Short-term outcomes and predictors of post-surgical seizures in patients with supratentorial low-grade gliomas

To explore the predictive factors and short-term outcomes of post-surgical seizures in patients with supratentorial low-grade gliomas (LGGs). A consecutive series of 70 supratentorial LGG patients with seizures were reviewed to determine the predictors and short-term outcomes of seizures. Univariate analyses and multivariate logistic regression analyses were performed to determine the predictive factors associated with postoperative seizure outcomes. We identified the preoperative seizure frequency threshold by plotting a receiver operating characteristic curve. A Kaplan-Meier curve was constructed to illustrate the seizure-free survival rate of our cohort over time. 54 patients who remained seizure -free post-surgery were classified into the Engel class I, and the other 16 patients whose seizures relapsed were classified into Engel classes II–IV. Univariate and multivariate logistic regression analyses showed that the preoperative seizure frequency (X² = 16.069, P = 0.001), extent of resection (x² = 5.031, P = 0.025), IDH1 mutation (x² = 4.435, P = 0.035) and adjuvant chemotherapy of temozolomide (X² = 4.081, P = 0.043) were related to the postoperative short-term seizure outcome. The ROC curve indicated that the area under the curve for the preoperative seizure frequency test was 0.805 (95% confidence interval 0.690–0.920, p < 0.05), which corresponded to an optimal threshold of 2 preoperative seizures. The IDH1^WT status and adjuvant chemotherapy with temozolomide were related to a better post-operative seizure outcome. Within the first year after the surgical resection, seizures reoccurred among 16 patients (22.9%) with a mean time of 10.8 months. The preoperative seizure frequency, extent of resection, IDH1 status, and adjuvant chemotherapy with temozolomide were predictive factors of short-term postoperative seizure outcomes for supratentorial LGGs. To obtain a favorable seizure outcome, early intervention and removal are warranted. IDH1 mutation is the predictive biomarker of postoperative seizure outcomes. The adjuvant chemotherapy with temozolomide appears to be associated with better seizure outcomes, and it may be useful in helping to control the postoperative seizures.     

添加拉莫三嗪治疗儿童部分性癫的疗效观察

目的 探讨添加拉莫三嗪治疗儿童部分性癫的临床疗效及耐受性.方法 观察42例部分性癫患儿添加拉莫三嗪治疗后疗效、不同发作类型的有效率及发作频率的改变.结果 添加拉莫三嗪治疗后,患儿月发作频率减少38.1%,简单部分性发作有效率68.4%,部分性发作转为全面性发作有效率66.7%,复杂部分性发作有效率72.7%,总有效率69.0%.治疗前后比较差异有统计学意义(P＜0.05).不良反应轻微.结论 拉莫三嗪添加治疗儿童部分性癫具有良好的临床疗效及耐受性.     

Prognosis of chronic epilepsy with complex partial seizures.

Clinical features associated with a successful or unsuccessful response to high dose antiepileptic drug therapy were evaluated prospectively in 82 patients with chronic complex partial seizures. Complete seizure control was observed during high dose drug therapy in 18 patients at plasma concentrations of either 9-35 micrograms/ml phenytoin, 32 and 40 micrograms/ml phenobarbitone, 8 micrograms/ml carbamazepine, or a combination of 25 micrograms/ml phenobarbitone and 4 micrograms/ml carbamazepine. Patients who became free of seizures had a markedly lower number of three seizures (range: 1-29) in the year before the high dose treatment as compared to 40 seizures (range: 3-328) in patients with an increased or unchanged seizure frequency (p less than 0.0001). Complex partial seizures without automatism were found only in patients with complete seizure control (22%). Patients whose seizures remained uncontrolled more frequently gave a history of severe depression or psychotic episodes, clusters of complex partial seizures, two or more seizures per day, and an aura preceding the attack. The results suggest that taking a careful history will uncover clinical features associated with a successful or unsuccessful response to high dose antiepileptic drug therapy in an epileptic out-patient with chronic complex partial seizures.     

