Clinical aspects

Treatment approach. The majority of newly diagnosed patients will have a good prognosis and become seizure-free with the first or second monotherapy, often requiring no more than modest or moderate drug doses (51; 06; 56; 14). They should be started on a single drug at low dose with increments over a number of weeks to establish an effective and tolerable regimen. Further dose adjustment can be made according to clinical response. An alternative drug is unavoidable when the patient develops intolerable adverse events. When and how to combine antiepileptic drugs remains controversial. Many authorities agree that it would be appropriate to consider combination therapy after 2 monotherapy attempts because the chance of success with a third drug is slim (17; 52; 07; 56; 30). Failure of 2 treatment schedules should prompt referral to a specialist center for further evaluation, including video-EEG telemetry to confirm the seizure or syndrome classifications, optimization of pharmacotherapy, and consideration of other therapeutic options, particularly epilepsy surgery.

Before 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 any imitators of epileptic seizures.
	2. The epileptic seizures of the patient need treatment. This requires precise diagnosis of the epileptic syndrome and the type of seizures, their frequency and severity, their likelihood of relapse or remission, precipitating factors and the patient and family concerns and understanding of the risks versus benefits of the antiepileptic drug. Hard and fast rules are not always applicable.
	3. The most appropriate antiepileptic drug is selected for this particular patient with this particular type of seizure. The appropriate antiepileptic drug is that which is the most likely of all others to be truly prophylactic as monotherapy (single­drug treatment) for the seizures of the patient without causing undue adverse drug reactions. Carefully consider and exclude antiepileptic drugs that may worsen or be ineffective in this particular type of seizures.
	4. The starting dose and titration of the selected drug should be in accordance with the appropriate recommendations, the age, and, primarily, the particular needs of the treated patient.

All these should be thoroughly explained to the patient or guardian, and it should be ensured they fully understand.

Drug selection. Not only do antiepileptic drugs differ in the way they work, they vary substantially in their efficacy and side-effect profiles. The ideal profile of a first­choice antiepileptic drug in the prophylactic treatment of epilepsies is determined by a number of factors (Table 2). The importance of these factors varies significantly according to whether the antiepileptic drug is used in monotherapy or polytherapy. A first-choice drug should have a spectrum of activity and side-effect and interaction profiles that has the potential to produce seizure freedom without intolerable toxicity and long-term sequelae for that individual. The choice should be matched to the patient's seizure type or epilepsy syndrome, age, gender, weight, psychiatric history, other disease states, concomitant medication, and lifestyle (16; 56). Therefore, this decision should be based on a thorough clinical history and physical examination aided by laboratory findings, including the EEG and brain imaging. The “package insert” (Food and Drug Administration in the United States) and the “summary of product characteristics” (European Medicines Agency in the European Union) are the most complete single sources of information on a drug. The package insert can be obtained from http://dailymed.nlm. The summary of package characteristics can be obtained in any European language from http://www.ema.europa.eu/ema. In United Kingdom these are also available from http://emc. medicines.org.uk.

Table 2. Factors of Antiepileptic Drugs to Consider When Prioritizing Their Use

• Seizure specificity • Strength of efficacy • Spectrum of efficacy • Safety • Tolerability • Adverse reactions (particularly if these are severe and life threatening) • Pharmacokinetics • Pharmacodynamics • Drug-drug interactions • Mechanisms of action • Speed of titration (time needed to reach effective dose) • Need for laboratory testing • Frequency of administration and ease of use • Cost of treatment

The antiepileptic drug indications for the treatment of epileptic seizures according to the Food and Drug Administration package inserts are as follows. Please note that these indications are not the same with those of the European Medicines Agency and are often significantly different from the prevailing clinical practice (Table 3).

Brivaracetam. Treatment of partial onset seizures in patients 16 years of age and older with epilepsy.

Carbamazepine

	1. Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures appear to show greater improvement than those with other types.
	2. Generalized tonic-clonic seizures (grand mal).
	3. Mixed seizure patterns that include the above or other partial or generalized seizures. Absence seizures (petit mal) do not appear to be controlled by carbamazepine

Clobazam. Adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 years of age or older.

Clonazepam. Adjunct in the treatment of the Lennox-Gastaut syndrome (petit mal variant) as well as akinetic and myoclonic seizures. In patients with absence seizures (petit mal) who have failed to respond to succinimides, clonazepam may be useful.

Divalproex sodium. Monotherapy and adjunctive therapy in the treatment of adult patients and pediatric patients as young as 10 years of age with:

	1. Complex partial seizures that occur either in isolation or in association with other types of seizures.
	2. Simple and complex absence seizures--and adjunctively in patients with multiple seizure types that include absence seizures.

Eslicarbazepine acetate. Treatment of partial-onset seizures in patients 4 years of age and older.

Ethosuximide. Treatment of absence (petit mal) epilepsy.

Felbamate. Felbamate is not indicated as a first-line antiepileptic treatment. Felbamate is recommended for use only in those patients who respond inadequately to alternative treatments and whose epilepsy is so severe that a substantial risk of aplastic anemia and/or liver failure is deemed acceptable in light of the benefits conferred by its use.

If these criteria are met and the patient has been fully advised of the risk and has provided written acknowledgement, felbamate can be considered for either monotherapy or adjunctive therapy in the treatment of partial seizures, with and without generalization, in adults with epilepsy and as adjunctive therapy in the treatment of partial and generalized seizures associated with Lennox-Gastaut syndrome in children.

Gabapentin. Adjunctive therapy in the treatment of:

	1. Partial seizures with and without secondary generalization in patients over 12 years of age with epilepsy.
	2. Partial seizures in pediatric patients age 3 to 12 years.

Lacosamide. Monotherapy or adjunctive therapy in patients 17 years and older with partial-onset seizures as adjunctive therapy. Injection for intravenous use is an alternative when oral administration is temporarily not feasible.

Lamotrigine. Adjunctive therapy for the following seizure types in patients 2 years of age or older: partial seizures, primary generalized tonic-clonic seizures, generalized seizures of Lennox-Gastaut syndrome.

Conversion to monotherapy in adults (16 years of age and older) with partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug.

Safety and effectiveness of lamotrigine tablets have not been established (1) as initial monotherapy; (2) for conversion to monotherapy from antiepileptic drugs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate; or (3) for simultaneous conversion to monotherapy from 2 or more concomitant antiepileptic drugs.

Levetiracetam. Adjunctive therapy in the treatment of:

	1. Partial onset seizures in adults and children 4 years of age and older with epilepsy.
	2. Myoclonic seizures in adults and adolescents 12 years of age and older with juvenile myoclonic epilepsy.
	3. Primary generalized tonic-clonic seizures in adults and children 6 years of age and older with idiopathic generalized epilepsy.

