Lamotrigine in add-on therapy: assessment of efficacy in drug resistant epilepsy

The authors presented the results of treatment with lamotrigine (LTG, Lamictal) in 13 patients with drug resistant epilepsy (add-on therapy). There were 8f, 5m. aged 16-60 years, mean age 28.8 years. Generalized seizures occurred in 8 patients (62%). In this group there was 1 patient (aged 16 years) with the Lennox-Gastaut syndrome and 1 patient (aged 20 years) with valproate resistant juvenile myoclonic epilepsy. Complex partial seizures and complex partial with secondary generalization occurred in 5 patients (38%). Before LTG addition mean seizure frequency was from 3/month to several times/day. The mean duration of epilepsy was 16.6 years. The 8 patients were treated with CBZ and VPA, one with PHT and VPA, one CBZ and VGB. Monotherapy with VPA was introduced in 3 patients. After 6 months of treatment with LTG the efficacy was evaluated. 12 patients took LTG with VPA, 1 LTG with CBZ. Complete reduction of seizures was achieved in 3 cases (23%), at least 50% reduction in 3 patients (23%), reduction below 50% in 4 patients (31%). In 3 cases (23%) the results of treatment were negative (increase or no change in seizure frequency). Beneficial psychotropic effect was observed in 9 patients (69%). Adverse effects occurred in 2 patients (15%). Headache, vertigo, sleepness were observed in one case. Rash occurred in 1 patient (treated with LTG and VPA). After 6 months 3 patients were excluded from the study because of negative effects of treatment. LTG is helpful and well tolerated in drug-resistant epilepsy.     

Seizure freedom with different therapeutic regimens in intellectually disabled epileptic patients.

BACKGROUND: Epilepsy is a frequent condition in persons with intellectual disability and is more often difficult to treat than in the average population. Seizure freedom is the primary therapeutic goal which has important implications for the patient's quality of life. The aim of this study was to find out which antiepileptic therapy regimens (monotherapy or combination therapy) are effective in achieving this goal in intellectually disabled epilepsy patients. We were especially interested in the impact of the new antiepileptic drugs (AEDs) which were introduced during the past decade. METHOD: We investigated retrospectively the antiepileptic regimens on which the resident patients of a large epilepsy centre (as a rule with additional intellectual disabilities of different degrees) were seizure free in 2002. Information on antiepileptic medication and seizure frequency was taken out of the individual case documentation. It was also determined whether seizure free patients had already been seizure free in 1992. RESULTS: Two hundred and forty out of 675 patients (35,6%) with epilepsy were seizure free. The proportion of seizure freedom was 43,7% in patients with borderline intelligence, 39,2% in mild, 33,2% in moderate, 31,9% in severe, and 21,9% in profound intellectual disability. One hundred and twenty-two (50,8%) seizure free patients were on monotherapy; 53 of them were on CBZ (PB: 34, VPA: 25, PHT: 7, LTG: 3). Ninety-three patients (38,7%) were on duotherapies, CBZ/PB (27 patients), PB/PHT (17), and LTG/VPA (14) being the commonest. Of 18 (7,5%) triple therapies, LTG/PB/VPA (4 patients) was the commonest. Taken together, the five most frequent therapeutic regimens were CBZ monotherapy, PB monotherapy, CBZ/PB, VPA monotherapy and PB/PHT (a clear preponderance of classic AEDs). A distinction was made between "old seizure free" (seizure free already in 1992) and "new seizure free" (in 1992 still seizures) patients. In the 132 old seizure free patients the classic AEDs prevailed again, monotherapies with CBZ, PB and VPA being the most frequent regimens. In comparison, in the 78 new seizure free patients the novel combination LTG/VPA was the third most frequent, after the classic regimens CBZ/PB and CBZ; PB monotherapies were rare. CONCLUSION:In a majority of intellectually disabled patients with epilepsy (including those who became seizure free since 1992), complete seizure control has been achieved by monotherapy or duotherapy with classic AEDs. Of the new AEDs LTG in combination with VPA appears to be an important innovation.     

