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The Clinical Issues Facing Neurologists Today
The neurology field is constantly changing as we acquire new data and tools that further our understanding of the complexities of the brain. As our knowledge increases, so too does the challenge to redefine our strategies for designing and implementing treatment plans for patients. This challenge is unique to each patient and to each disorder. In the case of epilepsy, neurologists are being called upon to shift their previous notions of clinical practice to a more evidence-based paradigm. This new paradigm, according to Nathan Fountain M.D., Associate Professor of Neurology at the University of Virginia, School of Medicine and Director of the FE Dreifuss Comprehensive Epilepsy Program “should be the cornerstone of anti-epileptic treatment and the basis for good clinical practice but has limitations.”
“The biggest change over the last decade in epilepsy treatment has been the way epilepsy itself has been redefined,” said Fountain. “In the past, all different seizure types and etiologies were lumped together under the diagnostic umbrella of epilepsy. The treatment of seizures with anti-epileptic drugs was based on this information. We now know that different types of seizures respond to different therapies. Focal-onset seizures can be treated with surgery, for example, while generalized seizures cannot. A long-standing example is that absence seizures may respond to ethosuximide while other seizure types do not. The FDA has taken this one step further to approve AEDs for use limited to only specific circumstances. Typically AEDs are now approved as either adjunctive therapy added to a patient’s existing medications or as monotherapy. Monotherapy is further approved as initial monotherapy for new onset seizures or as monotherapy for established epilepsy. This assortment of indications leads to confusion. Evidence based guidelines help make this intelligible for clinicians.”
Fountain asserts that the new evidence-based guidelines provide a comprehensive and unbiased analysis of the available data on the efficacy and safety of these AEDs, which the clinician can use in making treatment decisions. In addition, he believes that an even more important function of the guidelines is to illuminate the information that is not available regarding AEDs, thus providing clinicians with a clear path for further research.
He also points out the challenge clinicians face when choosing an AED for initial monotherapy using the FDA guidelines alone.“FDA approval provides little guidance in selecting the appropriate drug because many drugs were studied and approved across a number of decades. In particular, conventional drugs were not approved with regard to age or initial monotherapy, or with regard to monotherapy at all. All recently approved AEDs are indicated as adjunctive therapy. It is likely they are also effective as initial monotherapy. However, not all are indicated for this purpose, even for AEDs that have completed some monotherapy clinical trials.” He believes other factors need to be considered such as side effect profile, pharmacokinetics, dosing and cost since there are few, if any, head-to-head studies comparing the efficacy of the new AEDs.
Prescription of AEDs and Pregnancy
Another common treatment issue many neurologists face is deciding which AED to prescribe to a woman who is considering pregnancy.
“There has been a growing interest in epilepsy and women’s issues amongst clinicians because of the strong link between epilepsy and hormonal changes, and because conventional AEDs are thought to be teratogenic,” said Fountain. “Several pregnancy registries have been established in recent years in an attempt to determine the teratogenicity of new AEDs. However, the results are preliminary since the numbers in the registries are too small to provide comparative risk ratios for several AEDs.”
The overall risk of birth defects in the general population is 2%. This statistic increases two-fold for women with epilepsy (4%), and more so for women taking certain AEDs such as valproate (10 %).”The pregnancy registries confirm previous reports that major congenital malformations occur in about 5-10% of pregnancies in women with epilepsy on AEDs,” said Fountain. “There is consistent evidence that valproate carries the highest risk, but there is also published data that the risk is increased with phenobarbital. Lamotrigine appears to be equal to that of the general population, but larger numbers are needed to confirm this.” He further surmises that the reason we know so much more about the teratogenic effects of valproate and lamotrigine is because women often have idiopathic generalized epilepsy such as JME that begins during the child bearing years. Historically, women with these types of seizures were treated with valproate, and now, with lamotrigine.
Timing of Surgery for Epilepsy
There has been increasing awareness of the value of epilepsy surgery for the past decade based on many physician reports at epilepsy centers. The evidence appeared overwhelming to epilepsy specialists, but the lack of a randomized controlled trial led many patients and physicians to wonder whether the risk of surgery was worth the benefit. The role of evidence-based medicine is to provide information in exactly this type of circumstance, when there is not a clear consensus about an issue. This issue was addressed by the first and only randomized controlled trial of surgery for epilepsy and was published in 2001 by Dr. Samuel Wiebe and colleagues at the University of Western Ontario. They assigned 40 subjects with intractable epilepsy to get immediate evaluation for epilepsy surgery and 40 subjects to get the best available medication therapy. They found that 58% of patients were free of disabling seizures one year after temporal lobectomy while only 8% were seizure free if they remained only on medications. They found no serious complications from surgery. In fact, the only person to die in the study was in the group of subjects assigned to receive medications.
Fountain believes, “This study provides strong evidence based class I data that temporal lobectomy is much more effective than continued AEDs alone in the treatment of refractory epilepsy. People are understandably concerned that surgery might be a drastic step that could cause problems. This research unequivocally demonstrates that temporal lobectomy is safe and effective. Surgery for temporal lobe epilepsy is now standard of care, which illustrates how evidence based medicine is useful and has become an integral part of medical practice.”
“The next step logical question is: how early in the course of epilepsy should surgery be considered?” says Fountain. “It might seem logical that surgery should be considered as soon as temporal lobe epilepsy is diagnosed since surgery is effective later in the course of the disease. Early surgery could prevent accumulating the problems that can accompany long-standing epilepsy. However, some patients may go into remission and not require surgery and some patients don’t consider seizures serious enough to accept the risk of surgery, even though the risk is low.” To address this question the NIH is sponsoring a multicenter study of surgery compared to medications for the treatment of epilepsy that has been intractable for less than 2 years, the Early Randomized Surgery Epilepsy Trial (ERSET) Details can be found at ERSET.net. This study should provide class I evidence that will unequivocally answer this question.
Evidence-based Medicine and the Future
The rapid pace of epilepsy clinical research makes it difficult for physicians to keep abreast of new therapies or even the best way to use old therapies. Evidence-based guidelines clarify the current state of knowledge for some aspects of epilepsy treatment, such as the use of new AEDs for new-onset seizures and temporal lobectomy, but also point out the limitations of our current knowledge and suggest future avenues of research. Future research into AEDs in pregnancy and surgery early in the course of epilepsy will likely lead to useful evidence-based recommendations for treatment.
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