- Email: [email protected]
A patient with newly diagnosed temporal lobe epilepsy
Epilepsy & Behavior Epilepsy & Behavior 4 (2003) S29–S32 www.elsevier.com/locate/yebeh
Monotherapy and long-term treatment: efficacy onset and tolerability
A patient with newly diagnosed temporal lobe epilepsy Gregory K. Bergey* Johns Hopkins University, Phipps Building, Room 395, 600 North Wolfe Street, Baltimore, MD 21287, USA Received 11 February 2003; accepted 11 February 2003
1. Case history
2. The clinical problem
A 15-year-old right-handed male presented with episodes of altered awareness. He commented that he experiences a warning sign of an unusual feeling of nausea prior to each episode. He then has a period of approximately 1 minute when he is unable to speak and, although aware of his surroundings, he has difficulty processing information or responding to those around him. During these episodes, he has been observed to clench his left hand and fumble about with his right hand. Gradually, over several minutes, he returns to full awareness. On one occasion while cycling he fell off his bike, fortunately sustaining only minor injury. In retrospect, he thinks the episodes began 1–2 years ago. At the time of presentation, he was having one or two episodes of altered awareness per month, as well as other auras. He denied any episodes of tongue-biting or incontinence, and no one had observed any convulsive activity. His parents mentioned that he was the product of an uncomplicated pregnancy and delivery, had normal development, and had consistently been an honors student. However, he did have one prolonged febrile seizure at 2 years of age. He was not treated for this seizure and he did not have recurrent febrile seizures. His current neurologic examination was nonfocal and unremarkable. His epilepsy protocol magnetic resonance imaging (MRI) scan revealed a somewhat small right hippocampus, with increased signal on fluid-attenuated inversion recovery (FLAIR) images. The waking portion of his electroencephalogram (EEG) was unrevealing; however, during sleep his EEG revealed rare, random right-anterior temporal sharp activity.
2.1. Diagnostic considerations This patient presented with a classic history for complex partial seizures, with reproducible auras and brief periods of altered awareness. Although complex partial seizures can originate from various brain regions, the temporal lobe is the most common site, and the aura of nausea is a common aura for seizures originating from mesial temporal structures. In addition, dystonic posturing of the contralateral hand is one of the more reliable localizing signs for temporal lobe complex partial seizures. Furthermore, the EEG supported the diagnosis and the MRI scan suggested right hippocampal atrophy and sclerosis. An epilepsy protocol MRI scan with thin cuts through the temporal lobe can significantly increase the diagnosis of mesial temporal abnormalities. The prolonged febrile seizure may have predisposed him to mesial temporal sclerosis. Recognizing the characteristics of the clinical presentation of complex partial seizures from temporal or frontal lobe regions can assist in making the diagnosis but, in fact, the site of origin becomes important only if the patient is refractory to medication. When considering initial medical therapy, the site of origin does not influence antiepileptic drug (AED) selection; no AED has been demonstrated to be more effective for extratemporal or temporal lobe-onset partial seizures.
3. Strategies and evidence 3.1. Treatment considerations
*
Fax: +410-955-0207. E-mail address: [email protected].