Lamotrigine versus vigabatrin as an add-on therapy in refractory epilepsy: prospective study

Lamotrigine (LTG) and Vigabatrin (VGB) has been licensed widely as adjunctive therapy for partial and secondary generalized seizures. We compared the efficiency of Lamotrigine and Vigabatrin as adjuvant therapy for 33 patients (16 male and 17 female) with drug-resistant partial epileptic seizures (simple and complex) with secondary generalization receiving combination therapy (carbamazepine--CBZ and valproic acid--VPA). Patients were enrolled if they had experienced two partial seizures (simple or complex) and one secondary generalization/month, despite combination therapy. Neurologic evaluation including CT, MRI and EEG was performed every 3 months during observation. Blood specimens for CBZ and VPA plasma concentration were obtained prior to the first LTG or VGB dose and twice a year during the treatment. The assessment of LTG and VGB effectiveness was performed in 2-month intervals during 2-3 years for vigabatrin (mean daily dose 2.0 g) and 1-2 years for Lamotrigine (mean daily dose 0.3 g). The treatment (CBZ, VPA or both) with Vigabatrin or Lamotrigine as adjunctive therapy was effective in about a half of patients with refractory epilepsy. Findings suggest that the reduction in partial seizures (simple or complex) frequency with Vigabatrin is greater than that with Lamotrigine. On the other hand, Lamotrigine seems to be more effective in patients with partial epileptic seizures with secondary generalization.     

Valproate Monotherapy in 30 Patients with Partial Seizures

This retrospective pilot study describes 30 patients diagnosed and treated for complex partial seizures (CPS) and simple partial seizures (SPS) with and without generalization who received valproate (VPA) monotherapy after lack of response or allergic reaction for carbamazepine (CBZ), phenytoin (PHT), or phenobarbital (PB). Seizures were tabulated daily on seizure calendars by the patients. Three time periods were examined for seizure frequency, 90 days before VPA treatment and 90 and 180 days after VPA treatment. Twenty-two were "controlled" or "improved" (reduction of seizure activity by greater than or equal to 51%) 6 months following the initiation of VPA. VPA was particularly effective in 17 patients who had secondarily generalized tonic-clonic seizures (GTCS) as a subtype of partial seizures. Failure of response to VPA in eight patients appears to be related to their type of partial seizure (SPS or CPS alone, without GTCS) and duration of uncontrolled recurrent seizures. Etiology and compliance were not related to treatment failure. This study supports the need for a double-blind controlled trial with VPA in patients with partial seizures.     

Effectiveness and tolerance of adjunctive treatment of lamotrigine and conversion to monotherapy in pediatric patients with epilepsy. Preliminary studies

The examination concerned patients with intractable epilepsy aged 9-19 years with partial seizures simple or complex, developing into generalized ones years, treated with VPA (valproate) or CBZ (carbamazepine). They received VPA or CBZ for at least 4 weeks and even with the therapeutic concentration of these drugs in blood serum in the month preceding the examination they demonstrated seizures at least twice. For a period of 8 weeks lamotrigine (LTG) was progressively added to the therapy. Both drugs were administered for at least 8 weeks in a full dose. In case of achieving a good therapeutic effect assessed on the basis of at least 50% seizure reduction the use of VPA or CBZ was gradually discontinued. In the period of 12-week observation an application of LTG monotherapy 2/3 of patients achieved 50-100% reduction of seizures. These patients improved reasoning dynamics and memorizing ability. After LTG administration EEG showed normalization of background activity and reduction of number and time of epileptic discharges.     

A quantitative study of daytime sleepiness induced by carbamazepine and add-on vigabatrin in epileptic patients

Introduction – The clinical relevance of daytime sleepiness associated with carbamazepine (CBZ) and vigabatrin (VGB) was objectively assessed by the multiple sleep latency test (MSLT) and nocturnal sleep recordings. Material and methods – Twenty-six patients with partial epilepsy and mean monthly seizure frequency of 4, aged 18 to 48 years, receiving chronic monotherapy with CBZ and subsequent VGB addition for 2 months (14 patients), were compared with a group of healthy subjects. Subjective daytime sleepiness was complained by 13 patients on CBZ monotherapy and 9 patients during VGB add-on treatment. Results – No differences in nocturnal sleep parameters, but significantly shorter daytime sleep latencies at the MSLT, were detected in CBZ-treated patients as compared with healthy controls. Addition of VGB therapy did not further enhance objective daytime sleepiness. Conclusion – Some sleepiness occurs in chronically CBZ-treated epileptic patients, which can be objectively measured by the MSLT, but it is not aggravated by add-on VGB.     

