Rational Polypharmacy

Summary: The medical treatment of seizure disorders is a complex process, requiring extensive interaction and cooperation between physician and patient. The physician must have an accurate diagnosis of the patient's illness and a comprehensive understanding of seizures and seizure disorders. The physician must consider specific individual characteristics of the patient, especially those that will influence the choice of medical therapy, and the interrelationship between the patient's lifestyle and the seizure disorder must be appreciated to maintain an optimal quality of life. Finally, the physician must have a thorough understanding of the pharmacology of antiepi-leptic drugs (AEDs) and experience with their therapeutic applications. It is important for patients to be fully involved in the treatment of their illness. Each patient should be informed about their disorder, should be involved in all therapeutic plans and strategies, and should be a responsible and active participant in treatment.     

Felbamate

Summary: After the first year of clinical experience, felbamate (FBM) appears to be a valuable antiepileptic drug (AED) for the treatment of intractable epilepsy. However, many patients experience side effects that may discourage continued usage. These may be decreased by using a slower dose-escalation schedule and/or by being more aggressive in decreasing co-medication. The most common troublesome side effects are nausea and insomnia. With the recent observation of aplastic anemia, FBM should be considered only for persons with intractable epilepsy under the care of a physician familiar with FBM. Nevertheless, many patients have benefited significantly from FBM and have made a decision to continue receiving FBM at the presently known risk profile. A few more years of experience may be needed to more accurately determine the final place of FBM in the treatment of epilepsy.     

Antiepileptic Drugs in Pediatric Practice

Summary: Several factors characterize the current medical treatment of epilepsy during childhood. Children do not present the same types of seizures or epilepsies as adults, and certain epilepsy syndromes are seen only during childhood. Accordingly, the choice of antiepileptic drugs (AEDs) may differ in children. In addition, certain medical therapies, such as ACTH or pyridoxine, are used only in children. It is also common practice to prescribe AEDs in children for indications that are "off-label," such as the treatment of partial-onset seizures with car-bamazepine before the age of 6 years. The natural history of epilepsy and the risk for seizure recurrence may be different in the pediatric age range, and this may influence the decision to institute chronic prophylactic therapy in children. Similar considerations may apply to the decision to discontinue AED therapy. The pharmacokinetics of several AEDs are age-dependent, and dosages are more variable among patients. The adverse effects of AEDs may be age-dependent, and the pattern of exacerbation of certain seizures by AEDs may be different in children. In addition, several new AEDs are now available, or are about to be released, and the preferential sequence of AEDs of choice in children with epilepsy will need to be reassessed as experience grows and as the results of comparative studies become available.     

Efficacy and Adverse Effects of Established and New Antiepileptic Drugs*

Summary: Antiepileptic drug (AED) selection is based primarily on efficacy for specific seizure types and epileptic syndromes. However, efficacy is often similar for the different AEDs, and other properties such as adverse effects, pharmacokinetic properties, and cost may also be of importance. For idiopathic generalized epilepsies with absence, tonic-clonic, and myoclonic seizures, the AED of choice is valproate (VPA). Secondarily generalized epilepsies with tonic, atonic, and other seizure types are difficult to treat with any single AED or combination of AEds. The AEDs of choice for absence seizures are ethosuximide (ESM) and VPA. For control of primary generalized tonic-clonic seizures, any of the other major AEDs can be effective. If VPA cannot be prescribed, carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), or primidone (PRM) may be effective, but ESM or a benzodiazepine (BZD) must be added to control associated absence or myoclonic seizures. The AEDs of first choice for partial epilepsies with partial and secondarily generalized tonic-clonic seizures are CBZ and PHT. Increasing evidence suggests that VPA is a good alternative when CBZ and PHT fail. PB and PRM are second-choice selections because of adverse effects. A combination of two of the five standard AEDs may be necessary to treat intractable seizures, but no studies have been done to indicate an optimal combination. Other epilepsy syndromes such as neonatal and infantile epilepsies, febrile epilepsy, alcoholic epilepsy, and status epilepticus require specific AED treatment. Ultimately, AED selection must be individualized. No “drug of choice” can be named for all patients. The expected efficacy for the seizure type, the importance of the expected adverse effects, the pharmacokinetics, and the cost of the AEDs all must be weighed and discussed with the patient before a choice is made. A number of new AEDs with unique mechanisms of action, pharmacokinetic properties, and fewer adverse effects hold important promise of improved epilepsy treatment.     