Gabapentin as add-on therapy in children with refractory partial seizures: a 24-week, multicentre, open-label study

The efficacy and safety of gabapentin as add-on therapy for refractory partial seizures in 237 children, aged 3 to 12 years were evaluated over a 6-month period. All children received gabapentin at 24 to 70 mg/kg/day. Efficacy variables included the percent change in seizure frequency and the responder rate (defined as those patients who showed >50% reduction in seizure frequency). For all partial seizures, the median percent change in seizure frequency was -34% and the overall responder rate was 34%. Simple partial seizures showed a median reduction of -53%; complex partial seizures, -38%; and secondarily generalized tonic-clonic seizures, -35%. Thirteen patients (5%) withdrew during the 6-month period because of adverse events. Concurrent antiepileptic medication remained unchanged in 185 patients (78%), was decreased in 27 (11%), and increased in 25 (11%) patients. This 6-month follow-up study has demonstrated that gabapentin was well tolerated and appeared to show a sustained efficacy in a large population of children with refractory partial and secondarily generalized tonic-clonic seizures.     

Lorazepam: a controlled trial in patients with intractable partial complex seizures

Lorazepam was studied in a double-blind, placebo-controlled, crossover trial in eight patients with frequent partial complex seizures refractory to therapy with a combination of standard anticonvulsant drugs. Concomitant antiepileptic drugs were maintained at therapeutic serum levels throughout the study, and concentrations of lorazepam were monitored. Following an 8-week baseline observation, patients were randomly assigned to placebo or lorazepam (1 mg BID). The dose was increased biweekly until seizures stopped or unacceptable side effects occurred. Eight weeks later, patients were crossed over, and the same escalating dose paradigm was followed. When seizure frequency during the last 2 weeks of each treatment was compared, seven of eight patients had fewer seizures on lorazepam, and the eighth had decreased seizure duration (a significant difference: p less than 0.01, two-tailed sign test). Blood level data suggest a narrow therapeutic window, with seizure improvement occurring at concentrations of 20-30 ng/ml and side effects at greater than 33 ng/ml. Lorazepam appears to be a useful adjunct in refractory partial complex seizure therapy. It should not be stopped abruptly, as an increase in seizure frequency may result.     

Clorazepate therapy for intractable epilepsy

Thirty-one epileptic patients with seizures refractory to conventional anticonvulsants were treated by adding clorazepate dipotassium to their regimen. Twelve cases showed improvement in seizure frequency, three of whom attained a seizure free state. Response to clorazepate was not related to the type of epilepsy, but patients with secondary generalized epilepsy tended to be less responsive than those with partial epilepsy. Among the various seizure types, generalized tonic-clonic seizures and simple partial seizures showed, although not significant, a tendency to be more responsive to clorazepate therapy than other seizure types, including complex partial seizures, atypical absence, atonic seizures, and tonic seizures. Drowsiness was the main adverse effect, of which 14 patients complained. Six patients were withdrawn from clorazepate because of drowsiness, but in the remaining 8 patients, this side effect disappeared within a week. The appearance of adverse effect was not related to the dose of clorazepate given. Clorazepate may be an effective secondary anticonvulsant in the treatment of intractable epilepsy.     

Effect of vagus nerve stimulation on adults with pharmacoresistant generalized epilepsy syndromes.

INTRODUCTION: Although vagus nerve stimulation (VNS) therapy is approved for the treatment of partial onset seizures, its efficacy for generalized seizures has not been fully evaluated. This Investigational Device Exemption assessed the outcome of VNS therapy among patients with generalized epilepsy syndromes. METHODS: Sixteen patients with pharmacoresistant generalized epilepsy syndromes and stable antiepileptic drug (AED) regimens were implanted with the VNS therapy device and were evaluated for changes in seizure frequency and type between baseline and follow-up of 12-21 months. RESULTS: The patients experienced a statistically significant overall median seizure frequency reduction of 43.3% (P = 0.002, Wilcoxon signed rank test) after 12-21 months of VNS therapy. Types of seizures that may involve a fall or collapse decreased with reductions in the frequency of myoclonic (60% reduction, n = 9; P = 0.016, Wilcoxon signed rank test), tonic (75% reduction, n = 8, NS), atonic (98.6%, n = 3, NS), and clonic seizures (86.7%, n = 1, NS). Conclusion: The benefits of reduced seizure frequency and reduced risk of injury merit consideration of VNS therapy for patients with pharmacoresistant generalized seizure syndromes.     

