The drugs available to us today are not effective in treating seizures in about a third of those with epilepsy. What can be done to resolve the situation?
Like many of the people in theepilepsy (Kipion), 56-year-old Richard Shane also suffers from memory problems. But he can easily recall the first attack he experienced, 34 years ago. "I was talking to my father on the phone, and during the conversation I noticed that I was starting to sigh, and I partially lost consciousness," says Shane. After a similar incident occurred three weeks later, Shane consulted a doctor and learned that he had epilepsy, a neurological disorder caused by abnormal electrical activity in the brain. The first drug he received, Dilantin (Phenytoin), failed to stop the epileptic seizures or even bring relief to his condition. And so is the second medicine and the third medicine. It turned out that drug treatment is not effective for the type of epilepsy he had.
Over the next 22 years, Shane continued to have two to five elliptical seizures each week. He and his doctors tried every new anti-epileptic drug that came on the market, but they all failed. Finally, in 2004, as a last resort, Shane underwent neurosurgery in which a small part of his brain that was the source of the seizures was removed. "It was the least worst option among the options before me," says Shane, "the choice was between brain surgery and epilepsy." Since the operation Shane has not suffered any seizures.
No less than three million people in the US suffer from epilepsy and more than 30% of them receive inadequate drug treatment that does not alleviate their condition. Their proportion in the patient population remains the same even though since 1990 more than a dozen new antiepileptic drugs have been approved for use. And although some of the patients, like Shane, find a cure for their disease in a surgical procedure, uncontrollable epileptic seizures are still a continuous nightmare for many patients and an extremely difficult problem to solve for treating doctors and research staff alike. "It's not easy for me to admit this, but we don't know" why some people respond to drugs and others don't, says the neurologist Michael Rogawski, who is researching treatments for epilepsy at the University of California, Davis. Although an answer to this central problem has yet to be found, the search for new and innovative approaches to the treatment of the most difficult cases continues with full vigor.
Inadequate treatments
Epilepsy has been an unsolved mystery for thousands of years, since it was first described in ancient Babylonian texts more than 3,000 years ago. Over hundreds of years, various scholars and experts attributed the epileptic seizures to all sorts of different factors, starting with the accumulation of phlegm in the brain (as the ancient Greeks believed) and ending with evil spirits that possessed the person (according to the opinion that prevailed in the Middle Ages). The treatment of epilepsy throughout history ranges, accordingly, from drilling holes in the skull and sacrificing animals to exorcising demons and spirits.
The first effective drug to treat epilepsy, potassium bromine, which inhibits the excitation of nerve cells, came into use in the middle of the 19th century. The compound, whose place was later taken by drugs such as Phenobarbital and other drugs that cause fewer side effects, prevented epileptic seizures among about a quarter of the patients who took it and reduced the intensity of the seizures and their frequency in 43% of the patients. According to Rogawski, about 50% of patients today respond to the first drug they take and do not experience repeated attacks, while 20% of patients are able to control most attacks with the help of the second or third drug they try. In some ways, then, "we haven't been able to significantly improve the situation," Rogawski says.
About a million people with epilepsy in the US are therefore left without an answer, since not one of the more than 20 available drugs can bring relief to their condition. Rogawski and others involved in this field believe that surgery could benefit many more patients than those undergoing it today. About 60% of the patients who underwent surgery did not experience recurrent attacks during the following ten years. However, only less than a quarter of the patients who do not respond to drug treatment meet the medical criteria that allow one or another surgical procedure, and the main one is to locate the particular area of the brain that is the source of the seizures (as determined through Brain scans and tests EEG) and stating that this area does not overlap with areas involved in essential functions, such as language functions. Studies show that, like Shane, most patients who are suitable for surgery usually continue to live with the attacks for twenty to 25 years before they muster up the courage and decide to undergo surgery. Many postpone the decision due to their fear of possible complications, including brain infection and permanent paralysis.
As far as the matter is concernedOrin Devinsky, director of the Comprehensive Epilepsy Center at New York University Langone Medical Center, there is some irony in the fact that medicine is still at a loss for cases of difficult-to-treat epilepsy. "I turned to [the study of] epilepsy 25 years ago, paradoxically, because it was one of the few things in neurology that was treatable at the time," Devinsky says. The fact that about a third of his patients do not respond to drug treatment only worsens their condition over the years due to the long-term effects of the uncontrolled seizures. "People who experience repeated seizures, especially convulsive seizures, may suffer a persistent decline in cognitive functions [as well as personality changes]," Devinsky says. He attributes these complications to chronic disruption of brain function caused, in part, by the seizures and medication. Other accompanying problems include anxiety, depression, migraines and sleep disorders.
Epilepsy can also be fatal, by itself or as a cause of an accident. "In my estimation, epilepsy causes the death of at least 6,000 people every year in the US," says Devinsky. Half of these deaths occur from unknown causes, while the remaining cases are caused by drowning, traffic accidents, falls, burns, etc., related to seizures.
