Monograph

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Introduction

There is a strong consensus among epilepsy specialists that the initial treatment of epilepsy should begin with antiepileptic drug (AED) monotherapy.¹ If the patient fails the initial trial, the next step is to try monotherapy with a second AED. Combination therapy should be considered only if the patient fails at least 2 monotherapy trials.

Several uncontrolled trials have shown that AED monotherapy is equally or more effective than polytherapy in the treatment of both adults and children with epilepsy.^2-4 In addition, monotherapy is associated with fewer side effects and drug-drug interactions, better compliance, lower financial burden, and significant improvements in health-related quality of life in comparison to polytherapy treatment regimens.^3,4 For these reasons, monotherapy is considered to be the treatment of choice for nearly all patients with epilepsy.

The ultimate goal of any epilepsy therapy is to maintain optimal quality of life by achieving complete seizure freedom with no drug-induced side effects. Clinical studies have demonstrated that approximately one-half to two-thirds of all newly diagnosed patients who are started on monotherapy will remain seizure free for at least 1 year.^5,6 Moreover, based on published retrospective data, the probability that a patient will become seizure free on a polytherapy regimen after failing several AEDs as monotherapy is less than 10%. Cumulative evidence indicates that even the highest doses of the most efficacious adjunctive therapies, topiramate, oxcarbazepine, levetiracetam, and pregabalin will produce a significant reduction in seizure frequency (>50%) in only 32% to 37% of patients with refractory epilepsy.^7,8

Side effects are one of the most important determinants of quality of life (QoL) in patients with epilepsy.^9,10 Estimates suggest that nearly 20% of all newly diagnosed individuals discontinue their first AED because of intolerable side effects or idiosyncratic reactions.6 Since all AEDs are centrally acting drugs, they have the potential to cause central nervous system (CNS)-related adverse effects, such as drowsiness, fatigue, confusion, cognitive and memory impairments and ataxia. In children, symptoms of irritability, aggression, and hyperactivity may also be seen. CNS side effects, in general, tend to be additive. Hence, the patient who is receiving polytherapy has a greater risk of experiencing adverse events and idiosyncratic reactions since the likelihood of pharmacokinetic interactions and additive toxicities greatly increases when AEDs are combined.¹¹ Adding a second AED to the treatment regimen can alter baseline plasma drugs levels up or down, thus heightening the risk of toxicity or increasing the risk of seizures. Although the “therapeutic range” of an AED is only a general guide for clinical use, evidence suggests that the drug’s efficacy and safety may also change as a function of the number of drugs onboard. For example, the plasma concentration upper limit of tolerability is generally lower when an AED is used as polytherapy.¹² Since polytherapy does not often improve the efficacy:toxicity ratio, regimens should be evaluated in terms of their effect on the person as a whole-their seizure status, functionality, and overall QoL. Unless it can be demonstrated that polytherapy produces better seizure control with no additional side effects or the same level of seizure control with fewer side effects, patients typically benefit more from monotherapy with the drug that has the highest efficacy:toxicity ratio.¹¹

A past argument used in the past to support polytherapy is that it allows combining AEDs with different mechanisms of action, thus leading to enhanced efficacy. Although it is well known that the AEDs have different mechanisms of action, there are no controlled studies demonstrating any therapeutic advantage in combining AEDs with different mechanisms of action. Thus, polytherapy should be used only when there is a clear benefit over monotherapy in an individual patient for efficacy or tolerability, and not based on theoretical assumptions of “rational polytherapy”.

Switching to monotherapy has been shown to reduce the number and severity of AED side effects and improve health-related QoL while maintaining or improving seizure status.^13,14 In a group of patients with medically refractory epilepsy (n=35), none reported a worsening of seizure frequency 12 months after switching from poly- to monotherapy, 40% became seizure-free, and 40% had a 50% to 75% reduction in seizure frequency.¹⁵ Participants felt that their QoL improved on monotherapy in the specific domains of memory loss, concern over the long-term effects of medication, ease of taking medication, trouble with or restriction of leisure time activities, and overall state of health.

