Principles of Antiepileptic Drug Treatment in Epilepsies

Antiepileptic drug treatment is the mainstay of management of epilepsies. The decision to treat is based on a careful evaluation of the balance between the likelihood of further seizures and the risk of adverse effects of treatment. The laudable goal of AED treatment in epilepsies is to abolish seizures completely (freedom of seizures) with minimal if any drug-related adverse reactions. This is achieved in around 50–70% of patients with a single appropriately selected AED at target therapeutic doses. This seizure-free rate varies significantly with the type of seizure and epileptic syndrome. Polytherapy should be avoided if possible, but it is inevitable in approximately 30–50% of patients who fail to respond to single-drug therapy. Freedom of seizures should not be pursued at any cost and, in particular, at the expense of drug-induced adverse reactions. For some patients a few minor and often harmless seizures (mild myoclonic jerks, simple focal seizures or absences) may be allowed to occur instead of increasing AED numbers and dosages, which may jeopardise the otherwise social and mental well-being of the patient. Identifying drug-induced adverse effects in out-patient clinic visits is often neglected because of time constraints, confounding factors and the multiplicity of potential symptoms. Patients may also be reluctant to report them or they may confuse them with a consequence of their illness.

The drug treatment of epilepsies requires thorough knowledge of the AEDs with regard to mechanisms, pharmacokinetics, doses, indications, drug interactions and acute and chronic adverse effects. These are widely available through books, journal reviews, the prescribing information sheets of the manufacturers and credible Internet sources.

Important note

Important note
The “package insert” (USA) and “summary of product characteristics” (European Medicines Evaluation Agency and UK) that accompanies AED products is the most complete single source of information on the drug. These can be obtained through Web search engines. Simply search for:
x (name of the AED) package insert or
x (name of the AED) summary of product characteristics.
Also, these may often be found on the drug manufacturer’s website.
The European Medicines Evaluation Agency (EMEA) Web site is particularly important because the information is in all European languages: http://www.emea.europa.eu/htms/human/epar/a.htm
The “package insert” is reprinted in the Physician’s Desk Reference, which can be found in many libraries. Labelling for Food and Drug Administration (FDA) drugs approved after 1998 may often be found on the FDA approval page at: http://www.fda.gov/cder/approval or http://www.accessdata.fda.gov/scripts/cder/drugsatfda/
Additional information on a drug’s adverse effects can be requested through the FDA’s Freedom of Information Office: http://www.fda.gov/foi/default.htm

It is also fundamental to remember that special groups of patients with epileptic disorders require particular attention and management.¹ Children,^2–8 the elderly,^9–12 women (particularly of childbearing age)^12–23 and people with mental and physical disabilities^12,24 are vulnerable and their treatment is more demanding.

Cost should not be an issue in medicine, but with the majority of the global population in poverty and often in starvation, options are frequently limited to the old AEDs, which are often life-saving agents.

Starting Antiepileptic Drug Treatment

The decision to commence AED treatment needs thorough consideration and should not be a knee-jerk reaction to a crisis about a dramatic convulsive event (not necessarily an epileptic seizure).^25–27 One-quarter of patients on AEDs do not suffer from epilepsy. Of those with genuine epileptic seizures, these are newly identified ictal manifestations, usually convulsions, of an epileptic syndrome which has been previously undiagnosed or dismissed (either by the patient or the physician) or which may just have started. The aim of AED medication should be truly to treat and not just to medicate those in need of AEDs. Starting on an AED often implies continuous daily medication for many years, which is sometimes lifelong. Therefore, this should be strictly initiated for those with an unacceptably high rate of seizure recurrence or high risk of seizure injury. Some patients do not need prophylactic treatment as in febrile and benign childhood focal seizures. In others the avoidance of precipitating factors may be sufficiently prophylactic as in some reflex seizures or individuals with a low threshold to seizures. For those in need of prophylactic treatment, the first choice AED should primarily be in accord with the seizure type (Tables 4.1 and 4.2). Certain epileptic seizures are aggravated by some AEDs, which are beneficial in other epileptic seizures. A minimal requirement is to recognise the fundamental differences between focal epilepsy and IGE, since AEDs beneficial for focal epilepsy may be detrimental in IGE (Tables 4.1 and 4.2).^28–31 Indeed, even amongst IGEs, an AED beneficial in one type may be ineffective or aggravate another type of the triad of idiopathic generalised seizures (absences, myoclonic jerks and generalised tonic clonic seizures [GTCS]).^28–31 For example, tiagabine, vigabatrin, carbamazepine, oxcarbazepine and gabapentin may aggravate or be ineffective in absences or myoclonic jerks irrespective of their effect on GTCS (see details in the treatment of IGE page 333–7).

Table 4.1

Efficacy of main AEDs in seizure types

Table 4.2

Recommendations for AED treatment for children and adults when cost is of concern

Definitions of Pharmacokinetics and Pharmacodynamics

Clinical pharmacokinetics is the study of the time course of a drug and its metabolites in humans. This is a quantitative description of what happens to the drug once it enters the human body. To simplify, pharmacokinetics is the study of the effect of the human body on a drug. The primary parameters are absorption, distribution, metabolism and excretion.

Oral bioavailability is the proportion of a drug taken orally that reaches the systemic circulation. Most AEDs have nearly total bioavailabilty (80%–90%). Some like gabapentin are absorbed in a saturable fashion so that at higher doses their oral bioavailabilty may drop.

Of clinical significance is that different formulations of the same drug may have different bioavailabilties, which explains the loss of efficacy or emerging signs of toxicity when switching from one preparation to another. This is also the case with some controlled-release formulations such as carbamazepine, which has a lower bioavailabilty than the conventional forms.

Half-life of a drug (T1/2) is the length of time for its plasma concentration to decline by half. This determines time to steady state (approximately 5 half-lives) and provides indications of dosing intervals (usually less than one half-life). Steady state: equilibrium (after initiation of continuous AED treatment) is achieved when the rate of clearance equals the rate of administration that is the amount of drug ingested equals the amount of drug eliminated at the same time. A drug reaches the steady state when its clearance equals its dosing rate in other words when the rate of drug input equals the rate of drug output.

Protein binding: drugs are either free (unbound) or bound to serum protein. The active agent is usually the free drug. For extensively bound AEDs, clinically important alterations may occur as a result of physiological (pregnancy), pathological (hepatic, renal disease) or concomitant administration of drugs with higher or lower affinity for protein binding. A protein displaced drug (increase of free levels) may cause toxicity without elevation of its total plasma concentrations. Valproate and phenytoin are the main AEDs subjected to clinically important protein binding changes.

Pharmacodynamics refer to the biochemical and physiological effects of drugs and their mechanisms of action. Within clinical pharmacodynamics attempts are made to describe the relationship of both concentration and time to effect. Pharmacodynamics is the study of the effect of a drug on humans.

Clarifications on AED Recommendations in ‘Newly Diagnosed Epilepsy'

In the current era of evidence-based medicine, there is an accumulating literature on AED randomised control trials (RCTs) and formal recommendations on the treatment of ‘newly diagnosed epilepsy’ often used synonymously with the less accurate term ‘new onset epilepsy’.^30,35,38

‘Newly diagnosed epilepsy’ (or newly identified epilepsy) is a general term for encompassing all types of epilepsies that are newly identified and firmly diagnosed by physicians irrespective of the causes and prognoses. It includes any patient of any age with any form of seizure who seeks medical attention for the first time because of paroxysmal events that are diagnosed as epileptic seizures. It embraces idiopathic or symptomatic, focal or generalised, short-lived or lifelong and mild or severe forms of epilepsies. Thus, ‘newly diagnosed epilepsy’ is not a diagnostic or therapeutic entity. Its purpose should be to emphasise that these patients require meticulous medical support regarding diagnosis and treatment, which is thoroughly demanding. At this stage of first presentation, medical decisions may affect the rest of the patient’s life and often those of their families. Social and psychological support regarding the impact that such a diagnosis may have on them is a significant aspect of proper management.

Furthermore, ‘newly diagnosed epilepsy’ is not synonymous with ‘new onset epilepsy’ with which it is incorrectly equated.^34–37 It is evidence based that many patients have onset of seizures several years prior to seeking medical attention (see page 10).