New approaches
The first challenge in treating epilepsy patients is diagnosing the type of epilepsy the patient has. It is common to classify the disease into two main types: generalized epilepsy, in which the seizures begin simultaneously in all parts of the brain, andFocal epilepsy, in which focal epileptic seizures begin in a specific area of the brain, such as the temporal lobe. Each of these types can manifest itself in several subtypes of epileptic seizures, including a rare genetic condition known as Derva syndrome, which usually appears in children affected by it in their first year of life. Many different types of epileptic seizures are known, among others, Tonic-clonic seizures, which are accompanied by loss of consciousness and convulsions throughout the body, and Dissociation attacks, short epileptic seizures during which the patient disconnects from his environment for an average of five to ten seconds and is unaware of what is happening around him.
Epilepsy specialists like Devinsky decide which medication is right for their patients based on the type of seizures they experience, their medical history and other data, such as age, gender and body weight. The drugs work on molecular targets multiple in the brain, including dedicated molecules located in the nerve cells that help communicate between them and other nerve cells through the transfer of sodium, calcium and potassium ions into and out of the cells.
Unfortunately, patients who do not respond to the drugs currently on the market will have to wait a long time for the development of new drugs that may help them. "At this point, there are no significant drugs in development," Rogawski says. A possible explanation for this is given in a joint report published in 2013 by organizations dealing with epilepsy research: "Since the market is already flooded [with anti-epileptic drugs], many pharmaceutical companies are avoiding for the time being the development of new drugs that involve extremely high costs."
Faced with this hopeless situation, many patients and their families decided to take the initiative and conduct experiments independently. And so, in recent years, with the approval of the use ofמריחואנה For medical purposes in Colorado and other states in the US, parents of children with Derva syndrome began to give them doses of Cannabidiol, a component of the plant that is not psychoactive substance, which is produced for use as oil. In personal stories on the Internet and in the media, some of the families describe a dramatic reduction in seizures. Several clinical studies conducted following field experience in order to test the effect of cannabidiol also confirm the substance's potential for effective treatment of certain types of epilepsy.
In 2014, the British pharmaceutical company GW Pharmaceuticals received a special permit from the US Food and Drug Administration (FDA) to conduct a trial on a medicinal version of cannabidiol called Epidiolex. In a recent clinical trial of 225 patients that ended in September 2016, trial participants who took the drug (along with other antiepileptic drugs they regularly take) experienced a 42% reduction inPersistent seizures, compared to 17% in the group of participants who received Dummy drug.
Others who despaired of the situation decided to adopt and develop a classical nutritional approach to the treatment of epilepsy that was accepted in the past.Ketogenic diet (high in fat and low in carbohydrates) was widely used in the 20s as a means of reducing epileptic seizures, especially in children. Recent studies show that it does indeed have certain advantages as a means of reducing seizures, but in another study it was found that 20% of the children who participated in it did not persist in this diet, as it is far from tasty.
In view of the long period of time necessary for the development, testing and approval of new antiepileptic drugs, experts in the field believe that innovative surgical techniques and different methods forNerve cell regeneration Those that suppress abnormal electrical activity in the brain will be able to ease the condition of many more patients with severe epilepsy. Devinsky estimates that up to 20% of the patients in this group, those who suffer from focal epilepsy whose origin can be traced to a specific area of the brain, can be candidates for surgery when surgical access to this area is possible.
Another possibility, which has been applied for twenty years, is the implantation of a pacemaker to regulate the electrical activity in the brain. The goal is to prevent seizures by Stimulation of the vagus nerve in the neck area, using electrodes connected to a battery pack implanted in the chest. The pacemaker sends a moderate electrical current at a pre-programmed pulse rate that suppresses and calms the abnormal electrical activity in the brain. A meta-analysis of data conducted in 2011 and examining 74 clinical trials involving more than 3,300 participants indicated that seizures were reduced by more than half in 50% of patients treated by stimulation of the vagus nerve.
newer device, NeuroPace's RNS System, which was approved for use by the FDA in 2013, involves a nerve stimulator that is implanted in the skull, under the scalp. When the device detects abnormal electrical activity in the brain, it delivers an electric current through two electrodes to stop or even prevent a seizure. According to Devinsky, 10% to 15% of patients with epilepsy that cannot be treated by other means are possible candidates for this treatment. In clinical trials it was found, after three to six years of follow-up, that such implanted devices reduced seizures in the patient group by an average of 66%.
Meanwhile, in the laboratory, researchers conduct experiments on mice, flies and worms and use computers to develop new and more sophisticated models of epilepsy in animals, in an attempt to speed up the development of drugs for the disease. In 2016, for example, scientists from Florida Atlantic University and The Scripps Research Institute succeeded for the first time in inducing epileptic seizures in microscopic capillary worms, whose brains have only 302 cells. The scientists then successfully treated the worms with available anti-epileptic drugs. The research they conducted indicates the potential inherent in these organisms to test new drugs quickly and efficiently.
And as for Richard Shane, who has since become the owner of a travel company, epilepsy is still a part of his life. Admittedly, he no longer suffers from seizures, but there is something else that bothers him: "Sometimes I wonder what and who I could be if this electrical activity did not exist in my mind. In what way did this affect who I am today?"
This is an unanswered question, yet another disappeared in the vortex of disappearances surrounding drug-resistant epilepsy. But doctors like Gregory Bargi, who stands at the head Johns Hopkins Hospital Epilepsy Center, trying to instill hope while they face the many riddles that the disease raises: "I always tell my patients that we never give up."