Effect of antiepileptic drugs on spontaneous seizures in epileptic rats

The present study investigated whether spontaneously seizing animals are a valid model for evaluating antiepileptic compounds in the treatment of human epilepsy. We examined whether clinically effective antiepileptic drugs (AEDs), including carbamazepine (CBZ), valproic acid (VPA), ethosuximide (ESM), lamotrigine (LTG), or vigabatrin (VGB) suppress spontaneous seizures in a rat model of human temporal lobe epilepsy, in which epilepsy is triggered by status epilepticus induced by electrical stimulation of the amygdala. Eight adult male rats with newly diagnosed epilepsy and focal onset seizures were included in the study. Baseline seizure frequency was determined by continuous video-electroencephalography (EEG) monitoring during a 7 days baseline period. This was followed by a 2-3 days titration period, a 5-7 days treatment period, and a 2-3 days wash-out period. During the 5-7 days treatment period, animals were treated successively with CBZ (120 mg/kg/day), VPA (600 mg/kg/day), ESM (400 mg/kg/day), LTG (20 mg/kg/day), and VGB (250 mg/kg/day). VPA, LTG, and VGB were the most efficient of the compounds investigated, decreasing the mean seizure frequency by 83, 84, and 60%, respectively. In the VPA group, the percentage of rats with a greater than 50% decrease in seizure frequency was 100%, in the LTG group 88%, in the VGB group 83%, in the CBZ group 29%, and in the ESM group 38%. During the 7 day treatment period, 20% of the VPA-treated animals and 14% of the CBZ-treated animals became seizure-free. These findings indicate that rats with focal onset spontaneous seizures respond to the same AEDs as patients with focal onset seizures. Like in humans, the response to AEDs can vary substantially between animals. These observations support the idea that spontaneously seizing animals are a useful tool for testing novel compounds for the treatment of human epilepsy.     

Monotherapy versus polytherapy for epilepsy: a multicenter double-blind randomized study

PURPOSE: Monotherapy has been the gold standard in epilepsy treatment for the last 20 years, partly because of the reputation for increased toxicity of polytherapy. However, monotherapy and polytherapy have not been compared in a double-blind clinical trial. Open trials that compared the two treatments were not optimally designed and compared the two at unequal drug loads (i.e., at nonequivalent dosages). We report on a double-blind clinical trial in which a combination of carbamazepine (CBZ) and valproate (VPA) was compared with CBZ monotherapy. Patients started with equal drug loads, and neurotoxicity was the primary outcome measure. METHODS: The 130 adult patients with untreated generalized tonic-clonic and/or partial seizures were randomized to equal drug loads of either monotherapy (400 mg CBZ per day) or polytherapy (200 mg CBZ plus 300 mg VPA per day). Outcome was measured by seizure counts, clinimetric epilepsy scales, and neuropsychological tests at baseline, at 2 and 12 months, and irregularly between 2 and 12 months. RESULTS: No statistical differences were found between the two treatments in the reduction of seizure frequencies, in overall neurotoxicity, or in overall systemic toxicity. The frequencies and clinimetric scores of certain adverse effects did differ (e.g., more monotherapy patients remained sedated, and more polytherapy patients gained weight). Fewer polytherapy patients withdrew because of adverse effects (14 vs. 22%), although this did not reach statistical significance (p=0.15). Neuropsychological assessment did not show significant differences. CONCLUSIONS: No differences were found in overall neurotoxicity between monotherapy and polytherapy.     

Influence on ictal seizure semiology of rapid withdrawal of carbamazepine and valproate in monotherapy

