Antiepileptic drugs

Handbook of Clinical Neurology, Vol. 108 (3rd series) Epilepsy, Part II H. Stefan and W.H. Theodore, Editors # 2012 Elsevier B.V. All rights reserved

Chapter 42

Antiepileptic drugs: advantages and disadvantages BASSEL ABOU-KHALIL 1* AND DIETER SCHMIDT 2 Department of Neurology, Vanderbilt University, Nashville, TN, USA

1 2

Epilepsy Research Group, Free University of Berlin, Berlin, Germany

INTRODUCTION Drug treatment is the standard of care for epilepsy (French et al., 2004a). In suitable cases of drug-refractory epilepsy, it is combined with other measures such as resective surgery, neurostimulation, and ketogenic diet (French et al., 2004b). As with any pharmacological treatment, careful consideration of the advantages and disadvantages of antiepileptic drugs (AEDs) is important for optimum epilepsy care. This chapter offers a critical review of the advantages and disadvantages of epilepsy drug treatment including the risk–benefit balance for individual AEDs (Table 42.1). For extensive discussion of the principles of drug treatment including the choice and optimal use of drugs and pharmacoresistance, see respective chapters of this handbook, textbooks, and monographs (Shorvon, 2000; Levy et al., 2002; Engel and Pedley, 2007).

ADVANTAGES OF CURRENT ANTIEPILEPTIC DRUG TREATMENT Efficacy AEDs provide satisfactory control of seizures for most patients with epilepsy. Approximately 65% of patients with new-onset epilepsy will eventually become seizure free (Kwan and Brodie, 2000a; Sillanpa¨a¨ and Schmidt, 2006; Marson et al., 2007a, b).

Efficacy by seizure type AED efficacy varies by seizure type, particularly for generalized-onset seizures. In general, AEDs effective against partial-onset seizures will be effective against all types of partial-onset seizures, whereas efficacy against one type of generalized-onset seizure does not

necessarily predict efficacy against other generalized seizure types. In particular, generalized absence and generalized myoclonic seizures tend to have a very particular profile of AED efficacy (Table 42.2). Some AEDs such as valproate have a wide spectrum of efficacy against generalized seizure types. On the other hand, ethosuximide is selectively effective against generalized absence seizures. The AEDs carbamazepine, phenytoin, phenobarbital, gabapentin, oxcarbazepine, tiagabine, and pregabalin are not effective against generalized absence or myoclonic seizures and may even make these seizures worse. The new AEDs have had their efficacy rigorously established as adjunctive therapy for refractory partial-onset seizures. Efficacy as monotherapy for newly diagnosed partialonset seizures (as first-line monotherapy) or refractory partial-onset seizures (as conversion to monotherapy) has been ascertained only for some AEDs (Azar and Abou-Khalil, 2008). The same is true with respect to efficacy against generalized-onset seizures, as monotherapy or adjunctive therapy. Few trials have addressed AED efficacy as first-line therapy in generalized epilepsy.

Efficacy for partial-onset seizures: first-line therapy The initial treatment should be monotherapy with an AED that has been proven effective in a well-powered clinical trial. In addition, the AED prescribed should preferably not interfere with cognitive function and ideally should be devoid of long-term adverse effects. Among the classic AEDs, carbamazepine, phenytoin, valproate, and phenobarbital have been shown effective in clinical trials (Mattson et al., 1985, 1992). Phenobarbital was less well tolerated than carbamazepine and phenytoin in a large comparative trial, but its very low

*Correspondence to: Bassel Abou-Khalil, Vanderbilt University Department of Neurology, A-0118 Medical Center North, Nashville, TN 37232, USA. Tel: þ 1-615-936-0060, Fax: þ1-615-936-0223, E-mail: [email protected]

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Table 42.1 Antiepileptic drug treatment: major and advantages and disadvantages Advantages

Disadvantages

Efficacy Seizure freedom or reduced risk of seizures Uncertain: better health, lower morbidity and better survival Good tolerability and safety Absence of deleterious drug interaction* No hypersensitivity reaction* No organ damage*

Efficacy concerns Drug resistance No prophylactic usefulness Loss of effect “tolerance” No effect on disease modification Unpredictable individual effect Tolerability and safety concerns Idiosyncratic reactions* Dose-related toxicity Long-term complications* Teratogenicity Adverse drug interactions* Seizure aggravation*

*Applies to some but not all antiepileptic drugs.

cost and widespread availability make it the only available choice in many developing countries (Kwan and Brodie, 2004). Carbamazepine provided complete control of partial seizures more often than phenobarbital and primidone, and had a nonstatistically significant advantage over phenytoin (Mattson et al., 1985). It was also more effective than valproate for complex partial seizures, although the two drugs were equally effective for secondarily generalized seizures (Mattson et al., 1992). No AED has been demonstrated more effective than carbamazepine against partial-onset seizures. However, several new AEDs are equally efficacious but often better tolerated, and may have pharmacokinetic advantages (Dam et al., 1989; Brodie et al., 1995, 2007; Privitera et al., 2003). The newer AEDs oxcarbazepine, topiramate, lamotrigine, gabapentin, and levetiracetam can be considered for first-line therapy based on efficacy in large comparative trials. Topiramate’s cognitive adverse effects make it less attractive as a first-line agent unless there are comorbid conditions, such as migraine, for which topiramate is effective. Oxcarbazepine is structurally related to carbamazepine, but has much less and more selective liver enzyme induction, no autoinduction, and no interactions with erythromycin and other

Table 42.2 Efficacy and indications of antiepileptic drugs by seizure type (US or European indications) Seizure type indication

Antiepileptic drug Phenobarbital Primidone Phenytoin Methsuximide Ethosuximide Clonazepam, clobazam Carbamazepine Valproate Vigabatrin* Felbamate Gabapentin Lamotrigine Topiramate Tiagabine Levetiracetam Oxcarbazepine Zonisamide Pregabalin Lacosamide Rufinamide

Partial

Generalized tonic–clonic

Absence

Myoclonic

Tonic/atonic in the setting of Lennox–Gastaut syndrome

X X X e – A X X A A X X X A X X A A A –

X – X – – – X X – e – X X – A – e – – –

– – – X X e – X – – – e e – e – e – – –

– e – – – A – X – – – e e – A – e – – –

X – – – – A – X – A – A A – e – e – – A

*Also indicated for infantile spasms as monotherapy. A, adjunctive only; e, some evidence of efficacy without indication; X , monotherapy or not specified.