Antiepileptic Drug Therapy in Various Patient Subgroups

WOMAN OF CHILDBEARING AGE
The use of AED monotherapy in women of childbearing age is associated with a, nearly a two-fold reduction in major congenital malformations in exposed fetuses.^16,17

ELDERLY PATIENTS
The advantages of monotherapy are most apparent in elderly patients who are less tolerant of CNS side effects, more susceptible to drug-drug interactions, and more likely to have compliance and financial issues because they are taking multiple medications for other comorbid conditions.¹⁸ Although the elderly experience similar adverse effects as other patient subgroups to antiepileptic medications, they tend to occur more frequently and at lower doses and lower plasma drug concentrations than in younger people.^18,19 There are little QoL data in the elderly. However, the results from one review suggest that patients receiving conservative AED monotherapy may have the most favorable outcomes in terms of cognitive function, behavior, and overall health status.²⁰CHILDREN
QoL issues are critically important in children because of their rapid and ever-changing physical, cognitive and psycho-social maturation. Although most patients experience good long-term seizure control, childhood-onset epilepsy is associated with adverse long-term psychosocial outcomes.21 CNS and behavioral side effects of AEDs can have a negative impact on school performance and long-lasting effects on relationships with family members and friends. Age-related changes in absorption, volume of distribution, and metabolism may also alter the pharmacokinetics and pharmacodynamic effects of AEDs and increase a child’s susceptibility to organ toxicity. Monotherapy with a side effect-free AED that requires infrequent daily dosing and limited laboratory monitoring should enhance compliance, improve QoL, and maximize treatment outcomes.

Initiating Monotherapy

Epileptic seizures are highly individualized in their etiology, presentation, and response to AED therapy, and for this reason, the development of effective treatment regimens is often considered to be more of an art than a science. Selection of an appropriate AED should be based on careful consideration of age, sex, seizure type and syndrome, coexisting comorbidities, concomitant medications, and life style of the patient, in addition to the efficacy, tolerability, and side effect profile of the AED. Since more than half of all patients with new onset epilepsy will attain seizure freedom on their first AED, physicians should keep in mind that the initial drug treatment may be for long-term or even life-long use.⁶

Patients with seizures treated in the emergency room also face long-term health consequences if initially treated with the wrong medication. The inability to calculate the length of time the seizure was occurring can lead to misdiagnosis of seizure type. Prescribing medication for the incorrect seizure type may increase the amount of seizures or even cause uncontrolled seizures in some cases. Thus, it is important for patients to be re-evaluated soon after their emergency room visit to ensure they are placed on optimal therapy to control their seizure type.

The presence of comorbidities adds to the complexity of the management of individuals with epilepsy. Estimates suggest that 40% to 50% of children with epilepsy have coexistent behavioral or psychiatric comorbidities and if cognitive impairments are included, the percentage of affected children is even higher.²² In adults, the highest prevalence of psychiatric comorbidities (40% to 60%), primarily mood and anxiety disorders, is associated with refractory epilepsy.² Comorbid depression (11% to 62%) and migraine headache (20% to 24%) are also seen frequently in individuals with epilepsy.^2,23 The presence of these and other comorbidities confound the diagnosis and treatment of epilepsy by making it difficult for the clinician to separate drug-induced adverse effects on cognition and behavior from those caused by underlying comorbid disorder. Management of the patient with comorbidities can sometimes be simplified by choosing an AED that has dual efficacy, such as topiramate for migraine headache and lamotrigine for mood disorder.

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First and Second Generation AEDs

Nine newer, second-generation AEDs have been approved by the Food and Drug Administration (FDA) since 1993: felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV) oxcarbazepine (OXC), pregabalin (PGB), tiagabine (TGB), topiramate (TPM), and zonisamide (ZNS). Three of these, TPM, LTG, and LEV, have a broad spectrum of activity with proven efficacy in the treatment of both partial and generalized seizures. ZNS also appears to be efficacious in generalized epilepsy based on large open label series, but there are no randomized controlled trials demonstrating this. Broad spectrum activity simplifies the treatment of patients where the diagnosis of partial versus generalized onset is unclear or the rare case where the patient has both partial and generalized onset seizures.

The newer AEDs have different pharmacokinetics and varied mechanisms of action compared to first generation AEDs. Additionally, some drugs may have either multiple or unknown mechanisms of action. Newer AEDs also offer less toxicity and more favorable side effect profiles compared to older AEDs (Table 1 and Table 2). This is probably the greatest benefit of the newer AEDs since it allows physicians to tailor treatment more closely to the needs of special patient populations. However, in order to do so, physicians need to have a thorough understanding of the unique characteristics of each drug and how selection of a specific AED can maximize treatment outcome.

