Differential Cognitive Effects of Carbamazepine and Gabapentin

PURPOSE: The cognitive effects of the newer antiepileptic drugs (AEDs) compared with the older standard AEDs are uncertain. METHODS: We directly compared the cognitive effects of carbamazepine (CBZ) and gabapentin (GBP) in 35 healthy subjects by using a double-blind, randomized crossover design with two 5-week treatment periods. During each treatment condition, subjects received either GBP, 2,400 mg/day, or CBZ (mean, 731 mg/day) adjusted to a dose to achieve midrange standard therapeutic blood levels (mean, 8.3 microg/ml). Subjects were tested at the end of each AED treatment period and in four drug-free conditions [two pretreatment baselines and two post-treatment washout periods (1 month after each AED)]. The neuropsychological test battery included 17 measures yielding 31 total variables. RESULTS: Direct comparison of the two AEDs revealed significantly better performance on eight variables for GBP, but none for CBZ. Comparison of CBZ and GBP to the nondrug average revealed significant statistical differences for 15 (48%) of 31 the variables. Pairwise follow-up analyses of the 15 variables revealed significantly better performance for nondrug average on 13 variables compared with CBZ, and on four compared with GBP. GBP was better than nondrug average on one variable. CONCLUSIONS: Although both CBZ and GBP produced some effects, GBP produced significantly fewer untoward cognitive effects compared with CBZ at the dosages used in this study.     

Effects of Carbamazepine and Phenytoin on EEG and Memory in Healthy Adults

Summary: Using a randomized, double-blind, cross over design, we investigated the effects of carbamazepine (CBZ) and phenytoin (PHT) on memory and spectral EEG components in 15 healthy adults. Each subject was treated with each drug for 1 month, separated by a 1-month washout. Evaluations were conducted at baseline, at the end of each treatment month, and 1 month after the last treatment phase. EEG was collected during an eyes-closed resting condition and a verbal memory activation task. Spectral analysis of the EEG in the nondrug conditions showed that the memory task significantly reduced theta components and increased delta components. As compared with nondrug conditions, the antiepileptic drugs (AEDs) significantly impaired memory performance and produced mild EEG slowing. Memory performance did not differ statistically between the AEDs, but minor differences in spectral EEG components were noted. The results suggest that differences in the cognitive and EEG effects of CBZ and PHT are not clinically significant.     

Effects of gabapentin and carbamazepine on the EEG and cognition in healthy volunteers

PURPOSE: Antiepileptic drug (AED) therapy can be associated with neurotoxic side effects including cognitive dysfunction. Objective methods for detection of neurotoxicity in individual patients would be useful. We studied the effects of gabapentin (GBP) and carbamazepine (CBZ) on neurophysiologic and cognitive/behavioral measures in healthy volunteers. METHODS: In a 12-week, randomized, double-blind, parallel-group study of CBZ and GBP in healthy volunteers, 23 subjects completed the protocol. All achieved the target dose of 1,200 mg CBZ or 3,600 mg GBP. A structured EEG for quantitative analysis and a cognitive test battery were administered before AED therapy and again after 12 weeks of therapy. Test-retest differences were compared with those of 72 untreated control subjects. RESULTS: Both CBZ and GBP significantly decreased the peak frequency of the posterior (alpha) rhythm, with CBZ exerting a greater effect. Ten CBZ and six GBP subjects exceeded the 95% confidence interval (CI) for an individual. Cognitive tests revealed AED vs. control group effects for two of seven measures (Digit Symbol, Stroop) and all subjective measures. However, few subjects exceeded the 95% CI for any objective test. Differences between CBZ and GBP were not significant. Greater EEG slowing was associated with greater subjective neurotoxicity and poorer test-retest performance on a cognitive test summary measure. CONCLUSIONS: Prolonged CBZ and GBP therapy induced EEG slowing that correlated with cognitive complaints and often exceeded the confidence interval for individual subjects. Quantitative EEG measures may be useful in the objective determination of AED-related neurotoxicity.     