ANTIEPILEPTIC DRUGS: ADVANTAGES AND DISADVANTAGES drugs that cause carbamazepine accumulation. It can also be started at an effective dose. Lamotrigine is another AED that was equally effective but better tolerated than carbamazepine, particularly in elderly patients (Brodie et al., 1999; Rowan et al., 2005). However, lamotrigine requires a very slow titration that may be a disadvantage when a rapid onset of action is needed. In a large comparative randomized trial, lamotrigine was significantly better than carbamazepine, gabapentin, and topiramate, and had a nonsignificant advantage over oxcarbazepine with respect to time to treatment failure (Marson et al., 2007a). Levetiracetam was not included in this trial. However, another trial compared levetiracetam with controlled release carbamazepine in a large randomized and blinded trial, and found the two AEDs to be equivalent (Brodie et al., 2007). Levetiracetam has an advantage of rapid onset of action and an effective initial dose, in addition to no enzyme induction and no interactions.

Efficacy for partial-onset seizures: conversion monotherapy or add-on therapy The use of an AED as conversion monotherapy or addon therapy implies that the first AED has failed. If the AED failure was related to difficulty with tolerability, then the appropriate action is to convert to a different monotherapy. Any AED that is eligible for first-line therapy can be considered for replacement monotherapy, but the replacement AED should avoid the adverse effects that made the initial AED intolerable. Substitution monotherapy usually requires a period of adjunctive therapy, and the old AED is removed gradually after the new AED has reached its target dose. However, some AED transitions can be made overnight. One example is carbamazepine to oxcarbazepine transition, if the dose of oxcarbazepine is not too high (Albani et al., 2004). If the reason for the first AED failure was persistent seizures, studies show that there is no efficacy or tolerability advantage to either add-on therapy or substitution monotherapy (Kwan and Brodie, 2000b; Beghi et al., 2003). If substitution monotherapy is used, the replacement monotherapy AED should have been used successfully for refractory epilepsy. For example, oxcarbazepine and lamotrigine have had positive trials supporting monotherapy use in refractory epilepsy, while gabapentin monotherapy failed in this setting (Beydoun et al., 1997). Although there is a theoretical advantage to a mechanism of action different from that of the old AED, there is no trial evidence to support this. When an AED is considered for adjunctive therapy, there is a different set of considerations, and relative advantages and disadvantages. All of the newer AEDs have shown efficacy as adjunctive therapy for

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partial-onset seizures. However, there are advantages and disadvantages to each. The absence of adverse pharmacodynamic or pharmacokinetic interactions with the existing AED is an important advantage. Also, some interactions may be advantageous in some ways. For example, a much smaller dose of lamotrigine is needed when it is added to valproate, and the longer half-life of lamotrigine may also allow once daily dosing. A new AED mechanism of action that is different from that of the old AED may also be an advantage in this setting, particularly for tolerability. For example, the addition of a sodium channel blocker to another sodium channel blocker increases the chance of diplopia and dizziness as adverse effects (Besag et al., 1998). There is also some evidence that using two AEDs with different mechanisms of action may have an efficacy advantage over two AEDs with similar mechanisms (Kwan and Brodie, 2000b). Two AED combinations have evidence suggesting synergy: the combination of valproate and lamotrigine (Brodie and Yuen, 1997), and the combination of lamotrigine and levetiracetam (Kinirons et al., 2006).

Efficacy for generalized-onset seizures There are limited data to guide the initial therapy for generalized-onset seizures. The treatment very much depends on the seizure type in question. For patients who have only generalized tonic–clonic seizures, there are more AED choices. Even the AEDs phenytoin, carbamazepine, and oxcarbazepine that are considered specific for partial-onset seizures can be used, but they have a disadvantage in that they may exacerbate de novo or unrecognized absence and myoclonic seizures (Snead and Hosey, 1985; Genton et al., 2000; Gelisse et al., 2004). Valproate is an AED of choice because it is effective against all generalized seizure types. Valproate monotherapy was more effective than lamotrigine and topiramate in a large prospective randomized trial, as well as in retrospective analyses (Nicolson et al., 2004; Marson et al., 2007b). However, valproate has tolerability issues, particularly in women with childbearing potential. Levetiracetam has not been tested as first-line therapy in a well-powered trial but it was efficacious as adjunctive therapy for primary generalized tonic– clonic as well as myoclonic seizures (Berkovic et al., 2007; Noachtar et al., 2008); such evidence can potentially support its use in monotherapy in these conditions. Zonisamide has only anecdotal data to support its use as first-line therapy or adjunctive therapy in generalizedonset seizures (Kothare et al., 2004; Yamauchi and Aikawa, 2004). More evidence is available to support the use of AEDs as add-on therapy for generalized-onset seizures. Lamotrigine, topiramate, and levetiracetam have

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positive pivotal trials to support their use as adjunctive therapy in refractory primary generalized tonic–clonic seizures, and levetiracetam in refractory generalized myoclonic seizures (Biton et al., 1999, 2005; Berkovic et al., 2007; Noachtar et al., 2008). Ethosuximide, valproate, and lamotrigine were compared as monotherapy for patients with pure generalized absence seizures, in a large multicenter trial. In a preliminary communication, ethosuximide appeared to have the best efficacy and tolerability; valproate was equally effective but less well tolerated; while lamotrigine was a distant third in its efficacy Glauser et al., 2010. However, ethosuximide is not appropriate in the presence of any other seizure types, because of its very selective efficacy against absence. Although there are case reports and case series supporting topiramate, zonisamide, and levetiracetam as initial therapy for absence (Cross, 2002; Wilfong and Schultz, 2005; Verrotti et al., 2008), their efficacy still needs to be demonstrated in a prospective trial. No new AED has class I trial data supporting its use as adjunctive therapy for generalized absence seizures. However, there is some evidence supporting the use of lamotrigine, and weaker evidence supporting the use of the other wide-spectrum AEDs, topiramate, levetiracetam, and zonisamide (Mikati and Holmes, 1997; Wheless, 2000; Krauss et al., 2003; Ohtahara, 2006). Among the old AEDs, valproate and ethosuximide can be considered for adjunctive therapy, although they are usually first-line therapies. Methsuximide is related to ethosuximide but is probably less effective than ethosuximide for absence seizures. However, it has an advantage of wider spectrum, with some evidence of efficacy against partial seizures (Wilder and Buchanan, 1981; Browne et al., 1983). Clonazepam is also a wide-spectrum agent and may help absence seizures, but it has the disadvantage of tolerance. The AEDs gabapentin, pregabalin, tiagabine, and oxcarbazepine are effective only for partial-onset seizures, and may even exacerbate absence seizures and myoclonic seizures. For myoclonic seizures, there have been no randomized trials for use as first-line therapy. Valproate is considered the AED of choice based on open-label experience. Levetiracetam is the only new AED that has been rigorously tested as adjunctive therapy for myoclonic seizures. Case series also suggest that it could be considered for initial monotherapy. The new AEDs lamotrigine, topiramate, and zonisamide may also be effective, but lamotrigine may exacerbate myoclonic seizures in some individuals (Crespel et al., 2005). Clonazepam and related agents may also be used for myoclonic seizures, but they have the disadvantages of sedation and common development of tolerance.