This patient clearly required treatment. Like most patients presenting with complex partial seizures, he had a history of multiple seizures. Once a patient has had
1525-5050/03/$ - see front matter Ó 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S1525-5050(03)00050-7
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G.K. Bergey / Epilepsy & Behavior 4 (2003) S29–S32
as few as two or three seizures, the probability of an additional seizure is high; therefore, the decision to treat is straightforward. Indeed, even if this patient had presented with a single seizure, his abnormal EEG and MRI scan would have warranted treatment. While the patient did not have a history of secondarily generalized seizures, patients with partial seizures are obviously also at risk of these seizures, particularly if untreated. Initial treatment of complex partial seizures should always begin with AED monotherapy. Recent studies suggest that a significant number (perhaps 50%) of patients presenting with newly diagnosed epilepsy are easily controlled on the first AED tolerated and that only relatively modest doses are necessary [1,2]. Therefore, it may not be necessary for the initial AED selected to be the most potent, even if good studies were available to determine this (and they exist generally only for the older AEDs), nor would it be necessary to have a high therapeutic serum level as a target. Indeed, the goal should be seizure control with monotherapy at modest doses (and corresponding serum levels) and minimal side effects. Side effects from AEDs can be as important for quality-of-life issues as continued seizures. While some authorities feel that patients with partial seizures associated with mesial temporal sclerosis are more likely to ultimately have medically intractable seizures, this should not influence the initial approach to therapy for an individual patient. The patient here was a bright, active, male high school student. The issues associated with female patients (e.g., interactions with oral contraceptives, teratogenicity) are discussed in an accompanying case and are not applicable here. This patient planned to get his driverÕs license within the year. However, even as much as an 85% reduction in seizures (e.g., from two seizures per month to one every 3 months) would not permit him to drive. The important considerations in this case were achieving total seizure control with an AED monotherapy that would not produce side effects, particularly cognitive side effects. In this patient, who had both EEG and MRI scan abnormalities, the selection of an AED had to include the consideration that long-term therapy may be needed. 3.2. Efficacy of chosen therapy Selection of an AED should be based on its efficacy for the specific seizure type. With the exception of ethosuximide, most of the major AEDs, both new and old, are effective for complex partial seizures. Indeed, new AEDs are typically first assessed in patients with refractory complex partial seizures, partly because this is a readily available cohort of patients for AED trials. This patient had not yet had secondarily generalized seizures. The United States Food and Drug Administration (FDA)-approved indications for the new AEDs often fail to mention secondarily generalized seizures,
often because the double-blind trials did not have generalized tonic–clonic seizures as a primary outcome variable. Secondary generalized tonic–clonic seizures are often easier to control with the same AEDs than partial seizures, so the risk of a future generalized tonic–clonic seizure does not influence AED selection. Two Veterans Affairs (VA) cooperative trials [3,4] provide excellent comparative trials of the older agents carbamazepine, phenobarbital, phenytoin, primidone, and valproate, recognizing that the outcome variable of successful treatment incorporated both seizure reduction and tolerability. In the first trial, carbamazepine and phenytoin were better for the treatment of partial seizures than phenobarbital and primidone, even if sideeffect profiles were discounted. Carbamazepine had a somewhat better seizure-free profile. In the second VA cooperative trial, carbamazepine was more efficacious than valproate. Therefore, of the older agents carbamazepine and phenytoin would be reasonable initial choices for the treatment of partial seizures. Interestingly, phenytoin is much less widely used in countries other than the United States because of concerns about cosmetic and other side effects. The two VA cooperative trials included patients with relatively new-onset epilepsy. Many current trials have patients with highly refractory seizures as the treatment population. Comparative trials of efficacy of the newer AEDs are limited. There are, however, some trials of the newer agents in patients with new-onset epilepsy, a population relevant to initial treatment considerations. There are trials demonstrating that oxcarbazepine is equally