Whether ‘newly diagnosed epilepsy’ or ‘new onset epilepsy’ both terms are imprecise without defining the type of epilepsy,³⁹ which is possible for the majority of patients.⁴⁰

Unifying them as a single therapeutic category discourages diagnostic precision and encourages inappropriate AED trial strategies³⁰ such as “inclusion criteria do not specify seizure type or epilepsy syndrome so AED study results are generalised to the universe of patients with newly diagnosed epilepsy” ⁴¹ In turn, this promotes detrimental indiscriminate use of carbamazepine and valproate because “neither of them is regarded as the single drug of choice for all patients with newly diagnosed epilepsy” ⁴¹ despite established documentation that these are two different AEDs with different indications and contraindications in partial and generalised epilepsies.³⁰

Rating Classification System for Evidence-Based Medicine and Clarification for the Ratings of the So-Called “Therapeutics Articles”

The American Academy of Neurology has introduced a rating classification system for evidence-based medicine.

Class I: Prospective, randomised, controlled clinical trial with masked outcome assessment, in a representative population. The following are required: a) primary outcome(s) is/are clearly defined, b) exclusion/inclusion criteria are clearly defined, c) adequate accounting for drop-outs and cross-overs with numbers sufficiently low to have minimal potential for bias and d) relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

Class II: Prospective matched group cohort study in a representative population with masked outcome assessment that meets a–d above OR a RCT in a representative population that lacks one criterion a–d.

Class III: All other controlled trials (including well-defined natural history, controls or patients serving as own controls) in a representative population, where outcome assessment is independent of patient treatment

Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion

Important note

In the so-called “therapeutics articles” ^34–37 these schemes “have the sole purpose of eliminating bias in studies. They do not address whether the study results are clinically valid.”³⁸

AEDs, like all drugs, may be therapeutic when used appropriately, but they also possess toxic properties (Table 4.3).^32,33 Patients and parents should be well informed concerning the purpose of AED medication, efficacy, side effects and possible length of treatment. Otherwise, there are failures in compliance, disillusionment and erosion of patient/physician trust.

Table 4.3

Main adverse reactions of AED, which may be serious and sometimes life-threatening

Important note

To be meaningful, evidence-based AED management should be precise and respect an evidence-based diagnosis.
AED efficacy and adverse reactions are not determined by how long a diagnosis of seizures has been established prior to the onset of treatment.³⁰

Prior to starting prophylactic antiepileptic medication in a patient with newly diagnosed seizures a physician should be confident of the following.

1. The patient unequivocally has epileptic seizures. This requires definite exclusion of imitators of seizures (non-epileptic psychogenic seizures, migraine, normal episodic events and cardiogenic, metabolic, cerebral or other neurological disorders that may produce transient and intermittent symptoms mimicking epileptic seizures).

   Important note

   One-quarter of patients treated for ‘epilepsy’ do not suffer from genuine epileptic seizures.⁴⁹

2. The epileptic seizures of the patient need treatment. This requires thorough investigation of the type of seizures, their frequency and severity, their likelihood of relapse or remission, precipitating factors and the patient/family concerns and understanding of the risks versus benefits of the antiepileptic medication. Hard and fast rules are not always applicable. For example, the general clinical practice that ‘a patient with more than two epileptic seizures needs antiepileptic drug treatment’ is often inappropriate. AEDs are not needed for most febrile and benign childhood focal seizures and this is also true for all other types of ‘conditions with epileptic seizures that do not require a diagnosis of epilepsy’, such as alcohol withdrawal or drug-induced seizures, single seizures or isolated clusters of seizures and immediate and early post-traumatic seizures (see Table 1.6 and page 18). Conversely, AED treatment is mandated for recurring seizures in symptomatic epilepsies and most syndromes of IGE such as juvenile myoclonic epilepsy (JME).

   Important note

   Treatment should be initiated if the risks of further seizures outweigh the risks of adverse reactions induced from AED medication.

3. The most appropriate AED is selected for a particular patient with a particular type of seizure(s). This is an extremely demanding task particularly now there are so many choices amongst old and new AEDs (Tables 4.1 and 4.2). Thorough knowledge of AEDs is a prerequisite of any attempt to start AED treatment. We should have passed the time of the late 1980s when the hazardous advice was ‘start with valproate and if this fails change it to carbamazepine’. The appropriate drug is that which is the most likely of all others to be truly prophylactic as monotherapy (single-drug treatment) for the seizures without causing undue side effects interfering with the everyday performance and physical and mental well-being of the treated individual. Balancing between the therapeutic (Table 4.1) and toxic effects (Table 4.3) of an AED is a primary responsibility and the crux of epilepsy management. There is no point in treating epilepsy at the expense of drug-induced disease. This cannot be achieved satisfactorily without thorough evaluation of the patient’s seizures, medical history, possible co-medication for other diseases and circumstances of the individual patient.
   • Some AEDs may be very effective in some epileptic seizures and syndromes, but contra-indicated in others as emphasised in this book on many occasions.
   • Some AEDs are very effective in controlling seizures, but may be unsuitable for particular groups of patients because of side effects (Table 4.3) such as valproate in women, particularly women of childbearing age. Hepatic enzyme-modifiers have lower priority over others in the elderly and patients who are medicated with other drugs for systemic or other comorbid disorders.
   • Some AEDs may be effective in one or two but not all multiple types of seizures that a patient may have (Table 4.1). For example, in JME: valproate and levetiracetam control absences, jerks and GTCS, lamotrigine controls GTCS and absences but often exaggerates jerks; clonazepam is the main anti-myoclonic agent but does not control GTCS; and ethosuximide controls absences but not GTCS.
   • Providing that the physician is confident of his/her decision regarding the suitability of an AED, this should be thoroughly explained to the patient/carer and ensure that this is well understood.

   Important note

   An antiepileptic drug appropriate for one type of seizure may be deleterious for another type of seizure.
   The selected antiepileptic drug should be the most likely to be effective and the most unlikely to cause adverse reactions.

4. The starting dose and titration of the selected drug should be in accordance with the appropriate recommendations (Table 4.4) and the age and primarily the particular needs of the treated patient. Starting with small doses and with a slow titration rate is mandated for certain drugs such as lamotrigine (increased risk of skin rash) and topiramate (increased risk of cognitive impairment) and of less concern in others such as levetiracetam (Table 4.4). The disadvantage of AEDs demanding slow titration is that patients may not be initially protected against potentially hazardous seizures until therapeutic doses have been achieved.

   Important note

   The aim is to achieve seizure control in a possibly shorter time with or without minimal adverse reactions.
   The correct dose is the smallest one that achieves seizure control without adverse effects.

   The following should also be taken into consideration in deciding how to start and escalate the selected AED.

   • Patients, particularly with newly identified epilepsy, are prone to develop adverse reactions (biological, cognitive or behavioural), which in 15% of cases lead to AED discontinuation.
   • Some patients develop adverse reactions easily even at an AED dose below the minimal limit of the target (therapeutic) range, while others are resistant to AED adverse reactions even at the maximum limit of the target range.
   • Even for patients with the same type of seizures and for the same AED, seizure control may be achieved with a drug concentration below, within or above the target range.
   My practice is to allow the patient to self-regulate the rate of escalation both in terms of the dose and dosing intervals of the AED. I explain to the patient and give in writing the recommended dose and the rate of escalation of the AED to use. I clarify that minor adverse reactions such as fatigue or somnolence are usually dose related and should not discourage escalation unless they interfere with the patient’s daily activities. I also warn the patient that any type of idiosyncratic reactions such as rash (even if mild) should be reported immediately so as to prevent escalation to more serious and sometimes life-threatening events.
   • Adverse reactions. I ask that the first dose (test dose) be taken at night before sleep and then the planned scheme be continued if there are no adverse reactions. If adverse reactions cause significant discomfort then the test dose should be decreased to half and tried again the next night. Similarly, the patient is at liberty to prolong the escalation time and reduce the escalation dose to suit his/her own reaction to the AED.

   Important note

   Exceptions apply particularly to patients at high risk from ongoing seizures. These patients need appropriate AEDs, which preferably do not require slow titration (Table 4.4). Other AEDs should be introduced faster at the expense of possible adverse reactions. A small dose or very slow escalation in these patients is often insufficient for controlling seizures and their impact on the patient.

   • Control of seizures. If seizures are controlled at some stage during the escalation, I ask the patient to continue with the same scheme with which seizure control was achieved without further increasing the AED dose.