Oxcarbazepine.

	1. Monotherapy or adjunctive therapy in the treatment of partial seizures in adults.
	2. Monotherapy in the treatment of partial seizures in children aged 4 years and above.
	3. Adjunctive therapy in children aged 2 years and above with partial seizures.

Perampanel.

	1. Treatment of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy 12 years of age and older.
	2. Adjunctive therapy for the treatment of primarily generalized tonic-clonic seizures in patients with epilepsy 12 years of age and older.

Phenobarbital. Treatment of generalized and partial seizures.

Phenytoin. Treatment of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures and prevention and treatment of seizures occurring during or following neurosurgery.

Pregabalin. Adjunctive therapy for adult patients with partial onset seizures.

Primidone. Monotherapy or adjunctive treatment of grand mal, psychomotor, and focal epileptic seizures. It may control grand mal seizures refractory to other anticonvulsant therapy.

Rufinamide. Adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in pediatric patients 1 year of age and older and in adults.

Tiagabine hydrochloride. Adjunctive therapy in adults and children 12 years and older in the treatment of partial seizures.

Topiramate.

	1. Initial monotherapy in patients 2 years of age and older with partial onset or primary generalized tonic-clonic seizures.
	2. Adjunctive therapy for adults and pediatric patients ages 2 to 16 years with partial onset seizures or primary generalized tonic-clonic seizures, and in patients 2 years of age and older with seizures associated with Lennox-Gastaut syndrome.

Valproic acid.

	1. Monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures.
	2. Monotherapy and adjunctive therapy in the treatment of simple and complex absence seizures.
	3. Adjunctively in patients with multiple seizure types, including absence seizures.

Vigabatrin.

	1. Adjunctive therapy for adults and pediatric patients 10 years of age and older with refractory complex partial seizures who have inadequately responded to several alternative treatments and for whom the potential benefits outweigh the risk of vision loss. It is not indicated as a first-line agent for complex partial seizures.
	2. Monotherapy for pediatric patients with infantile spasms 1 month to 2 years of age for whom the potential benefits outweigh the potential risk of vision loss.

Zonisamide. Adjunctive therapy in the treatment of partial seizures in adults with epilepsy.

Table 3. Efficacy of Antiepileptic Drugs in Seizure Types

Antiepileptic drugs	Focal seizures (simple or complex)	Secondarily GTCSs	Primarily GTCSs	Myoclonic jerks	Absence seizures
Brivaracetam	Effective	Effective	Unknown	Effective?	Unknown
Carbamazepine	Effective	Effective	Effective	May exaggerate	May exaggerate
Clobazam	Effective	Effective	Effective?	Effective?	Effective?
Clonazepam	Effective?	Effective?	Ineffective?	Effective	Effective
Eslicarbazepine	Effective	Effective	Unknown	Unknown	Unknown
Ethosuximide	-	-	-	Effective?	Effective
Gabapentin	Effective	Effective	-	-	May exaggerate
Lacosamide	Effective	Effective	Unknown	Unknown	Unknown
Lamotrigine	Effective	Effective	Effective	May exaggerate	Effective
Levetiracetam	Effective	Effective	Effective	Effective	Effective
Oxcarbazepine	Effective	Effective	Effective	-	-
Perampanel	Effective	Effective	Effective	Unknown	Unknown
Phenobarbital	Effective	Effective	Effective	Effective	-
Phenytoin	Effective	Effective	Effective	-	-
Pregabalin	Effective	Effective	-	Exaggerates	-
Tiagabine	Effective	Effective	-	-	Exaggerates
Topiramate	Effective	Effective	Effective	Effective?	Effective?
Valproate	Effective	Effective	Effective	Effective	Effective
Vigabatrin	Effective	Effective	-	-	Exaggerates
Zonisamide	Effective	Effective	Effective?	Effective?	Effective?

This table is based predominantly on clinical information, literature reviews, and the summaries of product characteristics and product inserts. Modified from Panayiotopoulos (56). Common dosing of antiepileptic drugs is given in Table 4. Pharmacological properties for each drug are provided in Table 5.

Table 4. Dosing Guidelines for Antiepileptic Drugs Monotherapy in Adolescents and Adults

Drug	Starting dose (mg/day)	Commonest dose (mg/day)	Maintenance dose (mg/day)	Usual dosing interval
Established antiepileptic drugs
Carbamazepine Clobazam Clonazepam Ethosuximide Phenobarbital Phenytoin Primidone Sodium valproate	200 10 0.5 250 50 100 125 500	600 20 4 1000 100 300 500 1000	800-1200 10-40 2-8 500-1500 50-200 100-500 250-1500 1000-3000	2 times daily 1 times daily* 1-2 times daily 2-3 times daily 1times daily 1times daily 1-2 times daily 2 times daily
Newer antiepileptic drugs
Brivaracetam Eslicarbazepine Felbamate Gabapentin Lacosamide Lamotrigine Levetiracetam Oxcarbazepine Perampanel Pregabalin Rufinamide Tiagabine Topiramate Vigabatrin Zonisamide	50 400 1200 300-400 100 12.5-25 500 600 2-4 150 400 4-5 25-50 500 100	100 800 2400 2400 200 200-400 2000 900-1200 4-8 300 1600 40 200-400 2000 400	100-200 800-1200 1800-3600 1200-3600 200-400 100-500 1000-4000 900-1200 4-12 150-600 400-3200 20-60 100-600 2000-3000 400-600	2 times daily 1 time daily 3-4 times daily 3 times daily 2 times daily 1-3 times daily 2 times daily 2-3 times daily 1 time daily 2-3 times daily 2 times daily 2-4 times daily 2 times daily 1-2 times daily 1-2 times daily

* The FDA recommends its use as 2 times daily.

Efficacy and tolerability. The profile of activity against different seizure types varies among the antiepileptic drugs (Table 3). In addition, certain epilepsy syndromes have been found to be particularly responsive to specific antiepileptic drugs. For instance, juvenile myoclonic epilepsy responds well to valproate and levetiracetam, whereas vigabatrin is regarded by many as the drug of choice for infantile spasms. A double-blind randomized controlled trial showed that ethosuximide and valproic acid were more effective than lamotrigine for childhood absence epilepsy (29). Therefore, it is of paramount importance to classify accurately the seizure type and epilepsy syndrome and choose the most appropriate drug for that individual.

Systematic reviews of randomized, controlled trials comparing phenobarbital, primidone, phenytoin, carbamazepine, and valproate for partial and tonic-clonic seizures identified no significant difference in efficacy among these established antiepileptic drugs, with the possible exception of a small benefit of carbamazepine over valproate for partial seizures (45). Phenobarbital and primidone produced higher withdrawal rates due to their sedative effect, although these drugs are often well tolerated at moderate dosing in clinical practice.