In general, clinical studies have demonstrated that first and second generation AEDs have similar efficacy when given as monotherapy, with each class of drug controlling seizures in approximately half to two-thirds of the patients.^6,7,24-26 However, the newer AEDs tend to have less impact on hepatic metabolism, simpler pharmacokinetics, less frequent drug interactions, and fewer side effects than the older AEDs (Table 1 and Table 2). Patients also seem to tolerate monotherapy with the newer AEDs better, as evidenced by lower frequencies of adverse events and fewer discontinuations due to adverse events.³ This distinction is important since 20% of all patients will discontinue their first AED because of intolerable side effects or an idiosyncratic reaction.⁶ After consideration of seizure type, therefore, the most appropriate AED is often determined by patient preference and the potential for short- and long-term adverse effects.

Switching from Polytherapy to Monotherapy

It is not uncommon for neurologists to encounter a patient who is taking one or more AEDs that are inappropriate for their type of epilepsy. At best, these drugs are not contributing to seizure control; at worst, they may be increasing seizure frequency and exacerbating side effects. In this situation, switching from polytherapy to monotherapy makes intuitive sense. However, even the patient on a polytherapy regimen who has been seizure-free with no apparent side effects may benefit from switching to monotherapy. Subtle CNS effects can go unrecognized for years until the offending medication is withdrawn and the patient suddenly experiences an increase in mental clarity and functional capacity. Similarly, depression is common in epilepsy but may go unrecognized for years as a side effect of AEDs. The older AEDs, PRM, PB and PHT, are all associated with increased rates of depression.

It is not always an easy task to transition a patient from polytherapy to monotherapy. Due to complex pharmacokinetic and pharmacodynamic effects, it can be difficult to determine which AED is most responsible for seizure control or particularly bothersome side effects. Enzyme-inducing first generation AEDs reduce plasma levels of TPM, TGB, ZNS, LTG, and FBM and in doing so, reduce drug efficacy.²⁷ VPA, on the other hand, inhibits the metabolism of certain AEDs, such as LTG, resulting in higher plasma levels and the potential for toxic side effects. The fact that adverse effects can occur at plasma concentrations within the recommended “therapeutic range” and do not always correlate with serum drug levels further complicates the scenario.

There is no single, correct way to transition a patient from AED polytherapy to monotherapy. The strategy used depends upon the patient’s seizure type and frequency, history of AED exposure, the reason and urgency for the conversion, and consequences of breakthrough seizures. Success is dependent upon good doctor-patient communication and agreement on the goals and rationale for the medication change. The use of polytherapy implies that the patient has had seizures that have been difficult to control in the past. Consequently, physicians should proceed with caution and taper drugs slowly to ensure that the transition is executed safely with no increase in seizure frequency. Maintaining seizure status during the transition period can be challenging, often requiring frequent adjustments in the dose of the AED that has been selected for eventual monotherapy. In addition the medications that will eventually be removed from the treatment regimen. During withdrawal of certain AEDs, such as FBM and PB, breakthrough seizures may occur and actually increase in frequency. However, this occurs only briefly during the transition period and the seizures do not usually persist.²⁸ In general, most clinicians use a 1-3 month period to withdraw a second AED when transitioning to monotherapy. In summary, three factors that are most important in switching to monotherapy from polytherapy with AEDs are 1) titration (increase) of the monotherapy drug 2) titration (decrease) of the other drugs in the regimen and 3) time for adjustment to this new regimen.

Use of Monotherapy in Adults and Children

All of the newer AEDs that are approved for use as adjunctive therapy in adults with epilepsy, and with the exception of PGB and ZNS, are also approved for use in children (Table 3 and Table 4). Although clinical testing of their effectiveness as monotherapy has been slow, there is now evidence demonstrating the efficacy and tolerability of a number of the newer AEDs in specific patient populations.

Recommendations for the use of the newer AEDs as monotherapy vary depending on the source of the recommendation and the criterion used to assess the supporting evidence. Currently, the FDA grants approval for monotherapy for only those AEDs that have demonstrated superiority to another treatment (either placebo or a lower dose of the same or another AED) in a controlled clinical trial. The FDA does not recognize a trial demonstrating equivalence of a new AED to a standard treatment as sufficient evidence for monotherapy approval. Several experienced investigators have questioned the FDA’s monotherapy trial requirements and raised the concern that trials designed with a treatment arm that is, a priori thought to be less efficacious may violate the concept of equipoise, an important concept in clinical research ethics. To date, 4 second generation AEDs have met this criterion: OXC and TPM for initial monotherapy, and FBM, LTG, OXC, and TPM for conversion to monotherapy (Table 5). In 2004, the American Academy of Neurology (AAN) and the American Epilepsy Society (AES) established practice guidelines for the use of second generation AEDs as monotherapy in new-onset and refractory epilepsy based on an in-depth review of placebo-controlled clinical trials. The final assessment also included results of head-to-head comparisons and dose-controlled studies. Based on this review, the committee concluded that there was sufficient evidence to recommend the use of GBP, LTG, TPM, and OXC as monotherapy in adults and adolescents with newly diagnosed partial or mixed seizure types, but insufficient evidence to recommend the use of any of the newer AEDs as monotherapy in generalized epilepsy syndromes.²⁹ In addition, the committee indicated that there was sufficient evidence to recommend the use of OXC, TPM, and LTG as monotherapy in adults with refractory partial seizures.³⁰

