Evaluation and Management of Epilepsy Today: Introductory Remarks

In a survey performed in the last decade, neurologists were asked to define what they considered to be “good seizure control” in patients with epilepsy. The answers were rather surprising as they ranged from “one seizure every 3 months” to the achievement of complete seizure remission. Much has changed since then, as the only acceptable definition of good seizure control today is total seizure freedom. Indeed, neurologists today are more aware of the devastating consequences of persistent seizures, even if they occur sporadically, which can lead to injuries from falls, burns, and include sudden death. Furthermore, even rare seizures prevent patients from driving, limiting their maximal vocational and professional potential.

Significant changes have taken place in the past 18 years: (1) new antiepileptic drugs (AEDs) with better tolerability and novel mechanisms of action have been approved by the Food and Drug Administration; (2) epilepsy surgery has been recognized as a pivotal option for patients with pharmacoresistant epilepsy; (3) the need to identify patients with pharmacoresistant epilepsy within a shorter time period (18 months to 3 years) has been recognized and advocated for adult and pediatric patients alike; (4) new devices consisting of electrical stimulation of epileptic circuits in the central nervous system are being developed for patients with pharmacoresistant epilepsy who are not surgical candidates; and (5) the negative impact of comorbid medical, psychiatric, and cognitive disturbances in patients with epilepsy has started to become recognized as a real problem, as has the need to incorporate their treatment into a comprehensive management. This issue of Seminars in Neurology dedicated to epilepsy attempts to provide clinicians with a very practical yet modern perspective on the approach to the evaluation and management of patients with epilepsy.

Determining whether paroxysmal episodes suspected to be epileptic seizures are in fact seizures or nonepileptic events, either organic or psychogenic, is the first step of the evaluation process, as discussed by Dr. Carreño in her article. Indeed, since the advent of video-electroencephalogram (EEG)-telemetry studies, it has become clear that 1 out of every 4 to 5 patients referred to an epilepsy center with a diagnosis of refractory epilepsy does not suffer from epilepsy. Rather, these patients may be experiencing paroxysmal episodes of an organic type such as convulsive syncope, sleep disorders presenting with cataplectic episodes, or complicated migraines, to name a few. More frequently, however, the nonepileptic events are of psychogenic origin. A delay in the recognition of nonepileptic events carries serious consequences not only from a medical standpoint but also in the life of the patient, affecting both the professional and social domains. Furthermore, psychogenic nonepileptic events are often confused with status epilepticus (SE), which results in admissions to intensive care units (ICU) where patients are intubated and treated with parenteral AEDs, including coma protocols, all of which are potentially associated with serious complications. In fact, the iatrogenic complications associated with unnecessary AED treatments and unnecessary admissions to ICU represent the greatest source of morbidity of patients with psychogenic nonepileptic events.

The next step in the process of evaluating patients with suspected epileptic seizures is to identify the type of seizure and epileptic syndrome. Drs. Tuxhorn and Kotagal review the various classifications and discuss the strengths and limitations of each classification. The correct recognition of the type of seizure and syndrome is of the essence in the correct choice of the AED. It also provides clinicians with a realistic expectation of the therapeutic effect of pharmacotherapy in a given patient. For example, 80 to 90% of patients with primary generalized epilepsy are expected to become seizure-free with the proper AED, while such is the case in 40 to 50% of young adults with partial seizure disorders and 30 to 50% of patients with mesial temporal sclerosis (MTS). Thus, given the type of epileptic syndrome, clinicians should have a sense of what to expect from pharmacotherapy in each patient. This can allow them to formulate a treatment strategy prospectively that would result in the achievement of seizure-freedom or the identification of patients with pharmacoresistant epilepsy in the shortest time period.