None of the newer antiepileptic drugs have demonstrated superior efficacy when tested against the established agents in monotherapy studies for the treatment of newly diagnosed partial and tonic-clonic seizures. Evidence of better tolerability has been shown in some cases, in particular fewer neurotoxic side effects. Thus, lamotrigine and oxcarbazepine showed better overall effectiveness than carbamazepine and phenytoin, respectively.

Based on the findings from randomized, controlled trials, various national and international guidelines have been developed for the use of antiepileptic drugs as initial monotherapy for epilepsy. These guidelines focus on the efficacy and effectiveness aspects in the process of drug selection (25; 28; 54).

These guidelines are valuable in providing a working framework for the treatment of newly onset epilepsy. The differences in their recommendations may reflect fundamental differences in the purposes of the guidelines and in the approaches adopted by the groups developing them. It is important to bear in mind that these treatment guidelines focus on short-term efficacy and effectiveness evidence alone, and other patient-related factors, discussed below, must be considered when choosing the most appropriate treatment for the individual patient. Continuous advances in drug development also mean that these guidelines become rapidly outdated.

Table 5. Pharmacological Properties of Antiepileptic Drugs

Drug	Absorption (bioavailability %)	Protein binding (% bound)	Elimination half-life (hours)	Routes of elimination
Older antiepileptic drugs
Carbamazepine	Slow (75-80)	70-80	24-45 (single) 8-24 (chronic)	Hepatic metabolism Active metabolite
Clobazam	Rapid (90-100)	87-90	10-30	Hepatic metabolism Active metabolite
Clonazepam	Rapid (80-90)	80-90	30-40	Hepatic metabolism
Ethosuximide	Rapid (90-95)	0	20-60	Hepatic metabolism 25% excreted unchanged
Phenobarbital	Slow (95-100)	48-54	72-144	Hepatic metabolism 25% excreted unchanged
Phenytoin	Slow (85-90)	90-93	9-40	Saturable hepatic metabolism
Primidone	Rapid (90-100)	20-30	4-12	Hepatic metabolism Active metabolites 40% excreted unchanged
Valproate	Rapid (100)	88-92	7-17	Hepatic metabolism Active metabolite
Newer antiepileptic drugs
Brivaracetam	Rapid (100)	≤ 20%	9	Hydrolysis Renal excretion
Eslicarbazepine acetate ‡	Rapid (90)	40	13 - 20	Glucuronidation Renal excretion
Felbamate	Slow (95-100)	22-36	13-23	Hepatic metabolism Renal excretion
Gabapentin ‡	Slow (60)	0	6-9	Not metabolized Renal excretion
Lacosamide ‡	Rapid (95-100)	< 15	13	Hepatic metabolism 40% excreted unchanged
Lamotrigine	Rapid (95-100)	55	22-36	Glucuronidation
Levetiracetam	Rapid (95-100)	< 10	7-8	Non-hepatic hydrolysis Renal excretion
Oxcarbazepine	Rapid (95-100)	40†	8-10†	Hepatic conversion to active moiety
Perampanel	Rapid (95-100)	95	105	Hepatic primary oxidation and sequential glucuronidation
Pregabalin ‡	Rapid (90-100)	0	6	Renal excretion
Rufinamide	Slow	34	6-10	Hepatic metabolism
Tiagabine ‡	Rapid (95-100)	96	5-9	Hepatic metabolism
Topiramate	Slow (80)	9-17	20-24	Hepatic metabolism Renal excretion
Vigabatrin	Slow (60-80)	0	5-7	Not metabolized Renal excretion
Zonisamide	Rapid (95-100)	40-60	50-68	Hepatic metabolism Renal excretion

Polytherapy. Given that most patients respond to their first or second antiepileptic drug, combination therapy should usually be considered after failure of 2 monotherapy regimens due to lack of efficacy. If poor tolerability is the problem, a third monotherapy could reasonably be tried. Some patients experiencing many seizures immediately before diagnosis may be best treated with combination therapy following a partial response to the first antiepileptic drug, particularly if an underlying anatomical problem, such as cortical dysplasia or hippocampal atrophy, has been identified (37).

When making a decision about polytherapy, one should first scrutinize the possible or probable reasons why the monotherapy failed. The following possibilities, which often require re­evaluation of diagnosis (genuine epileptic seizures? what type of seizures?), would be considered (56):

	• The patient does not suffer from epileptic seizures.
	• The patient has both genuine epileptic and nonepileptic seizures.
	• The patient has focal and no generalized seizures or vice versa.
	• The antiepileptic drug used as monotherapy was not suitable for the particular type of seizures in this patient because of contraindications (tiagabine or carbamazepine in absences or myoclonic jerks and lamotrigine in myoclonic epilepsies), weak efficacy (valproate or GABA in in focal seizures), or total ineffectiveness (gabapentin in primarily GTCSs).
	• The patient is noncompliant. Noncompliance varies from unwillingness to take medication to occasionally forgetting or missing the antiepileptic drug dose or violating particularly eminent seizure­precipitating factors, such as photic stimulation, sleep deprivation, and alcohol or drug abuse.

The ideal profile of an antiepileptic drug for polypharmacy includes all the factors that are important for monotherapy (Table 2), but with particular emphasis on the following points (56):

Strength of efficacy. This may be increased or weakened by pharmacokinetic and pharmacodynamic interactions.

Safety and tolerability. These are often worsened by pharmacokinetic and pharmacodynamic interactions.

Drug interactions. Interactions with other antiepileptic drugs, whether pharmacokinetic, pharmacodynamic, or both, are particularly unwanted in polytherapy. Raising the levels of concomitant antiepileptic drugs and pharmacodynamic interactions may lead to toxic effects. Conversely, decreasing their levels may increase and worsen seizures causing a vicious cycle in clinical management. With the exception of lacosamide, levetiracetam, and gabapentin, most of the newer antiepileptic drugs exhibit sometimes complex, undesirable, drug-to-drug interactions. For example, consider that lamotrigine:

	• requires different dosage and titration schemes when combined with hepatic enzyme inducers and when combined with valproate.
	• pharmacodynamic interactions enhance toxicity and teratogenicity (although pharmacodynamic interactions have a beneficial effect on efficacy).
	• levels lower more than half during pregnancy or hormonal contraception.

Different mechanisms of action in relation to other concurrent antiepileptic drugs (Table 8). Antiepileptic drug-to-drug interactions may be purely additive, antagonistic, or synergistic. Antiepileptic drugs with the same mechanism of action would be expected to be additive, whereas combining antiepileptic drugs with different mechanisms of action may have synergistic effects. A sodium channel blocker antiepileptic drug combined with another that increases the GABA­ergic neuro transmission or that has multiple mechanisms is generally more effective than a combination of 2 sodium channel blockers (21; 17; 38). An antiepileptic drug is unlikely to have better success and more likely to have additive adverse drug reactions if added to another antiepileptic drug with the same mechanism of action.