PURPOSE: To quantify changes in ictal seizure semiology during rapid withdrawal of carbamazepine (CBZ) and valproate (VPA) from a monoregimen in presurgical evaluation. METHODS: Therapeutic intensive seizure analysis (TISA) with video-EEG monitoring was used in 33 patients with pharmacoresistant partial epilepsy undergoing complete withdrawal of CBZ (20 patients) or VPA (13 patients) from a monoregimen. Monitoring phases included a 3-day baseline phase, a 3-day rapid antiepileptic drug (AED) withdrawal phase, and another 3-day AED-free phase with AEDs in subtherapeutic levels. Seizure variables as complete processes and their various elements (ictal signs) were analyzed, including duration (seconds), intensity (on a scale of 0 to 3), frequency (number per 3 days), and total duration of seizures and ictal signs in 3 days (seconds). The localization of seizure patterns on ictal EEG recording (EEG seizure onset) and the first appearing clinical ictal phenomena (initial ictal signs) were recorded. RESULTS: A total of 188 seizures in the CBZ group and 57 seizures in the VPA group were investigated. Compared with the baseline phase, the CBZ group showed increases in duration, frequency of seizures, various ictal signs, and secondarily generalized tonic and clonic signs during the following two phases. Significantly increased values of the VPA group were observed in seizure duration and frequency of hypermotoric phenomena during the AED-free phase. More patients in the CBZ group had secondarily generalized clonic signs during the AED-free phase. EEG seizure onset and initial ictal signs showed no obvious changes between study phases. CONCLUSIONS: Withdrawal of CBZ is followed more quickly by an increase of seizure frequency and severity than is the case for VPA withdrawal. Both CBZ and VPA withdrawal influences seizure propagation rather than the seizure-onset characteristics, which speaks in favor of its use in presurgical evaluation.     

The effect of vigabatrin (gamma-vinyl GABA) on cerebral blood flow and metabolism.

OBJECTIVE: To investigate the effect of vigabatrin (VGB; gamma-vinyl gamma-aminobutyric acid [GABA]), a selective irreversible GABA-transaminase inhibitor, on cerebral metabolic rate for glucose (CMRGlc) and cerebral blood flow (CBF) measured with 18F-fluorodeoxyglucose (FDG) PET and 15O water PET. BACKGROUND: Antiepileptic drugs (AEDs) reduce CMRGlc to varying degrees. Phenobarbital causes a mean decrease of 30 to 40%. Phenytoin, carbamazepine (CBZ), and valproate (VPA) cause milder reductions in CMRGlc. The combination of VPA with CBZ results in a greater decrease than either drug alone. The effect of novel AEDs on both CBF and CMRGlc has not been studied extensively. METHODS: Fourteen patients with refractory complex partial seizures on CBZ monotherapy for 4 weeks were included in the study. All patients had baseline 18F-FDG and 15O water PET studies followed by double-blind randomization to placebo (PLC) or VGB while on continuous CBZ treatment. PET scans were repeated after an interval of 2 months on target dose of VGB (50 mg/kg) or PLC. Quantitative PET data analysis was performed using a region of interest template. Significance was tested with the Wilcoxon rank sum test. RESULTS: No statistically significant difference in age, duration of epilepsy, or CBZ levels was observed in the two patient groups. VGB reduced global CMRGlc by 8.1+/-6.5% and global CBF by 13.1+/-10.4%. The change in CMRGlc was different in patients taking VGB compared with those on PLC (p < 0.04). VGB patients showed regional decreases in both CMRGlc and CBF, particularly in temporal lobes. CSF total GABA increased in the VGB patient group (1.48+/-1.06 versus 4.03+/-4.19 nm/mL). The increase differed from the PLC group (p < 0.03). We found a strong relation between decreased total CSF GABA and increased CMRGlc in the VGB patient group (R2 = 0.82, p < 0.01). CONCLUSIONS: Vigabatrin (VGB) causes mild reductions in both cerebral blood flow (CBF) and cerebral metabolic rate for glucose (CMRGlc) in contrast to other drugs such as barbiturates, which are direct agonists at the gamma-aminobutyric acid-benzodiazepine receptor complex. Conventional AEDs depress CBF and CMRGlc to a greater degree than does VGB. The relatively mild reduction could be due to pre- as well as postsynaptic effects or a use-dependent mechanism.     

Felbamate monotherapy: controlled trial in patients with partial onset seizures.