Generalized tonic and generalized atonic seizures are usually seizure types of symptomatic generalized epilepsy, particularly Lennox–Gastaut syndrome, and tend to be very difficult to control. Valproate is usually chosen early in the treatment. There is very little evidence to support first-line therapies, but several agents have been studied as adjunctive therapy and found to be effective for these seizure types in Lennox–Gastaut syndrome. These agents include lamotrigine, topiramate, rufinamide, and felbamate (Felbamate Study Group, 1993; Motte et al., 1997; Glauser et al., 2000, 2008). Felbamate has the disadvantage of serious lifethreatening idiosyncratic toxicity, but the risks may be justified in severe forms of Lennox–Gastaut syndrome. Other wide-spectrum AEDs, levetiracetam, zonisamide, and benzodiazepines, may also be used based on open-label evidence.

Efficacy by syndrome Even though certain AEDs are thought to be particularly effective for certain syndromes, the efficacy of AEDs has been mostly ascertained by seizure type rather than by syndrome (Glauser et al., 2006). Nevertheless, some syndromes are characterized by a combination of seizure types, and that combination helps predict the best AED for the syndrome. For example, juvenile myoclonic epilepsy (JME) is characterized by generalized myoclonic seizures, which are a required seizure type to diagnose the syndrome, with generalized tonic–clonic seizures in about 90% of individuals and generalized absence seizures in about 30–40%. An AED that is effective against all the seizure types in a particular individual would be preferable. However, some individuals with JME may have a dominant seizure type, and the choice of AED could be targeted to that particular seizure type. In general, valproate is effective against all seizure types, but lamotrigine, levetiracetam, topiramate, and zonisamide may be considered and may be effective (Prasad et al., 2003; Sharpe et al., 2008). AEDs that can aggravate myoclonic and absence seizures are to be avoided. The list includes carbamazepine, phenytoin, gabapentin, oxcarbazepine, tiagabine, vigabatrin, and pregabalin (Genton et al., 2000). Some syndromes have received specific investigation for AED efficacy. Benign rolandic epilepsy may not necessarily need AED therapy, but, if it does, the new AEDs levetiracetam and oxcarbazepine were found to be effective and well tolerated (Coppola et al., 2007), and there is some evidence supporting the older AEDs carbamazepine and valproate, as well as sulthiame and gabapentin (Glauser et al., 2006). Seizure aggravation may occur rarely with carbamazepine (Corda et al., 2001). Lennox–Gastaut syndrome is a symptomatic

ANTIEPILEPTIC DRUGS: ADVANTAGES AND DISADVANTAGES generalized epileptic syndrome that includes tonic or atonic seizures. Combination therapy is almost always necessary. Valproate is often used as an early agent because of the combination of generalized seizure types. The efficacy of adjunctive lamotrigine, topiramate, felbamate, and rufinamide is supported by randomized controlled trials (Felbamate Study Group, 1993; Motte et al., 1997; Glauser et al., 2000, 2008). Occasionally, the syndrome diagnosis may make a certain medication or group of medications less or more desirable in a way that is not necessarily predicted from seizure type efficacy. For example, autosomal dominant nocturnal frontal lobe epilepsy, which is often related to a mutation of the nicotinic acetylcholine receptor, is particularly sensitive to carbamazepine and oxcarbazepine (Picard et al., 1999; Raju et al., 2007). Mutated receptors were found to be more sensitive to carbamazepine than valproate (Picard et al., 1999). Some AEDs may adversely influence the natural history of some forms of epilepsy. For example, severe myoclonic epilepsy of infancy (Dravet syndrome) can be adversely affected by lamotrigine and other medications acting mostly to block the sodium channel (Guerrini et al., 1998). The natural course of progressive myoclonic epilepsies, particularly Unverricht–Lundborg disease, can also be adversely affected by phenytoin (Eldridge et al., 1983).

Efficacy in comorbid conditions Epilepsy often coexists with other conditions, and AEDs may have advantages based on their efficacy in these comorbid conditions, or disadvantages based on their propensity to worsen these conditions. A common comorbidity is migraine, and both valproate and topiramate have indications as prophylactic therapy for this condition (Jensen et al., 1994; Silberstein et al., 2007). Other AEDs such as gabapentin, levetiracetam, and zonisamide may also be helpful, based on less rigorous evidence (Mathew et al., 2001; Brighina et al., 2006; Bermejo and Dorado, 2009). Valproate and lamotrigine both have indications for bipolar disorder, and carbamazepine and oxcarbazepine may also be useful in that setting. Gabapentin, pregabalin, and carbamazepine have indications for certain neuropathic pain syndromes, and pregabalin also has an indication for fibromyalgia. Clonazepam may be helpful for panic attacks and pregabalin for generalized anxiety disorder. Primidone and topiramate may be helpful for essential tremor, and clonazepam, gabapentin, and pregabalin for restless leg syndrome. Tiagabine may help spasticity. Clonazepam, pregabalin, gabapentin, and sedating AEDs may be helpful for insomnia. Some AEDs such as topiramate and zonisamide are associated with weight loss and could have an advantage in overweight individuals

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(Ben-Menachem, 2007). Conversely, AEDs associated with weight gain – valproate and pregabalin – have a disadvantage in overweight individuals (Ben-Menachem, 2007). Psychiatric adverse effects of levetiracetam, topiramate, and zonisamide are more likely in individuals with a past history of psychiatric disorders (Mula et al., 2007).

Good tolerability and safety With slow titration and use of the lowest effective daily dose many AEDs are well tolerated. In addition, a number of AEDs cause no life-threatening organ damage and are free of hypersensitivity reactions (Table 42.3). A further advantage of some drugs is the absence of deleterious drug interactions that may cause central nervous system toxicity or lower the efficacy of treating epilepsy and other diseases (see below).