   Important note

   For many AEDs and for many patients there is a ceiling dose of optimal efficacy, which may be lost by further dose increments. This may be due to a particular efficacy-related property of the AED or the introduction of adverse reactions that may exaggerate seizures.

5. The selected drug should not be abandoned prior to achieving recommended target doses unless unacceptable side effects occur, it is ineffective or exaggeration of seizures occurs. In either of these cases a second drug fulfilling therapeutic expectations for success should be initiated. If the seizures are controlled, the first drug should be gradually withdrawn so as to re-establish monotherapy again.

Table 4.4

Recommendations for slow titration and laboratory testing

Important note

Start monotherapy with the chosen first-line AED, initially at low doses titrating up to the low maintenance dose.⁵⁰ If seizures continue, titrate to the limit of tolerability, which will achieve additional seizure control in approximately 20% of patients. If, as in many patients, dosing to the limit of tolerability is not beneficial, the dose should be reduced.⁵⁰ Switching to an average dose of another first-line AED is another option for preventing over-treatment.⁵⁰

Rational Polytherapy

Rational polytherapy is often needed for 30–50% of patients with epilepsies who are unsatisfactorily controlled with a single AED.^57–59 This is much higher in patients with symptomatic focal epilepsies than patients with IGE. Nearly all epileptic encephalopathies such as Lennox–Gastaut syndrome require polytherapy.

Initially, a second drug is added to the agent that showed better efficacy and tolerability in monotherapy. The choice of a second or sometimes a third drug depends on many factors such as efficacy, adverse effects, interactions with other drugs, mode of action and the need for laboratory testing. Polytherapy with more than three drugs is discouraged because adverse reactions become more prominent, with little if any seizure improvement.

Important note

*The word “rational” has been used in conjunction with “polytherapy” in order to emphasise that this can also be irrational and hazardous if a diagnosis is incorrect and anti-epileptic drug indications/contraindications are violated.

The decision for polytherapy should first scrutinise the possible/probable reasons why the monotherapy failed. The following possibilities should be thoroughly examined, which often requires re-evaluation of the diagnosis (genuine epileptic seizures? and what type of seizures?).

• The patient does not suffer from epileptic seizures.
• The patient has both genuine epileptic and non-epileptic seizures.
• The patient has focal and no generalised seizures or vice versa.
• The AED used as monotherapy was not suitable for the particular type of seizures in this patient either because of contra-indications (tiagabine or carbamazepine in absences or myoclonic jerks, lamotrigine in myoclonic epilepsies), weak efficacy (valproate or gabapentin in focal seizures) or total ineffectiveness (gabapentin in primarily GTCS).
• Non-compliance can vary from unwillingness to take medication to occasionally forgetting or missing the AED dose. The latter is often improved with the use of AED-monitored dosage systems, which are widely available through pharmacies. These usually come in small boxes with a week or longer supply of each individual patient’s tablets or capsules to be taken at the time and date shown. These are useful even for patients who comply well, but who often may be uncertain whether or not they have taken their medication.
• Patients may violate instructions to avoid particularly eminent seizure-precipitating factors such as photic stimulation, sleep deprivation and alcohol or drug abuse.

Adding a new AED with another one to three AEDs that have already partially or totally failed or have made the situation worse is a formidable physician’s task for a disappointed and frustrated patient. Guidance that gives the physician just a list of options without prioritising them is unsatisfactory. For example, all new AEDs are licensed in polytherapy for focal seizures with or without secondarily GTCS. The priority of an AED over another AED depends on a number of characteristics as detailed in Chapter 12 for focal seizures (Table 12.4, page 431). Briefly, the criteria to determine the order of priority of the AED to be added are:

1. Efficacy. The more efficacious a drug is the more likely it is to control seizures and, if successful, withdrawal of other concomitant antiepileptic medications may be possible.
2. Safety. Adverse reactions may outweigh any beneficial effect achieved by reduction of the seizures.
3. Interactions with other AEDs are particularly unwanted in polytherapy. Raising levels of concomitant AEDs may lead to toxic effects. Conversely, decreasing their levels may increase and worsen seizures causing a vicious circle in clinical management.
4. Different mechanisms of action in relation to other concurrent AEDs (Table 4.5). An AED is unlikely to have better success and more likely to have additive adverse reactions if added to another AED with the same mechanisms of action.
5. Need for less laboratory monitoring. ^34–37 This refers to monitoring of the serum levels of the added AED or the co-medications that may be affected as well as blood or other tests needed for detecting possible adverse drug reactions such as hypernatraemia with oxcarbazepine (Table 4.4)

Table 4.5

Main mode of action of AEDs and seizure efficacy spectrum

Terminological Clarifications on Efficacy, Efficiency, Safety and Tolerability

In randomised control trial reports efficacy is often not used synonymously with effectiveness: ‘Efficacy is a relative term defined by the designers of a study, but is usually a specific effect of a treatment. In contrast, effectiveness has many potential components including tolerability, cognition, mood, or quality of life.’⁶⁰

Safety is not synonymous with tolerability. An AED may be well tolerated with regard to cognitive or other adverse effects but with a low safety margin. A typical example of this is vigabatrin, which had excellent tolerability according to all relevant controlled AED trials despite the fact that it was extremely unsafe as documented later in clinical practice with a high incidence of irreversible visual field defects. Similarly, there are significant differences between the safety and tolerability of lamotrigine.

Useful Definitions and Notes on Drug-Drug Interactions

Drug interactions: refer to phamacokinetic and pharmacodynamic changes that occur with concomitant use of drugs.

Drug interactions may be beneficial (increased effectiveness, reduced risk of unwanted adverse reactions or both) but more often are detrimental (decreased efficiency, increased side effects or both). Pharmacokinetic AED interactions are more frequently the consequence of drug-induced changes in hepatic metabolism through enzyme inhibition or induction. Changes of plasma protein binding are less common.

In enzyme inhibition, the added drug inhibits or blocks drug-metabolising enzymes which in turn decreases the rate of metabolism of the other drug thus resulting in higher plasma concentrations. In enzyme induction, prolonged administration of another a drug increases (induces) the activity of drug metabolising enzymes. This in turn increases the rate of metabolism of the parent drug thus resulting in lower serum concentrations.

If the affected drug has an active metabolite the impact of an inhibitor or inducer may be reduced but this depends on the subsequent metabolism of the metabolites. Induction for example may increase metabolite concentrations and enhance toxicity without elevation of the parent drug.

Pharmacodynamic interactions may be additive, synergistic or antagonistic.

Pragmatic Recommendations on New AEDs

The drug treatments with old and new AEDs in individual seizure types and individual epileptic syndromes are detailed in the relevant chapters of this book. Recent reviews,^{7,25,75,77–92} the practice parameters of the American Academy of Neurology,^34–37 the guidelines of the British National Institute for Clinical Excellence (http://www.nice.org.uk) ^93–96 and ongoing experience and information mandate pragmatic recommendations on the use of new AEDs in epilepsies.

Evidence-based prescribing has become a necessary part of treating epilepsies. However, there are major problems with this. A particular issue with evidence-based RCTs is that these are nearly exclusively used for new AEDs. Diagnostic uncertainties and methodological pressures confound analysis of these studies, which are primarily designed for justifying regulatory licence requirements rather than addressing clinical practice needs.^97–99 These issues may compromise purely evidence-based recommendations^34–37 as happened recently.³⁰ Partly as a result, such influential recommendations may mislead physicians in the appropriate use of new AEDs and inadvertently perpetuate suboptimal practice in new clinical trials. For multiple reasons, there are significant difficulties in extrapolating data from RCTs into clinical practice^97,98 as also indicated by the discrepancies between guidelines derived from such data.⁹⁶

Patient note

“New AED trials can determine the appropriate use of AEDs, but ultimately fail to determine the best use of AEDs and their exact role in treating patients. New AED trials rarely use clinically applicable measures of efficacy and it is difficult to extrapolate the data from populations used in AED trials to the wider population of patients with epilepsy. Furthermore, AED trials ignore the factors that are most likely to determine prognosis: the aetiology, seizure types and epilepsy syndrome. To resolve these issues, we need large multicentre studies in well-defined populations with well-characterised seizures, epilepsy syndromes and aetiologies. Being seizure free should be the primary measure of efficacy rather than meta-analyses and guidelines based upon incomplete data.”⁹⁷

“The studies performed to demonstrate the effectiveness of new AEDs in monotherapy in refractory partial seizure patients are difficult to interpret, because they are driven by FDA requirements to show superiority over placebo or pseudo-placebo rather than by clinical questions. The dosages used in the trials are often higher than those that might be used in practice, because the goal is to retain as many patients as possible and achieve a significant result. Most importantly, the goal of these studies is not to determine whether patients improve after they are converted to monotherapy. Rather, the goal is to determine whether they deteriorate less than the comparison group.”⁹⁸

My recommendations in this book are pragmatic in that they are based on a thorough review of the efficacy, tolerability, safety and interactions of new AEDs after examining the following:

1. Evidence-based reports, reviews and expert assessments of the treatment of children and adults with newly diagnosed or intractable focal and generalised seizures of symptomatic and idiopathic epilepsies.
2. Post-marketing open studies and case reports that have appeared as full papers or abstracts.
3. Expert physicians’ experience of the AED in clinical use that I obtained through critical discussions or correspondence with them.
4. Mechanisms of actions in animal models as supportive rather than conclusive evidence of clinical usefulness.