Felbamate (FBM) monotherapy was evaluated in 44 patients with uncontrolled partial onset seizures in a unique, single-center, randomized, double-blind, parallel-group trial. During the 56-day baseline period, patients were required to have at least 8 seizures and to be receiving only one standard antiepileptic drug (AED) at a therapeutic level; a second AED was allowed if at a subtherapeutic level. Patients were randomized to valproate (VPA), 15 mg/kg, or to FBM, 3,600 mg/day. In the treatment phase, previous AEDs were discontinued by study day 28 (by one-third decrements on study days 1, 14, and 28). Study end points were completion of 112 study days or the fulfilling of escape criteria. Criteria for escape relative to baseline were: two-fold increase in monthly seizure frequency, two-fold increase in highest 2-day seizure frequency, single generalized tonic-clonic seizure (GTC) if none occurred during baseline, or significant prolongation of GTCs. The predetermined primary efficacy variable was the number of patients escaping in each treatment group. Nineteen patients on VPA and 3 on FBM met escape criteria (p less than 0.001, chi-square test). When overall seizure frequency among study completers was compared with baseline, the FBM group had a 50 to 65% reduction in seizure frequency. FBM adverse experiences were all mild or moderate in severity, and the incidence of adverse experiences was lower in monotherapy. FBM monotherapy was effective in the treatment of partial onset seizures with or without generalization and demonstrated a favorable safety profile.     

Therapy of Infantile Spasms with Valproate: Results of a Prospective Study

In a prospective study, 22 children with recently manifested infantile spasms (18 patients with symptomatic and 4 with idiopathic infantile spasms) were treated with sodium valproate (VPA). Before VPA was instituted, a loading test was performed to exclude abnormal patterns of VPA metabolites by gas chromatography and mass spectroscopy of serum and urine. This test was repeated during VPA therapy; an abnormal pattern of VPA metabolites was not observed. VPA was started in increasing dosage until infantile spasms were controlled or a maximum dose of 100 mg/kg/day was reached. If VPA did not control seizures or at least reduce frequency significantly after a trial of 4-6 weeks, dexamathasone was added to VPA. If focal seizures occurred in association with localized epileptogenic EEG discharges, carbamazepine (CBZ) was added to VPA. After 4 weeks of VPA monotherapy, infantile spasms were controlled in 11 children. After 3 months of therapy, 16 children were free of seizures (14 patients VPA monotherapy), and 4 children had reduction of seizure frequency to less than 25%. VPA doses varied between 40 and 100 mg/kg/day (mean 74). The mean plasma concentration was 113 micrograms/ml (range 46-177). After 6 months of therapy, total seizure control was achieved in 20 of 22 patients (16 children VPA monotherapy). The mean observation time was 16 1/2 months (range 6-36 months). There were seven relapses in six children during the first 7 months of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical analysis of the effectiveness and safety of vigabatrin

The efficacy and safety of vigabatrin (VGB) has been extensively evaluated in preclinical and clinical studies but level of effectiveness in different type of seizures has yet to be established. The aim of our study is the prospective evaluation of anticonvulsant efficacy and toxicity of VGB. This long-term observation mainly focusing on efficacy of VGB in partial vs. secondarily generalized seizures were considered separately. In our study the criterion of drug resistance is occurrence per month of at least 1 tonic-clonic seizure or at least 2 complex partial seizures in 3 following months. The studies are based on 73 patients (39 F and 34 M), with average age of 26 years. After two weeks of treatment with sabril the drug was withdrawn in 5 patients because of side effects. The period of observation was 12 months. In group I--from total of 73 patients with partial seizures (including secondarily generalized)--31 (42%) of patients suffered only from partial seizures. Complex partial seizures occurred in 18 of patients; in this group were also 13 patients with simple partial seizures. Group II consisted of 42 patients (58%) who suffered from secondarily generalized tonic-clonic seizures. Number of seizures in group of patients with tonic-clonic seizures was from 1 to 16 per month (average 3.4) and in group of patients with complex partial seizures was from 1 to 70 per month (average 13.29). After titration period, Vigabatrin was given in doses of 500 to 3500 mg daily. Mean monthly fit frequency was calculated for over 3 months prior to the addition of vigabatrin and 12 months of therapy at the patient's maximum dose. Monthly fit frequency expressed as mean +/- standard error of the mean, and this statistical significance was determined using MANOVA for repeated measurement. Average monthly fit frequency of partial seizures has been reduced from 13.29 to 6.96 (p < 0.0001) and of generalized seizures from 3.38 to 1.38 (p < 0.0001). The percentage of patients achieving an increase of at least 75%--(Ratio < -0.6)--of seizures was greater in generalized seizures (27.3) than in partial ones (21.3). VGB is effective and well tolerated in refractory patients requiring add-on antiepileptic treatment and it has shown efficacy both in therapy of refractory partial seizures as well of secondarily generalized ones.     