Favorable pharmacokinetics From a clinical perspective, the ideal AED does not require monitoring of plasma concentrations, is metabolically inert, is not involved in adverse drug interactions, and can be conveniently given once or twice a day (Patsalos and Perucca, 2003). Unfortunately, a number of currently used classic AEDs induce (such as carbamazepine, phenobarbital, phenytoin) or, less commonly, inhibit the Cytochrome P 450 (CYP 450) system (such as with valproate) (Benedetti, 2000). In addition, valproate inhibits metabolic steps involving glucuronidation and can thus be involved in drug interactions. Fortunately, modern epilepsy drugs are available that are less enzyme inducing, such as oxcarbazepine, or are not metabolized by the oxidative CYP 450 system at all, such as gabapentin, levetiracetam, lacosamide, lamotrigine, pregabalin, topiramate, and zonisamide, and therefore are less likely to be involved in drug interactions based on enzyme induction (Table 42.4). The absence of drug interactions is a very important advantage for an AED. Most patients with epilepsy are treated for several years, and the majority need AEDs for their lifetime. Therefore, the long-term consequences need to be taken into account. For example, women might wish to take oral contraceptives in some years, and adults may become overweight with comorbid depression, anxiety disorders, or migraine, or common serious disorders such as cardiovascular disease, diabetes, or cancer may require additional medication. The increasing incidence of epilepsy in the elderly, who commonly have multimorbidity, also requires AEDs that do not interact. Finally, one in three patients with new-onset epilepsy will require a combination or a succession of AEDs in their lifetime for optimal seizure control. In addition, AEDs that are involved with drug interactions,

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Table 42.3 Simplified synopsis of drug interaction properties of common antiepileptic drugs (AEDs)

Anticonvulsive agent Clobazam (CLB) Felbamate (FBM) Gabapentin (GBP) Levetiracetam (LEV) Lacosamide (LCM) Zonisamide (ZNS) Topiramate (TPM) Carbamazepine (CBZ)

Clinically relevant interactions when added to other drugs including AEDs

Clinically relevant interactions when other drugs are added

No relevant change Increases plasma concentrations of VPA, PHT, PB, CBZ epoxide No relevant change No relevant change No relevant change No relevant change No relevant change Lower plasma concentrations of LTG, TGB, VPA and lower efficacy of other drugs*

No relevant change Plasma concentration reduced by enzyme inducers

Ethosuximide (ETS) Lamotrigine (LTG)

Uncertain No relevant change

Oxcarbazepine (OXC)

Rufinamide (RFM)

Lower plasma concentrations of LTG, PHT, TGB, VPA and lower efficacy of other drugs* at OXC doses of >900 mg* Lower plasma concentrations of LTG, OXC, PHT, TGB, VPA and lower efficacy of other drugs* Lower plasma concentrations of LTG, PHT, TGB, VPA and lower efficacy of other drugs* No relevant change Lower plasma concentrations of LTG, OXC, PHT, TGB, VPA and lower efficacy of other drugs* No relevant change

Valproate (VPA) Vigabatrin (VGB)

Higher toxicity of PHT, PHB, and PRM{ No relevant change

Phenobarbital (PHB)

Phenytoin (PHT) Pregabalin (PGB) Primidone (PRM)

No relevant change No relevant change Plasma concentration reduced by enzyme inducers Plasma concentration reduced by enzyme inducers Plasma concentration reduced by enzyme inducers Plasma concentration increased by a variety of drugs, including erythromycin, propoxyphene, isoniazid, cimetidine, verapamil, diltiazem, fluoxetine Plasma concentration reduced by enzyme inducers Plasma concentration increased by valproate and reduced by enzyme inducers and by estrogen Plasma concentration reduced by enzyme inducers

Plasma concentration increased by valproate and felbamate VPA competes for protein binding No relevant change Plasma concentration reduced by enzyme inducers

Plasma concentration increased by valproate and reduced by enzyme inducers Plasma concentration reduced by enzyme inducers No relevant change

*Inducers of cytochrome P450 enzyme system. { Inhibitor of uridin-diphosphate-glucuronyl-transferase system. (Benedetti, 2000; Patsalos and Perucca, 2003)

e.g., through enzyme induction or enzyme inhibition, will also disadvantageously affect the endogenous sexual and other hormone metabolism, and may contribute to adverse events. Taking enzyme-inducing carbamazepine, oxcarbazepine, phenobarbital, phenytoin, or primidone may – in contrast to gabapentin, lamotrigine, and topiramate at less than 200 mg/day – lead to reduced efficacy of comedication, including oral contraceptives, AEDs, and other medication. Adding an oral contraceptive may lower the plasma concentrations and the efficacy of lamotrigine. Valproate is not involved in interactions with oral contraceptives, but may inhibit glucuronidation of, for example, lamotrigine. Fewer clinically relevant interactions with drugs or endogenous substances occur when taking oxcarbazepine, topiramate, and valproate instead of classic

enzyme-inducing AEDs, which are the least advantageous agents in that respect. Finally, many classic AEDs share the disadvantage of both causing clinically relevant interactions and being affected by other drugs. For all these reasons, the absence of enzyme induction or enzyme inhibition is an advantage for any AED. Up to one in three patients with new-onset epilepsy will require a combination of different AEDs for seizure control. In uncommon cases, more than two AEDs may be needed. During combination therapy a number of drug interactions may arise when classic AEDs are used. Drug interactions may interfere with the drug efficacy. A prototypic example is the combination of carbamazepine and valproate. When valproate is added to carbamazepine, adequate valproate plasma concentrations

Table 42.4 Overview of adverse effects of individual antiepileptic drugs (AEDs) CBZ Early-onset adverse events Somnolence Dizziness Seizure aggravation Gastrointestinal Hypersensitivity (SJS/TEN) Rash Late-onset adverse events Encephalopathy Depression Behavioral problems Psychotic episodes Leukopenia Aplastic anemia Thrombopenia Megaloblastic anemia Pancreatitis Liver failure Nephrolithiasis Osteoporosis Hyponatremia Weight gain Weight loss Cognition impaired Teratogenicity

þ þ þ þ

CLB

ETS

þþ þþ þ

þ þ þþ þ

FBM

þ þ

GBP

LCM

LEV

LTG

OXC

þ þ þ (þ)

þ þ

þ þ

þ þ

þþ

þ þ

þ þ þ

þ þþ þ þ

(þ) þþ þ

(þ) þ þþ þ

þ

(þ)

PGB

PHB

þ

þþ

þ þ

þ (þ) (þ)

(þ)

PHT

TGB

TPM

þþ þ

þþ þþ þ

þþ þþ

þ þ

þ þþ (þ) þ þ

þ þ þ (þ) þ þ

þ

þ

þ

þ

þ

þ þ (þ)

VPA

þ

þ þþ (þ)

(þ)

VGB

ZNS

þ þ þþ

þþ þ

þþ þ þþ þþ

þ þ

(þ)

þ

(þ)

þ

þ þ

þ

þþ þþ

þ

þ

þþ

þ (þ) (þ) þ

þ þ

(þ)

þ þ

þ þþ

þ

þ þ

In general, although the exposure of some of the modern AEDs is still limited, treatment with a number of modern AEDs appears to be advantageous compared with some of the classic AEDs. It should be noted, however, that the incidence of many early adverse events shown here could be lowered by slow titration and avoiding above average dosage, and combination therapy, if possible. For AED abbreviations, see Table 42.3. SJS, Stevens-Johnson Syndrome; TEN, Toxic epidermal necrolysis. (þ), minimally increased risk in clinical use; þ, risk higher than for AEDs without þ sign; þþ, highest risk among AEDs. Modified from Schmidt (2009).