Vigabatrin

Summary: γ-Aminobutyric acid (GABA) was first proposed as a putative inhibitory neurotransmitter by Elliot and van Gelder in 1958. Since then, numerous efforts have been made to find ways to increase GABA at its receptor sites, based on the findings that decreased GABA results in convulsions in animals and that agents enhancing GABA-mediated functions can have antiepi-leptic effects. However, the relationship between GABA levels and seizures is not simple. Seizures can occur even in the presence of elevated GABA levels. Indeed, it is possible that regional biochemical differences in the brain can be important. The antiepileptic effects of GABA depend on the mechanism whereby GABA-mediated inhibition is enhanced. Since the 1970s, several compounds have been developed that are designed to act in some manner on the GABA system. These compounds affect GABA-mediated inhibition at different levels and appear to have varied effects, depending on their mechanism of action. To date, specific antiepileptic drugs (AEDs) with potential GABA-inhibitory effects have been designed either to have GABA agonist properties, to inhibit GABA catabolism, to inhibit GABA uptake, or to facilitate GABA release or facilitate GABA_A receptor activity. Vigabatrin (VGB) was designed specifically to inhibit GABA transaminase and thereby increase the availability of GABA in the brain. Study data and clinical experience over the past 14 years have demonstrated VGB to be an effective AED.     

Clinical Efficacy of New Antiepileptic Drugs in Refractory Partial Epilepsy: Experience in the United States With Three Novel Drugs

Summary: A number of new antiepileptic drugs (AEDs), including topiramate (TPM), felbamate (FBM), and gabapentin (GBP), are approved or believed to be close to approval for marketing in the United States. Key efficacy findings for these AEDs in refractory partial epilepsy were reviewed. Large and significant drug-placebo differences were observed with TPM in two large dose-finding trials conducted in the United States. The minimal effective dose of TPM in the population studied was determined to be approximately 200 mg/day, and doses above 600 mg/day produced good efficacy but little incremental benefit versus the lower dosages for the overall study population. FBM is active in partial epilepsy, although seizure reduction is less marked and drug interactions complicate the findings. GBP is also active in this population, but only the 1,800 mg/day dosage was significantly better than placebo with respect to percent re-sponders. It may be useful to explore higher dosage ranges for both FBM and GBP if they can be well tolerated.     

Lamotrigine in Treatment of 120 Children with Epilepsy

Summary: One hundred twenty children aged 10 months to 16 years 9 months were included in three studies with lamotrigine (LTG): a single-blind study (n = 60), a pharmacokinetic study (n = 23), and a compassionate group (n = 37). At 3 months, 11 patients had become seizure-free and 34 had >50% decrease in seizure frequency. The best results involved absence epilepsy, Lennox-Gastaut syndrome (LGS), and other symptomatic generalized epilepsy. Forty-two patients were followed > 1 year, 22 for a mean of 2.2 years, and there was no significant increase in seizure frequency as compared with 3-month follow-up. Fourteen patients became seizure-free for >6 months; all except 1 had generalized epilepsy. For 12 patients, treatment could be reduced to monotherapy, but for those with valproate (VPA) comedication LTG dosage had to be increased; 25% of patients with VPA monotherapy exhibited skin rash, appearing 3–18 days after starting LTG. For 4 patients, LTG could be reintroduced after VPA was withdrawn. Ten patients had ataxia and/or drowsiness and 2 had vomiting. For all other patients, tolerance was excellent.     

Lamotrigine Therapy for Partial Seizures: A Multicenter, Placebo-Controlled, Double-Blind, Cross-Over Trial

Summary: The efficacy and safety of lamotrigine (LTG), a new antiepileptic drug (AED), were evaluated in a multicenter, randomized, double-blind, placebo-controlled, cross-over study of 98 patients with refractory partial seizures. Each treatment period lasted 14 weeks. Most patients were titrated to a LTG maintenance dose of 400 mglday. Seizure frequency with LTG decreased by ≥50%, as compared with placebo, in one fifth of patients. Overall median seizure frequency decreased by 25% with LTG as compared with placebo (p < 0.001). With LTG, the number of seizure days decreased by 18% as compared with placebo (p < 0.01), and investigator global evaluation of overall patient clinical status favored LTG by 2: 1 (p = 0.013). Plasma LTG concentrations appeared to be linearly related to dosage. LTG had no clinically important effects on the plasma concentrations of concomitant AEds. Adverse experiences were generally minor and most frequently were CNS-related (e.g., ataxia, dizziness, diplopia, headache). Most were transient and resolved without discontinuing treatment. Five patients withdrew as a result of adverse experiences while receiving LTG, including 3 patients with rash. One placebo patient was also withdrawn because of rash. The addition of twice-daily LTG to an existing AED regimen was safe, effective, and well tolerated in these medically refractory partial seizure patients.     