The risks of polytherapy include:

• more adverse drug reactions • frequent unwanted interactions with other drugs • an increased risk of teratogenicity • inability to evaluate the efficacy and adverse drug reactions of individual antiepileptic drug agents • poor compliance.

Converting from polytherapy to monotherapy. Evidence from studies with older and newer antiepileptic drugs shows that a significant number of patients can be converted successfully from polytherapy to monotherapy without losing seizure control and, in some cases, with improved seizure control. In these cases, the antiepileptic drug that appears, after careful consideration, to be the least effective is gradually withdrawn. “Gradually” sometimes means in steps of weeks or months. This should be particularly slow for certain antiepileptic drugs, such as phenobarbital and benzodiazepines, in order to avoid withdrawal seizures.

Drug-to-drug interactions. Antiepileptic drug interactions are an important consideration in the treatment of epilepsy and, indeed, can be a major therapeutic challenge. The principal pharmacokinetic interaction relates to hepatic enzyme induction or inhibition whilst pharmacodynamic interactions principally entail adverse effect synergism, although examples of anticonvulsant synergism also exist. The older antiepileptic drugs are commonly associated with pharmacokinetic interactions by inducing the synthesis of a range of monooxygenase and conjugating enzymes (phenobarbital, primidone, phenytoin, and carbamazepine, in particular, accelerate the breakdown of many commonly prescribed lipid-soluble drugs, including oral contraceptives and warfarin). Valproate is a weak enzyme inhibitor, which can slow the clearance of other antiepileptic drugs, such as phenytoin and lamotrigine. Hepatic enzyme induction stimulates the production and increases the amount of CYP enzymes. This, in turn, increases the rate of metabolism of drugs metabolized by the CYP enzymes, thus, resulting in lower plasma concentrations. Conversely, hepatic enzyme inducers may increase the bioavailability of drugs that require metabolism for their activation. The effect of hepatic induction, unlike hepatic inhibition persists for several days following the withdrawal of the enzyme-inducing drug.

Some of the new antiepileptic drugs are less interacting primarily because many are renally excreted or not hepatically metabolized (eg, gabapentin, lacosamide, levetiracetam, topiramate, vigabatrin) and most do not (or minimally) induce or inhibit hepatic metabolism. The least pharmacokinetic interactions are associated with gabapentin, lacosamide, tiagabine, vigabatrin, and zonisamide, whereas lamotrigine, felbamate, oxcarbazepine, and rufinamide are associated with the most. To date, felbamate, gabapentin, oxcarbazepine, perampanel, pregabalin, rufinamide, stiripentol, and zonisamide have not been associated with any pharmacodynamic interactions (57).

Pharmacodynamics refers to the biochemical and physiological effects of drugs and their mechanisms of action. They may be additive, synergistic, or antagonistic. They may be beneficial, detrimental or both, as exemplified by lamotrigine combined with valproate (increased therapeutic efficacy but also increased risk of adverse drug reactions and teratogenicity).

Therapeutic drug monitoring. Monitoring of circulating concentrations of antiepileptic drugs became possible in the late 1960s, initially as a research tool but was rapidly adopted for widespread clinical use largely because phenytoin was shown to undergo saturation kinetics (62). It is important to bear in mind that the commonly quoted “therapeutic” or “reference” range has a probabilistic meaning; that is, it refers to the serum concentrations at which the majority of patients can be expected to show a response without undue adverse effects. Some patients will do well with drug concentrations below the lower limit of the range whereas others will tolerate amounts exceeding the upper level with benefit and without toxicity (58; 41). Therefore, the dose should not be increased or reduced just to attain a defined “therapeutic” concentration in patients who are seizure- and side-effect-free.

The ILAE position paper of 2008 is a practice guideline for therapeutic drug monitoring and is highly recommended for further reading (58). It also provides pharmacokinetic details, interactions with other antiepileptic drugs, and reference ranges for each antiepileptic drug and discusses the role of therapeutic drug monitoring in children and the elderly and during pregnancy.

Serum drug monitoring is best performed with a specific clinical question in mind. Situations in which serum drug monitoring are most likely to be of benefit include: (1) when a person has attained the desired clinical outcome, to establish an individual therapeutic concentration that can be used at subsequent times to assess potential causes for a change in drug response; (2) as an aid in the diagnosis of clinical toxicity; (3) to assess compliance; (4) to guide dosage adjustment in situations associated with increased pharmacokinetic variability (eg, children, the elderly, patients with associated diseases, drug formulation changes); (5) when a potentially important pharmacokinetic change is anticipated (eg, in pregnancy or when an interacting drug is added or removed); (6) to guide dose adjustments for antiepileptic drugs with dose-dependent pharmacokinetics, particularly phenytoin (58).

Monitoring the circulating concentration is of greatest value with agents that exhibit nonlinear pharmacokinetics, in particular phenytoin. Increases and decreases in dosing may result in disproportionately large changes in serum concentration. Substantial variation in carbamazepine levels over the course of a day--as much as 100% with twice-daily dosing--makes interpretation problematic unless the timing of dosing and blood sampling are standardized. Because valproate does not exhibit a clear-cut concentration-effect-toxicity relationship, monitoring of this drug is not very helpful. Concentration-response-toxicity studies with the newer antiepileptic drugs have not demonstrated consistent correlations between circulating levels and efficacy or side effects (31).

Trough antiepileptic drug plasma levels are important with regard to efficacy, whereas peak antiepileptic drug plasma levels are important with regard to toxicity.

Generic versus brand or generic-to-generic antiepileptic drug prescribing. There is considerable concern among physicians and patients about the efficacy and safety of brand-to-generic antiepileptic drug substitution or vice versa and also from one to another generic drug of different manufacturers (49). These concerns have been reasonably raised because of well-documented breakthrough seizures, emergency-treated epilepsy events, and toxicity as a result of such substitutions.

Substitution from one to another antiepileptic drug of the same active substance is safe only when these are of therapeutic equivalence; drug products are considered to be therapeutic equivalents if they can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labelling. However, even when the generic product is from a reliable source (something that is beyond the role of prescribing physicians) there may be problems with their therapeutic equivalence, particularly in terms of bioavailability and pharmacokinetic profiles.

Antiepileptic drugs are particularly vulnerable in these changes because most have a narrow reference concentration index between drug levels that are therapeutic and those that may cause adverse drug reactions.