In these recommendations I also take into account the following.

• Investigators and practising physicians often use these agents beyond their FDA or other formally approved specific indications and specified groups of patients. It is often the case that through this undesired but pragmatically necessary practice of ‘trial by success or error’ that an AED finds its true therapeutic potential or its unsuitability in the treatment of epilepsies. This practice of off-label prescribing AEDs is encouraged in all official recommendations.^{34–37,93–96} Therefore, it is fundamental that physicians are informed regarding existing evidence (established, probable or possible but not necessarily of class 1 studies that may never be performed to provide such evidence) indicating which of the AEDs and for what type of seizures are effective or potentially useful or ineffective, contra-indicated and harmful. Table 4.1 provides a list of old and new AEDs and their indications/contra-indications for common seizure types.
• The seizure-related efficacy of each new AED is a significant factor in preferring one drug over another when both may be indicated for the same type of seizure. Table 12.4 (p. 431) provides a list of new AEDs according to their efficacy and other properties in intractable focal seizures. Figure 12.20 (p. 435) compares the efficacy versus tolerability of new AEDs in patients with intractable focal seizures.¹⁰⁰
• Physicians and patients are concerned about the quality of adverse reactions and in particular potentially disabling or even fatal risks. These risks, even if of low frequency, weigh significantly in my recommendations for or against an AED. Table 4.3 provides a list of serious and common non-serious adverse events. Note that some of the serious adverse events are potentially fatal.
• Pharmacokinetics and interactions with commonly used medications or other AEDs are particularly important in monotherapy (which may also fail) and more importantly in AED polytherapy (Tables 4.6 and 4.7).^88,89 After all, one of the requirements for new AEDs was necessitated by the complex pharmacokinetics and frequent drug interactions of old AEDs. On this I quote from a recent clinical parameter:^35,37

Table 4.6

Pharmacokinetics: Comparisons between new and important old AEDs.

Table 4.7

Metabolic pathway, effect of AEDs on hepatic enzymes and drug-drug interactions (DDI)

Patient note

“The older AEDs as a class have complex pharmacokinetics. Four of the six AEDs available prior to 1990 (phenytoin, carbamazepine, phenobarbital and primidone) are hepatic enzyme inducers. Induction not only complicates combination AED therapy but also changes internal hormonal milieu in possibly important ways. Intrinsic compounds, such as sex steroids and vitamin D, are hypermetabolised. This can lead to reproductive dysfunction and osteopenia. Enzyme-inducing AEDs produce important interactions with many commonly used medications, such as warfarin, oral contraceptives, calcium channel antagonists and chemotherapeutic agents, to name a few. Valproate, in contrast, is a potent hepatic inhibitor. There is controversy about the impact of valproate on the hormonal milieu and inhibition leads to important drug interactions with AEDs as well as other classes. The newer agents are involved in many fewer drug interactions. Many of the newer agents have little if any effect on the CYP450 enzyme system and other metabolic pathways.” ^35,37

However, such a generalisation, although correct if old and new AEDs are considered as two different ‘classes’, is inadequate without specifying that certain new AEDs have similar or even worse drug–drug interactions in relation to certain old AEDs. Tables 4.6 and 4.7 provide lists of comparative pharmacokinetic parameters, drug–drug interactions and metabolic pathways of elimination for new and some common old AEDs. It should be noted that new AEDs are not innocent. All but levetiracetam (characterised as ideal)^101,104 and gabapentin exhibit sometimes complex undesirable drug–drug interactions.

• The speed of titration and the need for less laboratory testing are additional factors that may influence the choice of the AED to be used. Very slow titration may mean more seizures, which may also be traumatic. More laboratory testing means less compliance, more expense and more uncomfortable situations for patients.

Table 4.4 provides a list of AEDs and recommendations regarding titration and the need for laboratory testing.

Table 4.8 provides a guide to clinical practice dosage schemes for AEDs. Details can be found in Chapter 14.

Table 4.8

Typical comparative single AED dosage schemes in children, adults and elderly patients in clinical practice

Surgery for Epilepsies

The surgical treatment of drug-resistant epilepsy has become increasingly more valuable and often life saving due to major advances in structural and functional neuroimaging, EEG monitoring and surgical techniques.^105–113

• The outcome from current surgical methods has improved dramatically both in classical resective surgery and new methodologies being introduced.
• Paediatric surgical outcomes have become similar to those reported for adults.
• A class 1 RCT of surgery for mesial temporal lobe epilepsy¹¹⁴ found that 64% of those who received surgery were free of disabling seizures compared with 8% free in the group randomised to continued medical therapy. Quality-of-life and social function significantly improved in the operated patients; morbidity was infrequent and there was no mortality.
• Early surgical intervention, when successful, might also prevent or reverse the disabling psychosocial consequences of uncontrolled seizures during critical periods of development.

The spectacular progress in this field is indicated by the fact that one-third (over 300 pages) of a recent book on ‘the treatment of epilepsy’ is devoted to neurosurgical approaches.⁹² Despite all this progress in the safety and outcome of these procedures, surgery in epilepsies is underused^110,115 and appropriate candidates continue to be referred to epilepsy surgery programmes late in the course of their disorder or not at all.^115,116 The reasons for this delay include the fears of the patients and physicians about surgery and undue reliability on new AEDs and vagus nerve stimulation in patients who failed to respond to appropriate medical treatment for years.¹¹⁵

The applications and outcomes of surgical interventions in certain types of intractable seizures and epileptic syndromes are detailed in the relevant chapters of this book. This section refers to general aspects of surgery in epilepsies.

Stimulation Techniques

Neural stimulation is a new technology for the treatment of medically and/or surgically intractable seizures.^138,139 Vagus nerve stimulation (VNS) is the only method currently licensed in several countries as an adjunctive therapy.

Direct deep brain stimulation is being evaluated for clinical purposes in a number of centres. The rationale is that it has been applied with some success to the cerebellum, caudate nucleus, centromedian thalamus, anterior thalamus, subthalamus, hippocampus and directly to the neocortical seizure foci. Some preliminary results are encouraging, but not conclusive and the methods are still at experimental stages.^138,139

Furthermore, systems are being developed to apply a stimulus when a seizure is impending with the aim to terminate the electrical discharge prior to serious clinical events. The hardware and software of such ‘closed loop’ systems are complex and impractical for long-term use but have still shown promise.¹⁴⁰

Transcranial magnetic stimulation is simple and non-invasive, but the therapeutic results in patients with epilepsies are equivocal at best.^141–143

References

1.

Faught E, Pellock JM, editors. Matching the medicine to the patient. Epilepsia. 2001;42(Suppl 8):1–38.

2.

Bourgeois BF. New antiepileptic drugs in children: which ones for which seizures? Clin Neuropharmacol. 2000;23:119–32. [PubMed: 10895395]

3.

Camfield PR, Camfield CS. Treatment of children with “ordinary” epilepsy. Epileptic Disord. 2000;2:45–51. [PubMed: 10937172]

4.

Kaminska A. New antiepileptic drugs in childhood epilepsies: indications and limits. Epileptic Disord. 2001;3(Suppl 2):SI37–SI46. [PubMed: 11827845]

5.