Comparison of Cognitive Effects of Lamotrigine and Oxcarbazepine in Epilepsy Patients

Background and Purpose

This study compared the cognitive effects of 1 year of treatment with lamotrigine (LTG) and oxcarbazepine (OXC) in epilepsy patients.

Methods

This retrospective study investigated 60 epilepsy patients undergoing neuropsychological tests who were either newly diagnosed or untreated in the preceding 6 months. The cognitive function in 30 patients receiving LTG monotherapy and 30 age-matched patients receiving OXC monotherapy was compared after 1 year. The neuropsychological scores at baseline and all of the epilepsy-relevant variables except seizure type did not differ between the groups. The mean daily dosages of LTG and OXC at 1 year were 93 mg and 825 mg, respectively.

Results

The posttreatment list-learning performance was better in the LTG group than in the OXC group (p<0.05). The incidence of cognitive complaints did not differ between the two groups. The list-learning performance and Trail Making Test scores were better in each group after treatment.

Conclusions

LTG and OXC monotherapies have similar, slightly beneficial effects on cognitive function, and are probably not harmful.     

Safety of Topiramate: Adverse Events and Relationships to Dosing

Summary: To date, 1,809 individuals have been exposed to topiramate (TPM), primarily adults with partial-onset seizures. Of this total, 665 patients have been treated for more than 1 year, 177 for more than 3 years, and 67 for more than 5 years. The profile of treatment-emergent adverse reactions (TEAEs) observed with TPM at various dosages is based primarily on data from five double-blind, placebo-controlled trials in which 360 patients received TPM at target doses of 200–1,000 mg/day. Long-term safety is assessed on the basis of 1,001 patients treated with TPM in controlled and open trials for up to 5.3 years. Most of the commonly reported TEAEs were related to the central nervous system and were observed with greater frequency at dosages above the 200–600-mg/day range found to be optimal in dose ranging trials. Nephro-lithiasis not requiring surgery was seen in 1.5% of patients, and mild, dose-related weight loss was associated with TPM therapy. No clinically significant treatment-related abnormalities were observed in clinical laboratory parameters or in neurologic, electrocardiographic, oph-thalmologic, or audiologic tests.     

Human Safety of Lamotrigine

Summary: The clinical safety of lamotrigine (LTG), assessed in four completed randomized, double-blind, placebo-controlled crossover trials and an interim analysis of 27 12-month open studies, is discussed. LTG was added to existing anti-epileptic drugs (AEDs) of adult patients with refractory epilepsy, using a twice-daily regimen. In the pooled data from the four double-blind studies ( n = 92), the incidence of adverse experiences with LTG and placebo did not differ significantly. Two patients were withdrawn on LTG due to adverse experiences (one rash, one nausea and vomiting). In the open studies (pooled data; n = 572) the most commonly reported adverse experiences were dizziness, diplopia, somnolence, headache, ataxia, and asthenia (10–14% incidence). Forty-nine patients (8.6%) were withdrawn with adverse events, most commonly for rash (2.3%). No patients were withdrawn from any of the studies with physical, neurological, or ECG abnormalities thought attributable to LTG treatment. Laboratory measures, vital signs, and weight did not show any consistent changes of clinical significance, and no significant changes in plasma concentrations of concomitant AEDs after the addition of LTG were observed.     

Valproate, Carnitine Metabolism, and Biochemical Indicators of Liver Function

The effects of valproate (VPA) on carnitine and lipid metabolism and on liver function were assessed in 213 age- and sex-matched outpatients from five centers, with the following distribution: VPA monotherapy, 54; VPA polytherapy, 55; other monotherapies, 51; and untreated, 53. Mean total and free carnitine levels were significantly lower in patients with polytherapy; acylcarnitine was significantly higher for VPA monotherapy and the ratio of acyl- to free carnitine was significantly higher in all patients receiving VPA. Ammonia, uric acid, and bilirubin were the only tests selectively impaired with VPA. A significant correlation was found between serum ammonia and VPA dosage. Glucose, beta-lipoproteins, triglycerides, acetacetate, and beta-hydroxybutyrate were unchanged in the four groups. Sex and age appeared to interact with total and free carnitine values. Adverse drug reactions were apparently unrelated to carnitine metabolism impairment. Only a few patients had abnormal carnitine values. Our data support the assumption that carnitine deficiency and abnormal liver function due to VPA are mostly subclinical events.     