“For antiepileptic drugs, small variations in concentrations between name brands and their generic equivalents can cause toxic effects or seizures when taken by patients with epilepsy. The American Academy of Neurology believes that the authorities should give complete physician autonomy in prescribing antiepileptic drugs” (49). It is because of these problems that formal recommendations worldwide uniformly warn against such substitutions of antiepileptic drugs.

A patient who is stabilized with an antiepileptic drug in terms of seizure control and minimal adverse drug reactions should remain in the same brand or the particular generic product; interchanging products introduces risk.

When an antiepileptic drug is first prescribed, it can be a brand name or a generic product providing that the latter has been truly tested in regard to the credibility of its manufacturers and bioequivalence with the brand product. Titration and maintenance should be with the same antiepileptic drug product.

It is unreasonable to switch from one to another antiepileptic drug, either from an expensive branded antiepileptic drug to a cheaper bioequivalent generic product or vice versa. Switching is unnecessary and may impose significant risk to the patient. When such substitution is attempted, the patient should be well informed of possible consequences, such as seizure relapse or adverse drug reactions.

Prescriptions should clearly indicate the type of antiepileptic drug formulation to be used, even for generic products (20; 56; 60). However, generic antiepileptic drugs with Food and Drug Administration-validated bioequivalence appear to be safe clinical choices (32; 61).

Indications

Depending on study methodology and inclusion criteria, the chance of recurrence after a single unprovoked seizure reported in the literature ranges from 23% to 71% (09). Because a substantial proportion of patients will not have further episodes, and randomized studies suggest that early treatment does not improve prognosis (53; 44), most specialists do not recommend antiepileptic drug therapy after a single seizure. However, when the chance of recurrence is high, eg, in the presence of an underlying cerebral lesion or epileptiform discharge on EEG, treatment may commence after the first tonic-clonic seizure.

Patients reporting more than one well-documented or witnessed seizure usually require treatment. Exceptions can include widely separated events, provoked seizures (eg, concomitant illness, photosensitive epilepsy, alcohol withdrawal), and benign childhood epilepsy syndromes. In addition, there is little chance of successful treatment in patients such as alcohol abusers, drug addicts, and conscientious objectors who are unlikely or unwilling to take medication. The decision whether or not to start treatment should be made after ample discussion with the patient and his or her family of the risks and benefits of both courses of action.

Contraindications

Patients whose seizures are nonepileptic, including psychogenic or “pseudoseizures,” should not be treated with antiepileptic drugs. Those whose seizures can be prevented by avoidance of provoking factors such as alcohol, illicit drugs, sleep deprivation, or flashing lights may not require long-term antiepileptic drug therapy.

An antiepileptic drug is contraindicated not only when it exaggerates seizures but also when it is ineffective in controlling the seizures it is supposed to treat. It may cause unnecessary adverse drug reactions and deprive the patient of the therapeutic effect that could be provided by another appropriate antiepileptic drug (56).

Outcomes

Treatment with an antiepileptic drug may fail due to lack of efficacy, intolerable adverse effects, or both. In the Glasgow series of 780 newly diagnosed patients, 47% became seizure-free with the first monotherapy, over 80% of whom required no more than modest to moderate doses. Another 10% responded to the second monotherapy. Only 2.3% of the cohort entered remission with the third monotherapy or with polytherapy (51; 52). Results from this and other studies suggest that failure of the first drug due to lack of efficacy is a powerful predictor of subsequent refractoriness and that the probability of remission after the failure of 2 to 3 successive drug regimens is slim (34; 52).

When the newer antiepileptic drugs were studied as add-on treatment in randomized, controlled trials in refractory epilepsy, a reduction in seizure frequency by 50% from the baseline was achieved in only 30% to 50% of patients. The clinical relevance of a 50% reduction in seizure frequency has been called into question (50). Studies including patients treated surgically (27) or medically (12) suggest that absolute seizure freedom is the only outcome consistently associated with improvement in quality of life. A meta-analysis showed that the overall weighted pooled-risk difference in favor of the newer antiepileptic drugs over placebo for seizure-freedom during the limited study periods was only 6% (10).

Adverse effects

Adverse effects are a leading cause of treatment failure with antiepileptic drugs. They result in early treatment discontinuation in up to 25% of patients and may preclude attainment of fully effective doses and have a negative effect on patient adherence. Furthermore, adverse effects of antiepileptic drugs are a major source of disability, morbidity, and mortality and a substantial burden on use and costs of health care. Substantial effort has been made to define, quantify, and address their clinical relevance (64; 59).

According to the World Health Organization classification, there are 5 types of drug-related adverse effects:

1. Acute, related to the pharmacological properties of the drug (type A) 2. Idiosyncratic (type B) 3. Chronic (type C) 4. Delayed (type D) 5. Secondary to drug interactions (type E)

Some of the more common or serious adverse effects are shown in Table 6. Serious and life-threatening adverse effects are highlighted by the Food and Drug Administration in boxed warnings of the package inserts.

Table 6. Primary Adverse Reactions of Antiepileptic Drugs: Sometimes serious and Rarely Life-Threatening

Antiepileptic drug	Primary adverse reactions	Life threatening?
Brivaracetam	Somnolence, dizziness, fatigue	New medication with few exposures
Carbamazepine	Idiosyncratic (rash), sedation, headache, ataxia, nystagmus, diplopia, tremor, impotence, hyponatremia, cardiac arrhythmia	Antiepileptic drug hypersensitivity syndrome (AHS), hepatic failure, hematological
Clobazam	Severe sedation, fatigue, drowsiness, behavioral and cognitive impairment, restlessness, aggressiveness, hypersalivation, coordination disturbances, tolerance, withdrawal syndrome	No
Clonazepam	As for clobazam	No
Eslicarbazepine	Idiosyncratic (rash), dizziness, somnolence, headache, ataxia, inattention, diplopia, tremor, nausea, vomiting, hyponatremia, PR prolongation in ECG	No
Ethosuximide	Idiosyncratic (rash), gastrointestinal disturbances, anorexia, weight loss, drowsiness, photophobia, headache	AHS, renal and hepatic failure, hematological
Gabapentin	Weight gain, peripheral edema, behavioral changes, impotence, viral infection	Acute pancreatitis, hepatitis, Stevens-Johnson syndrome, acute renal failure‡
Lacosamide	Dizziness, headache, diplopia, nausea, vomiting, blurred vision, PR prolongation in ECG	No
Lamotrigine	Idiosyncratic (rash), tics, insomnia, dizziness, diplopia, headache, ataxia, asthenia	AHS, hepatic failure, hematological
Levetiracetam	Irritability, behavioral and psychotic changes, asthenia, dizziness, somnolence, headache	Hepatic failure, hepatitis
Oxcarbazepine	Idiosyncratic (rash), headache, dizziness, weakness, nausea, somnolence, ataxia and diplopia, hyponatremia	AHS, hematological
Perampanel	Serious or life-threatening psychiatric and behavioral adverse reactions including aggression, hostility, irritability, anger, and homicidal ideation and threats. Dizziness, gait disturbances, fatigue, falls, weight gain	Yes
Phenobarbital	Idiosyncratic (rash), severe drowsiness, sedation, impairment of cognition and concentration, hyperkinesia and agitation in children, shoulder-hand syndrome	AHS, hepatic failure, hematological
Phenytoin	Idiosyncratic (rash), ataxia, drowsiness, lethargy, sedation, encephalopathy, gingival hyperplasia, hirsutism, dysmorphism, rickets, osteomalacia	AHS, hepatic failure, hematological
Pregabalin	Weight gain, myoclonus, dizziness, somnolence, ataxia, confusion	Renal failure, congestive heart failure, AHS
Tiagabine	Stupor or spike-wave stupor, weakness	Status epilepticus
Topiramate	Somnolence, anorexia, fatigue, nervousness, difficulty with concentration or attention, memory impairment, psychomotor slowing, metabolic acidosis, weight loss, language dysfunction, renal calculi, acute angle-closure glaucoma and other ocular abnormalities, paraesthesia	Hepatic failure, anhidrosis
Valproate	Nausea, vomiting, dyspepsia, weight gain, tremor, hair loss, hormonal issues in women	Hepatic and pancreatic failure
Vigabatrin	Irreversible visual field defects, fatigue, weight gain	No
Zonisamide	Idiosyncratic, drowsiness, anorexia, irritability, photosensitivity, weight loss, renal calculi	AHS, anhidrosis