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Subsequently, since the committee’s publication of the guidelines in 2004, there have been additional indications for LTG, LEV, and TPM that have been approved by the FDA. The additional clinical trial data supporting the new indications will likely be evaluated in the next update of the AES/AAN guidelines.

Epilepsy specialists often use AEDs for indications that are not FDA approved, relying on literature reports to substantiate their potential efficacy and use in special patient populations. Off-label use of AED monotherapy in children, however, is the rule rather than the exception because there have been very few controlled clinical trials evaluating and comparing the efficacies of second generation drugs in these patients. Hence, physicians are forced to extrapolate efficacy data from adult studies, keeping in mind that the pharmacokinetic and pharmacodynamic effects of AEDs may be different in children and that the side effects may be qualitatively and quantitatively unlike those seen in adults. The fact that certain seizure types are seen only during childhood enhances the challenge of dealing with this age group.

The following is a brief discussion of the clinical evidence that supports the use of the newer AEDs as monotherapy in adults and children with epilepsy. The data presented is from both short-term withdrawal studies that provide proof-of-concept, as well as intermediate and long-term controlled clinical trials that demonstrate monotherapy efficacy.

Oxcarbazepine (OXC)

OXC is FDA approved for use as initial monotherapy in individuals >4 years of age with partial seizures (simple, complex, or secondarily generalized). Three randomized, double-blind, multicenter clinical trials support the use of OXC monotherapy in adults with newly diagnosed partial-onset or primary generalized seizures.^31-33 Taken together, the results from these studies demonstrated that OXC monotherapy was equally as effective as CBZ, PHT, and VPA in the treatment of new-onset epilepsy, as indicated by statistically equivalent seizure-free rates within the range of 50% to 60%. OXC was tolerated equally as well as VPA, and was associated with fewer severe adverse events and fewer premature discontinuations due to adverse events than either CBZ or PHT, respectively.

Cumulative results from 3 studies provide evidence supporting the use of OXC monotherapy in patients with refractory epilepsy. In the first study, the efficacy of OXC monotherapy was evaluated in hospitalized patients who had been withdrawn from all AEDs prior to undergoing presurgical evaluation.³⁴ By the end of the 10-day trial period, 47% of OXC-treated patients had dropped out of the study in comparison to 84% of those treated with placebo. Results from the second study demonstrated an efficacy advantage of high dose OXC monotherapy (2400 mg/day) over low dose therapy (300 mg/day) in individuals with refractory epilepsy in two outcome measures-time to exit due to lack of efficacy and percentage of patients achieving seizure freedom.³⁵ Lastly, in an open-label extension study of OXC monotherapy in 76 patients with medically refractory partial epilepsy, 6.6% of the patients reportedly remained seizure free during the 48-week-long evaluation period (median OXC dose = 2400 mg/day).³⁶ OXC was generally well tolerated in these studies. Adverse events tended to be transient in nature and included dizziness, sedation, nausea, diplopia, fatigue, and rash.^34-36

A retrospective chart review of 60 children (aged 6 months to 18 years) with partial onset epilepsy who had been receiving OXC monotherapy anywhere from 3 months to 8 years, determined that 42% were seizure-free and 85% had achieved a >50% reduction in seizure frequency.³⁷ Adverse events were reported in 16.6% of the children and included drowsiness, aggressive behavior, ataxia, dizziness, diplopia, and leg cramps. There were no reports of skin rash or hyponatremia. Twenty-four of the 60 patients had been previously switched from CBZ to OXC monotherapy because of lack of efficacy and/or intolerable side effects. Of these, 37.5% had attained seizure freedom and 79% had achieved >50% reduction in seizure frequency on OXC monotherapy.

