What causes breakthrough seizures?
There are a number of potential causes of the unexpected occurrence of a breakthrough seizure. One important factor that clinicians may forget to examine is the possibility of non-adherence to (non-compliance with) prescribed antiepileptic drugs (AEDs). While adherence to medication is important in all disorders, it is especially important in epilepsy as nonadherence can lead to the emergence of breakthrough seizures and all of the associated complications. When assessing the causes of a breakthrough seizure, the clinician must first establish whether the patient in question has been adherent to the prescribed AEDs.

Both patient and medication factors can contribute to the occurrence of a breakthrough seizure. Patient factors include the onset of an infection, severe emotional stress, sleep deprivation, or metabolic events such as a decrease in sodium levels or severe changes in blood sugar level. Provocative factors such as flashing lights or playing video games have also been known to induce a seizure. A drop in serum AED level can provoke a seizure, and there are diverse potential causes for a reduced level. For example, the introduction of an agent that induces hepatic metabolism can lower the level of some AEDs metabolized in the liver, leading to higher risk for a seizure. There are also certain medications that are known to lower the seizure threshold, and the addition of such an agent would certainly predispose patients to a breakthrough seizure; a comprehensive list of factors is presented in Table 1. Other possibilities include the discontinuation or tapering of an AED, which could lead to potential withdrawal seizures. Paradoxically, there have been rare cases in which elevation of AED levels have induced seizures as well. For example, this has been described in the case of phenytoin toxicity. Sometimes, specific causes cannot be identified other than the manifestation of the underlying epileptic disorder.

What are the factors leading to loss of adherence to or discontinuation of antiepileptic drug therapy?
There are many potential causes of non-adherence in epilepsy. Adverse effects such as cognitive dysfunction or fatigue are commonly associated with use of AEDs, and the occurrence of these events may compel patients to take less of their medication—sometimes without even notifying their physician. Other adverse effects could include weight gain or sexual dysfunction—topics that patients may be disinclined to discuss. Complexity in the dosing regimen may contribute to the problem. For example, large numbers of pills that need to be ingested, different doses at varying times of the day, or how often a patient has to stop his or her daily routine to self-medicate can all potentially reduce adherence. Language barriers can also hinder the clinician’s ability to effectively convey the importance of adherence and dosing instructions to the patient. A patient’s lack of familiarity with his or her prescription plans and insurance issues can also play a role.

Forgetting to take a medication also contributes to non-adherence, and although this can happen to anyone (including clinicians), it can have potentially devastating ramifications for patients with epilepsy. There is also a chance that patients simply do not fully understand the nature of the treatment and the importance of remaining adherent; if a patient happens to have a long period in which he or she is seizure-free in the face of non-adherence, that patient may be lulled into a false sense of confidence that skipping medications will have minimal consequences.