Lack of Interaction of Gabapentin with Carbamazepine or Valproate

Summary: Gabapentin (GBP) studies were conducted in patients with epilepsy receiving carbamazepine (CBZ, n= 12) or valproate (VPA, n = 14) monotherapy. The effects of GBP coadministration on steady-state CBZ or VPA concentrations and of these antiepileptic drugs (AEDs) on GBP pharmacokinetics were investigated. GBP (400 mg) was coadministered every 8 h for 3% days with CBZ or for 5 1/3 days with VPA. GBP was well tolerated. Mean steady-state plasma CBZ/CBZ-10, ll-epoxide (CBZ-E) and serum VPA concentrations before, during, and after GBP administration were not significantly different. Mean steady-state GBP pharmacokinetic parameters during CBZ or VPA coadministration were similar to steady-state parameters reported in healthy subjects. Thus, no pharmacokinetic interaction exists between CBZ or VPA and GBP. No dosage adjustment is necessary when GBP and CBZ or VPA are coadministered.     

Efficacy and Tolerance of Long-Term, High-Dose Gabapentin: Additional Observations

Summary: Gabapentin (GBP) has shown antiepileptic efficacy and good tolerance in clinical trials. Much remains to be learned about its clinical use. As a participating center in the US Gabapentin Study Group, we report observations that have practical implications for patient management. Twenty-three patients with intractable partial-onset seizures initiated open-label treatment after a blinded placebo-controlled add-on dose efficacy study. In the titration phase, GBP and concurrent antiepileptic drugs (AEDs) were adjusted to achieve optimal efficacy on maximally tolerated GBP doses. Nine patients had no significant improvement in seizure control and discontinued GBP. The remaining 14 patients were observed while treated long-term with stable-dose GBP and concurrent AEDs. Improvement was maintained as long as patients were followed: ≤4 years. The protocol-allowed upper dose limit, 2,400 mg/day, was well tolerated by 16 of 23 patients, indicating that higher doses may be tolerated. GBP discontinuation did not cause rebound increases in seizure frequency. The most common adverse events (AEs) (in 14 of 23) were similar to those induced by concurrent AEDs and responded to reduction of concurrent AEDs. Many patients reported positive psychostimulatory effects. These observations extend previous findings indicating that GBP is an effective and well-tolerated drug for treatment of partial-onset seizures.     

Gabapentin and cognition: a double blind, dose ranging, placebo controlled study in refractory epilepsy.

OBJECTIVE: To assess the effect of different doses of gabapentin (GBP) on cognitive function in treated epileptic patients. METHODS: Twenty seven patients with refractory partial seizures commenced a double blind, dose ranging, placebo controlled, crossover study of adjuvant GBP. Each treatment phase lasted three months, during which the dose of GBP or matched placebo was increased stepwise at intervals of four weeks (1200 mg/day, 1800 mg/day, and 2400 mg/day in three daily doses). Psychomotor and memory testing was carried out at the end of each four week period, at which time the patient also completed subjective measures of cognition, fatigue, worry, temper, and dysphoria. A visual analogue scale was used to assess drowsiness and a questionnaire was employed to gauge the severity of side effects. RESULTS: In the 21 patients completing the study, GBP produced a significant reduction in median monthly seizure frequency from 7 to 4.3 (P = 0.02), the decrease being most pronounced for secondarily generalised seizures (from 1.0 to 0.3, P = 0.01). Forty three per cent of patients reported a reduction in seizure frequency of at least 50% throughout all GBP doses. Mean (SD) plasma concentrations of GBP at 1200, 1800, and 2400 mg/day were 4.7 (2.6), 6.8 (3.8), and 8.6 (3.3) mg/l respectively. The drug had no effect on composite psychomotor and memory scores; nor was there alteration in any self assessment subscore. The mean drowsiness (P = 0.03) score was higher during treatment with 2400 mg GBP daily compared with matched placebo. Composite psychomotor (r = -0.47, P < 0.01), tiredness (r = 0.42, P < 0.01), and side effect (r = 0.61, P < 0.001) scores correlated significantly with seizure frequency but not with GBP dose. CONCLUSION: GBP is a well tolerated and effective antiepileptic drug which had no measurable effect on cognition but did produce sedation at the highest dose. This study also supports the suggestion that seizures can cause cognitive impairment.     

