs were available; today there are more than 30 drugs. A prerequisite for successful treatment is the reliability and cooperation of the person with epilepsy and his or her family members. In fact, therapy must generally be continued for several years and sometimes for a lifetime, without any interruption, and with medication being taken at regular intervals.
Antiepileptic drugs stabilize the electrical properties of the nerve cell membrane thus preventing abnormal electrical discharges. They can act on several targets such as:
- Voltage-dependent sodium channels
- Voltage-dependent calcium channels
- GABA (inhibitory neurotransmitter that is differentiated into GABA- A and GABA-B)
- Glutamate (excitatory neurotransmitter)
Several new treatments are currently being studied, from drugs with a mechanism similar to GABA-A receptor agonists, to those with novel mechanisms such as melatonin receptor stimulation.
Among recently approved drugs, it is worthwhile mentioning:
Cannabidiol
In 2018, the Food and Drug Administration, approved the first drug derived from the cannabis plant. In Italy it has been approved for the treatment of seizures associated with Complex Tuberous Sclerosis, Dravet syndrome, and Lennox-Gastaut syndrome, in combination with clobazam in children aged 2 years and older.
Dravet syndrome is a rare, refractory epileptic encephalopathy that occurs in healthy infants and in the first year of life with clonic/tonic-clonic, unilateral, generalized seizures.
Complex Tuberous Sclerosis is a rare neurocutaneous syndrome that, among other symptoms, can cause seizures. Lennox-Gastaut syndrome belongs to the group of severe epileptic encephalopathies of childhood.
Some randomized clinical trials have shown that in children (2-8 years old) the combination of cannabidiol and clobazam resulted in greater efficacy outcomes: the median frequency of seizures decreased from 12.4 to 5.9 per month, and 43% of patients treated showed at least a 50% reduction in seizure frequency. Five percent of patients treated with CBD became seizure free.
Fenfluramine
Fenfluramine (FFA) is used as a weight-loss drug, but has demonstrated an antiepileptic effect through the release of serotonin, which stimulates multiple 5-HT receptor subtypes, and by acting as a positive modulator of sigma-1 receptors. Recently it has also been approved in Italy for the treatment of epileptic seizures associated with Dravet syndrome, as adjunctive therapy to other antiepileptic drugs for patients aged two years and older. The drug has been shown to be significantly effective in reducing seizures in phase 3 studies in patients with Dravet syndrome. In some of these studies, 62% of patients showed a 50% reduction in seizure frequency.
Cenobamate
This drug, available also in Italy, is indicated for the treatment of focal-onset seizures with or without secondary generalization in adult patients who have not been adequately controlled despite a history of treatment with at least 2 antiepileptic drugs.
This drug acts by a dual mechanism of action: it can increase the inactivated state of voltage-dependent sodium channels and act as a positive allosteric modulator of GABA-A receptors.
A multicenter randomized trial of patients, with uncontrolled focal seizures, showed that cenobamate, with dose groups of 100, 200, and 400 mg/day, resulted in a consistent reduction in the frequency of focal seizures after 18 weeks of treatment, with the greatest reduction observed in the 200- and 400- mg/day dose groups. Cenobamate is overall well tolerated, but further studies are still needed to understand the ideal dosage and to evaluate the time window of cenobamate on seizure control; other data will help to confirm or not the seizure reduction in clinical practice as well. The potential interactions of cenobamate with other antiepileptic drugs will also need to be investigated further.
The ketogenic diet
When drug and surgical therapies fail, alternative intervention strategies can be used to improve seizure control and quality of life for people with epilepsy. Among these interventions, there is the ketogenic diet, a dietary regimen based on the reduction of carbohydrates, and the increased consumption of fats, thus forcing the body to produce autonomously the glucose necessary for survival. This mechanism induces the liver to synthesize ketogenic bodies (ketosis) such as acetone, acetoacetate, D-Beta-hydroxybutyrate that nourish the brain.
Specifically, in the pediatric population with severe forms of epilepsy, the ketogenic diet has been shown to reduce seizure frequency by 50% in 40-67% of cases. Moreover, in specific metabolic-based epilepsy syndromes (e.g., epilepsy secondary to GLUT-1 deficiency), the ketogenic diet is even considered the first-choice therapy, proving effective in more than 80% of cases, especially in case of early detection and timely treatment. In Italy, this diet is still little used.
Gene therapy
We are only at the beginning of studies of these treatments for epilepsy, even if these look really promising. Gene therapy may indeed be an alternative to conventional drugs and surgery for epilepsy. However, it is not easy to find the right therapy because there is no single genetic variant that causes epilepsy: actually, there are over four hundred.
To date, gene therapy has been tested in preclinical (animal) models. The real challenge is to find the right vector that delivers the correct gene into the body, as well as choosing the appropriate therapeutic target. Several options are being investigated: from overexpression of inhibitory neuropeptides to modulation of the expression of neurotransmitters or ion channels. In addition, emerging optogenetics and chemogenetics approaches, as well as genome editing tools, could further enhance the prospects of gene therapy in epilepsy.
References
- Riva A, Golda A, Balagura G, Amadori E, Vari MS, Piccolo G, Iacomino M, Lattanzi S, Salpietro V, Minetti C, Striano P. New Trends and Most Promising Therapeutic Strategies for Epilepsy Treatment. Front Neurol. 2021 Dec 7;12:753753.
- Zhang L, Wang Y. Gene therapy in epilepsy. Biomed Pharmacother. 2021 Nov;143:112075.
- Libro Bianco dell’Epilessia, LICE, 2019 https://www.lice.it/pdf/Libro_bianco.pdf, Ultimo accesso: 13 febbraio 2023
- Shorvon SD. Drug treatment of epilepsy in the century of the ILAE: the second 50 years, 1959-2009. Epilepsia. 2009 Mar;50 Suppl 3:93-130
- Perucca E, Tomson T. The pharmacological treatment of epilepsy in adults. Lancet Neurol. 2011 May;10(5):446-56.
- FDA, FDA Approves First Drug Comprised of an Active Ingredient Derived from Marijuana to Treat Rare, Severe Forms of Epilepsy, 26 gennaio 2023 – Ultimo accesso: 13 febbraio 2023
- Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, Scheffer IE, Thiele EA, Wright S; Cannabidiol in Dravet Syndrome Study Group. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Engl J Med. 2017 May 25;376(21):2011-2020.
- Krauss GL, Klein P, Brandt C, Lee SK, Milanov I, Milovanovic M, Steinhoff BJ, Kamin M. Safety and efficacy of adjunctive cenobamate (YKP3089) in patients with uncontrolled focal seizures: a multicentre, double-blind, randomised, placebo-controlled, dose-response trial. Lancet Neurol. 2020 Jan;19(1):38-48.