Comparison of add-on valproate and primidone in carbamazepine-unresponsive patients with partial epilepsy

PurposeEvaluation of the efficacy of add-on valproate (VPA) or primidone (PRM) in patients with partial epilepsy unresponsive to carbamazepine (CBZ).MethodsThe trial was prospective and open. Patients, aged 8–58 years, with partial epilepsy who did not become seizure free on CBZ were randomized to either VPA add-on or PRM add-on. The baseline period and the evaluation period were both 3 months. Proportions of patients with different degrees of reduction in seizure frequency were determined.ResultsSignificantly more patients on VPA (51% of 68 patients) achieved a greater than 50% seizure reduction than on PRM (34% of 68 patients). There was no significant difference in percentage seizure free (26% and 16%, respectively) or in percentage treatment withdrawals due to adverse effects.ConclusionOur results indicated that the efficacy of the CBZ/VPA combination tends to be greater than the efficacy of the CBZ/PRM combination.     

New statistical method for analyzing time to first seizure: example using data comparing carbamazepine and valproate monotherapy

INTRODUCTION: Time to first seizure is a common outcome in antiepileptic drug (AED) studies. Previous studies have typically failed to find statistically significant differences between carbamazepine (CBZ) and valproate (VPS). We re-analyzed a meta-analysis comparing CBZ and VPS monotherapy with new powerful statistical methods that incorporate baseline seizure rate information. Methods: Individual patient data were available on 1,265 patients from a meta-analysis of five trials. The outcome measure was time to first seizure after randomization, adjusted for background variables and baseline seizure rate. RESULTS: We found strong evidence of an interaction between treatment and epilepsy type, and between treatment and age. For generalized onset seizures, VPS was statistically significantly better than CBZ: VPS delayed the first seizure after treatment 58%, 52%, 44%, and 36% longer than CBZ for individuals aged 10, 20, 30, or 40, respectively. For partial onset seizures in individuals older than 30, CBZ was significantly better then VPS; CBZ delayed the time to first seizure by 9%, 25%, 44%, and 66% longer than VPS for individuals aged 20, 30, 40, or 50, respectively. CONCLUSION: The results show clear age-varying differences between the effectiveness of CBZ and VPS for generalized onset and partial onset seizures, which have not been identified in previous studies using standard statistical methods. In future trials of AED monotherapy or add-on where time to first or Nth seizure is an outcome, methodology that can incorporate baseline seizure rate information would allow more powerful comparisons between treatments or between treatment and placebo.     