efficacious to the older agents valproate [5], phenytoin [6,7], and carbamazepine [8], but better tolerated than phenytoin or carbamazepine. Lamotrigine has been demonstrated to be equally effective as phenytoin [9] and carbamazepine [10] but, again, to be better tolerated. In a recent study, gabapentin and lamotrigine were equally efficacious and tolerated in newly diagnosed partial seizures [11]. There have been no studies demonstrating differences in efficacy between the new AEDs; however, this is perhaps not too surprising in populations with newly diagnosed epilepsy. The revelation that some AEDs are better tolerated than others has important implications for successful AED treatment. Meta-analysis of responder rates from different clinical trials should be avoided [12] as some trials are relatively low-dose trials (e.g., gabapentin, lamotrigine) and other trials are relatively high-dose trials (e.g., levetiracetam, topiramate). 3.3. Initial monotherapy With the exceptions of oxcarbazepine and felbamate, none of the newer AEDs are approved in the United States for initial monotherapy [13]. FDA approval is typically for combination therapy, reflecting the actual
G.K. Bergey / Epilepsy & Behavior 4 (2003) S29–S32
trial design. Indeed, the current FDA requirements for monotherapy approval require a trial design that has been criticized as unethical, as it requires placebo or low-dose active controls in refractory patients and does not allow trials designed to demonstrate equivalency. Such equivalency trials in Europe (see above) have shown that lamotrigine and oxcarbazepine are equivalent to older agents in efficacy and are often better tolerated in patients with new-onset partial seizures (the patient population most likely to be on monotherapy, unlike refractory patients). In the United States, lamotrigine alone has approval for conversion to monotherapy, reflecting the design of the published trial. Obviously, any AED effective in monotherapy conversion will be effective as initial monotherapy. It is hoped that the FDA will allow more ethical and appropriate trial designs for future monotherapy trials. At present, additional approved monotherapy indications for the newer AEDs are unlikely to be forthcoming in the United States. It would be expected that all current AEDs approved for use in combination therapy will be effective as initial monotherapy. Selection of initial therapy should be based on the best AED for the particular patient, using FDA-approved indications as guides rather than limitations. 3.4. Pharmacokinetic considerations (dosing and serum levels) In this case of a patient with only simple and complex partial seizures, AED treatment could be gradually introduced. If there were generalized tonic–clonic seizures, particularly frequent ones, then more rapid introduction of therapy would be needed. Only phenytoin, phenobarbital, and valproate are currently available as parenteral formulations, and phenobarbital loading produces major sedation with a risk of respiratory depression. A parenteral formulation of readily soluble levetiracetam is expected by 2004. Rapid, oral initiation can be achieved with phenytoin, valproate, levetiracetam, and gabapentin, as it takes five half-lives to reach a steady state. Carbamazepine requires relatively slow introduction because of autoinduction and its long initial half-life (35 hours) in the uninduced patient. However, there is no autoinduction with oxcarbazepine, potentially allowing for more rapid introduction than carbamazepine; however, as is the case with many AEDs, tolerability is improved with slower introduction. Lamotrigine requires slow introduction to minimize the risk of a serious rash (e.g., Stevens–Johnson syndrome or toxic epidermolysis). Indeed, if lamotrigine is titrated slowly, the risk of these serious idiosyncratic reactions is no greater than with phenytoin or carbamazepine. Phenobarbital, primidone, topiramate, and zonisamide require slow introduction to minimize sedation and
S31
cognitive side effects. Phenobarbital and zonisamide have the longest half-lives of the AEDs (100 and 60 hours, respectively, as monotherapy) and, therefore, take correspondingly longer to reach a steady state. However, the benefit of a long half-life is the ability to dose once daily. Generally, compliance is not significantly compromised if AED dosing is once or twice daily. Moving to three times daily or four times daily regimens, particularly in patients like the young man in the case study described here, does pose a hardship that may compromise compliance and even socially stigmatize the young patient. Older patients, particularly those on multiple medications, may be better able to adhere to three times daily or four times daily regimens. The sustained-release formulations of carbamazepine (Tegretol XR and Carbatrol) have the benefit of twice daily dosing and should be considered in all patients for whom carbamazepine is