In a double-blind, controlled clinical trial, OXC monotherapy has been shown to be equally efficacious and better tolerated than PHT in children and adolescents, 5 to 18 years old, with newly diagnosed partial seizures or primary generalized tonic-clonic seizures.³⁸ Whereas seizure free rates were about 60% in each treatment group, discontinuation rates due to adverse events were significantly higher in those treated with PHT (14.6% PHT vs 2.1% OXC).³⁸

Topiramate (TPM)

The efficacy of TPM as initial monotherapy is well documented and the drug is currently FDA approved for broad spectrum use in patients 10 years of age and older with partial onset or primary generalized tonic-clonic seizures. The results from two multi-drug comparative trials enrolling adults or children with newly diagnosed epilepsy have shown that 100 and 200 mg/day TPM are equivalent to 600 mg/day CBZ and 1250 mg/day VPA in terms of time to exit, time to first seizure, and percentage of patients remaining seizure-free for at least 6 months.^39,40 In both of these studies, the low, 100mg/day dose of TPM was associated with fewer side effects leading to discontinuation than CBZ, VPA, or TPM 200 mg/day, although this difference was not statistically significant.

Comparison of low (25 or 50 mg/day) and high (200 or 500 mg/day) dose TPM in a randomized, double blind study of adults and children (> 3yrs) with recently diagnosed localization-related epilepsy over a 4 month period, revealed an efficacy advantage of high dose therapy in terms of seizure free rates (54% vs 39%) and median time to first seizure (317 days vs 108 days).41 The most common adverse events, paresthesia, weight loss, diarrhea, and hypoesthesia, were dose-related. In an open label study of adults and children (>2 yrs) with a variety of seizure types who were either treatment naïve or had failed prior treatment with one AED, 44.2% became seizure free on TPM monotherapy (100 to 400 mg/day) and 76.2% achieved > 50% reduction in seizure frequency.⁴² More patients with generalized epilepsy (61.5%) than with focal epilepsy (39.4%) attained seizure freedom. Nearly 9% of patients discontinued treatment because of medication intolerance, the most frequent adverse event being paresthesia.

There is very little data on the use of TPM in children younger than 2 years of age. However, the results from 2 small studies, one retrospective chart review and one dose-escalation trial, suggest that TPM monotherapy may be a safe and effective alternative for a variety of seizure types seen in this age group, including infantile spasms which reportedly respond favorably to doses <12 mg/kg/day in 30% of patients.^43,44

In elderly patients (>65 yrs) with new-onset epilepsy, open label, slow titration of TPM to a maximum dose of 400 mg/day produced seizure freedom in 64% of the enrolled patients and 87% achieved a 50% reduction in seizure frequency over the 7 month-long follow-up period.⁴⁵ Fourteen percent withdrew from the study because of poor tolerability.

There is limited data surrounding the use of TPM monotherapy in refractory epilepsy. However, there is one single-center study comparing the efficacy of TPM at 100 and 1000 mg/day doses in 48 patients with refractory partial seizures.⁴⁶ Seizure-free rates were reportedly 13% in the high dose group versus 0% in the low dose group. Adverse events were similar in nature but less frequent than those reported in add-on trials.

Although TPM is also indicated for the prophylaxis of migraine headache in adults, its use in epileptic patients with comorbid migraine has not been systematically evaluated. The results from one observational study in 15 patients suggest that TPM 100 mg/day may significantly reduce the severity and duration of migraine attacks while decreasing the frequency of epileptic seizures.⁴⁷

Felbamate (FBM)

FBM was the first AED with proven efficacy in Lennox-Gastaut syndrome in children 2-14 years of age.⁴⁸ However, because of the potential for serious side effects, it is currently approved for use only as adjuvant therapy for this disorder. FBM is not recommended for initial monotherapy because of the potential for the serious adverse effects of aplastic anemia and hepatotoxicity. However, it can be considered for use, either alone or in combination, in patients whose epilepsy is so severe that the potential benefits are deemed greater than the risks. Currently the drug is approved for use as monotherapy for partial onset seizures and tonic-clonic seizures in adults >14 years of age.

The safety and efficacy of FBM monotherapy was compared to placebo in 52 patients with refractory partial seizures who had all AEDs withdrawn before undergoing evaluation for epilepsy surgery. At the end of the 10 day study period, the daily seizure frequency in the FBM group (maximum dose 3600 mg/day) was significantly lower than that of placebo controls. In 9 of the patients who completed the study, seizure frequency decreased by 89.5% in comparison to baseline. The results from a single-center, double-blind study demonstrated an efficacy advantage of FBM 3600 mg/day over valproate 15 mg/kg/day following conversion to monotherapy in 44 patients with uncontrolled partial onset seizures.⁴⁹ FBM monotherapy was associated with a lower incidence of adverse events, lower number of patients meeting escape criteria, and a 50% to 65% reduction in seizure frequency.