Kopec K. New anticonvulsants for use in pediatric patients (part I). J Pediat Health Care. 2001;15:81–6. [PubMed: 11246198]

6.

Pellock JM, Dodson WE, Bourgeois BFD, editors. Pediatric epilepsy. New York: Demos; 2001.

7.

Camfield P, Camfield C. Childhood epilepsy: what is the evidence for what we think and what we do? J Child Neurol. 2003;18:272–87. [PubMed: 12760431]

8.

Pellock JM. Antiepileptic Drugs in Children with Developmental Delays and Behavioral Problems. Curr Treat Options Neurol. 2003;5:121–8. [PubMed: 12628061]

9.

Willmore LJ. Choice and use of newer anticonvulsant drugs in older patients. Drugs Aging. 2000;17:441–52. [PubMed: 11200305]

10.

Tallis RC. Management of epilepsy in the elderly person. In: Shorvon S, Perucca E, Fish D, Dodson E, editors. The treatment of epilepsy. 2. Oxford: Blackwell Publishing; 2004. pp. 201–14.

11.

Bergey GK. Initial treatment of epilepsy: special issues in treating the elderly. Neurology. 2004;63:S40–S48. [PubMed: 15557550]

12.

Briggs DE, French JA. Levetiracetam safety profiles and tolerability in epilepsy patients. Expert Opin Drug Saf. 2004;3:415–24. [PubMed: 15335297]

13.

Crawford P, Appleton R, Betts T, Duncan J, Guthrie E, Morrow J. Best practice guidelines for the management of women with epilepsy. The Women with Epilepsy Guidelines Development Group. Seizure. 1999;8:201–17. [PubMed: 10452918]

14.

Morrell MJ. Epilepsy in women: the science of why it is special. Neurology. 1999;53:S42–8. [PubMed: 10487515]

15.

Bauer J, Isojarvi JI, Herzog AG, Reuber M, Polson D, Tauboll E, et al. Reproductive dysfunction in women with epilepsy: recommendations for evaluation and management. J Neurol Neurosurg Psychiatry. 2002;73:121–5. [PMC free article: PMC1737978] [PubMed: 12122167]

16.

Bruno MK, Harden CL. Epilepsy in Pregnant Women. Curr Treat Options Neurol. 2002;4:31–40. [PubMed: 11734102]

17.

Karceski S, Morrell MJ. Women with epilepsy: current treatment strategies. J Gend Specif Med. 2002;5:22–6. [PubMed: 12380197]

18.

McAuley JW, Anderson GD. Treatment of epilepsy in women of reproductive age: pharmacokinetic considerations. Clin Pharmacokinet. 2002;41:559–79. [PubMed: 12102641]

19.

Yerby MS. Management issues for women with epilepsy: neural tube defects and folic acid supplementation. Neurology. 2003;61:S23–S26. [PubMed: 14504306]

20.

Yerby MS. Clinical care of pregnant women with epilepsy: neural tube defects and folic acid supplementation. Epilepsia. 2003;44(Suppl 3):33–40. [PubMed: 12790884]

21.

Boon P, Hauman H, Legros B, Sadzot B, van Rijckevorsel K, Van Zandycke M. Belgian consensus on recommendations for standards of care for women with epilepsy before, during and after pregnancy. Acta Neurol Belg. 2004;104:6–12. [PubMed: 15143956]

22.

Tatum WO, Liporace J, Benbadis SR, Kaplan PW. Updates on the treatment of epilepsy in women. Arch Intern Med. 2004;164:137–45. [PubMed: 14744836]

23.

Kaplan PW. Reproductive health effects and teratogenicity of antiepileptic drugs. Neurology. 2004;63:S13–S23. [PubMed: 15557546]

24.

Brobtkorb E. Management of epilepsy in people with learning difficulties. In: Shorvon S, Perucca E, Fish D, Dodson E, editors. The treatment of epilepsy. 2. Oxford: Blackwell Publishing; 2004. pp. 215–26.

25.

Gil-Nagel A. Review of new antiepileptic drugs as initial therapy. Epilepsia. 2003;44(Suppl 4):3–10. [PubMed: 12823564]

26.

Hart YM. Management of newly diagnosed epilepsy. In: Shorvon S, Perucca E, Fish D, Dodson E, editors. The treatment of epilepsy. 2. Oxford: Blackwell Publishing; 2004. pp. 161–73.

27.

Perucca E. General principles of medical treatment. In: Shorvon S, Perucca E, Fish D, Dodson E, editors. The treatment of epilepsy. 2. Oxford: Blackwell Publishing; 2004. pp. 139–59.

28.

Genton P, Gelisse P, Thomas P, Dravet C. Do carbamazepine and phenytoin aggravate juvenile myoclonic epilepsy? Neurology. 2000;55:1106–9. [PubMed: 11071486]

29.

Benbadis SR, Tatum WO, Gieron M. Idiopathic generalized epilepsy and choice of antiepileptic drugs. Neurology. 2003;61:1793–5. [PubMed: 14694051]

30.

Panayiotopoulos CP, Benbadis SR, Covanis A, Dulac O, Duncan JS, Eeg-Olofsson O, et al. Efficacy and tolerability of the new antiepileptic drugs; commentary on the recently published practice parameters. Epilepsia. 2004;45:1646–9. [PubMed: 15571526]

31.

Gelisse P, Genton P, Kuate D, Pesenti A, Baldy-Moulinier M, Crespel A. Worsening of seizures by oxcarbazepine in juvenile idiopathic generalized epilepsies. Epilepsia. 2004;45:1282–8. [PubMed: 15461683]

32.

Greenwood RS. Adverse effects of antiepileptic drugs. Epilepsia. 2000;41(Suppl 2):S42–S52. [PubMed: 10885739]

33.

Gilliam FG, Fessler AJ, Baker G, Vahle V, Carter J, Attarian H. Systematic screening allows reduction of adverse antiepileptic drug effects: a randomized trial. Neurology. 2004;62:23–7. [PubMed: 14718691]

34.

French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Harden CL, et al. Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004;62:1261–73. [PubMed: 15111660]

35.

French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Harden CL, et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004;62:1252–60. [PubMed: 15111659]

36.

French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Harden CL, et al. Efficacy and Tolerability of the New Antiepileptic Drugs, II: Treatment of Refractory Epilepsy: Report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society. Epilepsia. 2004;45:410–23. [PubMed: 15101822]

37.

French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Harden CL, et al. Efficacy and Tolerability of the New Antiepileptic Drugs, I: Treatment of New-Onset Epilepsy: Report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society. Epilepsia. 2004;45:401–9. [PubMed: 15101821]

38.

French JA. Response: efficacy and tolerability of the new antiepileptic drugs. Epilepsia. 2004;45:1649–51. [PubMed: 15571526]

39.

Panayiotopoulos CP. Importance of specifying the type of epilepsy. Lancet. 1999;354:2002–3. [PubMed: 10622332]

40.

King MA, Newton MR, Jackson GD, Berkovic SF. Epileptology of the first-seizure presentation: a clinical, electroencephalographic, and magnetic imaging study of 300 consecutive patients. Lancet. 1998;352:1007–11. [PubMed: 9759742]

41.

Privitera MD, Brodie MJ, Mattson RH, Chadwick DW, Neto W, Wang S. Topiramate, carbamazepine and valproate monotherapy: double-blind comparison in newly diagnosed epilepsy. Acta Neurol Scand. 2003;107:165–75. [PubMed: 12614309]

42.

Hamer HM, Morris HH. Hypersensitivity syndrome to antiepileptic drugs: a review including new anticonvulsants. Cleve Clin J. Med. 1999;66:239–45. [PubMed: 10199060]

43.

Beller TC, Boyce JA. Prolonged anticonvulsant hypersensitivity syndrome related to lamotrigine in a patient with human immunodeficiency virus. Allergy Asthma Proc. 2002;23:415–9. [PubMed: 12528608]

44.

Baba M, Karakas M, Aksungur VL, Homan S, Yucel A, Acar MA, et al. The anticonvulsant hypersensitivity syndrome. J Eur Acad Dermatol Venereol. 2003;17:399–401. [PubMed: 12834448]

45.

Sheth RD. Metabolic concerns associated with antiepileptic medications. Neurology. 2004;63:S24–S29. [PubMed: 15557547]

46.