selected as initial therapy. Valproate, even in the entericcoated preparation (Depakote), is a delayed rather than sustained-release formulation and, therefore, should usually be given three times daily. Some patients with easily controlled seizures can take Depakote twice daily, but these are often patients with primary generalized rather than partial seizures. The true extended-release formulation of valproate (Depakote ER) has recently been approved for epilepsy, but has reduced bioavailability compared with other valproate preparations (75%). If this reduced bioavailability was accounted for, then this preparation could be used in patients with easily controlled seizures. Dilantin, Mylan, and Phenytek preparations of sustained-release phenytoin can be taken four or two times daily. Of the newer AEDs, it is recommended that gabapentin be taken three times daily, while the other new AEDs are indicated for twice daily dosing. Serum levels are fairly well established for the older AEDs and general ranges are known for the newer agents. As mentioned previously, patients whose seizures are readily controlled may require only modest AED doses (e.g., 600–800 mg/day carbamazepine, 750– 1000 mg/day valproate, 900–1200 mg/day oxcarbazepine, 1000 mg/day levetiracetam, and 150–200 mg/day lamotrigine). In these patients the need for monitoring of serum levels is small, particularly if the patient is on a newer AED, since these agents have generally broad therapeutic ranges. If patients are on other agents (e.g., oral contraceptives, anticoagulants) it is preferable to avoid using enzyme-inducing AEDs as initial therapy. These considerations are addressed in some of the accompanying case reports. 3.5. Cognitive side effects Cognitive side effects are some of the most important considerations in AED selection [14]. Consideration of
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G.K. Bergey / Epilepsy & Behavior 4 (2003) S29–S32
the cognitive profiles of AEDs should be foremost in the treatment of most patients, but particularly so for students and the elderly. Of the older agents, carbamazepine, phenytoin, and valproate have the best cognitive profiles. Phenobarbital and primidone are used much less frequently, and only very rarely as initial monotherapy, because of their adverse cognitive profiles. A number of the newer AEDs have favorable cognitive profiles and there is accumulating evidence to suggest that gabapentin and lamotrigine may have better profiles than carbamazepine, which is generally well tolerated and perhaps the most commonly selected AED for the initial treatment of complex partial seizures. It has been suggested that oxcarbazepine, because it has no epoxide metabolite, may have a better cognitive profile than carbamazepine; however, comparative trials are needed. Levetiracetam also has a favorable cognitive profile. Tiagabine, topiramate, and zonisamide are not commonly used as initial monotherapy because of the potential for cognitive effects, although slow titration can minimize this risk. All AEDs are better tolerated when used as monotherapy. 3.6. Other side effects It is beyond the scope of this discussion to address the specific side-effect profiles of the various AEDs, but clearly these can play important roles in AED selection. Phenytoin is rarely used initially in children and young adults because of the risk of gum and other cosmetic changes. When weight gain is undesirable, valproate is not an ideal initial treatment choice for partial seizures. Patients predisposed to osteoporosis are perhaps better treated with agents other than those that may contribute to this problem (generally the hepatic enzyme inducers). A history of nephrolithiasis would make selection of topiramate or zonisimide less desirable as initial therapy.
4. Summary The VA cooperative trials measured successful treatment as both reduction in seizure number and medication tolerability. Recent trials of new AEDs have focused more on responder rates and seizure number. However, for patients, side effects and seizures both impact on quality of life. Initial considerations of effective treatment must therefore incorporate both seizure freedom and tolerability into the treatment algorithm. At present, we lack the comparative trials needed to determine the relative efficacy of many of the newer AEDs. However, in the patient with readily controlled
seizures, the AED side-effect profile, particularly the cognitive profile, is equally important as relative efficacy. In the young patient in this case study, who had new-onset partial seizures without secondary generalization, carbamazepine, lamotrigine, levetiracetam, and oxcarbazepine would all be desirable initial monotherapy. Other, less preferable, alternatives include phenytoin, gabapentin, and valproate. Even if the newer AEDs are found to be no more effective than the older agents, there is a likelihood that most will be better tolerated.