Gabapentin: Discussion

Summary: Gabapentin (GBP, Neurontin) is a novel anti-epileptic drug (AED) that was shown to be effective against refractory partial seizures in five placebo-controlled trials. However, a number of patients with complex partial seizures experienced an increase in seizure frequency, suggesting that patients suffering from complex partial seizures are not a homogeneous group. In fact, we found that currently available AEDs are likely to be ineffective when staring is a prominent component of complex partial seizures. The poor response of this group of patients may reflect the fact that staring spells are inhibitory seizures and that the AEDs prescribed for partial seizures appear to facilitate inhibitory mechanisms. GBP resembles phenytoin (PHT) and carbamazepine (CBZ) in depressing segmental and reticular excitatory mechanisms and facilitating segmental inhibitory mechanisms, just as it resembles PHT and CBZ in efficacy against some partial seizures and against secondarily generalized seizures. Perhaps the patients in whom GBP increased seizure frequency had complex partial seizures with staring and were therefore unlikely to benefit from drugs such as GBP, CBZ, and PHT, which enhance inhibitory mechanisms in the brain. These findings suggest that future AED trials would greatly benefit from a categorization of complex partial seizures into no-sologically distinct groups.     

Cognitive Effects of Antiepileptic Drugs

Antiepileptic drugs (AEDs) can adversely affect cognitive function by suppressing neuronal excitability or enhancing inhibitory neurotransmission. The main cognitive effects of AEDs are impaired attention, vigilance, and psychomotor speed, but secondary effects can manifest on other cognitive functions. Although the long-term use of AEDs can obviously elicit cognitive dysfunction in epilepsy patients, their cognitive effects over short periods of up to a year are inconclusive due to methodological problems. In general, the effects on cognition are worse for older AEDs (e.g., phenobarbital) than for placebo, nondrug condition, and newer AEDs. However, topiramate is the newer AED that has the greatest risk cognitive impairment irrespective of the comparator group. Since the cognitive impact of AEDs can be serious, clinicians should be alert to adverse events by evaluating cognitive function using screening tests. Adverse cognitive events of AEDs can be avoided by slow titration to the lowest effective dosage and by avoiding polytherapy.     

Gabapentin-induced modulation of interictal epileptiform activity related to different vigilance levels.

OBJECTIVES: Gabapentin (GBP) is a novel antiepileptic drug (AED), currently used as add-on therapy in patients with partial seizures. Similar to other AEDs, little is known about its effects on nocturnal sleep, despite the strict relationship between sleep and epileptic discharges. The aim of our study was to evaluate the effects of chronic therapy with GBP on both nocturnal sleep and on interictal epileptiform abnormalities (IEA) in relation to the different sleep stages. METHODS: Eighteen patients affected by partial seizures resistant to common AEDs were submitted to nocturnal polygraphic recordings under baseline conditions and after 4 months of add-on GBP treatment. RESULTS: We observed a significant increase in unilateral/focal IEA during light NREM sleep and a significant reduction in bilateral/diffuse IEA during wakefulness after sleep onset (WASO) with respect to the baseline condition. A significant increase in REM sleep and slow wave sleep (SWS) associated with a reduction in the number of awakenings and Stage 1 was also observed after GBP chronic therapy. CONCLUSIONS: GBP therapy improves the sleep pattern of epileptic patients and it seems to modulate the expression of IEA with different effects in relation to the various vigilance levels.     

Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy

PurposePsychiatric and behavioral side effects (PBSEs) are common, undesirable effects associated with antiepileptic drug (AED) use. The objective of the study was to compare the PBSE profiles of older and newer AEDs in a large specialty practice-based sample of patients diagnosed with epilepsy.MethodsAs part of the Columbia and Yale AED Database Project, we reviewed patient records including demographics, medical history, AED use, and side effects for 4085 adult patients (age: 18 years) newly started on an AED regimen. Psychiatric and behavioral side effects were determined by patient or physician report in the medical record, which included depressive mood, psychosis, anxiety, suicidal thoughts, irritability, aggression, and tantrum. Significant non-AED predictors of PBSE rate were first determined from 83 variables using logistic regression. Predictors were then controlled for in the comparison analysis of the rate of PBSEs and intolerable PBSEs (PBSEs that led to dosage reduction or discontinuation) between 18 AEDs.ResultsPsychiatric and behavioral side effects occurred in 17.2% of patients and led to intolerability in 13.8% of patients. History of psychiatric condition(s), secondary generalized seizures, absence seizures, and intractable epilepsy were associated with increased incidence of PBSE. Levetiracetam (LEV) had the greatest PBSE rate (22.1%). This was statistically significant when compared with the aggregate of the other AEDs (P < 0.001, OR = 6.87). Levetiracetam was also significantly (P < 0.001) associated with higher intolerability rate (17.7%), dose decreased rate (9.4%), and complete cessation rate (8.3%), when compared with the aggregate of the other AEDs. Zonisamide (ZNS) was also significantly associated with a higher rate of PBSE (9.7%) and IPBSE (7.9%, all P < 0.001). On the other hand, carbamazepine (CBZ), clobazam (CLB), gabapentin (GBP), lamotrigine (LTG), oxcarbazepine (OXC), phenytoin (PHT), and valproate (VPA) were significantly associated with a decreased PBSE rates (P < 0.001). Carbamazepine, GBP, LTG, PHT, and VPA were also associated with lower IPBSE rates when compared individually with the aggregate of other AEDs. All other AEDs were found to have intermediate rates that were not either increased or decreased compared with other AEDs. When each AED was compared to LTG, only CBZ had a significantly lower PBSE rate. The main limitations of this study were that the study design was retrospective and not blinded, and the AEDs were not randomly assigned to patients.ConclusionsPsychiatric and behavioral side effects occur more frequently in patients taking LEV and ZNS than any other AED and led to higher rates of intolerability. Lower PBSE rates were seen in patients taking CBZ, CLB, GBP, LTG, OXC, PHT, and VPA. Our findings may help facilitate the AED selection process.     

Effect of gabapentin on the anticonvulsant activity of antiepileptic drugs against electroconvulsions in mice: an isobolographic analysis

PURPOSE: The objective of this study was the isobolographic evaluation of the interactions between the novel antiepileptic drug (AED) gabapentin (GBP) and a number of other AEDs against electroconvulsion-induced convulsions in mice. METHODS: Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the end point). Adverse effects were evaluated with the chimney test (motor performance) and passive-avoidance task (long-term memory). Plasma levels of AEDs were measured by immunofluorescence or high-pressure liquid chromatography. RESULTS: GBP (< or =50 mg/kg) remained ineffective on the electroconvulsive threshold. According to the isobolographic analysis, GBP appears to act synergistically with carbamazepine, valproate, phenytoin, phenobarbital (PB), lamotrigine (LTG), and LY 300164. The pharmacokinetic events may be responsible for the interactions of GBP/PB and GBP/LTG, because only PB and LTG significantly elevated the plasma concentration of this AED. Conversely, GBP did not affect the plasma levels of other AEDs used in this study. No adverse effects were induced by combinations of GBP with these AEDs. CONCLUSIONS: The isobolographic analysis revealed that combinations of GBP with other AEDs generally results in synergistic (supraadditive) interactions.     