Nieto-Barrera M, Nieto-Jimenez M, Candau R, Ruiz dP. Anhidrosis and hyperthermia associated with treatment with topiramate. Rev Neurol. 2002;34:114–6. [PubMed: 11988904]

47.

de Carolis P, Magnifico F, Pierangeli G, Rinaldi R, Galeotti M, Cevoli S, et al. Transient hypohidrosis induced by topiramate. Epilepsia. 2003;44:974–6. [PubMed: 12823583]

48.

French JA. Antiepileptic Drugs: Don’t Sweat It! Epilepsy Curr. 2004;4:33–4. [PMC free article: PMC324584] [PubMed: 15346145]

49.

Lesser RP. Psychogenic seizures. Neurology. 1996;46:1499–507. [PubMed: 8649537]

50.

Schmidt D. Strategies to prevent overtreatment with antiepileptic drugs in patients with epilepsy. Epilepsy Res. 2002;52:61–9. [PubMed: 12445961]

51.

Chadwick D. Monotherapy comparative trials: equivalence and differences in clinical trials. Epilepsy Res. 2001;45:101–3. [PubMed: 11461807]

52.

Taylor S, Tudur S, Williamson PR, Marson AG. Phenobarbitone versus phenytoin monotherapy for partial onset seizures and generalized onset tonic-clonic seizures. Cochrane Database Syst Rev. 2001:CD002217. [PMC free article: PMC4176628] [PubMed: 11687150]

53.

French JA, Schachter S. A workshop on antiepileptic drug monotherapy indications. Epilepsia. 2002;43(Suppl 10):3–27. [PubMed: 12460242]

54.

Gilliam FG. Limitations of monotherapy trials in epilepsy. Neurology. 2003;60:S26–S30. [PubMed: 12796518]

55.

Gates JR. Using New Antiepileptic Drugs As Monotherapy. Curr Treat Options Neurol. 2004;6:223–30. [PubMed: 15043805]

56.

Kwan P, Brodie MJ. Effectiveness of first antiepileptic drug. Epilepsia. 2001;42:1255–60. [PubMed: 11737159]

57.

The renaissance of rational polytherapy: the new generation of antiepileptic medications. Neurology. 1995;45:S35–S38. [PubMed: 7898744]

58.

Schmidt D. Modern management of epilepsy: Rational polytherapy. Baillieres Clin Neurol. 1996;5:757–63. [PubMed: 9068879]

59.

Deckers CL, Czuczwar SJ, Hekster YA, Keyser A, Kubova H, Meinardi H, et al. Selection of antiepileptic drug polytherapy based on mechanisms of action: the evidence reviewed. Epilepsia. 2000;41:1364–74. [PubMed: 11077449]

60.

Gilliam F, Vazquez B, Sackellares JC, Chang GY, Messenheimer J, Nyberg J, et al. An active-control trial of lamotrigine monotherapy for partial seizures (a reply). Neurology. 2000;54:777–8. [PubMed: 9781523]

61.

Kwan P, Sills GJ, Brodie MJ. The mechanisms of action of commonly used antiepileptic drugs. Pharmacol Ther. 2001;90:21–34. [PubMed: 11448723]

62.

Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P, Bajjalieh SM, Matagne A, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci USA. 2004;101:9861–6. [PMC free article: PMC470764] [PubMed: 15210974]

63.

Baulac M. Rational conversion from antiepileptic polytherapy to monotherapy. Epileptic Disord. 2003;5:125–32. [PubMed: 14684346]

64.

Schmidt D, Elger C, Holmes GL. Pharmacological overtreatment in epilepsy: mechanisms and management. Epilepsy Res. 2002;52:3–14. [PubMed: 12445955]

65.

Commission on Antiepileptic Drugs, International League Against Epilepsy. Guidelines for therapeutic monitoring on antiepileptic drugs. Epilepsia. 1993;34:585–7. [PubMed: 8330563]

66.

Glauser TA. Expanding first-line therapy options for children with partial seizures. Neurology. 2000;55:S30–S37. [PubMed: 11147566]

67.

Glauser TA, Pippenger CE. Controversies in blood-level monitoring: reexamining its role in the treatment of epilepsy. Epilepsia. 2000;41(Suppl 8):S6–15. [PubMed: 11092608]

68.

Troupin AS. Antiepileptic drug therapy: A clinical overview. In: Wyllie E, editor. The treatment of epilepsy:Principles and practice. Philadelphia: Lea & Febiger; 1993. pp. 785–90.

69.

Tran TA, Leppik IE, Blesi K, Sathanandan ST, Remmel R. Lamotrigine clearance during pregnancy. Neurology. 2002;59:251–5. [PubMed: 12136066]

70.

de Haan GJ, Edelbroek P, Segers J, Engelsman M, Lindhout D, Devile-Notschaele M, et al. Gestation-induced changes in lamotrigine pharmacokinetics: a monotherapy study. Neurology. 2004;63:571–3. [PubMed: 15304599]

71.

Pennell PB, Newport DJ, Stowe ZN, Helmers SL, Montgomery JQ, Henry TR. The impact of pregnancy and childbirth on the metabolism of lamotrigine. Neurology. 2004;62:292–5. [PubMed: 14745072]

72.

Sabers A, Ohman I, Christensen J, Tomson T. Oral contraceptives reduce lamotrigine plasma levels. Neurology. 2003;61:570–1. [PubMed: 12939444]

73.

Contin M, Riva R, Albani F, Avoni P, Baruzzi A. Topiramate therapeutic monitoring in patients with epilepsy: effect of concomitant antiepileptic drugs. Ther Drug Monit. 2002;24:332–7. [PubMed: 12021622]

74.

Chong E, Dupuis LL. Therapeutic drug monitoring of lamotrigine. Ann Pharmacother. 2002;36:917–20. [PubMed: 11978172]

75.

Johannessen SI, Battino D, Berry DJ, Bialer M, Kramer G, Tomson T, et al. Therapeutic drug monitoring of the newer antiepileptic drugs. Ther Drug Monit. 2003;25:347–63. [PubMed: 12766564]

76.

Jannuzzi G, Cian P, Fattore C, Gatti G, Bartoli A, Monaco F, et al. A multicenter randomized controlled trial on the clinical impact of therapeutic drug monitoring in patients with newly diagnosed epilepsy. The Italian TDM Study Group in Epilepsy. Epilepsia. 2000;41:222–30. [PubMed: 10691121]

77.

Bauer J, Reuber M. Medical treatment of epilepsy. Expert Opin Emerg Drugs. 2003;8:457–67. [PubMed: 14661999]

78.

Bourgeois BF. Chronic management of seizures in the syndromes of idiopathic generalized epilepsy. Epilepsia. 2003;44(Suppl 2):27–32. [PubMed: 12752459]

79.

Coppola G. Treatment of partial seizures in childhood : an overview. CNS Drugs. 2004;18:133–56. [PubMed: 14871158]

80.

Brodie MJ, French JA. Role of levetiracetam in the treatment of epilepsy. Epileptic Disord. 2003;5(Suppl 1):S65–S72. [PubMed: 12915344]

81.

Faught E. Clinical trials for treatment of primary generalized epilepsies. Epilepsia. 2003;44(Suppl 7):44–50. [PubMed: 12919339]

82.

Nguyen DK, Spencer SS. Recent advances in the treatment of epilepsy. Arch Neurol. 2003;60:929–35. [PubMed: 12873848]

83.

Ryvlin P, Kahane P, Semah F, Hirsch E, Arzimanoglou A, Thomas P. Should new generation antiepileptic drugs be prescribed as first-line treatment of newly diagnosed epilepsy in adolescents and adults? Rev Neurol. (Paris). 2003;159:936–41. [PubMed: 14615684]

84.

Sander JW. The natural history of epilepsy in the era of new antiepileptic drugs and surgical treatment. Epilepsia. 2003;44(Suppl 1):17–20. [PubMed: 12558826]

85.

Sirven JI. The current treatment of epilepsy: a challenge of choices. Curr Neurol Neurosci Rep. 2003;3:349–56. [PubMed: 12930706]

86.

Wheless JW. Acute management of seizures in the syndromes of idiopathic generalized epilepsies. Epilepsia. 2003;44(Suppl 2):22–6. [PubMed: 12752458]

87.