References [1] Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342:314–9. [2] Kwan P, Brodie MJ. Effectiveness of first antiepileptic drug. Epilepsia 2001;42:1255–60. [3] Mattson RH, Cramer JA, Collins JF, et al. Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic–clonic seizures. N Engl J Med 1985;313:145–51. [4] Mattson RH, Cramer JA, Collins JF. A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic–clonic seizures in adults. The Department of Veterans Affairs Epilepsy Cooperative Study No. 264 Group. N Engl J Med 1992;327:765–71. [5] Christe W, Kramer G, Vigonius U, et al. A double-blind controlled clinical trial: oxcarbazepine versus sodium valproate in adults with newly diagnosed epilepsy. Epilepsy Res 1997;26:451–60. [6] Bill PA, Vigonius U, Pohlmann H, et al. A double-blind controlled clinical trial of oxcarbazepine versus phenytoin in adults with previously untreated epilepsy. Epilepsy Res 1997;27:195–204. [7] Guerreiro MM, Vigonius U, Pohlmann H, et al. A double-blind controlled clinical trial of oxcarbazepine versus phenytoin in children and adolescents with epilepsy. Epilepsy Res 1997;27:205– 13. [8] Dam M, Ekberg R, Loyning Y. A double-blind study comparing oxcarbazepine and carbamazepine in patients with newly diagnosed, previously untreated epilepsy. Epilepsy Res 1989;3:70–6. [9] Steiner TJ, Dellaportas CI, Findley LJ, et al. Lamotrigine monotherapy in newly diagnosed untreated epilepsy: a doubleblind comparison with phenytoin. Epilepsia 1999;40:601–7. [10] Brodie MJ, Richens A, Yuen AW. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. UK Lamotrigine/Carbamazepine Monotherapy Trial Group. Lancet 1995;345:476–9. [11] Brodie MJ, Chadwick DW, Anhut H, et al. Gabapentin versus lamotrigine monotherapy: a double-blind comparison in newly diagnosed epilepsy. Epilepsia 2002;43:993–1000. [12] Cramer JA, Fisher R, Ben-Menachem E, French J, Mattson RH. New antiepileptic drugs: comparison of key clinical trials. Epilepsia 1999;40:590–600. [13] French JA, Schachter S. A workshop on antiepileptic drug monotherapy indications. Epilepsia 2002;43(Suppl 10):3–27. [14] Meador KJ, Gilliam FG, Kanner AM, Pellock JM. Cognitive and behavioral effects of antiepileptic drugs. Epilepsy Behav 2001;2:S1–S17.
Monotherapy and long-term treatment: efficacy onset and tolerability
A patient with newly diagnosed temporal lobe epilepsy Gregory K. Bergey* Johns Hopkins University, Phipps Building, Room 395, 600 North Wolfe Street, Baltimore, MD 21287, USA Received 11 February 2003; accepted 11 February 2003
1. Case history
2. The clinical problem
A 15-year-old right-handed male presented with episodes of altered awareness. He commented that he experiences a warning sign of an unusual feeling of nausea prior to each episode. He then has a period of approximately 1 minute when he is unable to speak and, although aware of his surroundings, he has difficulty processing information or responding to those around him. During these episodes, he has been observed to clench his left hand and fumble about with his right hand. Gradually, over several minutes, he returns to full awareness. On one occasion while cycling he fell off his bike, fortunately sustaining only minor injury. In retrospect, he thinks the episodes began 1–2 years ago. At the time of presentation, he was having one or two episodes of altered awareness per month, as well as other auras. He denied any episodes of tongue-biting or incontinence, and no one had observed any convulsive activity. His parents mentioned that he was the product of an uncomplicated pregnancy and delivery, had normal development, and had consistently been an honors student. However, he did have one prolonged febrile seizure at 2 years of age. He was not treated for this seizure and he did not have recurrent febrile seizures. His current neurologic examination was nonfocal and unremarkable. His epilepsy protocol magnetic resonance imaging (MRI) scan revealed a somewhat small right hippocampus, with increased signal on fluid-attenuated inversion recovery (FLAIR) images. The waking portion of his electroencephalogram (EEG) was unrevealing; however, during sleep his EEG revealed rare, random right-anterior temporal sharp activity.
2.1. Diagnostic considerations This patient presented with a classic history for complex partial seizures, with reproducible auras and brief periods of altered awareness. Although complex partial seizures can originate from various brain regions, the temporal lobe is the most common site, and the aura of nausea is a common aura for seizures originating from mesial temporal structures. In addition, dystonic posturing of the contralateral hand is one of the more reliable localizing signs for temporal lobe complex partial seizures. Furthermore, the EEG supported the diagnosis and the MRI scan suggested right hippocampal atrophy and sclerosis. An epilepsy protocol MRI scan with thin cuts through the temporal lobe can significantly increase the diagnosis of mesial temporal abnormalities. The prolonged febrile seizure may have predisposed him to mesial temporal sclerosis. Recognizing the characteristics of the clinical presentation of complex partial seizures from temporal or frontal lobe regions can assist in making the diagnosis but, in fact, the site of origin becomes important only if the patient is refractory to medication. When considering initial medical therapy, the site of origin does not influence antiepileptic drug (AED) selection; no AED has been demonstrated to be more effective for extratemporal or temporal lobe-onset partial seizures.
