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Optimizing Antiepileptic Drug Therapy in Refractory Epilepsy
Introduction: When are patients “refractory”?
Establishing whether your patient has refractory epilepsy is a topic well covered in Chapter 14. In general, epilepsy patients fall into two categories in terms of the ease of treatment: those for whom nearly anything will work and those for whom seemingly nothing will work. This bimodal distribution of patient characteristics was established clearly by a retrospective study by Kwan and Brodie of all patients presenting with a first seizure; about two-thirds of patients were rendered seizure-free with trials of the first one or two medications. Notably, the likelihood of successful treatment did not differ between newer-generation antiepileptic drugs (AEDs) and older drugs. Also, patients who achieve seizure freedom with initial monotherapy often do so at AED dosage below “standard” levels, such as carbamazepine at 600 mg/day. Thus, the majority of new-onset patients can be successfully treated with moderate doses of whichever AED presents the most favorable tolerability profile, assuming it is indicated for their seizure type. Although there is no sharp boundary between patients whose seizures will remit with treatment and those who will be refractory, it is clear that the odds of achieving seizure freedom drop off with each successive drug failure. Thus, many epileptologists consider the criteria for refractoriness to be the failure of two or three appropriate drug trials in either monotherapy or polytherapy.
Before declaring a treatment regimen a failure, it is important to avoid some dangerous pitfalls. The most notable of these is the possibility that the patient does not in fact have epilepsy. Patients with psychogenic nonepileptic episodes constitute a sizeable fraction of individuals admitted to the inpatient video–EEG monitoring service of any tertiary care epilepsy center, and these patients have often undergone several – sometimes many – fruitless AED trials. Identifying these patients after just one or two failed AED trials can spare years of needless AED exposure and open the possibility of successful psychiatric treatment. A more difficult problem is that of noncompliance. Missing even one dose of AEDs may be sufficient to provoke a seizure in some patients. It is hard for the epilepsy practitioner to know just how often this happens and how much it is a factor in apparent refractoriness to treatment. Subtherapeutic AED levels obtained at the time of emergency department visits are sometimes the only clear evidence of noncompliance, so I always ask ED providers to obtain these if they call about one of my patients, even for “sendout” levels of newer AEDs. Diabetes doctors have the benefit of tracking hemoglobin A1C levels and daily finger-stick glucose levels in their most difficult patients in order to assess compliance. Epilepsy doctors have no such luxury. Thus, I continually preach the importance of the low-tech pill container (subdivided into day-of-the- week compartments) as the best way to assure compliance. Another provoker of refractory seizures, especially in some forms of generalized epilepsy, is alcohol abuse. I’ve stumbled on the source of a few patients’ refractoriness when a loved one tipped me off to their alcoholism – and witnessed a remarkable improvement when they cut down on their drinking.
TIPS AND TRICKSMore antiepileptic drug trials versus surgery
For some refractory localization-related epilepsy patients, epilepsy surgery is a viable option. Knowing when to quit further AED trials and when to offer surgical referral is a judgment call that has to be considered carefully because the surgical evaluation process is time-consuming and expensive and sometimes takes on a life of its own. I find it helpful to present the possible outcomes in rough probability terms that even unsophisticated patients can understand. For those who have gone through at least three AED trials and for whom the epilepsy diagnosis is secure, I suggest that the likelihood of seizure freedom with further AED trials is about 1 in 10, with temporal lobe resection about 6 in 10, and with extratemporal resection less than half. Many patients prioritize the possibility of discontinuing all AEDs as a reason for surgery. It’s important to emphasize from the beginning that AEDs might only be reduced, not discontinued altogether, post-surgery, because only about half of patients successfully discontinue all AEDs after temporal lobectomy. Conversely, although some studies have shown that overall quality of life is most meaningfully increased if surgery results in seizure freedom, it is important to consider that a significant decrease in seizure frequency from “unsuccessful” surgery does mean a decreased risk of injury or sudden death from seizures. Presenting all of these contingencies to the patient contemplating surgery versus further medication trials may require multiple clinic visits so that the patient can fully digest the risks and benefits.
General approach to the refractory patient
For those patients for whom further AED trials are warranted, there are some general principles to consider. First off, the statistical likelihood of success with further medical treatment applies to a population, but every individual is different. Thus, it is important not to deprive the patient of hope or of motivation to go forward. Refractory does not equate to impossible. (For this reason I avoid the word intractable, which I think has a more negative connotation.) Even in refractory patients exposed to multiple prior medications, success can be achieved if one tries enough different combinations of medications.
Establishing the epilepsy diagnosis is vital, and for most refractory epilepsy patients should involve long-term video–EEG monitoring to capture typical seizures. The utility of this test stems from multiple considerations: weeding out patients with nonepileptic spells (even patients with interictal abnormalities on routine EEG can have superimposed nonepileptic spells), establishing which localization-related epilepsy patients may be surgical candidates, and discriminating generalized from localization-related epilepsies so as to better refine AED choice (more on this in the succeeding text).
Once the epilepsy diagnosis is secure and the question of surgery settled, it is important to guide AED therapy on the basis of data. This means asking patients or their caregivers to keep a seizure diary. Most people know without a diary whether or not they are seizure-free but otherwise can lose track of how frequently seizures are occurring. Without this information, it is difficult to tell whether progress is being made as medication regimens are altered. Likewise, obtaining occasional AED serum levels will confirm compliance and provide some guidance as to whether reasonably therapeutic drug levels are being reached. While obtaining drug levels is not recommended as a substitute for decision making based on asking patients how they are doing, drug levels sometimes reveal pharmacokinetic surprises (e.g., low levels of lamotrigine while on oral contraceptives or when pregnant, low levels of P450-metabolized drugs in combination with hepatic inducers like carbamazepine).
On the topic of pharmacokinetics, it would seem that drugs with relatively long serum elimination half-lives might be more effective than those with greater diurnal variations in their serum concentrations. Unfortunately, there is little empirical evidence for this idea, but given the choice it is reasonable to opt for extended-release versions of drugs or drugs with intrinsically long half-lives (zonisamide, perampanel, lamotrigine in combination with valproate). In the USA extended-release versions of second-generation AEDs (lamotrigine, levetiracetam) are now available in generic versions. Conversely, drugs with shorter half-lives may need to be dosed three times daily (pregabalin, levetiracetam).
Most patients will have arrived at the refractory treatment pathway by virtue of having failed at least two drugs in monotherapy. The practice especially in the USA has been to titrate each drug in monotherapy to its limit of tolerability before declaring it a failure. It is typical at that point to begin treating with combinations of drugs, and it is safe to say that the majority of refractory patients will be treated with combinations of AEDs. It is reasonable to wonder what to expect from adding a second or third drug to a patient’s regimen: Is there an added benefit in reduction in seizure frequency that is the sum of each drug’s effect when used in monotherapy? Does adding three drugs produce more benefits than two? What about four or more AEDs at a time?
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