Lamotrigine (LTG)

LTG has established efficacy in a broad range of seizure types, including partial seizures, primary generalized tonic-clonic seizures, and the generalized seizures of Lennox-Gastaut syndrome in adults and children as young as 2 years of age. Although it has not received FDA approval for use as initial monotherapy, it is indicated for conversion to monotherapy in adults with partial seizures who are taking the enzyme-inducing AEDs, CBZ, PHT, PB, PRM, or VPA as a single AED. Recent guidelines recommend the use of LGM monotherapy for the treatment of patients with both new-onset and refractory partial epilepsy.^29,30

Several studies, comparing the efficacy of LTG with that of CBZ, PHT, or GBP monotherapies in patients with newly diagnosed epilepsy, have shown that the 4 drugs are equally efficacious in newly diagnosed partial seizures with and without secondary generalization or populations of patients with either partial onset or primary generalized tonic clonic seizures. Specifically, data from one double-blind, parallel group study demonstrated similar seizure-free rates in patients treated with LTG and CBZ (39% vs 37%), but lower discontinuation rates due to adverse events in those receiving LTG (15% vs 27%).⁵⁰ The most frequent side effect leading to discontinuation of either drug was rash. Two additional double-blind monotherapy trials, comparing the efficacy of LTG with that of either PHT or GBP in a similar patient population, found that LTG was as effective as PHT (43% vs 36%) and GBP (75.5% vs 76%) in terms of the percentage of patients achieving seizure freedom.^51,52 Tolerability also appeared to be comparable between the 3 drugs, as indicated by similar discontinuation rates due to adverse events. Whereas skin rash was the most frequent side effect reported by patients on LTG, asthenia, somnolence, and ataxia were more common in those taking PHT.⁵¹ Skin rash is a disturbing side effect of LTG therapy that can occur in up to 10% to 12% of patients.⁵³ The type of rash can range from morbilliform and erythema multiforme to Steven-Johnson syndrome and toxic epidermal necrolysis. Steven-Johnson syndrome is somewhat rare, occurring in about 0.3% of adults and 0.5% of children. With slow titration, the risk of rash can be reduced.

A large retrospective study of newly diagnosed adolescents and adults found that patients with partial epilepsy had the highest seizure-free rates when on LTG monotherapy (63%) in comparison to CBZ (45%) or VPA (42%).⁵⁴ In contrast, patients with primary generalized epilepsy responded most favorably to VPA monotherapy (68%) followed by LTG (45%) and then CBZ monotherapy (31%). Discontinuation rates due to adverse events were higher in patients treated with CBZ (16%) than with VPA (7%) or LTG (7%).

In an 18-center parallel study, 593 elderly individuals with new onset epilepsy were randomized to receive GBP 1500 mg/day, LTG 150 mg/day, or CBZ 600 mg/day.55 At the end of the 12 month follow-up period, there were no significant differences noted between the seizure-free rates displayed by patients in any of the 3 treatment groups. Adverse event rate was the main factor determining patient retention in the study. Terminations due to adverse events were highest in those treated with CBZ (31%), followed by GBP (21.6%), and LTG (21.1%).One study that used a “responder-enriched” trial design where open-label dose escalation was followed by placebo-controlled, double-blind testing of LTG in children with absence epilepsy, found that 82% achieved seizure-freedom at a median dose of 5 mg/kg/day.⁵⁶ Moreover, significantly more children on LTG (62%) remained seizure free in comparison to those treated with placebo (21%). A second open-label study demonstrated that LTG and VPA monotherapies were equally efficacious in the treatment of children and adolescents with newly diagnosed typical absence seizures, as indicated by comparable seizure free rates (52.6% vs 68.4%, respectively) at 12 month follow-up.⁵⁷ Adverse events tended to be mild and transient in nature and occurred at a frequency of 31.8% in patients taking LTG and 10.6% in those taking VPA.

One double blind, double dummy, active control study established efficacy of LTG monotherapy in adult outpatients with refractory partial seizures in comparison to a low dose VPA, pseudoplacebo arm.⁵⁸ LTG was superior to VPA in terms of the time to exit from the study (median, 57 days vs 168 days) and percentage of patients completing the study (56% vs 20%).

