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ImageRefractory Epilepsy - Feature Article

Although anti-epileptic drugs (AEDs) work reasonably well in patients with epilepsy, about one-thirds of the patient population fails to respond favorably to them. This phenomenon is called ‘refractoriness’. For this issue of the Northeast Regional Epilepsy Group newsletter, clinical researcher Sloka Iyengar, PhD talked to us about refractory epilepsy, the clinical and basic science behind refractory epilepsy, and steps that can be taken if one has this condition.  

What is Medically Refractory Epilepsy?  

Epilepsy is one of the most common neurological disorders, and is characterized by the presence of spontaneous, recurrent seizures and accompanying comorbidites such as cognitive difficulties, anxiety and depression. The first line of treatment for epilepsy is administration of anti-epileptic drugs (AEDs). Unfortunately, a subset of individuals with epilepsy fails to respond favorably to anti-epileptic drugs – this phenomenon is called ‘refractory epilepsy’. For this issue of the Northeast Regional Epilepsy Group newsletter, clinical researcher Sloka Iyengar, PhD talked to us about refractory epilepsy, the clinical and basic science behind refractory epilepsy, and steps that can be taken if one has this condition.  

What is refractory epilepsy? What is its incidence? 

Although anti-epileptic drugs (AEDs) work reasonably well in patients with epilepsy, about one-thirds of the patient population fails to respond favorably to them. This phenomenon is called ‘refractoriness’. Alternative terms are ‘drug-resistant’, ‘uncontrolled’ or ‘intractable’. 

The International League Against Epilepsy (ILAE) is a global organization consisting of healthcare professionals with the aim of promoting epilepsy research and disseminating knowledge about epilepsy to the general public. According to the ILAE, the definition of refractory epilepsy is the failure of two trials of well-chosen AEDs to achieve seizure freedom. The trials could be monotherapy (one drug) or polytherapy (more than one drug). 

Refractory epilepsy is problematic because uncontrolled seizures can lead to a diminished quality of life. Mortality in the form of SUDEP (Sudden Unexpected Death in Epilepsy) is also more common when seizures are not well controlled. Hence, uncontrolled seizures can have a profound negative impact on physical and psychological health of the individual. 

What are the challenges in defining refractoriness when one looks at the clinical population on a day-to-day basis? 

When talking about refractory epilepsy, it is important to differentiate between true and apparent refractoriness. What does this mean? True refractoriness could be caused by a biological change in the brain that does not allow the AED to function like expected. On the other hand, there may be cases where refractoriness is because of other reasons. For example, incorrect diagnosis and lifestyle factors (e.g. alcohol intake, lack of sleep) can hinder the way the AED is supposed to function. In addition, imitators of epilepsy such as syncope, movement disorders such as tics and sleep disorders like narcolepsy will not respond to AEDs, giving the (false) impression of refractoriness. The same issue lies with PNES (psychogenic non-epileptic seizures) which requires psychological treatment rather than AEDs. Experienced clinicians are skilled at figuring out the difference between epilepsy and these other conditions. 

Another thing to consider is that the concept of refractoriness and responsiveness is a fluid one. An individual can start off being responsive to an AED and become refractory over the course of the condition, and the opposite can also be true. Resection surgery can also change the way an individual responds to AEDs.  

What are the causes of refractory epilepsy? 

The causes of refractoriness are many. Some of them depend on the patient – e.g. noncompliance to AEDs can lead to breakthrough seizures. Hence, it is of utmost importance to stick to the regimen as prescribed to you by your neurologist. Lifestyle factors also play a role here, and vary with the individual. Some triggers that may lead to unsatisfactory response to AEDs are lack of sleep, alcohol, flashing lights or certain patterns of lights, stress and recreational drugs. The thought would be that if the individual were to modify his/her lifestyle, the seizures would come under control effectively. 

On the other hand, there are two main causes of ‘true’ refractoriness- these are the ‘multidrug transporter hypothesis’ and the ‘target hypothesis’. Certain protein molecules known as P-glycoproteins (P-gp) are known as transporter proteins, and their job is to remove the drugs from the brain. Increase in levels of P-gp will lead to a decrease in the amount of available drug; as a result, the AED will not be able to stop seizures effectively. The ‘target hypothesis’ states that AEDs stop working because their targets get altered in structure. This would mean that if an AED that reduces seizures by acting receptor ‘X’ can’t do that if receptor ‘X’ gets changed in its form or function. 

Are there any predictors of refractory epilepsy? 

Being able to predict who would develop refractory epilepsy would be very valuable because it would help us save time and resources, and possibly even decrease mortality due to SUDEP. Unfortunately, we do not know a lot about this topic, but we do know that individuals who have many seizures before therapy and those who exhibit inadequate response to the first AED stand a greater chance of being refractory to subsequent AEDs. Hence, it is important to be proactive and seek help from an epileptologist sooner rather than later. 

What can be done to deal w refractory epilepsy? 

Clearly, refractoriness to AEDs is not an ideal outcome, but it is heartening to know that steps can be taken even if one has refractory epilepsy. Techniques like magnetic resonance imaging (MRI) and video-encephalography (vEEG) can be done to figure out the exact cause of epilepsy. A seizure diary can be maintained if one suspects that seizures coincide with the menstrual cycle (this is known as ‘catamenial’ epilepsy). Vagus nerve stimulation (VNS), deep brain stimulation (DBS), transcranial magnetic stimulation (TMS) and surgical resection are alternative options for treatment. In addition, dietary options like the ketogenic diet can also be looked into. It is also possible that the individual has psychogenic nonepileptic seizures (PNES); more information can be found on our website. For any and all of these options, it is important to work closely with your epileptologist and come up with a management plan.  

Thank you, Dr. Iyengar for this very useful information.  

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