Drugs & Updates

Understanding Drug-Resistant Epilepsy

Epilepsy is a chronic non-communicable brain disease characterised by recurrent and episodic abnormal neuronal activity leading to seizures. This central nervous system disease accounts for a significant proportion of the world’s disease burden, affecting around 50 million people worldwide. Sometimes, these epileptic seizures are not controlled with antiseizure medications and can thus give rise to Drug-resistant epilepsy. 

Drug-resistant epilepsy occurs when a person has failed to become (and stay) seizure free with adequate trials of two antiseizure medications and gives rise to severe outcomes such as: 

  1. Learning problems and intellectual disability in children if drug-resistant seizures begin early on
  2. Epilepsy-related injury
  3. Increased risk of Sudden Unexpected Death in Epilepsy (SUDEP)
  4. Increased risk of emotional and behavioral problems
  5. Poorer occupational outcomes
  6. Increased risk of side effects to multiple antiseizure medications

Pathogenesis of Drug-resistant Epilepsy: 

The pathogenesis of epilepsy is complex and is mainly caused by the excitatory and inhibitory imbalance of the central nervous system. So far, the hypotheses regarding the pathogenesis of drug-resistant epilepsy include the transporter hypothesis and the target hypothesis

Most antiepileptic drugs work via the blood-brain barrier. In the transporter hypothesis, there is an overexpression of multidrug transporters which causes leaking of the drug from the capillary endothelial cells (which forms the blood-brain barrier). This results in decreased or altered intracellular drug concentration and renders the drug ineffective in the epileptogenic zones of the brain (minimum amount of cortex to produce seizure freedom) leading to drug resistance.  At present, multidrug transporters that are frequently studied include P-glycoprotein, multidrug resistance protein and breast cancer resistance protein. 

Target hypothesis proposes that mutations in the ion channels alters the structure and function of the antiepileptic drug (AED) target and leads to uncontrollable epilepsy attacks. One of the ion channels in question, the voltage-gated sodium channel, is expressed in excitatory cells, and is the main target of the traditional first-line AEDs. Studies have shown that mutations in the SCN1A gene (sodium channel, neuronal type I, alpha subunit) leads to severe epilepsy in infancy. 

Additionally, gene knockout experiments in mice have also verified that SCN1A mutations cause reduced expression level of sodium channel subtype Nav1.1, leading to decreased activity of inhibitory neurons and uncontrolled neuronal excitation. Sodium channel gene mutations cause the loss of function of the AED targets, decreased amplitude and duration of inhibitory sodium current, increased excitability of the whole neural network, and action potential spreading to the whole or partial brain, and thereby forming epileptic discharge. 

Treatment Strategies: 

If epilepsy is drug resistant, it is important to be seen by an epilepsy specialist (epileptologist) to evaluate why, and if there are better treatment options. Some of the treatment strategies include: 

  1. Resective Epilepsy Surgery: ​Resective epilepsy surgery consists of removing the area of the brain that is causing the seizures. This is a very risky procedure and should only be done if the area of the brain where seizures originate is clearly identified and if it can be safely removed with surgery. The probability to achieve seizure freedom with epilepsy surgery is dependent on the structures of the brain involved. For example, patients whose seizures originate in the temporal lobe have a 50% to 70% chance of achieving seizure-freedom. Researchers are also coming up with newer, less-invasive techniques that are being used in the place of resective surgery. These include the use of lasers, in which a laser probe burns the area of the brain causing seizures.
  2. Specific Metabolic Treatment: ​While metabolic causes of epilepsy are uncommon, identifying some of these conditions can lead to specific treatments to allow the body to compensate for the metabolic change. A ketogenic diet for GLUT1 deficiency, treatment with pyridoxine or pyridoxal-5-phosphate for vitamin dependent epilepsies, and creatine supplementation for creatine deficiency syndromes.
  3. Specific Genetic Causes: Identifying a specific genetic cause can help formulate the best treatment for seizures. In case of SCN1A variants, medications such as Oxcarbazepine (Trileptal), Carbamazepine (Tegretol) or Phenytoin (Dilantin) should be avoided. Some specific treatments which target the underlying problem caused by the genetic variant are in clinical trials, and may also help to improve learning and development along with seizures.
  4. Immunotherapy: Many studies have explored and identified the role of inflammatory processes in certain types of epilepsy. In these cases, medications that counteract these processes such as steroids (corticosteroids, glucocorticoids), intravenous immunoglobulin, steroid-sparing drugs such as azathioprine help to treat epilepsy. Immunotherapy can effectively nullify the side effects of antiepileptic drugs, and also prevent traumatic brain injury, stroke and intracranial infection. 

Currently, surgical treatment may be the only clear cut way to cure drug-resistant epilepsy. However, due to the complicated etiology and unclear pathogenesis of drug-resistant epilepsy, surgical treatment alone is always difficult to achieve a radical effect. Exploring comprehensive antiepileptic treatments along with surgery is required so as to achieve remission and even cure drug-resistant epilepsy.

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