In patients with a new-onset unprovoked seizure, clinicians must establish whether the seizure is in fact the first seizure and identify the type of seizure and, when applicable, the epileptic syndrome. This information will dictate whether to start pharmacotherapy (and if so, the choice of AED) and provide a prognosis. Often, clinicians consider the first “obvious” seizure in the form of a generalized tonic-clonic (GTC) seizure to be the first seizure. In fact, this is one of the more frequent errors, as GTC seizures are often preceded by absence seizures and myoclonic seizures for months (or even years) in primary generalized epilepsy, and simple partial seizures (e.g., auras) in seizure disorders of focal origin. Clearly in such cases, a diagnosis of epilepsy is unquestionable and the start of therapy should not be delayed. In the case of a first unprovoked seizure, treatment with AEDs is not always required. A set of criteria, however, can guide clinicians in making the best decision to start or delay pharmacotherapy. For example, the presence of epileptiform activity in EEGs, abnormal findings on neuroimaging studies like brain magnetic resonance imaging (MRI), or an abnormal neurologic exam should favor the start of treatment. This important issue is reviewed in great detail by Drs. Haut and Shinnar.

In the past, patients with new-onset epilepsy would be started on phenytoin or carbamazepine. Indeed, prior to the 1990s, clinicians had a limited number of AEDs available in their pharmacologic armamentarium to treat epilepsy. Most of the AEDs had a variety of adverse events and most of them had significant pharmacokinetic interactions with other AEDs, with concomitant medications, as well as with endogenous substrates such as hormones and vitamins, either through acceleration (e.g., phenobarbital, primidone, phenytoin, and carbamazepine) or inhibition (e.g., valproic acid) of their metabolism. Such interactions resulted in loss of efficacy or toxicity of concomitant medications or caused iatrogenic disorders affecting bone density (e.g., osteoporosis or osteopenia) or menstrual and sexual drive disturbances, to name a few. Today, we have 19 AEDs available and the recommended strategy is to tailor the selection of AEDs to the individual patient. The choice of AED has to be based not only on the type of seizure and epileptic syndrome, but also on the age, gender, and presence of concomitant medications and comorbid medical, psychiatric, and neurologic disorders. In addition, clinicians must take into consideration the pharmacokinetic properties of the drug and its tolerability profile. Thus, the old dogma “you need to learn to accept the adverse effects of your medication” has been replaced with the statement “the treatment must not be worse than the disease.” In case of adverse events, clinicians have the option to choose alternative AEDs. Indeed, recent studies have demonstrated that toxicity to AEDs is an independent predictor of poor quality of life, and in patients who have refractory epilepsy, it is with depression the only predictor. In other words, when managing patients with pharmacoresistant epilepsy, ensuring the absence of adverse events is likely to improve their quality of life and paradoxically, even more than lowering their seizure frequency. Drs. Azar and Abou-Khalil devote one article to reviewing the process involved in the choice of AEDs, while Drs. Toledano and Gil-Nagel discuss the adverse events of AEDs.

The teratogenic potential of AEDs has been the source of great concern of clinicians and patients, as most of the first generation of drugs has been found to double the risk of major malformations in the fetus, relative to those occurring in healthy women on no AEDs. It appears from the available data that some of the new generation of AEDs may yield a lower risk, though for most new AEDs the data are still rather scant. Of some concern is the evidence that the impact of AEDs may not be limited to the development of major malformations but may affect the cognitive and behavioral development of children. Such is the case of valproic acid, which in a prospective multicenter study was found to cause a worse cognitive performance on neuropsychological tests in 2-year-olds exposed in utero to this AED than in 2-year-olds not similarly exposed. Drs. Kluger and Meador review this important topic in this issue.

The last decade has witnessed a significant interest in the management of epileptic seizures in special populations (e.g., women, children), and particularly in the elderly, as epilepsy has been recognized as the third most frequent neurologic disorder in this age group, with an incidence twice to 3 times higher than in younger adults, and increasing with advancing age. The evaluation and management of epilepsy in the elderly has its own specific needs, which if ignored can result in multiple problems. In contrast to seizure disorders in children and adolescents, most elderly patients suffer from localization-related epilepsy. Yet reaching a correct diagnosis often takes longer in this age group, particularly in patients who have only experienced complex or simple partial seizures, as elderly people suffer from a variety of paroxysmal episodes resulting from other neurologic disorders. Delay in the diagnosis can have dire consequences as the potential complications of individual seizures can be devastating in this age group (e.g., fractures of the hip associated with high morbidity and mortality risks). The same can be said about the occurrence of SE, which in some patients may be the initial (and often the only) manifestation of the seizure disorder and which can be associated with a significantly greater mortality than in younger patients. On the other hand, the response to pharmacotherapy with AEDs is significantly better than that of younger adults. Yet, the dosification schedules of AEDs must be modified significantly in geriatric patients, given their lower metabolic rates, requiring significantly lower doses of AEDs. Finally, given the frequent comorbid medical and psychiatric disorders in this age group, the choice of an AED must factor in the type of concomitant medications and their potential pharmacokinetic and pharmacodynamic interactions. Thus, the addition of enzyme-inducing AEDs may result in loss of efficacy of concomitant medications metabolized in the liver, unless their dose is adjusted. In the case of AEDs that inhibit the metabolism of certain drugs (valproic acid, felbamate), lowering of the dose of concomitant medications is necessary to avert toxicity. This important topic is reviewed in detail by Drs. Mapes Jetter and Cavazos.