LTG has demonstrated antidepressant efficacy in bipolar depression and is currently indicated for maintenance therapy in Bipolar I Disorder. Limited data suggest that LTG may also improve mood in adult patients with epilepsy and comorbid mild depression.⁵⁹ A retrospective chart review of children with bipolar spectrum disorder and epilepsy comorbidity revealed that in the 30 instances when AED monotherapy was attempted, CBZ, VPA, LTG, and OXC were associated with significantly better psychiatric outcomes than other monotherapies.⁶⁰

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Gabapentin (GBP)

Several studies have explored GBP’s potential as monotherapy in new-onset and refractory partial epilepsy. In a large multicenter, randomized, double-blind study, 292 adolescents and adults with newly diagnosed partial or generalized epilepsy were randomized to receive GBP 300, 900, or 1800 mg/day or CBZ 600 mg/day.⁶¹ Patients remained in the study for 6 months or until they experienced an exit event. The results revealed that mean time to exit was significantly longer in groups receiving 900 and 1800 mg/day GBP as opposed to 300 mg/day GBP. Although a similar percentage of patients in the GBP (900 and 1800 mg/day) and CBZ groups completed the study (≈38%), more patients in the CBZ group withdrew because of adverse events. Dizziness, fatigue, and somnolence were experienced more frequently by those receiving CBZ monotherapy.

One head-to-head study compared GBP (1200 to 3600 mg/day) and LTG (100 to 300 mg/day) monotherapy in 309 patients with new-onset partial epilepsy.62 Both monotherapies were found to be equally effective, with 75.5% and 76.0% of patients achieving seizure freedom with GBP and LTG, respectively. Although a comparable percentage of GBP- and LTG-treated patients completed the study, the median time to exit was longer in the GBP group (69 days) than in the LTG group (48 days).

Two additional studies evaluated the efficacy of GBP in medication-resistant epilepsy. The first compared 300 mg and 3600 mg GBP monotherapy in patients who had withdrawn from AED therapy prior to video EEG monitoring.^63-64 Median time to exit from the study was significantly longer in the high dose group than in the low dose group (151 vs 85 hrs) and significantly more patients in the high dose group completed the 8-day trial. No patient withdrew from the study because of intolerable side effects. In the second multicenter, double-blind, parallel group study, 275 outpatients with refractory partial epilepsy were switched to GBP 600, 1200, or 2400 mg/day and then monitored for 26 weeks.⁶¹ Time to exit (due to an increase in seizure frequency) did not differ between the 3 treatment groups and only 3% of the patients discontinued because of adverse events.

Limited data from one small study suggest that GBP monotherapy (19 mg/kg/day) is no better than placebo in controlling seizures in children with newly diagnosed absence epilepsy.⁶⁵ Somnolence and dizziness were reportedly the most frequent adverse events experienced by children taking GBP.

Levetiracetam (LEV)

LEV is FDA approved for use as adjunctive therapy for partial-onset seizures in adults and children >4 years of age. Currently, there is limited data regarding the efficacy of this AED as monotherapy. However, two small retrospective studies of patients with a history of partial seizures, with and without secondary generalization, reportedly found that 38% to 54% achieved seizure freedom and approximately 45% obtained >50% reduction in seizure frequency with LEV monotherapy.^66,67 Similar findings were observed in a small cohort of elderly patients (n=13)-61.5% became seizure free and 31% attained at least a 50% reduction in seizure frequency with LEV monotherapy.⁶⁸

Very recent results from a Phase III randomized, double-blind, head-to-head comparison of CBZ controlled release (CR) and LEV monotherapy in 576 patients with newly diagnosed partial onset or generalized tonic-clonic seizures (excluding idiopathic generalized epilepsy) demonstrated that LEV was equally efficacious and better tolerated than CBZ-CR. In this study, patients were titrated up to an initial dose of 1000 mg/day LEV or 400 mg/day CBZ-CR over a 3 week period and then observed for 6 months. If a seizure occurred, doses were increased to LEV 2000 mg/day or CBZ-CR 800 mg/day. Once seizure freedom had been maintained for 6 months, patients entered into a 6 month maintenance period. The results revealed that 73.0% and 72.8% of patients on LEV and CBZ-CR, respectively, maintained seizure freedom for 6 months and that 56.6% and 58.5% maintained seizure freedom for 12 months. Significantly fewer patients receiving LEV required a dose change or discontinued from the study because of adverse events (61.1% vs 23%, respectively).⁶⁹ An additional Phase III Clinical trial is currently enrolling patients to compare the safety and efficacy of LEV and LTG as initial monotherapy in new onset epilepsy.⁷⁰

Data supporting the use of LEV monotherapy in medication-resistant epilepsy is also limited. In one double-blind, placebo-controlled study, patients with refractory partial epilepsy who had responded favorably to 3000 mg/day LEV adjunctive therapy were switched to LEV (1500 twice a daily) monotherapy and then monitored for 12 weeks.⁷¹ In comparison to baseline, the median percent reduction in partial seizure frequency was 73.8% and 59.2% experienced > 50% reduction in seizure frequency. The switch was generally well-tolerated and 18.4% of the patients remained seizure-free.