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cannot be achieved in most cases because carbamazepine lowers the plasma concentration of valproate. However, drug interactions may also increase the plasma concentrations to toxic plasma levels, e.g., lamotrigine in the presence of valproate. Although beneficial for many patients, tremor may develop and the combination has been shown to be more teratogenic than lamotrigine alone or in combination with an AED other than valproate. However, modern AEDs such as gabapentin, levetiracetam, lacosamide, pregabalin, or tiagabine are much better suited for combination therapy, as they are much less involved or not involved at all in drug interactions among AEDs. By starting epilepsy treatment with modern noninteracting AEDs such complications can be prevented. A large number of patients with epilepsy rely on additional medication to AEDs for birth control or management of associated disorders. Depression, anxiety disorders, and migraine are common in patients with epilepsy. Patients with epilepsy are not protected from common diseases such as stroke, myocardial infarction, leukemia, or cancer, which all require medication that may be affected by classic enzyme-inducing AEDs. Antibiotic treatment may be needed, which increases plasma concentration of AEDs and may thus cause toxicity. By starting epilepsy treatment with modern noninteracting AEDs such complications can be prevented.

LIMITATIONS OF CURRENT DRUG TREATMENT Although AED treatment is beneficial for most patients, AEDs do not prevent epilepsy in persons at risk of drugresistant epilepsy even when given early. Aggravation of mostly myoclonic or absence seizures by a drug for partial seizures is another problem. Unpredictability of effect and loss of effect during prolonged treatment are further issues of drug treatment. The major concerns of current drug treatment are poor efficacy and unacceptable adverse effects (Table 42.1).

EFFICACY CONCERNS DRUG

RESISTANCE

Although AEDs provide satisfactory control of seizures for 65% of patients with epilepsy, 35% continue to have uncontrolled seizures (Hauser, 1992; Kwan and Brodie, oscher, 2005; Schmidt, 2009). 2000a; Schmidt and L€ Approximately 7% of newly treated patients are extensively drug resistant and never enter 1-year remission from the start of treatment, despite the use of many drugs (Sillanpa¨a¨ and Schmidt, 2006). However, an additional 15–20% of patients switch in and out of drug resistance during the course of their epilepsy (Sillanpa¨a¨ and Schmidt, 2006). This observation is supported by

several studies showing that approximately one in five patients previously considered to be drug resistant eventually becomes seizure free with a change of medical regimen (Selwa et al., 2003; Callaghan et al., 2007; Schiller and Najjar, 2008). These data show that drug resistance is potentially reversible and the intrinsic severity of the epilepsy can decrease over time – at least in a significant subgroup of patients with drug-resistant epilepsy. These findings allow a revision of earlier suggestions that a patient who does not achieve seizure control with the first two or three drug regimens (including combinations), within the first 2–3 years of starting treatment, is unlikely to ever achieve remission and usually can be considered to have multidrug-resistant epilepsy (Kwan and Brodie, 2000a). Current theories on drug resistance in epilepsy include the drug transporter hypothesis, the drug target hypothesis, and a novel approach called the inherent severity model of epilepsy, which posits that the severity of the disease determines its relative response to medication. Valuable as each of these hypotheses is, none is currently a stand-alone theory that is able to convincingly explain drug resistance in human epilepsy. The observation that a high frequency of seizures prior to onset of treatment is a prognostic signal of increased severity and future drug refractoriness suggests that common neurobiological factors may underlie both disease severity and pharmacoresistance (Sillanpa¨a¨ and Schmidt, 2009). Such a link has been proposed for depression; however, the evidence for a direct mechanistic link, genetic or otherwise, between drug response and disease severity of human epilepsy is still elusive. Although emerging data from experimental studies suggest that alterations in GABAA receptors may present one example of a mechanistic link, clearly more work is needed to explore whether common neurobiological factors may underlie both epilepsy severity and drug refractoriness. Whatever the mechanism may be, if several drugs have not brought remission within several years, the diagnosis of epilepsy and of the epilepsy syndrome should be reevaluated, and, if refractory epilepsy is confirmed, surgical options should be considered in suitable candidates.

LACK OF CLEAR EVIDENCE FOR DISEASE MODIFICATION Immediate AED treatment reduces the occurrence of seizures in the next 1–2 years, but does not affect long-term remission in individuals with single or infrequent seizures (Marson et al., 2005). Number of seizures of all types at presentation, presence of a neurological disorder, and an abnormal electroencephalogram (EEG) were significant factors in indicating future seizures. Individuals with two or three seizures, a neurological disorder, or an abnormal EEG were identified as the medium-risk

ANTIEPILEPTIC DRUGS: ADVANTAGES AND DISADVANTAGES group, those with two of these features or more than three seizures as the high-risk group, and those with a single seizure only as the low-risk group. A subsequent analysis showed that there is little benefit to immediate treatment in patients at low risk of seizure recurrence, but potentially worthwhile benefits are seen in those at medium and high risk (Kim et al., 2006). This and other concurring evidence suggests that, based on solid current evidence, AEDs are able to lower the risk of subsequent seizures but there seems to be no valid evidence that AEDs are able to modify the underlying disease.

PROPHYLACTIC

TREATMENT

Risk of epilepsy is increased more than 10 years after a mild brain injury, severe brain injury, and skull fracture (Christensen et al., 2009). The long-lasting high risk of epilepsy after brain injury might provide a window for prevention of posttraumatic epilepsy. Phenytoin and carbamazepine significantly reduce the incidence of provoked seizures. Phenobarbital and the combination of phenobarbital and phenytoin also look promising for reducing provoked seizures, but small sample sizes in the studies evaluating these drugs do not allow definitive conclusions. None of the drugs studied (phenytoin, phenobarbital, their combination, carbamazepine, valproate, or magnesium) have shown reliable evidence that they prevent, or even suppress, epileptic seizures after traumatic brain injury. For most of the regimens tested (the phenytoin–phenobarbital combination being the exception), the best estimate of effect is under a 25% reduction in posttraumatic seizures, well less than the 50% reduction most studies were designed to detect. The evaluation of the tested drugs has serious limitations, however, and AEDs developed since 1980 and other compounds have barely been tested at all (Temkin, 2009). Current prophylactic treatment with anticonvulsant drugs after the head injury reduces the probability of early posttraumatic seizures during the first few weeks after the injury but does not prevent the development of permanent posttraumatic epilepsy months or years later. Early treatment after a second tonic–clonic seizure does not improve the long-term outcome of the epilepsy. It is now clear that, while the new generation of AEDs is very useful, many patients in whom previous drug regimens were ineffective will not respond to the drugs. A challenge for the scientific community is to determine the causes for these drug failures and circumvent obstacles to seizure control by developing novel treatment strategies.