Gabapentin as Add-On Therapy in Children with Refractory Partial Seizures: A 12-Week, Multicentre, Double-Blind, Placebo-Controlled Study

PURPOSE: To evaluate the efficacy and safety of gabapentin (Neurontin; GBP) as add-on therapy for refractory partial seizures in paediatric patients aged 3-12 years. METHODS: After a 6-week baseline period, 247 patients (54 centres) entered a 12-week double-blind phase and were randomized to receive either GBP (t.i.d., titrated to 23-35 mg/kg/ day) or placebo. Seizure activity and type were recorded daily. Efficacy variables included Response Ratio (RRatio), responder rate, and percentage change in frequency (PCH) for all partial seizures; PCH and RRatio for individual types of partial seizures; and investigator and parent/guardian global assessments of seizure frequency and patient well-being. RESULTS: RRatio for all partial seizures was significantly lower (better) for GBP-treated patients (p = 0.0407). Responder rate favored GBP, but the difference between treatment groups was not statistically significant. Median PCH for all partial seizures for the GBP treatment group (-17.0%) was better than that for the placebo group (-6.5%). Median PCH for specific seizure types showed GBP to be most effective in controlling complex partial seizures (-35%) and secondarily generalized seizures (-28%) when compared with placebo (-12%, +13%, respectively). A greater percentage of GBP-treated patients exhibited improvement according to investigator and parent/guardian global assessments, with a statistically significant difference observed in the parent/guardian global assessment of seizure-frequency reduction (p = 0.046). Three GBP patients and one placebo patient were seizure free during the double-blind treatment period. GBP was well tolerated. CONCLUSIONS: GBP was effective and well tolerated as an add-on therapy for partial seizures in paediatric patients with previously drug-resistant seizures.     

Gabapentin add-on treatment: how many patients become seizure-free?: An open-label multicenter study

The aim of the study was to find out the percentage of patients with localization-related epilepsy achieving complete seizure control with gabapentin (GBP) add-on therapy. Patients under anti-epileptic drug monotherapy during 8 weeks baseline (BSL) with 6 or more seizures were treated with GBP for 26 weeks up to 2400 mg/day. Patients obtaining complete seizure control of all seizures or any partial seizure type during the last 8 weeks were calculated. Seizure frequency was compared between BSL and last 8 weeks. In all, 110 patients were enrolled (92 completed, 18 discontinued): mean age of the completers: 37.6 years (range 16–72), median seizure frequency per 28 days at BSL: 6.8 (2.5–24.5), mean duration of epilepsy: 17.6 years (0.2–51.4), mean duration with GBP for completers: 182.8 days (144–187). Complete seizure control of all seizures was achieved in 8.7% of patients (simple partial seizures: 13.3%, complex partial seizures 24.3%, secondarily generalized seizures: 61.5%): 38% of the patients became seizure-free in at least 1 seizure-type; 40% experienced adverse events. Assessment for quality of life (QoL) and trough plasma levels of GBP did not correlate with the good effect of GBP.     

Double-Blind Study of Gabapentin in the Treatment of Partial Seizures

Forty-three patients completed a double-blind, placebo-controlled study of Gabapentin (GBP) as add-on therapy in partial and secondarily generalized seizures. All patients were followed for an initial 3-month baseline period, after which they were randomly allocated to receive either a placebo or 900 or 1,200 mg/day GBP for 3 months. A statistically significant difference in seizure frequency from the baseline to the treatment phase was noted between patients receiving placebo and GBP 1,200 mg, in whom seizure frequency decreased 57%. The GBP dosage of 900 mg appeared to be ineffective. A close relationship was observed between the serum GBP concentrations and the GBP dosage based on the seizure frequency. Serum GBP concentrations greater than 2 micrograms/ml resulted in a lower frequency of seizures. The adverse effects were minor and consisted mainly of transient drowsiness. GBP appears to be effective in the treatment of partial epileptic seizures in a dosage-related manner.     