Wheless JW, Sankar R. Treatment Strategies for Myoclonic Seizures and Epilepsy Syndromes with Myoclonic Seizures. Epilepsia. 2003;44(Suppl 11):27–37. [PubMed: 14641568]

88.

Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs. Lancet Neurol. 2003;2:347–56. [PubMed: 12849151]

89.

Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: interactions between antiepileptic drugs and other drugs. Lancet Neurol. 2003;2:473–81. [PubMed: 12878435]

90.

Tidwell A, Swims M. Review of the newer antiepileptic drugs. Am J Manag Care. 2003;9:253–76. [PubMed: 12643343]

91.

LaRoche SM, Helmers SL. The new antiepileptic drugs: scientific review. JAMA. 2004;291:605–14. [PubMed: 14762040]

92.

Shorvon S, Perucca E, Fish D, Dodson E, editors. The treatment of epilepsy. 2. Oxford: Blackwell Publishing; 2004. pp. 1–913.

93.

Perucca E. NICE guidance on newer drugs for epilepsy in adults. BMJ. 2004;328:1273–4. [PMC free article: PMC420157] [PubMed: 15166043]

94.

Mayor S. NICE gives guidance on use of new antiepileptic drugs in children. BMJ. 2004;328:1093. [PMC free article: PMC406346] [PubMed: 15130965]

95.

Langley PC. The NICE reference case requirement: implications for drug manufacturers and health systems. Pharmacoeconomics. 2004;22:267–71. [PubMed: 14974876]

96.

Beghi E. Efficacy and tolerability of the new antiepileptic drugs: comparison of two recent guidelines. Lancet Neurol. 2004;3:618–21. [PubMed: 15380158]

97.

Walker MC, Sander JW. Difficulties in extrapolating from clinical trial data to clinical practice: the case of antiepileptic drugs. Neurology. 1997;49:333–7. [PubMed: 9270558]

98.

Shorvon SD. The choice of drugs and approach to drug treatments in partial epilepsy. In: Shorvon S, Perucca E, Fish D, Dodson E, editors. The treatment of epilepsy. 2. Oxford: Blackwell Publishing; 2004. pp. 317–33.

99.

Mohanraj R, Brodie MJ. Measuring the efficacy of antiepileptic drugs. Seizure. 2003;12:413–43. [PubMed: 12967570]

100.

Hovinga CA. Levetiracetam: a novel antiepileptic drug. Pharmacotherapy. 2001;21:1375–88. [PubMed: 11714211]

101.

Patsalos PN. Pharmacokinetic profile of levetiracetam: toward ideal characteristics. Pharmacol Ther. 2000;85:77–85. [PubMed: 10722121]

102.

Anderson GD. Pharmacogenetics and enzyme induction/inhibition properties of antiepileptic drugs. Neurology. 2004;63:S3–S8. [PubMed: 15557548]

103.

Danielson PB. The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans. Curr Drug Metab. 2002;3:561–97. [PubMed: 12369887]

104.

Patsalos PN. The pharmacokinetic characteristics of levetiracetam. Methods Find Exp Clin Pharmacol. 2003;25:123–9. [PubMed: 12731458]

105.

Binnie CD, Polkey CE, editors. Commission on Neurosurgery of the International League Against Epilepsy (ILAE) 1993–1997: recommended standards. Epilepsia. 2000;41:1346–9. [PubMed: 11051133]

106.

Jones MW, Andermann F. Temporal lobe epilepsy surgery: definition of candidacy. Can J Neurol Sci. 2000;27(Suppl 1):S11–S13. [PubMed: 10830321]

107.

Wieser HG, Blume WT, Fish D, Goldensohn E, Hufnagel A, King D, et al. ILAE Commission Report. Proposal for a new classification of outcome with respect to epileptic seizures following epilepsy surgery. Epilepsia. 2001;42:282–6. [PubMed: 11240604]

108.

Buchhalter JR, Jarrar RG. Therapeutics in pediatric epilepsy, Part 2: Epilepsy surgery and vagus nerve stimulation. Mayo Clin Proc. 2003;78:371–8. [PubMed: 12630591]

109.

Hardy SG, Miller JW, Holmes MD, Born DE, Ojemann GA, Dodrill CB, et al. Factors predicting outcome of surgery for intractable epilepsy with pathologically verified mesial temporal sclerosis. Epilepsia. 2003;44:565–8. [PubMed: 12681006]

110.

Shaefi S, Harkness W. Current status of surgery in the management of epilepsy. Epilepsia. 2003;44(Suppl 1):43–7. [PubMed: 12558832]

111.

Zimmerman RS, Sirven JI. An overview of surgery for chronic seizures. Mayo Clin Proc. 2003;78:109–17. [PubMed: 12528886]

112.

Schmidt D, Baumgartner C, Loscher W. Seizure recurrence after planned discontinuation of antiepileptic drugs in seizure-free patients after epilepsy surgery: a review of current clinical experience. Epilepsia. 2004;45:179–86. [PubMed: 14738426]

113.

Polkey CE. Clinical outcome of epilepsy surgery. Curr Opin Neurol. 2004;17:173–8. [PubMed: 15021245]

114.

Wiebe S, Blume WT, Girvin JP, Eliasziw M. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med. 2001;345:311–8. [PubMed: 11484687]

115.

Engel J Jr, Wiebe S, French J, Sperling M, Williamson P, Spencer D, et al. Practice parameter: temporal lobe and localized neocortical resections for epilepsy. Epilepsia. 2003;44:741–51. [PubMed: 12790886]

116.

Berg AT. Understanding the delay before epilepsy surgery: who develops intractable focal epilepsy and when? CNS Spectr. 2004;9:136–44. [PubMed: 14999169]

117.

Engel J Jr. Surgery for seizures. N Engl J Med. 1996;334:647–52. [PubMed: 8592530]

118.

Wieser HG. ILAE Commission Report. Mesial temporal lobe epilepsy with hippocampal sclerosis. Epilepsia. 2004;45:695–714. [PubMed: 15144438]

119.

Schmidt D, Baumgartner C, Loscher W. The chance of cure following surgery for drug-resistant temporal lobe epilepsy What do we know and do we need to revise our expectations? Epilepsy Res. 2004;60:187–201. [PubMed: 15380563]

120.

Villemure JG, Rasmussen T. Functional hemispherectomy in children. Neuropediatrics. 1993;24:53–5. [PubMed: 8474613]

121.

Devlin AM, Cross JH, Harkness W, Chong WK, Harding B, Vargha-Khadem F, et al. Clinical outcomes of hemispherectomy for epilepsy in childhood and adolescence. Brain. 2003;126:556–66. [PubMed: 12566277]

122.

Cook SW, Nguyen ST, Hu B, Yudovin S, Shields WD, Vinters HV, et al. Cerebral hemispherectomy in pediatric patients with epilepsy: comparison of three techniques by pathological substrate in 115 patients. J Neurosurg. 2004;100:125–41. [PubMed: 14758940]

123.

Pulsifer MB, Brandt J, Salorio CF, Vining EP, Carson BS, Freeman JM. The cognitive outcome of hemispherectomy in 71 children. Epilepsia. 2004;45:243–54. [PubMed: 15009226]

124.

Rougier A, Claverie B, Pedespan JM, Marchal C, Loiseau P. Callosotomy for intractable epilepsy: overall outcome. J Neurosurg Sci. 1997;41:51–7. [PubMed: 9273859]

125.

Pendl G, Eder HG, Schroettner O, Leber KA. Corpus callosotomy with radiosurgery. Neurosurgery. 1999;45:303–7. [PubMed: 10449075]

126.

Pinard JM, Delalande O, Chiron C, Soufflet C, Plouin P, Kim Y, et al. Callosotomy for epilepsy after West syndrome. Epilepsia. 1999;40:1727–34. [PubMed: 10612336]

127.

Pressler RM, Binnie CD, Elwes RD, Polkey CE. Return of generalized seizures and discharges after callosotomy. Adv Neurol. 1999;81:171–82. [PubMed: 10609014]

128.

Kwan SY, Wong TT, Chang KP, Yang TF, Lee YC, Guo WY, et al. Postoperative seizure outcome after corpus callosotomy in reflex epilepsy. Chung Hua I Hsueh Tsa Chih (Taipei). 2000;63:240–6. [PubMed: 10746422]

129.

