Epilepsy is a chronic neurological disorder characterized by recurrent unprovoked seizures. It is one of the most common neurological disorders worldwide, affecting over 50 million people globally. Seizures occur due to abnormal electrical activity in the brain which can be caused due to various reasons such as brain injury, genetic factors, infections, tumors etc. While epilepsy cannot be cured, it can be effectively managed with anti-seizure or antiepileptic drugs in majority of cases.
First Generation Antiepileptic Drugs
The first generation antiepileptic Epilepsy Drugs were introduced in the early 1900s and continue to be widely used even today. Some commonly used first generation drugs include phenytoin, carbamazepine, valproate and phenobarbital. These drugs work by reducing neuronal excitability and propagation of seizure activity in the brain. Phenytoin and carbamazepine block sodium channels to stabilize neuronal membranes. Valproate enhances inhibitory GABA neurotransmission to dampen seizure activity. Phenobarbital stimulates inhibitory GABA receptors. While effective in controlling seizures, these older drugs are associated with more drug interactions and side effects compared to newer drugs.
Second Generation Antiepileptic Drugs
Newer second generation antiepileptic drugs were developed and introduced starting in the 1990s to address some of the limitations of older drugs. These include drugs like lamotrigine, gabapentin, levetiracetam, topiramate, pregabalin, lacosamide etc. Many of the newer drugs have novel mechanisms of action different from the older drugs. For example, gabapentin and pregabalin enhance inhibitory GABA and reduce excitatory glutamate neurotransmission. Lamotrigine and levetiracetam stabilize neuronal membranes. Topiramate blocks sodium and calcium channels along with enhancing GABA activity. The second generation drugs tend to have improved tolerability and side effect profiles compared to first generation drugs.
Refractory Epilepsy Treatment
Approximately 30% of epilepsy patients do not achieve adequate seizure control despite trying two or more anti-seizure medication schedules. This is termed refractory or drug-resistant epilepsy. Surgery is a potential treatment option for carefully selected refractory epilepsy patients who have a clearly defined seizure focus that can be surgically resected without damaging critical brain areas. Vagus nerve stimulation involves implanting a pacemaker-like device under the skin in the chest wall connected to the vagus nerve in the neck. It delivers mild electrical pulses intermittently and has been found helpful in some refractory epilepsy patients. Ketogenic diet, which is high in fat and low in carbohydrates, is another non-drug option that provides benefit in some refractory cases, especially in children.
Newer Antiepileptic Drugs
Continued research efforts have led to development and approval of newer antiepileptic drugs in the last decade. Perampanel was approved in 2012 and is the first drug that specifically targets and inhibits AMPA-type glutamate receptors. It is used as an adjunctive therapy for partial-onset and primary generalized tonic-clonic seizures. Brivaracetam launched in 2016 and enhances inhibitory synaptic transmission through selective targeting of synaptic vesicle protein 2A. Cannabidiol was approved in 2018 and has a novel non-psychoactive mechanism of action modulating excitatory and inhibitory neurotransmission through indirect interactions with multiple receptor systems. These newer antiepileptic medications provide additional treatment options especially for drug-resistant patients. Several other new drugs are currently under clinical investigation.
there have been significant advances in epilepsy treatment driven by better understanding of the disorder and development of new anti-seizure drugs over the past few decades. While epilepsy cannot be cured, it can be effectively managed or controlled in the majority of cases with appropriate medication. The availability of diverse treatment options from multiple drug classes now allows for individualized, precision therapy based on a patient's specific epilepsy type, seizure pattern, tolerability and other factors. Continued progress in ongoing research will hopefully lead to newer effective therapies and improve quality of life for epilepsy patients worldwide.
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