Rufinamide for the adjunctive treatment of partial seizures in adults and adolescents: A randomized placebo-controlled trial

Purpose:   To evaluate efficacy and safety of adjunctive treatment with rufinamide 1600 mg twice daily in subjects aged ≥16 years with refractory partial seizures.
Methods:   This double-blind, placebo-controlled, randomized, parallel-group, multicenter trial included an 8-week baseline phase and a 13-week double-blind phase. Treatment was initiated with rufinamide 400 mg twice daily or placebo; rufinamide was titrated to 1600 mg twice daily. Percentage change in partial seizure frequency was the primary outcome measure. Secondary outcome measures included total partial seizure frequency and the percentage of subjects experiencing a ≥50% reduction in partial seizure frequency.
Results:   Three hundred thirteen subjects were randomized; 156 subjects received rufinamide and 157 received placebo. Rufinamide-treated subjects experienced a 20.4% median reduction in partial seizure frequency relative to baseline, while placebo-treated subjects had an increase of 1.6% (p = 0.02). Exclusion of subjects taking carbamazepine in a post hoc analysis resulted in a reduction of 29.2% versus 0.7% in the placebo group (p = 0.05), whereas the treatment difference in subjects taking carbamazepine was not significant. Of rufinamide-treated subjects, 28.2% experienced a ≥50% decrease in partial seizure frequency versus 18.6% of placebo-treated subjects (p = 0.04). The most common adverse events associated with rufinamide treatment were dizziness, nausea, diplopia, and ataxia; they occurred primarily during the titration phase.
Discussion:   Adjunctive therapy with rufinamide 3200 mg/day compared with matching placebo demonstrated efficacy and was generally well tolerated in adults with partial seizures. Further study of this agent in adults with partial seizures taking a range of baseline AEDs is warranted.     

Randomized, Double-Blind, Placebo-Controlled, Clinical Trial of D-α-Tocopherol (Vitamin E) as Add-on Therapy in Uncontrolled Epilepsy

Summary: In a double-blind, cross-over trial, vitamin E, and placebo were compared as add-on therapy in 43 patients with uncontrolled epilepsy. The study consisted of a 3-month baseline period followed by two treatment phases of vitamin E or placebo with cross-over to the second phase after 3 months. No significant side effects were noted during the study. Mean seizure frequency in the baseline period was 15.9 ± 10.5 as compared with 11.8 ± 10.9 during the placebo phase and 13.7 ± 11.1 during the vitamin E phase. No significant change in seizure frequency was observed with vitamin E as compared with placebo (p > 0.1). Similar observation was noted in subgroups with generalized seizures (n = 25), partial with secondarily generalized seizures (n = 11), or complex partial seizures (CPS) (n = 7). This study did not corroborate the earlier claims of therapeutic efficacy of vitamin E as add-on therapy in refractory epilepsy in adults.     

Reduction of Two-Drug Therapy in Intractable Epilepsy

The effects of reducing two-drug treatment to single-drug therapy were studied prospectively in 36 patients with intractable complex partial seizures. In 30 patients (83%) this was possible without an increase in seizure frequency. In six patients (17%) the number of seizures was higher during single-drug therapy. The slow transfer was not complicated by unwanted withdrawal effects. The plasma concentration of the single drug was raised if necessary until clinical drug toxicity was observed. An improvement in seizure control was surprisingly noted in 13 patients (36%). In two patients seizures were completely controlled. In one patient a seizure reduction of 87% was observed. The number of patients with clinical side effects was similar during two-drug and single-drug therapy. The number of side effects was lower during single-drug therapy. Reduction of polypharmacy may be beneficial for patients with intractable epilepsy.     

