A seizure is a sustained elevation in the brain’s electrical activity that clinically manifests itself in a variety of ways depending on the part of the brain affected, including loss of consciousness and convulsions. Many different factors can lead to seizures, including metabolism, acute infections, drug overdose and alcohol withdrawal.
However, when seizures arise spontaneously, they are considered epileptic. Individuals with epilepsy suffer from recurrent unprovoked seizures over the long-term. According to the World Health Organization, epilepsy is the most common serious brain disorder globally. Affecting 50 million people worldwide, epilepsy is associated with increased rates of mortality, cognitive impairment and psychosocial dysfunction, culminating in an annual economic cost of $12 billion to the United States.
Yet, despite decades of research, we still do not have a truly satisfactory epilepsy treatment. This week, I shall review existing epilepsy therapies and discuss problems regarding preclinical development of more efficacious treatments.
Historically speaking, dietary modification is the earliest form of epilepsy treatment with its roots traced back to Ancient Greece.
Around 460-377 B.C., Hippocrates observed that fasting reduces seizure frequency. In 1921, Wilder discovered that fasting causes the brain’s fuel source turns from glucose to ketone, leading to the development of a high-fat and low-carb diet for epilepsy treatment, also known as a ketogenic diet. Originally, a typical ketogenic meal may have consisted of sausage grease. In the 1990’s, more palatable options were developed, including lettuce burgers. While the ketogenic diet does reduce seizures, it can make people sick and causes complications such as constipation.
Termed antiepileptic drugs (AEDs), medications are the most popular epilepsy treatment starting with the introduction of Bromides in 1858. Since then, more than 20 AEDs have been developed. Despite a recent surge in AED development, AEDs are ineffective 25 percent of the time and can exert severe side effects, such as cognitive impairments and brain degeneration.
Consequently, surgeries often emerge as a therapeutic option when medications fail to work. Seizures often first arise from a specific region of the brain called the seizure focus. If surgeons are able to remove this region, then the epilepsy patient has a considerable chance of becoming seizure-free. However, surgeries can be risky, as they can cause secondary complications and, in some cases, death. More importantly, the seizure focus can’t always be localized, since seizures often spread throughout the entire brain. Thus, surgeries are not a viable therapeutic option in cases of generalized seizures.
The fourth and newest therapeutic strategy for epilepsy is neural stimulation. This strategy involves implantation of electrodes that deliver electrical shocks to seizure onset zones in order to abort epileptic seizures. However, neural stimulation techniques are no more effective than medicines with regards to seizure-free outcome.
In summary, epilepsy is not well-treated. Current therapeutic options fail to abort seizures in a significant population of patients and exert drug-related adverse effects that significantly detract from the quality of life. The lack of a truly satisfactory treatment emphasizes the desperate need for newer and more efficacious therapies. Thus, what can we do to speed up the development of more effective epilepsy treatment?
For a long time, prevention of seizures has formed the therapeutic basis for the development of epilepsy therapies. However, it is important to recognize that seizures are merely secondary consequences of epileptogenesis, a term that describes the biological processes that render the brain epileptic. For example, individuals who underwent successful medication treatments still exert seizure-like brain electrical activity even after becoming seizure-free. This means that current therapies aim to eliminate the symptom of the disease rather than target the underlying biological basis. Without eliminating the mechanism of the disease, we will never find a bona fide cure.
The prevalence of this anti-seizure approach to epilepsy treatment may very well explain why we still lack an effective therapy despite years of research and investigations. For a truly effective cure to be developed, we must move away from the anti-seizure strategy to the anti-epileptogenic approach, where the basic mechanisms of spontaneous seizures are targeted. In other words, we must focus not only on aborting seizures, but also on how to prevent the epileptogenic process that makes the brain sick.
Unfortunately, epileptogenesis is not well understood, as it is a complex interaction among intricate biological processes. Our understanding of epileptogenesis is further convoluted by a myriad of contradictory studies. Thus, we need to pay attention to the basic science of epilepsy so that we can learn more about the fundamental pathways that cause the disease. Ultimately, a greater insight into the mechanism of epilepsy will profoundly accelerate research progress in developing a genuine cure for the disease.
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