Gabapentin increases slow-wave sleep in normal adults

PURPOSE: The older antiepileptic drugs (AEDs) have a variety of effects on sleep, including marked reduction in rapid-eye-movement (REM) sleep, slow-wave sleep (SWS), and sleep latency, and an increase in light sleep. The effects of the newer AEDs on sleep are unknown. Our purpose was to study the effect of gabapentin (GBP) on sleep. METHODS: Ten healthy adults and nine controls were the subjects of this study. All underwent baseline and follow-up polysomnography (PSG) and completed sleep questionnaires. After baseline, the treated group received GBP titrated to 1,800 mg daily. Polygraphic variables and Epworth Sleepiness Scale (ESS) scores, a subjective measure of sleep propensity, were compared by using the Wilcoxon signed rank test. RESULTS: Nine of the treated subjects achieved the target dose; one was studied with 1,500 mg daily because of dizziness experienced at the higher dose. GBP-treated subjects had an increase in SWS compared with baseline. No difference in the ESS or other polygraphic variables was observed. However, a minor reduction in arousals, awakenings, and stage shifts was observed in treated subjects. CONCLUSIONS: GBP appears to be less disruptive to sleep than are some of the older AEDs. These findings may underlie the drug's therapeutic effect in the treatment of disorders associated with sleep disruption.     

Cognitive and Behavioral Effects of Antiepileptic Drugs

Summary: All antiepileptic drugs (AEDs) have the potential for adverse effects on cognition and behavior. Most of the major AEDs, administered in therapeutic doses, cause little or no cognitive or behavioral impairment in group studies. However, individual variability is considerable, and some patients do not tolerate low serum levels, whereas others tolerate high levels without subjective or objective effects. In the past, carbamazepine (CBZ) and valproate (VPA) have been reported to have the fewest adverse cognitive and behavioral effects in children and adults. However, several recent, well-controlled studies have not found significant differences between the effects of phenytoin (PHT) and those of CBZ or VPA. Greater adverse effects have been found for phenobarbi-tal (PB). However, we must use environmentally relevant measures of cognitive and behavioral functioning to measure effects on daily functioning. Future studies must define cognitive and behavioral toxicity in subpopulations (e.g., post-traumatic epilepsy, mental retardation, depression) and with the new AEds.     

An In Vitro Study of New Antiepileptic Drugs and Astrocytes

Summary:  Purpose: The aim of our research was to study some biochemical modifications elicited in primary rat astrocyte cultures by treatment with gabapentin (GBP), carbamazepine (CBZ), lamotrigine (LTG), topiramate (TPM), oxcarbazepine (OXC), tiagabine (TGB), and levetiracetam (LEV), commonly used in the treatment of epilepsy. We investigated the biologic effects of these anticonvulsants (AEDs) at concentrations of 1, 10, 50, and 100 μg/ml.
Methods: The study was performed by examining cell viability (MTT assay), cell toxicity [lactate dehydrogenase (LDH) release in the medium], glutamine synthetase (GS) activity, reactive oxygen species (ROS) production, lipoperoxidation level (malondialdehyde; MDA), and DNA fragmentation (COMET assay). The level of the expression of 70-kDa heat-shock protein (HSP70) and inducible nitric oxide synthase (iNOS) as oxidative stress–modulated genes also was determined.
Results: Our experiments indicate that CBZ, TPM, and OXC induce stress on astrocytes at all concentrations. GBP, LTG, TGB, and LEV, at low concentrations, do not significantly change the metabolic activities examined and do not demonstrate toxic actions on astrocytes. They do so at higher concentrations.
Conclusions: Most AEDs have effects on glial cells and, when used at an appropriate cell-specific concentrations, may be well tolerated by cortical astrocytes. However, at higher concentrations, GBP, LTG, TGB, and LEV seem to be better tolerated than are CBZ, TPM, and OXC. These findings may reveal novel ways of producing large numbers of new AEDs capable of reducing the extent of inflammation, neuronal damage, and death under pathological conditions such as epilepsy and/or traumatic brain injury.     

Risk factors for carbamazepine elevation and toxicity following epilepsy surgery.