SEIZURE

AGGRAVATION

Seizure aggravation is an important limitation of current AEDs (Schmidt, 2009). Idiopathic generalized epilepsies are particularly prone to pharmacodynamic aggravation:

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typical absences are constantly increased by carbamazepine, vigabatrin, tiagabine, and gabapentin, while phenytoin is less aggravating. Juvenile myoclonic epilepsy is often aggravated by carbamazepine, less constantly by phenytoin and other AEDs. Generalized tonic–clonic seizures found in idiopathic generalized epilepsies may respond to AEDs that aggravate the other seizure types. Nonconvulsive status epilepticus has been associated with tiagabine. Gabapentin-associated myoclonus appears to be relatively frequent. It is usually mild and can easily be overlooked. Discontinuation of therapy is not necessary in most cases. In symptomatic generalized epilepsies, patients often have several seizure types that respond differently to AEDs: myoclonias are generally aggravated by the same drugs that aggravated idiopathic generalized epilepsies; tonic seizures in the Lennox–Gastaut syndrome respond to carbamazepine, which may, however, aggravate atypical absences. In severe myoclonic epilepsy of infancy, there is a nearly constant aggravating effect of lamotrigine. In some patients with benign rolandic epilepsy, a clear aggravation may be produced by carbamazepine, with occurrence of negative myoclonias, atypical absences, drop attacks, and at the maximum evolution into a state of electrical status epilepticus during sleep. Only a few medications can control idiopathic generalized epilepsies without potentially causing seizure aggravation. Broad-spectrum AEDs such as valproate, lamotrigine, and topiramate are extremely effective at controlling a variety of seizures without causing excessive seizure aggravation. Among these drugs, valproate has the longest clinical experience history and the largest body of published data.

LOSS

OF EFFECT (TOLERANCE)

Development of tolerance (i.e., the reduction in response to a drug after repeated administration) is an adaptive response of the body to prolonged exposure to the drug, and tolerance to AEDs is no exception. Tolerance develops to some drug effects much more rapidly than to others. The extent of tolerance depends on the drug and individual (genetic?) factors. Tolerance may lead to attenuation of side-effects but also to loss of efficacy of AEDs and is reversible after discontinuation of drug treatment. Different experimental approaches are used to study tolerance in laboratory animals. Development of tolerance depends on the experimental model, drug, drug dosage, and duration of treatment, so that a battery of experimental protocols is needed to evaluate fully whether tolerance to effect occurs. Two major types of tolerance are known. Pharmacokinetic (metabolic) tolerance, due to induction of AED-metabolizing enzymes, has been shown for most first-generation AEDs,

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and is easy to overcome by increasing dosage. Pharmacodynamic (functional) tolerance is due to “adaptation” of AED targets (e.g., by loss of receptor sensitivity) and has been shown experimentally for all AEDs that lose activity during prolonged treatment. Functional tolerance may lead to complete loss of AED activity and cross-tolerance to other AEDs. Convincing experimental evidence indicates that almost all first-, second-, and third-generation AEDs lose their anticonvulsive activity during prolonged treatment, although to a different extent. Because of diverse confounding factors, detecting tolerance in patients with epilepsy is more difficult but can be done with careful assessment of decline during long-term individual patient response. After excluding confounding factors, tolerance to anticonvulsive effect for most modern and old AEDs can be shown in small subgroups of responders by assessing individual or group response. Development of tolerance to the antiepileptic activity of an AED may be an important reason for failure of drug treatment. Knowledge of tolerance to AED effects as a mechanism of drug resistance in previous responders is important for patients, physicians, and scientists (L€ oscher and Schmidt, 2006).

UNPREDICTABILITY

OF EFFECTS

Drug treatment of epilepsy is characterized by unpredictability of efficacy, adverse drug reactions, and optimal doses in individual patients, which, at least in part, is a consequence of genetic variation. Since genetic variability in drug metabolism was reported to affect the treatment with phenytoin more than 25 years ago, the ultimate goal of pharmacogenetics is to use the genetic makeup of an individual to predict drug response and efficacy, as well as potential adverse drug events. However, determining the practical relevance of pharmacogenetic variants remains difficult, in part because of problems with study design and replication. The published work on pharmacogenetic alterations that may affect efficacy, tolerability, and safety of AEDs has been extensively reviewed (L€ oscher et al., 2009), including variation in genes encoding drug target (SCN1A), drug transport (ABCB1), drug metabolizing (CYP2C9, CYP2C19), and human leukocyte antigen (HLA) proteins. Although the current studies associating particular genes and their variants with seizure control or adverse events have inherent weaknesses and have not provided unifying conclusions, several results, for example that Asian patients with a particular HLA allele, HLAB*1502, are at a higher risk for Stevens–Johnson syndrome when using carbamazepine, are helpful to increase our knowledge of how genetic variation affects the treatment of epilepsy. Although genetic testing raises ethical and social issues, a better understanding

of the genetic influences on epilepsy outcome is key to developing the much-needed new therapeutic strategies for individuals with epilepsy (L€oscher et al., 2009).

Tolerability concerns Possible adverse effects of AEDs are listed in Table 42.3 (Alvestad et al., 2007; Zaccara et al., 2007; Elger and Schmidt, 2008; Schmidt, 2009). Approximately 50% of all patients receiving treatment for new-onset epilepsy report side-effects (Marson et al., 2007a, b). Many drugs require laboratory and clinical safety monitoring. Patients receiving carbamazepine should have their complete blood count monitored for the first year of therapy. If the white blood cell or red blood cell counts decrease significantly, the drug should be discontinued immediately. Patients receiving valproate should have liver function tests every 3 months for 1 year; if serum transaminases or ammonia levels increase significantly (to more than two times the upper limit of normal), the drug should be discontinued. An increase in ammonia up to 1.5 times the upper limit of normal can be tolerated safely. Adverse effects of AED treatment can be minimized by slow dose escalation up to average daily maintenance doses (unless increments are needed for seizure control), by avoiding enzyme-inducing agents and polytherapy, if possible, and by using appropriate welltolerated modern AEDs both for new-onset cases and refractory epilepsy (Schmidt, 2009).

ADVANTAGES AND DISADVANTAGES OF INDIVIDUAL ANTIEPILEPTIC DRUGS The advantages and disadvantages of individual AEDs are given in Table 42.5.