Vigabatrin: 2008 Update

Vigabatrin (VGB) is a structural analogue of γ‐aminobutyric acid (GABA) that irreversibly inhibits GABA‐transaminase (GABA‐T), increasing brain levels of GABA. VGB is under assessment for treatment of infantile spasms (IS) and refractory complex partial seizures (CPS). Response can be rapid with spasm cessation following approximately 2 weeks of therapy. Patients with symptomatic tuberous sclerosis (TS) and other patients have achieved spasm cessation. Comparison with ACTH has been performed. Patients with refractory CPS have responded as well. Adverse effects and structural findings on imaging occur with VGB treatment. T2 hyperintensities within brain have been observed. Psychotic disorders or hallucinations have occurred rarely. A specific adverse effects is associated VGB, with a peripheral visual field defect (VFD) detected in some patients. Prevalence and incidence of the VGB‐induced peripheral VFD varied depending on the age of the patient and the extent of exposure to VGB, with 25% to 50% prevalence in adults; the prevalence in children was 15% and retinal defect in infants ranged from 15% to 31%. A bilateral nasal defect may be the first clinical indication and may progress to a concentric, bilateral field defect observed in many affected patients; central visual acuity is almost always preserved. The earliest finding of the first abnormal field examination in adults was after 9 months of treatment; with a mean duration of VGB exposure of 4.8 years. In children, the earliest onset of a first abnormal field examination was after 11 months, with a mean time to onset of 5.5 years. The earliest sustained onset of the VGB‐induced retinal defect in infants was 3.1 months. Recommendation: Cognitive, age‐appropriate visual field testing is required at baseline and then repeated at intervals in patients who continue therapy. Infants are tested at baseline and at 3‐month intervals for the first 18 months of treatment, and then every 6 months thereafter. Adults with CPS are tested at baseline and at 6‐month intervals. To select patients who are appropriate for VGB therapy, physicians must consider the benefits of fewer seizures and improved quality of life versus the potential risk of developing a VGB‐induced peripheral VFD. Effectiveness of VGB can be detected within 12 weeks of initiating therapy. There appears to be minimal risk associated with a 2‐ to 3‐month trial of VGB to evaluate effectiveness before there is a demonstrable risk of developing the VGB‐induced peripheral VFD. If patients do not have a clinical benefit from VGB within 12 weeks of treatment initiation, VGB should be discontinued. If patients have a meaningful reduction in seizures or achieve seizure freedom, then the physician and patient or caregiver must determine if the benefits outweigh the potential risk of developing a peripheral VFD. When VGB is prescribed, the patient must be closely monitored for visual field changes. In cases where spasm or seizure improvement is not achieved within 12 weeks of initiation, VGB should be discontinued. In cases where complete spasm cessation, seizure control, or meaningful improvement is achieved within 12 weeks, continued treatment with VGB is warranted; subsequent periodic monitoring for the peripheral VFD is necessary and should be used to mitigate the risk of the defect. The risk of developing the peripheral VFD with short‐term exposure seems to be low, therefore, VGB is an appropriate option for patients with IS or refractory CPS who receive a clinical benefit from its effectiveness, given the clinical consequences of uncontrolled seizures and spasms.     

Concomitant use of divalproex sodium and lamotrigine in developmentally disabled patients with epilepsy: a retrospective evaluation of efficacy and tolerability

Objective. Epilepsy in institutionalized severe developmentally disabled patients poses a therapeutic challenge. Frequently these patients have multiple seizure (sz) types that are often intractable. Both divalproex sodium (VPA) and lamotrigine (LTG) have demonstrated efficacy. We sought to examine the efficacy of this specific combination in a group of institutionalized, developmentally disabled patients with epilepsy.Methods. Medical and pharmacy records of all patients with developmental disabilities and intractable seizures were reviewed to identify those who had received VPA and LTG. This retrospective evaluation was structured with respect to time frame and outcome measure. Phase 1 consisted of baseline monotherapy with VPA. Phase 2 consisted of titration/dose escalation. Phase 3 was treatment observation period with the combination of both. Seizure frequency and adverse effect data were obtained from nursing or residential staff records. Primary outcome measures were change in seizure frequency between Phases 1 and 3. Additional measures were percentage of patients seizure-free and those with >75% reduction in seizures. A Wilcoxan signed rank test was used for statistical analysis.Results. Of 293 patients, 25 (12M/13F, 31.7+/-10.2 years) had VPA monotherapy following which LTG was added. Mean doses of VPA and LTG were 1474+/-728 and 165+/-111mg/day, respectively. Baseline seizure frequency ranged from 1 to 25 per month. Mean seizure frequency significantly decreased (6.5+/-vs2.0+/-4.0seizures/month, P<0.001). Sixty-four percent of these patients had >/=75% reduction in seizures 28% became seizure-free.Conclusions. The combination of VPA and LTG appears efficacious in this group of developmentally disabled patients with intractable seizures. Rash, which has been associated with this combination, was notably absent and this may reflect the slower titration schedule used.     