A randomised double-blind placebo-controlled crossover add-on trial of lamotrigine in patients with treatment-resistant partial seizures

Efficacy and safety of lamotrigine (LTG) as add-on therapy was assessed in a randomised double-blind placebo-controlled trial of this drug in 23 adult patients with refractory partial seizures. Fifteen patients showed an improvement on LTG treatment, with a greater than 50% decrease in total seizure count in 7 patients. Fourteen patients experienced fewer simple and complex partial seizures, with 8 patients benefitting by more than a 50% decrease in seizure frequency. The drug was well tolerated over the 2 month treatment period. The plasma concentration of concomitant antiepileptic drugs remained unchanged. No haematological or chemical abnormalities were noted.     

Gabapentin and lamotrigine in Indian patients of partial epilepsy refractory to carbamazepine

52 patients (25 males and 27 females) suffering from refrectory partial seizures, of not more than two years duration and on carbamazepine monotherapy were enrolled in this study. Patients were randomly put on gabapentin (19 males and 8 females) or lamotrigine (6 males and 19 females) as add on therapy. The efficacy of the drugs was assessed by the seizure frequency, pattern of seizures and seizure free interval. The safety was evaluated from the biochemical investigations and the adverse effects observed or reported by the patients during the course of the study. The average frequency of basal partial seizures was 6.26+3.86 and 5.04+2.47 which decreased significantly (p<. 001) after 12 weeks of add on therapy to 1.75+2.16. and 1.68+2.94 in the GBP and LTG group respectively. However, there was no significant difference between the two drugs after 12 weeks of add on therapy. The PCB (primary change in basal seizure frequency) values decreased to -72+34.92 and -76.22+29.68 in the GBP and LTG group respectively. The difference in these two groups was not significant. The responder rate was 77.7% and 92% respectively in GBP and LTG group respectively. GBP was found to be more effective in partial seizures with secondarily generalization while LTG was effective in all subtypes of partial seizures. The abnormal scalp EEG was recorded in 33.3% (9 of 27 patients) in GBP group and 40 %( 10 of 25 patients) in LTG group and it did not revert to normal in 33.3% and 40% of patients in either of groups (GBP/LTG). Minor side effects which were self limiting were noticed in 80% in groups I and 74% were groups II.     

Photosensitive complex partial seizures aggravated by phenytoin

A 10-year-old girl is described with pure photosensitive complex partial seizures which consisted of a frightening visual phenomenon of seeing “shadow people“, then staring blankly with lip smacking and sometimes becoming limp. The seizures were triggered by bright sunlight. With the institution of phenytoin therapy, her seizure frequency increased dramatically without any clinical evidence of toxicity and her phenytoin blood levels were within the therapeutic range. Discontinuation of phenytoin led to a return to baseline seizure frequency. The mechanism by which antiepileptic drugs may aggravate seizures is still not understood; therefore, awareness of this phenomenon is crucial for early diagnosis and appropriate treatment.     

Aggravation of partial seizures by antiepileptic drugs: is there evidence from clinical trials?

OBJECTIVES: To assess clinical trials for evidence that antiepileptic drugs (AED) aggravate partial seizures. To determine if the methodology used to examine drug efficacy can also be used to examine seizure aggravation. BACKGROUND: It is widely accepted that AED aggravate epilepsy in some patients. However, there is little published objective or quantitative evidence. Most reports concern generalized epilepsies. METHODS: Pharmaceutical companies responsible for the development of five of the new AED were asked to provide data concerning seizure increases during randomized placebo-controlled, add-on clinical trials in patients with uncontrolled partial seizures. Seizure frequency in individual patients taking drug or placebo was compared with the baseline pretreatment seizure frequency. The counterpart of the 50% reduction used in efficacy analyses is a 100% increase, because both represent a twofold change. A dose-response relationship was also explored. RESULTS: More than 40% of subjects in clinical trials of tiagabine (TGB), topiramate (TPM), and levetiracetam (LEV) experienced an increase in seizures while taking a placebo. Seizure increases were no more likely to occur when taking any of the three drugs than taking placebo. A doubling or more of seizure frequency was less likely to occur with TPM or LEV than with placebo but more likely with TGB. However, for TGB, this did not reach significance. There was some evidence for a dose-response effect with TGB but a negative effect with TPM (aggravation less likely with increasing dose). Data on gabapentin and lamotrigine were not provided. CONCLUSIONS: Many patients with partial seizures experience an increase in seizures when a new AED is added to their therapy. However, it occurs no more frequently when taking drug than placebo. It probably represents the spontaneous fluctuation of seizure frequency. When a patient who has started a new AED deteriorates, this is not necessarily a drug effect.     