Morrell F, Whisler WW, Bleck TP. Multiple subpial transection: a new approach to the surgical treatment of focal epilepsy. J Neurosurg. 1989;70:231–9. [PubMed: 2492335]

130.

Smith MC, Byrne R. Multiple subpial transection in neocortical epilepsy: Part I. Adv Neurol. 2000;84:621–34. [PubMed: 11091900]

131.

Wyler AR. Multiple subpial transections in neocortical epilepsy: Part II. Adv Neurol. 2000;84:635–42. [PubMed: 11091901]

132.

Mulligan LP, Spencer DD, Spencer SS. Multiple subpial transections: the Yale experience. Epilepsia. 2001;42:226–9. [PubMed: 11240594]

133.

Polkey CE. Multiple subpial transection: a clinical assessment. Int Rev Neurobiol. 2001;45:547–69. [PubMed: 11130916]

134.

Shimizu T, Maehara T, Hino T, Komori T, Shimizu H, Yagishita A, et al. Effect of multiple subpial transection on motor cortical excitability in cortical dysgenesis. Brain. 2001;124:1336–49. [PubMed: 11408329]

135.

Faught E. Collective Data Supports Efficacy of Multiple Subpial Transection. Epilepsy Curr. 2002;2:108. [PMC free article: PMC321030] [PubMed: 15309133]

136.

Spencer SS, Schramm J, Wyler A, O’Connor M, Orbach D, Krauss G, et al. Multiple subpial transection for intractable partial epilepsy: an international meta-analysis. Epilepsia. 2002;43:141–5. [PubMed: 11903459]

137.

Morrell F, Whisler WW, Smith MC, Hoeppner TJ, de Toledo-Morrell L, Pierre-Louis SJ, et al. Landau-Kleffner syndrome. Treatment with subpial intracortical transection. Brain. 1995;118:1529–46. [PubMed: 8595482]

138.

Theodore WH, Fisher RS. Brain stimulation for epilepsy. Lancet Neurol. 2004;3:111–8. [PubMed: 14747003]

139.

Chkhenkeli SA, Sramka M, Lortkipanidze GS, Rakviashvili TN, Bregvadze ES, Magalashvili GE, et al. Electrophysiological effects and clinical results of direct brain stimulation for intractable epilepsy. Clin Neurol Neurosurg. 2004;106:318–29. [PubMed: 15297008]

140.

Goodman JH. Brain stimulation as a therapy for epilepsy. Adv Exp Med Biol. 2004;548:239–47. [PubMed: 15250598]

141.

Tassinari CA, Cincotta M, Zaccara G, Michelucci R. Transcranial magnetic stimulation and epilepsy. Clin Neurophysiol. 2003;114:777–98. [PubMed: 12738425]

142.

Theodore WH. Transcranial Magnetic Stimulation in Epilepsy. Epilepsy Curr. 2003;3:191–7. [PMC free article: PMC321221] [PubMed: 15346149]

143.

Brasil-Neto JP, de Araujo DP, Teixeira WA, Araujo VP, Boechat-Barros R. Experimental therapy of epilepsy with transcranial magnetic stimulation: lack of additional benefit with prolonged treatment. Arq Neuropsiquiatr. 2004;62:21–5. [PubMed: 15122428]

144.

Ben Menachem E. Vagus-nerve stimulation for the treatment of epilepsy. Lancet Neurol. 2002;1:477–82. [PubMed: 12849332]

145.

Boon P, Vonck K, De Reuck J, Caemaert J. Vagus nerve stimulation for refractory epilepsy. Seizure. 2002;11(Suppl A):448–55. [PubMed: 12185767]

146.

George MS, Nahas Z, Bohning DE, Kozel FA, Anderson B, Chae JH, et al. Vagus nerve stimulation therapy: a research update. Neurology. 2002;59:S56–S61. [PubMed: 12270970]

147.

Heck C, Helmers SL, DeGiorgio CM. Vagus nerve stimulation therapy, epilepsy, and device parameters: scientific basis and recommendations for use. Neurology. 2002;59:S31–S37. [PubMed: 12270966]

148.

Henry TR. Therapeutic mechanisms of vagus nerve stimulation. Neurology. 2002;59:S3–14. [PubMed: 12270962]

149.

Privitera MD, Welty TE, Ficker DM, Welge J. Vagus nerve stimulation for partial seizures. Cochrane Database Syst Rev. 2002:CD002896. [PubMed: 11869641]

150.

Schachter SC. Vagus nerve stimulation: where are we? Curr Opin Neurol. 2002;15:201–6. [PubMed: 11923636]

151.

Schachter SC. Vagus nerve stimulation therapy summary: five years after FDA approval. Neurology. 2002;59:S15–S20. [PubMed: 12270963]

152.

Wilber DJ, Morton JB. Vagal stimulation and atrial fibrillation: experimental models and clinical uncertainties. J Cardiovasc Electrophysiol. 2002;13:1280–2. [PubMed: 12521346]

153.

Frost M, Gates J, Helmers SL, Wheless JW, Levisohn P, Tardo C, et al. Vagus nerve stimulation in children with refractory seizures associated with Lennox-Gastaut syndrome. Epilepsia. 2001;42:1148–52. [PubMed: 11580762]

154.

Helmers SL, Wheless JW, Frost M, Gates J, Levisohn P, Tardo C, et al. Vagus nerve stimulation therapy in pediatric patients with refractory epilepsy: retrospective study. J Child Neurol. 2001;16:843–8. [PubMed: 11732771]

155.

Parker AP, Polkey CE, Robinson RO. Vagal nerve stimulation in the epileptic encephalopathies: 3-year follow-up. Pediatrics. 2001;108:221. [PubMed: 11452969]

156.

Winston KR, Levisohn P, Miller BR, Freeman J. Vagal nerve stimulation for status epilepticus. Pediatr Neurosurg. 2001;34:190–2. [PubMed: 11359111]

157.

Binnie CD. Vagus nerve stimulation for epilepsy: a review. Seizure. 2000;9:161–9. [PubMed: 10775511]

158.

Murphy JV, Wheless JW, Schmoll CM. Left vagal nerve stimulation in six patients with hypothalamic hamartomas. Pediatr Neurol. 2000;23:167–8. [PubMed: 11020644]

159.

Aicardi J. Vagal nerve stimulation in epileptic encephalopathies. Pediatrics. 1999;103:821–2. [PubMed: 10103314]

160.

Camfield PR, Camfield CS. Vagal nerve stimulation for treatment of children with epilepsy [editorial] J Pediatr. 1999;134:532–3. [PubMed: 10228282]

161.

Parker AP, Polkey CE, Binnie CD, Madigan C, Ferrie CD, Robinson RO. Vagal nerve stimulation in epileptic encephalopathies. Pediatrics. 1999;103:778–82. [PubMed: 10103302]

162.

Fisher RS, Krauss GL, Ramsay E, Laxer K, Gates J. Assessment of vagus nerve stimulation for epilepsy: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 1997;49:293–7. [PubMed: 9222210]

163.

McLachlan RS. Vagus nerve stimulation for intractable epilepsy: a review. J Clin Neurophysiol. 1997;14:358–68. [PubMed: 9415383]

164.

Buoni S, Mariottini A, Pieri S, Zalaffi A, Farnetani MA, Strambi M, et al. Vagus nerve stimulation for drug-resistant epilepsy in children and young adults. Brain Dev. 2004;26:158–63. [PubMed: 15030903]

165.

Holmes MD, Silbergeld DL, Drouhard D, Wilensky AJ, Ojemann LM. Effect of vagus nerve stimulation on adults with pharmacoresistant generalized epilepsy syndromes. Seizure. 2004;13:340–5. [PubMed: 15158706]

166.

Uthman BM, Reichl AM, Dean JC, Eisenschenk S, Gilmore R, Reid S, et al. Effectiveness of vagus nerve stimulation in epilepsy patients: a 12-year observation. Neurology. 2004;63:1124–6. [PubMed: 15452317]

167.

Park YD. The effects of vagus nerve stimulation therapy on patients with intractable seizures and either Landau-Kleffner syndrome or autism. Epilepsy Behav. 2003;4:286–90. [PubMed: 12791330]

168.

Sheth RD, Stafstrom CE. Intractable pediatric epilepsy: vagal nerve stimulation and the ketogenic diet. Neurol. Clin. 2002;20:1183–94. [PubMed: 12616687]