Occurrence of psychosis in patients with epilepsy randomized to tiagabine or placebo treatment

PURPOSE: Patients with drug-resistant epilepsy have a higher incidence of psychiatric problems and possibly greater intolerance to antiepileptic drugs (AEDs) than do other patients with epilepsy. Concern has been raised that gamma-aminobutyric acid (GABA)ergic drugs may be associated with treatment-emergent psychosis. Tiagabine (TGB; Gabitril), a new AED that blocks synaptic GABA uptake, was developed in trials of drug-resistant patients with epilepsy. We conducted ad hoc analyses of adverse events, drug intolerance, and treatment response to evaluate the association between TGB treatment and psychosis and whether psychiatric history might be predictive of tolerance or effectiveness of this GABAergic drug. METHODS: Data were analyzed from two multicenter, randomized, double-blind, placebo-controlled trials of add-on TGB therapy (32 or 56 mg daily) in 554 adolescents and adults with complex partial seizures (CPSs). After an 8- or 12-week baseline phase, double-blind treatment consisted of a 4-week titration period (with TGB dose gradually increased to 32 or 56 mg daily) and an 8- or 12-week fixed-dose period. Adverse events commonly associated with psychosis were evaluated. Treatment intolerance and effectiveness (> or =50% reduction in CPS rate) were compared among patients with and without psychiatric histories. RESULTS: Psychotic symptoms (hallucinations) were observed in three (0.8%) of 356 TGB-treated patients and none of 198 placebo-treated patients (p = 0.556, NS). Statistical analysis showed no interaction between psychiatric history and drug intolerance or treatment outcome. CONCLUSIONS: TGB administration appears to carry no significant increased risk of treatment-emergent psychosis. Psychiatric history was not predictive of the tolerance or effectiveness of the drug.     

Pharmacokinetic Profile of Topiramate in Comparison with Other New Antiepileptic Drugs

Summary: Antiepileptic drugs (AEDs) in broad use today have a number of pharmacokinetic liabilities, including a propensity for clinically meaningful drug interactions. Therefore, new AEDs with improved pharmacokinetic characteristics would be welcomed. The pharmacokinetic proftles of six newer AEDs—topiramate (TPM), gaba-pentin (GBP), vigabatrin (VGB), lamotrigine (LTG), ox-carbazepine (OCBZ), and felbamate—were reviewed. Some of these AEDs offer an improvement in one or more pharmacokinetic parameters compared with traditional AEDs, with TPM, GBP, VGB, and OCBZ demonstrating the most advantageous overall pharmacokinetic profiles.     

Clinical Pharmacology of Lamotrigine

Summary: The pharmacokinetics and pharmacodynamics of lamotrigine (LTG), a new antiepileptic drug (AED), were studied in healthy volunteers. In an open dose-escalating study, LTG 240 mg produced peak plasma concentrations of around 3 μg/mg with no significant adverse events. Subsequent pharmacokinetic studies revealed complete oral absorption, first-order kinetics with a mean half-life of approximately 1 day, and elimination mainly as a glucuronide in the urine. Early studies in patients with epilepsy revealed more rapid metabolism when given with enzyme-inducing AEDs and delayed metabolism by valproate. A placebo-controlled, double-blind study compared LTG 120 and 240 mg with phenytoin (PHT) 500 and 1,000 mg, and diazepam (DZP) 10 mg. Visual analogue scales showed sedation after PHT 1,000 mg and DZP 10 mg, but not after LTG. Smooth pursuit eye movements and adaptive tracking were impaired by DZP and PHT 1,000 mg. LTG did not affect these variables. A comparison of LTG 150 and 300 mg and carbamazepine (CBZ) 200, 400, and 600 mg demonstrated impairment of smooth pursuit and saccadic eye movements by CBZ 600 and 400 mg, but not by LTG. Additionally, CBZ 600 mg impaired adaptive tracking and increased body sway and heart rate. These studies have shown LTG to have desirable and predictable pharmacokinetic properties for an AED. Pharmacodynamic effects were absent, suggesting a high therapeutic index.