The table above is based predominantly on information obtained from the summaries of product characteristics (SmPCs3-19) and package inserts (56). It is an assessment of common adverse drug reactions and those of clinical importance. It is not an exhaustive list of all adverse drug reactions; for these, readers should refer to the summaries of product characteristics or package inserts of each antiepileptic drug. There is a comprehensive review of the safety profile of the newest antiepileptic drugs: brivaracetam, eslicarbazepine acetate lacosamide, and perampanel (55).

Type A effects can be ascribed to the known mechanism of action of the drug; they usually arise at the beginning of treatment or after dose escalation and typically abate over time or after dose reduction. The most representative type A effects of antiepileptic drugs affect the CNS and include drowsiness, fatigue, dizziness, unsteadiness, blurred or double vision, difficulty concentrating, memory problems, irritability, and depression. These are often dose-related and can be anticipated by adopting a slow-titration schedule. It is unclear why some patients develop intolerable neurotoxic side effects at starting doses whereas others can tolerate substantial amounts of the same agent with impunity (16). Genetic factors likely play a role.

Type B effects (idiosyncratic). The most common idiosyncratic reaction to antiepileptic drugs is skin rash, which can range from a trivial evanescent exanthem to life-threatening severe cutaneous reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis) (04). Maculopapular rashes are noted in 5% to 17% of patients started on carbamazepine, phenytoin, phenobarbital, and lamotrigine. Severe mucocutaneous reactions, such as drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome, and toxic epidermal necrolysis, affect 1 to 10 in 10,000 new users of these antiepileptic drugs. Risk factors for cutaneous reactions include genetic predisposition, pediatric or old age, a previous history of cutaneous reactions with other drugs, high initial dose and rapid escalation schedules, concomitant immune system disorders, and specific concurrent drugs. Presence of the human leukocyte antigen HLA-B 1502 is strongly correlated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in patients with ancestry across broad areas of Asia, and evidence suggests these findings can also apply to phenytoin, lamotrigine, and oxcarbazepine. Among other HLA genotypes that predispose to antiepileptic-induced reactions, the antigen HLA-A 3101 has been found to be associated with multiple carbamazepine-induced cutaneous reactions in Chinese, Japanese, and European populations.

Other serious idiosyncratic reactions to antiepileptic drugs include hepatotoxic effects with valproate, histologically evident as a microvesicular steatosis, in less than 1 in 20,000 patients, but this reaction is of particular concern in children under 3 years of age receiving multiple antiepileptic drugs (22). Felbamate usage is associated with aplastic anemia and hepatotoxicity in around 1 in 4000 patients. Rare cases of acute angle-closure glaucoma and myopia have been reported with topiramate (24).

Type C effects (long-term complications). Type C effects include chronic reactions related to cumulative drug exposure. They can be insidious because of their slow progressive development. Although some of these effects recede after discontinuation of the drug, others can be irreversible. Long-term complications of antiepileptic drugs tend to be drug-specific. Chronic usage by many of the older agents can lead to dysmorphic changes, such as gum hypertrophy and hirsutism with phenytoin (15) and weight gain and polycystic ovarian syndrome with valproate (48). Weight gain is particularly associated with valproate, gabapentin, pregabalin, vigabatrin, and perampanel. Weight loss is associated with topiramate and zonisamide.

A serious type C effect is bilateral visual field loss induced by vigabatrin, which is irreversible and can worsen with continued treatment. Prevalence ranges from 14% to 92%. Suggested risk factors include male sex, older age, cumulative dose and mean daily dose of vigabatrin, and duration of exposure.

Treatment with topiramate and zonisamide carries a small risk of renal calculi via their shared carbonic anhydrase-inhibiting activity. This property may also account for their association with hypohidrosis, which can be symptomatic for patients living in tropical countries (08).

Long-term antiepileptic drug therapy can produce hypocalcemia and decrease biologically active vitamin D levels, leading to reduced bone mineral density and a higher risk of fractures. Both enzyme-inducing and nonenzyme-inducing agents are implicated, and their effects may be additive. A variety of mechanisms have been suggested, the most significant of which is an increased rate of bone turnover. Patients at high risk of osteoporosis, eg, those on polytherapy or with poor mobility, are recommended to take calcium and vitamin D supplements and to have regular bone density measurements (01).

Psychiatric complications. Adverse psychiatric effects are noted in about 15% to 20% of patients with epilepsy who take antiepileptic drugs. These effects include behavioral or personality changes (irritability, hyperactivity, agitation, and aggressive behavior), depression, and psychosis. Some antiepileptic drugs, such as phenobarbital, topiramate, and vigabatrin are associated with neuropsychiatric complications and should be used cautiously in patients with a history of mental illness. Behavioral problems such as agitation, aggression, hostility, psychosis, anxiety, and depression have been reported in up to 7% of patients treated with levetiracetam, particularly those with a prior history of psychiatric illness (74). Zonisamide can also produce or exacerbate psychiatric comorbidities, particularly depression (18).