3. Strategies and evidence 3.1. Treatment considerations
*
Fax: +410-955-0207. E-mail address: [email protected].
This patient clearly required treatment. Like most patients presenting with complex partial seizures, he had a history of multiple seizures. Once a patient has had
1525-5050/03/$ - see front matter Ó 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S1525-5050(03)00050-7
S30
G.K. Bergey / Epilepsy & Behavior 4 (2003) S29–S32
as few as two or three seizures, the probability of an additional seizure is high; therefore, the decision to treat is straightforward. Indeed, even if this patient had presented with a single seizure, his abnormal EEG and MRI scan would have warranted treatment. While the patient did not have a history of secondarily generalized seizures, patients with partial seizures are obviously also at risk of these seizures, particularly if untreated. Initial treatment of complex partial seizures should always begin with AED monotherapy. Recent studies suggest that a significant number (perhaps 50%) of patients presenting with newly diagnosed epilepsy are easily controlled on the first AED tolerated and that only relatively modest doses are necessary [1,2]. Therefore, it may not be necessary for the initial AED selected to be the most potent, even if good studies were available to determine this (and they exist generally only for the older AEDs), nor would it be necessary to have a high therapeutic serum level as a target. Indeed, the goal should be seizure control with monotherapy at modest doses (and corresponding serum levels) and minimal side effects. Side effects from AEDs can be as important for quality-of-life issues as continued seizures. While some authorities feel that patients with partial seizures associated with mesial temporal sclerosis are more likely to ultimately have medically intractable seizures, this should not influence the initial approach to therapy for an individual patient. The patient here was a bright, active, male high school student. The issues associated with female patients (e.g., interactions with oral contraceptives, teratogenicity) are discussed in an accompanying case and are not applicable here. This patient planned to get his driverÕs license within the year. However, even as much as an 85% reduction in seizures (e.g., from two seizures per month to one every 3 months) would not permit him to drive. The important considerations in this case were achieving total seizure control with an AED monotherapy that would not produce side effects, particularly cognitive side effects. In this patient, who had both EEG and MRI scan abnormalities, the selection of an AED had to include the consideration that long-term therapy may be needed. 3.2. Efficacy of chosen therapy Selection of an AED should be based on its efficacy for the specific seizure type. With the exception of ethosuximide, most of the major AEDs, both new and old, are effective for complex partial seizures. Indeed, new AEDs are typically first assessed in patients with refractory complex partial seizures, partly because this is a readily available cohort of patients for AED trials. This patient had not yet had secondarily generalized seizures. The United States Food and Drug Administration (FDA)-approved indications for the new AEDs often fail to mention secondarily generalized seizures,
often because the double-blind trials did not have generalized tonic–clonic seizures as a primary outcome variable. Secondary generalized tonic–clonic seizures are often easier to control with the same AEDs than partial seizures, so the risk of a future generalized tonic–clonic seizure does not influence AED selection. Two Veterans Affairs (VA) cooperative trials [3,4] provide excellent comparative trials of the older agents carbamazepine, phenobarbital, phenytoin, primidone, and valproate, recognizing that the outcome variable of successful treatment incorporated both seizure reduction and tolerability. In the first trial, carbamazepine and phenytoin were better for the treatment of partial seizures than phenobarbital and primidone, even if sideeffect profiles were discounted. Carbamazepine had a somewhat better seizure-free profile. In the second VA cooperative trial, carbamazepine was more efficacious than valproate. Therefore, of the older agents carbamazepine and phenytoin would be reasonable initial choices for the treatment of partial seizures. Interestingly, phenytoin is much less widely used in countries other than the United States because of concerns about cosmetic and other side effects. The two VA cooperative trials included patients with relatively new-onset epilepsy. Many current trials have patients with highly refractory seizures as the treatment population. Comparative trials of efficacy of the newer AEDs are limited. There are, however, some trials of the newer agents in patients with new-onset epilepsy, a population relevant to initial treatment considerations. There are trials