Phenytoin withdrawal and seizure frequency

We withdrew phenytoin from 17 inpatients maintained on combination therapy with carbamazepine for complex partial seizures and analyzed seizure occurrence in relation to plasma levels and time from initiation of withdrawal. The ratio of maximum to mean weekly seizure frequency did not vary with initial level or rate of withdrawal. The week with most frequent seizures began a median of 10 days after phenytoin levels became undetectable, and mean daily seizure frequency was higher at undetectable than at falling levels for the entire 2- to 10-week study period. Four patients had a total of 6 clusters of generalized tonic-clonic seizures; only 2 occurred while levels were falling and the other 4 at 3, 9, 28, and 42 days after reaching undetectable levels. Our data argue against the occurrence of withdrawal seizures in these patients and suggest that worsening of seizures following phenytoin discontinuation more likely reflects loss of therapeutic drug effect than a true abstinence phenomenon.     

Efficacy of gabapentin as adjunctive therapy in a large, multicenter study. The Steps Study Group.

The objective of this study was to determine the efficacy of gabapentin as adjunctive therapy in doses required to achieve the most effective seizure control. There were 2016 patients with partial seizures requiring adjunctive therapy who received gabapentin at doses up to 3600 mg/day in this open-label, multicenter, 16-week study. Of the 1055 patients evaluable for efficacy, 573 received gabapentin < or =1800 mg/day and 482 received > 1800 mg/day as the highest dose received. For the overall efficacy evaluable population, the percentage of patients achieving at least a 50% reduction in seizure frequency was 76.0%; 46.4% of the patients were seizure free. Patients whose highest gabapentin dose did not require > 1800 mg/day had, at baseline, fewer seizures and were receiving fewer concomitant antiepileptic drugs (AEDs) at baseline than those patients requiring > 1800 mg/day. This suggests that patients requiring higher doses of gabapentin were more refractory to drug treatment at the start of the study. Gabapentin was well tolerated at all doses in this study. The results of the study demonstrate that gabapentin is effective as adjunctive therapy in patients with partial seizures whose seizures are inadequately controlled by traditional AEDs.     

Variation of seizure frequency with ovulatory status of menstrual cycles

Purpose: To determine if seizure frequency differs between anovulatory and ovulatory cycles. Methods: The data came from the 3‐month baseline phase of an investigation of progesterone therapy for intractable focal onset seizures. Of 462 women who enrolled, 281 completed the 3‐month baseline phase and 92 had both anovulatory and ovulatory cycles during the baseline phase. Midluteal progesterone levels ≥5 ng/ml were used to designate cycles as ovulatory. Among the 92 women, average daily seizure frequency (ADSF) for all seizures combined and each type of seizure considered separately (secondary generalized tonic–clonic seizures – 2°GTCS, complex partial seizures – CPS, simple partial seizures – SPS) were compared between anovulatory and ovulatory cycles using paired t‐tests. A relationship between the proportional differences in ADSF and estradiol/progesterone (EP) serum level ratios between anovulatory and ovulatory cycles was determined using bivariate correlational analysis. Key Findings: ADSF was 29.5% greater for 2°GTCS during anovulatory than during ovulatory cycles. ADSF did not differ significantly for CPS or SPS or for all seizures combined. Proportional differences in anovulatory/ovulatory 2°GTCS ADSF ratios correlated significantly with differences in anovulatory/ovulatory EP ratios. Among the 281 women, the three seizure types did not differ in ovulatory rates, but EP ratios were greater for cycles with 2°GTCS than partial seizures only. Significance: Seizure frequency is significantly greater for 2°GTCS, but not CPS or SPS, during anovulatory cycles than ovulatory cycles. Because the proportional increases in 2°GTCS frequency during anovulatory cycles correlate with the proportional increases in EP level ratios, these findings support a possible role for reproductive steroids in 2°GTCS occurrence.