Pregabalin (PGB)

PGB just recently received FDA approval as add-on therapy in adults with partial epilepsy with or without secondary generalization. To date, there have been no monotherapy, randomized, controlled trials for PGB.

Although PGB also has demonstrated efficacy in neuropathic pain and generalized anxiety disorders, its use in epileptic patients with these comorbidities has not been systematically evaluated.⁷²

Tiagabine (TGB)

To date, there is little data regarding the efficacy of TGB monotherapy in patients with epilepsy. In a double-blind, randomized study of patients with medication-resistant complex partial seizures who were converted to 6 or 36 mg/day TGB monotherapy, significantly more patients in the high dose group experienced > 50% reduction in seizure frequency over the 4 week observation period than those in the low dose group.⁷³ The adverse events associated with monotherapy were similar to those seen with adjunctive therapy. A second, smaller study evaluated the effectiveness of TGB relative to placebo in 11 hospitalized patients with complex partial seizures.⁷³ Baseline AEDs were either withdrawn slowly (PB, PRI) or discontinued abruptly at the time of randomization. TGB was then titrated up to a maximum dose of 66 mg/day. Although seizure frequencies increased following discontinuation of baseline AEDs in both TGB- and placebo-treated patients, the increase was greatest in the placebo group.

Patients with epilepsy have a greater risk of experiencing cognitive impairments than nonepileptic individuals. The results from 2 pooled, randomized, 52-week-long studies demonstrated that successful TBG monotherapy with 20-30 mg/day was not associated with a significant decline in cognitive scores.⁷⁴ Rather, patients treated with TGB monotherapy had a cognitive profile similar to that of untreated epileptic patients with a single seizure type and no different from that of successful long-term monotherapy with CBZ 400 to 800 mg/day.

Zonisamide (ZNS)

ZNS has recently been approved in the United States and Europe as adjunctive therapy for partial epilepsy with or without secondary generalization. The available evidence suggests that ZNS monotherapy is safe and effective in adults and children with a variety of seizure types. One long-term study of adult epileptic patients identified through chart review who received ZNS monotherapy for an average of 24.3 months found that 42% had achieved seizure freedom and 29% had obtained a >50% reduction in seizure frequency at the last follow-up visit.75 The most commonly reported adverse events, weight loss (5.4%), fatigue (4.5%), and sedation (2.7%), were all mild to moderate in intensity. In a second chart review of adults and children with a variety of seizure types from a large multi-group clinic, 63% became seizure free on ZNS monotherapy and nearly half of these patients achieved seizure freedom at the initial 100 mg dosage.⁷⁶

Once-a-day dosing, a rapid onset of action, good safety profile, and lack of significant drug interactions make ZNS an attractive therapeutic option, specifically for children and adolescents. A retrospective analysis of patients with juvenile myoclonic epilepsy (JME) who were treated with ZNS monotherapy (200 to 500 mg/day) revealed that 38% were free of generalized tonic-clonic, myoclonic, and absence seizures within 4 to 8 weeks.⁷⁷ Evidence from another retrospective chart review found that 79% of children with partial epilepsy and 71% of those with generalized epilepsy responded well to ZNS monotherapy and attained a >50% reduction in seizure frequency. A total of 79% and 63% of these individuals, respectively, achieved seizure freedom.⁷⁸ Adverse events were reported in 26% of patients and included weight loss, cognitive impairment, sleepiness, dizziness and decreased appetite. Ten percent discontinued use of ZNS because of intolerable side effects.

Conclusions

Monotherapy is the preferred treatment for patients with epilepsy. The newer AEDs offer improved pharmacokinetics, an expanded spectrum of action, and more favorable side effect profiles than conventional AEDs. This gives physicians the freedom and flexibility to tailor treatment to meet the needs and preferences of each individual patient. Although there is still a great need for additional clinical trial data, especially in children, there is a growing body of evidence suggests that many of the newer AEDs, particularly GBP, LTG, OXC, LEV and TPM, may provide an attractive monotherapy alternative to the conventional treatment of new onset and refractory epilepsy.

Physician and patient fear of losing seizure-free status or seeing an increase in baseline seizure frequency during the transition from a polytherapy to monotherapy regimen can be a significant barrier to change. However, with proper management, the transition can be relatively smooth and uneventful. The ultimate benefits of monotherapy, simplified medication schedule, fewer side effects, and improved QoL, are all very rewarding reasons to choose AED monotherapy for patients with epilepsy.

References

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