Furthermore, growing evidence suggests that individual vulnerability plays an important part. For example, family and personal psychiatric history, family history of epilepsy, personal history of febrile convulsions, and presence of tonic-atonic seizures are independent predictors for occurrence of psychiatric symptoms during treatment with topiramate. A positive psychiatric history seems to be an important risk factor for development of adverse psychiatric effects with other antiepileptic drugs (59). The United States Food and Drug Administration analyzed data from 199 placebo-controlled trials of 11 antiepileptic drugs and found an increase in risk of suicidal behavior or ideation among patients receiving antiepileptic drugs (0.43%) compared to those receiving placebo (0.22%) (US Food and Drug Administration 2008). There were 4 completed suicides among the 27,863 patients randomized to receive antiepileptic drugs compared with none among the 16,029 in the placebo groups. Although the difference was statistically significant, the absolute magnitude of the difference was small considering the sample size analyzed. Given that antiepileptic drug therapy was evidently indicated for these patients, the implication of such findings on treatment alternatives is unclear. Whether other factors, such as indication of treatment- and drug-specific effects, may play a role is controversial. A subsequent large-scale community-based study found that the current use of antiepileptic drugs was not associated with an increased risk of suicide-related events among patients with epilepsy, but it was associated with an increased risk of such events among patients with depression and among those who did not have epilepsy, depression, or bipolar disorder (03). A community-based study of patients with treated epilepsy documented increased risk of suicidal behavior only in those receiving the newer antiepileptic drugs with a high risk of depression (levetiracetam, tiagabine, topiramate, vigabatrin) (02). These reports have raised renewed concern over adverse psychiatric effects of antiepileptic drugs in general, and it is advisable that patients receiving antiepileptic drugs should be monitored for the emergence or worsening of suicidal thoughts or behavior.

Type D effects. Teratogenic and carcinogenic effects are included in the type D category. It is generally accepted that antiepileptic drug treatment during the first trimester of pregnancy is associated with a small, but significant, increase in the risk of major congenital malformations (defined as structural abnormalities with surgical, medical, or cosmetic importance). This risk is:

	• probably no different or only slightly higher than the background (around 1% to 2%) in women with epilepsy who are not taking antiepileptic drugs.
	• probably less than twice the background rate with commonly used antiepileptic drugs (other than valproate and topiramate) as monotherapy, although the relative risk may vary with individual antiepileptic drugs.
	• certainly increased with valproate monotherapy to 3 to 5 times the background rate.
	• likely to be high with topiramate, though the relevant studies are still inadequate.
	• certainly higher with polytherapy than monotherapy; valproate is a significant contributor to the high risk of major congenital malformations in polytherapy, particularly in combination with lamotrigine (10%).
	• likely to be dose-dependent, at least for valproate and probably for lamotrigine (ie, the higher the plasma antiepileptic drug concentration, the higher the relative risk of major congenital malformations) (Tomson et al. 2011).

See details in articles on Pregnancy and epilepsy as well as in Fetal anticonvulsant syndrome.

Adverse cardiac effects of antiepileptic drugs. There is a conspicuous poverty of information and recommendations on cardiac adverse drug reactions of antiepileptic drugs and their effect on the electrocardiogram. The situation may now change in view of the increasing number of studies on SUDEP (05) and the attention now given to cardiac function when assessing drug safety during the regulatory process, particularly with respect to ventricular repolarization as reflected in the prolongation of the ECG QT interval. Premarketing investigation of the safety of a new pharmaceutical agent now includes rigorous characterization of its effects on the QT/QTc interval labelled “Thorough QT/QTc Study” (56; 67). Antiepileptic drugs of sodium channel blockade contribute to ECG changes and probably SUDEP (05).

Table 7. Adverse Cardiac Effects to Antiepileptic Drugs

Carbamazepine	Cardiac conduction disorders, hypertension or hypotension, bradycardia, arrhythmia, atrioventricular block with syncope, circulatory collapse, congestive heart failure, aggravation of coronary artery disease, thrombophlebitis, thrombo-embolism (eg, pulmonary embolism)
Eslicarbazepine acetate	PR prolongation
Gabapentin	Palpitations
Lacosamide	PR prolongation
Pregabalin	Tachycardia, atrioventricular block first degree, sinus tachycardia, sinus arrhythmia, sinus bradycardia, congestive heart failure
Rufinamide	Shortening of the QT interval
Zonisamide	Shortening of the QT interval
Lamotrigine Levetiracetam Phenytoin Perampanel Pregabalin Topiramate Valproate	None is reported in the summaries of product characteristics

Table 7 information presented as cited in the summaries of product characteristics; modified from (56).

Type E effects (adverse drug interactions). Adverse drug interactions are common with epilepsy treatment and are usually clinically relevant because:

	• Most antiepileptic drugs have a narrow therapeutic index, and small changes in pharmacokinetics results in reduced efficacy or increased toxic effects.
	• Many antiepileptic drugs affect the activity of drug-metabolizing enzymes.
	• Most antiepileptic drugs are substrates of the same enzymes because these drugs are typically taken for many years, the probability is high that at some point in life, people with epilepsy will be exposed to interactions with other drugs used to treat intercurrent or concomitant disorders.
	• Moreover, adverse drug interactions can arise when 2 or more antiepileptic drugs are co-prescribed (59).

Long term outcome. Long-term outcome studies suggest that 60% to 70% of newly diagnosed patients will become seizure-free with antiepileptic drug therapy (39), mostly while taking their first or second antiepileptic drug regimen (34; 51; 14). In line with this observation, the International League Against Epilepsy (ILAE) has proposed a consensus definition to define refractory or drug resistant epilepsy as “a failure of adequate trials of 2 tolerated and appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom” (33). It should be noted that the classification of a patient’s epilepsy as drug-resistant at a given point in time does not invariably imply that the patient will never become seizure-free on further antiepilepsy drug therapy (19; 43). Indeed, although approximately 60% of patients with newly diagnosed epilepsy appeared to have a constant course (either early remission or never seizure free), prognosis in the other 40% was less predictable, with some becoming seizure free after a delay and 1 in 6 demonstrating a “remitting-relapsing” course, fluctuating between periods of seizure freedom and recurrence (14). Thus, drug response can be a dynamic process. At least in the short term, prognosis for patients who do not respond to their first few drug regimens should not always be viewed nihilistically. Nonetheless, patients with epilepsy fulfilling the definition should be referred for a comprehensive review of the diagnosis and management, preferably at a specialist center. Workup for epilepsy surgery can be considered at this stage, particularly if a potentially operable structural abnormality, such as mesial temporal sclerosis, has been identified (17). If non-drug treatment options are not appropriate, further pharmacological modifications can still occasionally produce a worthwhile and sustained response.