ADVANTAGES AND DISADVANTAGES OF ANTIEPILEPTIC DRUGS BYAGE GROUP Children One important consideration in children is that the AED should not interfere with learning and should not cause behavioral difficulties. As a result of the above, AEDs that are sedating should be avoided. These include barbiturates and benzodiazepines. Topiramate and zonisamide, which have cognitive adverse effects, should also be avoided as first-line treatment, although low doses of topiramate were associated with less cognitive dysfunction (Glauser et al., 2007). The safety and tolerability profile of AEDs may be different in children than in adults. For example, lamotrigine-associated serious rash is more common in children whereas aplastic anemia, which may occur with felbamate, has not been reported below age 13. Hepatic failure from valproate is more common in children younger than 2 and in the setting

Table 42.5 Major advantages and major disadvantages of individual antiepileptic drugs (AEDs) for the treatment of epilepsy AED

Major advantage

Major disadvantage

Carbamazepine

Efficacy against partial-onset seizures unsurpassed among current old and modern AEDs May be effective in some comorbidities Extended release preparation

Clobazam

Efficacy: partial-onset seizures; no significant drug interactions No hypersensitivity reactions Very effective against absence seizures; no drug interactions No hypersensitivity reactions Wide spectrum of efficacy

Less well tolerated than lamotrigine and gabapentin; not well tolerated in the elderly (CNS side-effects, cognition); drug interactions (it is a potent P450 enzyme inducer and is susceptible to interactions from a number of medications that result in its accumulation). Hypersensitivity reactions including Stevens–Johnson syndrome and Lyell syndrome; HLA-B*1502 allele carriers of Asian descent are at a significantly higher risk. Not useful for treatment of idiopathic generalized epilepsy; may aggravate absence or myoclonic seizures Depression; development of tolerance; sedative interaction with sedative drugs and alcohol

Ethosuximide

Methsuximide

Felbamate

Gabapentin

Lacosamide

Lamotrigine

Levetiracetam

Oxcarbazepine

Monotherapy and add-on efficacy in partial-onset seizures, add-on efficacy for drop attacks in Lennox–Gastaut syndrome Absence of sedation Efficacy: partial-onset seizures; better tolerated than immediate-release carbamazepine No drug interactions No hypersensitivity reactions Works also in neuropathic pain

Add-on efficacy: partial-onset seizures; rash is uncommon No significant pharmacokinetic drug interactions Excellent efficacy for partial-onset seizures, wide spectrum of efficacy includes generalizedonset seizures Better tolerated than conventional carbamazepine; absence of sedation Mood stabilizer Efficacy: partial-onset seizures, add-on efficacy: generalized tonic–clonic and myoclonic seizures in idiopathic generalized epilepsy No drug interactions No hypersensitivity skin reactions Can be started at an effective dose, has a rapid onset of action Intravenous preparation Extended release preparation Efficacy: partial-onset seizures; better tolerated than conventional carbamazepine

Narrow spectrum of efficacy Difficulty with tolerability in some patients: nausea, hiccups Rare: psychotic episodes, anorexia Less effective than ethosuximide against absence seizures Tolerability issues, particularly gastrointestinal adverse effects Aplastic anemia, liver failure; insomnia, gastric irritation Drug interactions (inhibition of P450 enzymes)

Less efficacious than carbamazepine Inconsistent absorption Weight gain Increased side-effect risk in patients with low glomerular filtration rate requires a lower dose Seizure aggravation in idiopathic generalized epilepsy (absence or myoclonic seizures) No efficacy against absence or myoclonic seizures May have pharmacodynamic interactions with other drugs acting on the sodium channel Interactions (clearance decreased by valproate, increased by estrogen, and enzyme inducers), hypersensitivity reactions Slow uptitration

Psychiatric side-effects, mainly irritability and aggression May cause a paradoxical increase in seizures at higher doses

Drug interactions (selective P450 inducer: reduces efficacy of oral contraceptives), hyponatremia, particularly in combination with diuretics – may require sodium monitoring Seizure aggravation in idiopathic generalized epilepsy (absence or myoclonic seizures) Continued

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Table 42.5 Continued AED

Major advantage

Major disadvantage

Pregabalin

Add-on efficacy: partial-onset seizures; no drug interactions No hypersensitivity skin reactions Works also in neuropathic pain and generalized anxiety disorders Efficacy: partial-onset seizures and generalized myoclonic seizures Rash is uncommon Phenobarbital is widely available and inexpensive Parenteral formulation Efficacy: partial-onset seizures Long accumulated experience Can be loaded orally or intravenously (intravenous phenytoin or the prodrug fosphenytoin)

Weight gain Increased side-effect risk in patients with low glomerular filtration rate requires a lower dose Seizure aggravation in idiopathic generalized epilepsy (absence or myoclonic seizures) Drug interactions (may lower the efficacy of concomitant medications metabolized by the P450 hepatic enzyme system) Sedation, cognitive slowing, arthralgia

Phenobarbital/ primidone

Phenytoin

Pregabalin

Rufinamide

Efficacy: partial-onset seizures as add-on; greater efficacy than gabapentin More reliable absorption than gabapentin Effective in the comorbidities of neuropathic pain, generalized anxiety disorders, and fibromyalgia No drug interactions Efficacy: Lennox–Gastaut syndrome

Tiagabine

Efficacy: partial-onset seizures Does not affect other AEDs Relatively favorable cognitive profile

Topiramate

Efficacy: partial-onset seizures and generalized seizures Rash is uncommon Efficacy against migraine Weight loss Wide spectrum of efficacy against partial-onset seizures and generalized seizures No hypersensitivity skin reactions Works for bipolar disorder and migraine Intravenous preparation Extended-release preparation Add-on efficacy for partial-onset seizures and West syndrome No interactions Efficacy: partial-onset seizures; generalizedonset seizures (evidence not rigorous) Long half-life (allows once daily dosing) Weight loss

Valproate

Vigabatrin

Zonisamide

CNS, central nervous system. Modified from Elger and Schmidt (2008).