Psychiatric disorders including mood, anxiety, psychotic, and attention deficit disorders are among the most common comorbidities identified in patients with epilepsy. While they have been considered to be complications of the seizure disorder, recent data suggest a bidirectional relation between epilepsy and certain types of these psychiatric disorders such as mood and attention deficit hyperactivity disorders (ADHD). In other words, not only are patients with epilepsy at greater risk of developing depression or ADHD, but patients with these two conditions are at greater risk of developing epilepsy. Furthermore, comorbid psychiatric disorders have been found to have very negative impact on the quality of life of patients with epilepsy. In fact, in patients with pharmacoresistant epilepsy, depressive disorders and toxicity to AEDs are the two independent predictors of poor quality of life, while seizure frequency and severity play lesser roles. Clearly, anyone treating patients with epilepsy must have an adequate understanding of the use of psychotropic drugs. Unfortunately, there are many misconceptions about the safety of certain types of psychotropic drugs, like antidepressants and central nervous system stimulants, which are thought by many clinicians to cause seizures. Accordingly, comorbid ADHD and mood disorders go often untreated in many patients. I discuss this important problem in great detail in this issue.

SE is one of the neurologic emergencies that require immediate intervention. Seizure activity is expected to remit in ~50 to 60% of patients with the first pharmacologic intervention. Often however, SE fails to be recognized, particularly when it presents as nonconvulsive SE or as subtle generalized convulsive SE. The pivotal role of continuous EEG monitoring in the successful treatment of SE has been demonstrated by several authors. Furthermore, continuous EEG monitoring is necessary to guide the pharmacologic treatment of SE, particularly in patients with refractory SE who require coma protocols to achieve seizure remission. Drs. Arif and Hirsch review this very important problem in epilepsy.

Approximately 60 to 70% of patients with epilepsy are expected to become seizure-free with pharmacotherapy. For patients with pharmacoresistant epilepsy, surgical treatment has become a potential therapeutic option. While not every patient is a surgical candidate, those who are can expect to achieve a seizure-free state with a probability ranging from 50 to 80%, depending on the location of the epileptogenic area and cause of the seizure disorder. For example, patients with temporal lobe epilepsy secondary to MTS are expected to derive the best seizure outcome, while patients with extratemporal, nonlesional partial epilepsy may achieve lower seizure-free rates. Nonetheless, an early identification of patients with refractory epilepsy is one of the pivotal aims today of the evaluation of any patient with epilepsy, as these patients could be good candidates for surgical treatment. In fact, pharmacoresistance can be demonstrated within the first 2 years of the seizure disorder in most patients. Unfortunately, it is taking 15 to 20 years for patients to be referred for presurgical evaluations. Drs. Balabanov and Rossi discuss the role of epilepsy surgery and vagus nerve stimulation in the treatment of patients with pharmacoresistant epilepsy.

Finally, the best way to improve our skills as clinicians is to learn from our errors. I devote the last article to reviewing the most frequent errors made in the process of evaluation and management of patients with epilepsy. Some of the concepts addressed in this article will have been reviewed elsewhere in the issue. Yet the decision to revisit them serves to highlight their importance in the overall management of patients and the frequency with which they are a source of mistakes.

All the authors hope that this issue will serve as a very practical source of information in the evaluation and management of patients with epilepsy.