SUMMARY: A proportion of patients undergoing epilepsy surgery, and receiving carbamazepine (CBZ), experience significant elevations in CBZ plasma concentrations, some with associated CBZ toxicity. The objective of this study was to identify significant risk factors for elevations (>12 microg/ml) in CBZ concentrations and CBZ-induced toxicity following epilepsy surgery. METHODS: We retrospectively examined charts of 74 inpatients (31 children and 43 adults) chronically receiving CBZ and undergoing epilepsy surgery between January 1996 and June 2000. Patient demographics, medications, type of surgery, seizure history, adverse events, CBZ doses and concentrations were evaluated. RESULTS: 51.2% of adults and 51.6% of pediatric patients had drug elevations. In the pediatric group, 12.9% had symptoms of toxicity compared to 9.3% in the adult group. Five risk factors-pre-operative CBZ dose, fentanyl dose, surgery day CBZ concentration, body weight, and blood loss-were related to post-operative CBZ concentrations. Three risk factors: age <18 years, pre-operative CBZ dose, and the surgery day CBZ (immediate pre-operative) concentration, were significantly related to the outcome measure of abnormal CBZ concentration (>12 microg/ml). Two variables significantly related to toxicity were average post-operative CBZ dose and the surgery day CBZ concentration. Increases in concentrations occurred at a mean 33+/-13.7 h (range: 11-74 h) after surgery. DISCUSSION: Based upon our results in patients with one or more risk factors, we suggest that reduction of post-operative CBZ doses be considered.     

The effects on cognitive function and behavioral problems of topiramate compared to carbamazepine as monotherapy for children with benign rolandic epilepsy

PURPOSE: To evaluate the cognitive and behavioral effects of topiramate (TPM) versus carbamazepine (CBZ) using efficacious doses of each drug as monotherapy for children with benign rolandic epilepsy. METHODS: A multicenter, randomized, open-label, observer-blinded, parallel-group clinical trial was conducted. TPM was introduced at a dose of 12.5 mg/day with the minimum target dose of 50 mg/day in patients <30 kg and 75 mg/day in patients >30 kg over 4 weeks. CBZ was started at a dose of 10 mg/kg/day with the minimum target dose of 20 mg/kg/day over 4 weeks. Additional individual escalation was allowed up to a maximum target dose. The primary study end point was change on a neuropsychological test battery after 28 weeks of treatment. RESULTS: Neuropsychological data were available for 88 patients (45 patients for TPM and 43 patients for CBZ). Of the cognitive variables measured, arithmetic showed significant worsening in TPM (p = 0.037). An additional test, for maze, also showed a significantly greater improvement for CBZ (p = 0.026). Of behavioral variables, no significant changes were found but the scores had a negative trend for the TPM. When 30 patients on the minimum target dose for TPM were compared to 40 patients treated with minimum target CBZ, there was no significant worsening of cognitive and behavioral effects in the TPM. CONCLUSION: The pattern of neuropsychometric changes with TPM seemed to be slightly worse overall than CBZ. However, outcome with the minimum target dose did not differ significantly in comparisons between the treatment groups.     

Comparison of the cognitive effects of tiagabine and carbamazepine as monotherapy in newly diagnosed adult patients with partial epilepsy: pooled analysis of two long-term, randomized, follow-up studies

PURPOSE: Patients with epilepsy are at greater risk for cognitive impairment than are age- and education-matched controls. Cognitive decline is a significant adverse event associated with many first-generation anticonvulsant drugs (AEDs); however, the past decade has seen the introduction of several new AEDs with more-favorable cognitive profiles. Tiagabine (TGB) is indicated as adjunctive therapy for the treatment of partial seizures. The cognitive effects of TGB and carbamazepine (CBZ) monotherapy were evaluated in adult epilepsy patients with partial seizures. METHODS: This analysis pooled data from two randomized studies with similar populations, dosing, and cognitive assessments. TGB was titrated to 20-30 mg/day and CBZ to 400-800 mg/day over a 6-week period. A control or no-drug group of untreated patients with a single epileptic seizure was included for comparison. Cognitive function was assessed at baseline and 52 weeks. RESULTS: Of the 105 epilepsy patients enrolled, 79 completed the 52 weeks of monotherapy (TGB, 74%; CBZ, 77%). Altogether, 19 untreated patients composed the no-drug group. During the 52-week follow-up, only one statistically significant difference was found between the treatment groups and the no-drug group [verbal fluency task: F(2, 92) = 3.16; p = 0.047]. On further analysis, it was determined that this statistical difference was solely based on the patients receiving CBZ performing worse than the control group (p = 0.048). Statistically significant improvements (p < 0.05) were found on six (26%) of 23 variables with TGB and CBZ, as well as the no-drug group, although the variables differed between the groups. Significant worsening in the test scores was not seen in any of the study groups. CONCLUSIONS: The results of this 52-week, follow-up study show that successful TGB monotherapy with 20-30 mg/day has a cognitive profile similar to that of successful long-term CBZ monotherapy with 400-800 mg/day in newly diagnosed patients with epilepsy and to that of untreated patients with a single seizure. We observed no significant decline in cognitive scores associated with TGB monotherapy.     