demonstrating that oxcarbazepine is equally efficacious to the older agents valproate [5], phenytoin [6,7], and carbamazepine [8], but better tolerated than phenytoin or carbamazepine. Lamotrigine has been demonstrated to be equally effective as phenytoin [9] and carbamazepine [10] but, again, to be better tolerated. In a recent study, gabapentin and lamotrigine were equally efficacious and tolerated in newly diagnosed partial seizures [11]. There have been no studies demonstrating differences in efficacy between the new AEDs; however, this is perhaps not too surprising in populations with newly diagnosed epilepsy. The revelation that some AEDs are better tolerated than others has important implications for successful AED treatment. Meta-analysis of responder rates from different clinical trials should be avoided [12] as some trials are relatively low-dose trials (e.g., gabapentin, lamotrigine) and other trials are relatively high-dose trials (e.g., levetiracetam, topiramate). 3.3. Initial monotherapy With the exceptions of oxcarbazepine and felbamate, none of the newer AEDs are approved in the United States for initial monotherapy [13]. FDA approval is typically for combination therapy, reflecting the actual
G.K. Bergey / Epilepsy & Behavior 4 (2003) S29–S32
trial design. Indeed, the current FDA requirements for monotherapy approval require a trial design that has been criticized as unethical, as it requires placebo or low-dose active controls in refractory patients and does not allow trials designed to demonstrate equivalency. Such equivalency trials in Europe (see above) have shown that lamotrigine and oxcarbazepine are equivalent to older agents in efficacy and are often better tolerated in patients with new-onset partial seizures (the patient population most likely to be on monotherapy, unlike refractory patients). In the United States, lamotrigine alone has approval for conversion to monotherapy, reflecting the design of the published trial. Obviously, any AED effective in monotherapy conversion will be effective as initial monotherapy. It is hoped that the FDA will allow more ethical and appropriate trial designs for future monotherapy trials. At present, additional approved monotherapy indications for the newer AEDs are unlikely to be forthcoming in the United States. It would be expected that all current AEDs approved for use in combination therapy will be effective as initial monotherapy. Selection of initial therapy should be based on the best AED for the particular patient, using FDA-approved indications as guides rather than limitations. 3.4. Pharmacokinetic considerations (dosing and serum levels) In this case of a patient with only simple and complex partial seizures, AED treatment could be gradually introduced. If there were generalized tonic–clonic seizures, particularly frequent ones, then more rapid introduction of therapy would be needed. Only phenytoin, phenobarbital, and valproate are currently available as parenteral formulations, and phenobarbital loading produces major sedation with a risk of respiratory depression. A parenteral formulation of readily soluble levetiracetam is expected by 2004. Rapid, oral initiation can be achieved with phenytoin, valproate, levetiracetam, and gabapentin, as it takes five half-lives to reach a steady state. Carbamazepine requires relatively slow introduction because of autoinduction and its long initial half-life (35 hours) in the uninduced patient. However, there is no autoinduction with oxcarbazepine, potentially allowing for more rapid introduction than carbamazepine; however, as is the case with many AEDs, tolerability is improved with slower introduction. Lamotrigine requires slow introduction to minimize the risk of a serious rash (e.g., Stevens–Johnson syndrome or toxic epidermolysis). Indeed, if lamotrigine is titrated slowly, the risk of these serious idiosyncratic reactions is no greater than with phenytoin or carbamazepine. Phenobarbital, primidone, topiramate, and zonisamide require slow introduction to minimize sedation and
S31
cognitive side effects. Phenobarbital and zonisamide have the longest half-lives of the AEDs (100 and 60 hours, respectively, as monotherapy) and, therefore, take correspondingly longer to reach a steady state. However, the benefit of a long half-life is the ability to dose once daily. Generally, compliance is not significantly compromised if AED dosing is once or twice daily. Moving to three times daily or four times daily regimens, particularly in patients like the young man in the case study described here, does pose a hardship that may compromise compliance and even socially stigmatize the young patient. Older patients, particularly those on multiple medications, may be better able to adhere to three times daily or four times daily regimens. The sustained-release formulations of carbamazepine (Tegretol XR and Carbatrol) have the benefit of twice daily dosing and should be considered in all patients for