Drug interaction (through P450 enzyme induction and extensive protein binding) Nonlinear pharmacokinetics (small changes in dose or bioavailability may produce large fluctuations in level) Ataxia, rash Seizure aggravation in idiopathic generalized epilepsy (absence or myoclonic seizures) Weight gain Aggravation of generalized myoclonic and absence seizures

Drug interactions (clearance decreased by valproate and increased by enzyme inducers; may reduce efficacy of oral contraceptives) Only indicated as adjunctive therapy Requires a slow titration, given three or four times daily Can cause nonconvulsive status epilepticus or encephalopathy that resembles nonconvulsive status epilepticus, even in the absence of prior epilepsy Weight loss; aphasia and cognitive impairment, nephrolithiasis, metabolic acidosis, hypohidrosis Requires slow titration rate because of adverse cognitive effects Weight gain; encephalopathy, tremor, Parkinsonian syndrome Teratogenicity and permanent adverse cognitive outcome in fetus Drug interaction (due to inhibition of P450 enzymes and extensive protein binding) Concentric visual field defects, irreversible

Weight loss, aphasia and cognitive impairment, nephrolithiasis, metabolic acidosis; anhidrosis in children (fever)

ANTIEPILEPTIC DRUGS: ADVANTAGES AND DISADVANTAGES of polytherapy. Oxcarbazepine-associated hyponatremia is uncommon in children and very unlikely to be of any clinical significance in this age group. Levetiracetam-associated behavior disorders are more common in children than in adults, as are behavioral changes with gabapentin and tics with lamotrigine. Hypohidrosis noted with topiramate and zonisamide is also more common in children. Most of the new AEDs were investigated in children as adjunctive therapy rather than first-line therapy. Some, including tiagabine, zonisamide, pregabalin, and lacosamide, have received insufficient investigation in children.

The elderly The healthy elderly may not be very different from younger adults. However, the frail elderly and the elderly with multiple medical problems require specific considerations in the choice of an AED. The elderly have a reduction in absorption, a reduction in lean body mass, a reduction in protein binding, and a reduction in renal and hepatic clearance. The overall effect of these physiological changes is higher serum levels of AEDs than expected from the dose. The elderly are frequently taking other medications and as a result an AED with fewer interactions or no interactions is preferable. Three comparative trials were performed specifically in new-onset epilepsy in the elderly. One compared lamotrigine and immediate-release carbamazepine and found lamotrigine to be equally efficacious to carbamazepine but with a lower dropout rate due to adverse events, and less somnolence (Brodie et al., 1999). A large cooperative veterans administration trial compared lamotrigine, gabapentin, and immediate-release carbamazepine and found that early terminations occurred more often in the carbamazepine group, mostly because of adverse events. There were no significant differences in seizure-free rates at 12 months. This suggested that lamotrigine and gabapentin should be considered as initial therapy for older patients (Rowan et al., 2005). A more recent international multicenter trial found that lamotrigine and sustainedrelease carbamazepine were not statistically different in efficacy or tolerability but there was still a trend for better tolerability with lamotrigine (Saetre et al., 2007). However, enzyme-inducing AEDs should be avoided in the elderly owing to their propensity to interact with other medications and to make these medications less effective. Besides lamotrigine and gabapentin, levetiracetam has characteristics that make it particularly advantageous in the elderly. Although it has not been subjected to a large comparative trial in the elderly, it has no drug–drug interactions, has been found equally effective to sustainedrelease carbamazepine in a general population of patients with newly diagnosed partial epilepsy, and has had several

735

reports of good tolerability in the elderly (Cramer et al., 2003; Ferrendelli et al., 2003). Its rapid onset of action and the existence of an intravenous formulation and an extended-release preparation are additional advantages. The old AED, valproate, is not an enzyme inducer. However, one large study found it to be less effective and less well tolerated than carbamazepine for partial seizures, which are the main seizure type in the elderly. Chronic valproate use in elderly patients has been associated with reversible parkinsonism and cognitive impairment (Armon et al., 1996; Ristic et al., 2006; Jamora et al., 2007). Oxcarbazepine has had extensive investigation as a first-line AED for partial epilepsy, but limited experience in the elderly. Although it has better tolerability and fewer drug–drug interactions than carbamazepine, it has a greater propensity to cause hyponatremia, which could be problematic in the elderly with multiple medical problems (Isojarvi et al., 2001; Ortenzi et al., 2008). Topiramate and zonisamide may have the disadvantage of cognitive adverse effects, but could be considered at low doses. Tiagabine, pregabalin, and lacosamide have had limited experience in the elderly. None of these drugs has an indication for first-line therapy, but may be considered with caution as adjunctive therapy in old age.

Women The most important considerations in women are potential for teratogenicity and interactions with oral contraceptives. Among all existing AEDs, valproate appears to have the greatest potential for causing birth defects as well as cognitive adverse outcomes in the exposed fetus (Meador et al., 2008). Both of these effects are dose dependent. Valproate doses of 1000 mg/day or less are not more likely to cause birth defects than other classic AEDs (Vajda et al., 2004). However, the safe dose for avoiding adverse cognitive outcomes is not known. The old AEDs phenobarbital and phenytoin are also associated with slightly increased risk of teratogenicity, but carbamazepine monotherapy appeared to be favorable in more recent registry data. Much less is known about the potential of the new AEDs to cause birth defects. The most extensively studied is lamotrigine, which, overall, does not seem to increase the risk of congenital malformations (Cunnington and Tennis, 2005). Limited data for oxcarbazepine, levetiracetam, and gabapentin also appear favorable. The old enzyme-inducing drugs phenobarbital, primidone, carbamazepine, and phenytoin reduce the efficacy of oral contraceptives, as do oxcarbazepine, topiramate at doses greater than 200 mg/day, and felbamate. The AEDs valproate, lamotrigine, gabapentin, levetiracetam, zonisamide, and pregabalin do not seem to significantly affect oral contraceptive efficacy.

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Other advantages and disadvantages of AEDs in women may relate to the effect of pregnancy and hormones on the metabolism of these AEDs. Several AEDs are affected by pregnancy, but particularly AEDs that are metabolized through glucuronidation, which is induced by estrogen. Perhaps the most affected is lamotrigine, which requires adjustments in dose during pregnancy to avoid breakthrough seizures (Ohman et al., 2008). There is evidence that enzyme-inducing AEDs and valproate may alter endogenous steroid hormones. Valproate is associated with hyperandrogenism and a higher risk of polycystic ovaries, both reversed in some women when valproate was replaced with lamotrigine (Isojarvi et al., 2005). Other new AEDs that are not enzyme inducing are likely to have less effect on the hormonal milieu, but most have not yet been carefully studied.

CONCLUSION The majority of patients with epilepsy will achieve lasting remission on drug treatment. The chances of success of therapy can be optimized by considering AED advantages and disadvantages for the specific seizure type, epilepsy syndrome, patient category, and comorbidities. For those patients who do not achieve remission, significant risks of mortality and morbidity exist owing to uncontrolled seizures. Seizure freedom is therefore very important. Several new drugs have been added to the armamentarium and these should be considered in each refractory patient. These may produce remission in up to 5% per year (Callaghan et al., 2007). However, they are not always effective, and surgical options should be explored when appropriate after failure of two or three AED trials. Adverse effects of AED treatment can be minimized by slow dose escalation up to average daily maintenance doses (unless increments are needed for seizure control), by avoiding enzyme-inducing agents and polytherapy, if possible, and by using appropriate well-tolerated modern AEDs both for new-onset cases and refractory epilepsy.

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