Lamotrigine–valproic acid combination therapy for medically refractory epilepsy

Purpose:   A retrospective study of lamotrigine (LTG)–valproic acid (VPA) combination therapy in medically refractory epilepsy.
Methods:   Patients were identified with an adult epilepsy clinic database and were included if they had been on LTG–VPA combination therapy for at least 6 months. Patient demographics and information about epilepsy type, severity, and degree of medical intractability were obtained by retrospective chart review. The primary outcome measure was change in baseline seizure frequency, and patients were stratified into three groups: (i) seizure-free, (ii) improved (at least 50% reduction in baseline seizure frequency), and (iii) not improved.
Results:   Thirty-five patients met all inclusion–exclusion criteria. Epilepsy type was generalized in 25 patients (71%) and partial in 10 patients (29%). Before LTG–VPA treatment, 27 of 35 (77%) experienced disabling seizures on a monthly basis, and 17 of 35 (49%) of patients had at least one disabling seizure per week. Patients had previously failed treatment with a median of five antiepileptic drugs (AEDs), alone or in combination. With LTG–VPA therapy, 18 (51.4%) remained completely seizure-free, four (11.4%) were improved, and 13 (37.1%) were unimproved. Median follow-up was 42 months. Of the 22 patients who improved, 11 had previously failed LTG and VPA monotherapy. There was no significant difference between improved and unimproved patients with respect to demographics, epilepsy type or severity, or number of previously failed AEDs.
Discussion:   The combination of LTG and VPA should be considered in patients with medically refractory epilepsy. The effectiveness of this combination appears to be independent of epilepsy type or patient demographics.     

Outpatient sleep recording during antiepileptic drug monotherapy

The effects of sleep and sleep deprivation on epilepsy are well known, but the effects of seizures and antiepileptic drugs (AEDs) on sleep have been less well studied. We recorded nocturnal sleep in 17 patients receiving antiepileptic monotherapy with ambulatory cassette EEG devices. Twelve patients had complex partial seizures and five had tonic-clonic convulsions. Two patients' seizures were largely nocturnal, and no seizures occurred during sleep recording. Five patients each were taking phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA), and two were taking clonazepam (CZP), all with therapeutic serum levels and no toxic symptoms. Total sleep time was reduced, wakefulness increased, and sleep latency prolonged in partial seizures as compared with generalized epilepsy. REM sleep was reduced and its latency decreased in partial seizure patients. Both groups had decreased slow wave sleep; that of partial seizure patients was decreased more markedly. PHT increased sleep latency and decreased sleep time, and CBZ increased awakening and diminished slow wave and REM sleep. Patients taking VPA had slight reduction in slow wave sleep; those taking CPZ had decreased sleep and REM latencies. Epilepsy may affect nocturnal sleep, and the effects of partial and generalized seizure disorders may be different. AEDs may also have differential effects on nighttime sleep. These may prove important in the long-term management of epileptic patients.     

Adverse effects of carbamazepine,phenytoin, valproate and lamotrigine monotherapy in epileptic adult Chinese patients

Objective

Antiepileptic drugs (AEDs) have been widely used in patients with epilepsy but the adverse effects in adult Chinese patients have not been investigated. This study evaluated the adverse effects of four commonly prescribed AED monotherapies with carbamazepine (CBZ), phenytoin (PHT), valproate (VPA), and lamotrigine (LTG) in adult Chinese patients with epilepsy.

Methods

The prospective open-label clinical trial was conducted at the Chongqing Epilepsy Center. The study enrolled 505 adults with newly diagnosed epilepsy, including generalized tonic–clonic (n = 110), partial and partial secondarily generalized (n = 395) seizures. Patients were evaluated by two clinicians at the Center and were prescribed one type of AED monotherapy with CBZ, PHT, VPA or LTG for a 24-month period. An adverse effect profile, as well as efficacy of monotherapy, was obtained through a face-to-face interview with the patient at each visit. A physical examination and routine laboratory tests were performed during a clinical screening.

Results

A total of 62.6% (316/505) patients successfully completed the AED monotherapy study: 64.3% of those receiving CBZ, 55.9%—PHT, 61.5%—VPA, and 66.2%—LTG. However, 34.7% of the patients discontinued the AED monotherapy because of unsatisfactory seizure control. Overall, 18% of patients experienced adverse effects: for CBZ (25/168; 14.9%), PHT (18/59; 30.5%), VPA (32/192; 16.7%) and LTG (16/86; 18.6%). The most common drug-related adverse events included gastrointestinal disturbances, loss of appetite and nausea, weight gain and fatigue/tiredness. Tremor and nystagmus occurred in some patients receiving PHT and VPA. Two CBZ, one PHT and four LTG patients (n = 7) discontinued the study due to rash.

Conclusion

Adult Chinese patients with epilepsy accepted and tolerated monotherapy with CBZ, PHT, VPA, and LTG. No fatal adverse events occurred. Unsatisfactory seizure control was a primary reason for withdrawal from the AED monotherapy study.