Effects of antiepileptic drugs on sleep architecture: a pilot study

OBJECTIVES: The effects of antiepileptic drugs (AEDs) on sleep architecture are not well understood, especially in patients with localization-related epilepsy, in whom seizures themselves can disrupt sleep. To clarify the effects of AEDs on sleep architecture, we performed a prospective study, looking at sleep architecture in patients with epilepsy admitted for video-EEG monitoring. METHODS: Adult patients with localization-related epilepsy treated with a single AED and admitted between 10/1997 and 04/2001 were included. Control patients on no AEDs were also included. Both groups were withdrawn from other AEDs. Overnight polysomnography was recorded and was scored according to the standard method. Adult patients with localization-related epilepsy on no medication were also recorded and served as controls. Patients with no seizure during the recording and no seizure in the 24 h preceding the recording were analyzed in this paper. Patients with a seizure in the 24 h preceding the recording and patients with a seizure during the recording were analyzed separately. RESULTS: A total of 72 nights were recorded in 39 patients, and patients taking each AED were compared to controls. We did not find any statistically significant effect of carbamazepine (CBZ). Phenytoin (PHT) disrupted sleep by increasing stage 1 sleep (PHT: 13.2+/-7.3%; control: 7.7+/-4.8%; P=0.008), and decreasing slow wave sleep (SWS) (PHT: 7.9+/-4.2%; control: 11.3+/-4.4%; P=0.03) and REM sleep (PHT: 13.9+/-6.2; control: 18.8+/-5.1; P=0.01). Valproic acid (VPA) disrupted sleep by increasing stage 1 sleep (VPA: 16.8+/-9.8%; control: 7.7+/-4.8%; P=0.007). Gabapentin (GBP) improved sleep by increasing SWS (GBP: 19.4+/-4.2%; control: 11.3+/-4.4%; P=0.0009). PHT and VPA disrupt sleep in the absence of seizures, while CBZ and lamotrigine have no significant effects. GBP improves sleep by increasing SWS. CONCLUSIONS: AEDs have differing effects on sleep structure, which can be beneficial or detrimental. Consideration of these potential effects is important in maintaining optimal sleep in patients with epilepsy.     

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.     

Factors influencing serum levels of carbamazepine and carbamazepine-10,11-epoxide in children

Carbamazepine-10,11-epoxide (CBZ-E), the principal metabolite of carbamazepine (CBZ), is reported to have antiepileptic and toxic effects similar to CBZ. Steady-state CBZ and CBZ-E levels (high performance liquid chromatography, HPLC assay) were reviewed in 225 outpatient children and young adults taking CBZ with or without other antiepileptic drugs (AEDs). In patients on CBZ alone, mean serum concentration of CBZ was 7.9 +/- 1.9 micrograms/ml and of CBZ-E was 1.5 +/- 0.6 micrograms/ml. The CBZ-E/CBZ ratio was 19.6 +/- 2.4%. Serum CBZ increased with increasing age and with CBZ dose. CBZ-E increased with increasing CBZ dose but was unaffected by age. The CBZ-E/CBZ ratio progressively declined with age. Co-medication with barbiturates or valproic acid significantly increased CBZ-E. Phenytoin showed a similar trend while ethosuximide caused the least change. Patients on CBZ and two or more other AEDs had highest CBZ-E levels and CBZ-E/CBZ ratio. CBZ and CBZ-E levels are variably affected by age, CBZ dose, and co-medication with other AEDs. When other AEDs are administered, careful monitoring is especially indicated in order to avoid toxicity.