Medication can be withdrawn slowly without seizure recurrence (at least over the following several years) in around 60% to 70% of adults who have been seizure-free for 2 years or more (46). Patients reporting few seizures before and after starting treatment, those taking a single drug, those seizure-free for many years, and those with no structural abnormality on brain imaging are likely to have the best outcomes. Myoclonic epilepsies carry a high risk of recurrence.

The value of the EEG in predicting relapse is small, particularly in adults (47). A normal EEG does not mean that antiepileptic drug withdrawal is safe. Conversely, ictal EEG abnormalities associated with clinical manifestations (eg, jerks or absences) is a definite indicator for continuing proper antiepileptic drug treatment.

The decision whether or not to withdraw treatment should be made, whenever possible, by the patient, taking into account the likelihood of relapse and its potential psychosocial impact (eg, on driving and employment) balanced against the risk of adverse events from continued treatment (eg, teratogenicity) (56).

Consideration of total withdrawal of antiepileptic drugs is needed in the following patients:

	• Patients who do not suffer from epileptic seizures.
	• Patients suffering from age­related and age­limited epileptic syndromes who have reached an appropriate age of remission.
	• Patients who are seizure-free for more than 3 to 5 years, provided that they do not suffer from epileptic syndromes requiring long­term treatment, such as juvenile myoclonic epilepsy.

Discontinuation of antiepileptic drugs should be extremely slow, in small doses and in long steps of weeks or months. The rate of relapse increases with a faster rate of antiepileptic drug discontinuation. Furthermore, with fast discontinuation of antiepileptic drugs, there is a risk of seizures that are directly related to the withdrawal effects of certain drugs (phenobarbital and benzodiazepines). Before antiepileptic drug withdrawal, there is a need for a thorough re­evaluation of the patient. The presence of even minor and infrequent seizures specifies active disease. Conversely, the occurrence of such seizures in the process of drug discontinuation mandates restoration of antiepileptic drug medication.

A significant report presents evidence-based nomograms to facilitate prediction of outcomes following drug withdrawal for the individual patient, including both the risk of relapse and the chance of long-term freedom from seizures (40). Independent predictors of seizure recurrence were epilepsy duration before remission, seizure-free interval before antiepileptic drug withdrawal, age at onset of epilepsy, history of febrile seizures, number of seizures before remission, absence of a self-limiting epilepsy syndrome (childhood absence epilepsy, Rolandic epilepsy, or Panayiotopoulos syndrome), developmental delay, and epileptiform abnormality on EEG before withdrawal. Independent predictors of seizures in the last year of follow-up were epilepsy duration before remission, seizure-free interval before antiepileptic drug withdrawal, number of antiepileptic drugs before withdrawal, female sex, family history of epilepsy, number of seizures before remission, focal seizures, and epileptiform abnormality on EEG before withdrawal (40).

Over-medication in terms of the number of antiepileptic drugs and doses and length of exposure is undesirable but common. Treatment should be reviewed at regular intervals to ensure that patients are not maintained for long periods on drugs that are ineffective, poorly tolerated, or not needed and that concordance with prescribed medication is maintained.

Special considerations

Although it would be ideal for a woman contemplating pregnancy to have antiepileptic drug treatment withdrawn, for many this would result in recurrence or exacerbation of seizures, which can be dangerous for both mother and baby. If the criteria for discontinuation are met, this should be done prior to conception in a planned pregnancy counseling program. If antiepileptic drugs cannot be withdrawn completely, treatment should be tapered to a minimally effective dose of, if possible, a single drug. See details in the article on Pregnancy and epilepsy.

Scientific basis

Epileptic seizures result from abnormal, excessive, and synchronous excitation of neuronal populations. Antiepileptic drugs suppress their occurrence by modifying the bursting properties of neurons and by reducing hypersynchronization, thereby inhibiting the spread of abnormal neuronal firing (63). Although an antiepileptogenic effect has been noted for some antiseizure drugs in selected animal models (65), such a property has not been demonstrated in clinical trials (71).

The mechanisms of action of the currently marketed antiepileptic drugs involve alterations in the balance between neuronal excitation and inhibition (Table 8). Three basic mechanisms are recognized: (1) modulation of voltage-gated ion channels (including sodium, calcium, and potassium channels), (2) enhancement of synaptic inhibitory neurotransmission, and (3) attenuation of brain excitation (Table 8). Many antiepileptic drugs have multiple modes of action, whereas the mechanisms for others are still unclear.

Table 8. Main Mode of Action of Antiepileptic Drugs

Blocking voltage-dependent Na+ channels (decreased Na+)
	• Carbamazepine • Lamotrigine • Oxcarbazepine • Phenytoin
Multiple, mainly or including blocking voltage-dependent Na+ channels
	• Phenobarbital (decreased Na+, decreased Ca2+, increased GABA, decreased glutamate) • Topiramate decreased Na+, decreased Ca2+, increased GABA, decreased glutamate) • Valproate decreased Na+, decreased Ca2+, increased GABA, decreased glutamate) • Zonisamide decreased Na+, decreased Ca2+)
Increasing GABA inhibition (increased GABA)
	• Clobazam (GABAA) • Clonazepam (GABAA) • Tiagabine (inhibitor of GABA uptake into neurons and glial cells) • Vigabatrin (selective, irreversible GABA transaminase inhibitor)
Blocking T-type Ca2+ channels (decreased Ca2+)
	• Ethosuximide
Modifying Ca2+ channels and neurotransmitter release
	• Gabapentin • Pregabalin
Novel
	• Brivaracetam: probably by synaptic to synaptic vesicle protein SV2A but still uncertain • Levetiracetam: binding to synaptic vesicle protein SV2A • Lacosamide: selectively enhancing slow inactivation voltage-gated Na+ channels • Perampanel: selective, noncompetitive, AMPA receptor antagonist

Table 8 information based on data from summaries of product characteristics and product inserts; modified from (56).

Voltage-gated ion channels regulate the electrical behavior of neurons as well as the release of neurotransmitters. Drugs such as phenytoin, carbamazepine, and lamotrigine act primarily by limiting sustained, repetitive firing via blockade of voltage-gated sodium channels. This property is shared by some of the newer drugs, such as oxcarbazepine, zonisamide, and eslicarbazepine. Gabapentin and pregabalin exert their antiseizure and other pharmacological effects by binding to the alpha2-delta subunit of the calcium channel.

Several antiepileptic drugs act primarily by enhancing GABAergic inhibition. The barbiturates and benzodiazepines modulate GABAA receptors. Vigabatrin and tiagabine inhibit the enzymatic degradation and reuptake of GABA, respectively.

Levetiracetam (binding to synaptic vesicle protein SV2A), lacosamide (selectively enhancing slow inactivation voltage-gated sodium channels), and perampanel (selective, noncompetitive, AMPA receptor antagonist) have novel modes of action.