whom carbamazepine is selected as initial therapy. Valproate, even in the entericcoated preparation (Depakote), is a delayed rather than sustained-release formulation and, therefore, should usually be given three times daily. Some patients with easily controlled seizures can take Depakote twice daily, but these are often patients with primary generalized rather than partial seizures. The true extended-release formulation of valproate (Depakote ER) has recently been approved for epilepsy, but has reduced bioavailability compared with other valproate preparations (75%). If this reduced bioavailability was accounted for, then this preparation could be used in patients with easily controlled seizures. Dilantin, Mylan, and Phenytek preparations of sustained-release phenytoin can be taken four or two times daily. Of the newer AEDs, it is recommended that gabapentin be taken three times daily, while the other new AEDs are indicated for twice daily dosing. Serum levels are fairly well established for the older AEDs and general ranges are known for the newer agents. As mentioned previously, patients whose seizures are readily controlled may require only modest AED doses (e.g., 600–800 mg/day carbamazepine, 750– 1000 mg/day valproate, 900–1200 mg/day oxcarbazepine, 1000 mg/day levetiracetam, and 150–200 mg/day lamotrigine). In these patients the need for monitoring of serum levels is small, particularly if the patient is on a newer AED, since these agents have generally broad therapeutic ranges. If patients are on other agents (e.g., oral contraceptives, anticoagulants) it is preferable to avoid using enzyme-inducing AEDs as initial therapy. These considerations are addressed in some of the accompanying case reports. 3.5. Cognitive side effects Cognitive side effects are some of the most important considerations in AED selection [14]. Consideration of
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the cognitive profiles of AEDs should be foremost in the treatment of most patients, but particularly so for students and the elderly. Of the older agents, carbamazepine, phenytoin, and valproate have the best cognitive profiles. Phenobarbital and primidone are used much less frequently, and only very rarely as initial monotherapy, because of their adverse cognitive profiles. A number of the newer AEDs have favorable cognitive profiles and there is accumulating evidence to suggest that gabapentin and lamotrigine may have better profiles than carbamazepine, which is generally well tolerated and perhaps the most commonly selected AED for the initial treatment of complex partial seizures. It has been suggested that oxcarbazepine, because it has no epoxide metabolite, may have a better cognitive profile than carbamazepine; however, comparative trials are needed. Levetiracetam also has a favorable cognitive profile. Tiagabine, topiramate, and zonisamide are not commonly used as initial monotherapy because of the potential for cognitive effects, although slow titration can minimize this risk. All AEDs are better tolerated when used as monotherapy. 3.6. Other side effects It is beyond the scope of this discussion to address the specific side-effect profiles of the various AEDs, but clearly these can play important roles in AED selection. Phenytoin is rarely used initially in children and young adults because of the risk of gum and other cosmetic changes. When weight gain is undesirable, valproate is not an ideal initial treatment choice for partial seizures. Patients predisposed to osteoporosis are perhaps better treated with agents other than those that may contribute to this problem (generally the hepatic enzyme inducers). A history of nephrolithiasis would make selection of topiramate or zonisimide less desirable as initial therapy.
4. Summary The VA cooperative trials measured successful treatment as both reduction in seizure number and medication tolerability. Recent trials of new AEDs have focused more on responder rates and seizure number. However, for patients, side effects and seizures both impact on quality of life. Initial considerations of effective treatment must therefore incorporate both seizure freedom and tolerability into the treatment algorithm. At present, we lack the comparative trials needed to determine the relative efficacy of many of the newer AEDs. However, in the patient with readily controlled
seizures, the AED side-effect profile, particularly the cognitive profile, is equally important as relative efficacy. In the young patient in this case study, who had new-onset partial seizures without secondary generalization, carbamazepine, lamotrigine, levetiracetam, and oxcarbazepine would all be desirable initial monotherapy. Other, less preferable, alternatives include phenytoin, gabapentin, and valproate. Even if the newer AEDs are found to be no more effective than the older agents, there is a likelihood that most will be better tolerated.
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