Cognition and behavior in children with benign epilepsy with centrotemporal spikes (BECTS).

Characteristics of cognitive deficits in benign childhood epilepsy with centrotemporal spikes (BECTS) remain unclear. The authors screened 200 BECTS children presenting for a clinical trial, finding relative weaknesses in fine motor control, visual learning, and attention in the presence of overall normal intellect, with simple partial seizures associated with more difficulty. Parental concerns for psychosomatic and learning problems were noted. Monitoring select cognitive and behavioral features in BECTS appears appropriate.

Spinal cord schistosomiasis: a pediatric case mimicking intrinsic cord neoplasm.

We present the clinical, myelographic, MRI, and histologic data on a 7-year-old girl with confirmed Schistosoma mansoni infection of the spinal cord. MRI of the granulomatous spinal lesion revealed extensive enlargement of the cord in the T11-12 area, with some intramedullary swelling extending to T-5 through T-7. The clinical manifestations of spinal schistosomiasis can be diverse, and there should be a high index of suspicion for all patients from endemic areas.

A double-blind trial of gabapentin monotherapy for newly diagnosed partial seizures. International Gabapentin Monotherapy Study Group 945-77.

BACKGROUND: Gabapentin is widely approved as add-on therapy for epilepsy treatment for partial seizures with and without secondary generalization. To investigate the efficacy of gabapentin administered as monotherapy in patients with newly diagnosed partial epilepsy, a randomized double-blind trial was performed. METHODS: Eligible patients were randomized to receive one of three masked doses of gabapentin (300, 900, or 1,800 mg/day) or open-label carbamazepine (600 mg/day) and kept daily seizure diaries throughout the study. After titration, patients entered a 24-week evaluation phase. Patients were required to exit the study if they experienced an exit event, defined as a total of three simple or complex partial seizures, one generalized tonic-clonic (GTC) seizure, or status epilepticus. Patients could be withdrawn for lack of efficacy, adverse events, or noncompliance. Kaplan-Meier statistics were used to estimate the probability that patients would continue in the study without having an exit event. RESULTS: Time to exit event was longer for patients on 900 mg/day (n = 72) or 1,800 mg/day (n = 74) of gabapentin than for patients receiving 300 mg/day (n = 72; p = 0.0395 and 0.0175, respectively). The most clinically relevant measure of retention on treatment (exit event plus adverse event withdrawal rate) was similar for carbamazepine (n = 74) and 1,800 mg/day gabapentin (54% versus 57%) but was lower (better) for 900 mg/day gabapentin (44%). No unexpected new adverse events emerged with gabapentin monotherapy. CONCLUSIONS: Gabapentin at 900 or 1,800 mg/day is effective and safe as monotherapy for patients with newly diagnosed partial epilepsy.

Cognitive abilities and adjustment with gabapentin: results of a multisite study.

The cognitive and quality of life effects of gabapentin are not yet well explored. While preliminary work in the area has provided positive findings, a large double-blinded study has been needed to explore this area more thoroughly. From 24 sites in North America, 201 adults were studied who had uncontrolled complex partial seizures with or without secondary generalization. Attempts were made to convert each patient from one or two marketed antiepileptic drugs (AEDs) taken in baseline to gabapentin monotherapy (600, 1200, or 2400 mg/day). Tests of cognitive abilities and adjustment were administered at the end of the 8-week baseline period and at the end of the 26-week double-blind treatment period. Analyses of baseline to treatment period changes were conducted for each dose group in comparison with a reference group of placebo-treated patients from another study. In the area of cognitive functioning, no changes in any of the gabapentin groups were found in comparison with the reference group. In the area of adjustment and mood, however, improvement with gabapentin administration was noted on several variables pertaining to emotional and interpersonal adjustment. These results are consistent with findings from previous studies.

EEG abnormalities aid diagnosis of Rett syndrome.

Nine girls with Rett syndrome had 22 electroencephalographic studies performed over 5 years. Nineteen walking tracings demonstrated moderate background slowing. Focal epileptiform activity was observed in 13 studies, 10 of which had bilateral independent foci. Spikes were invariably maximal in central regions, diphasic or triphasic, and of very short duration. In 3 patients, epileptiform activity preceded clinical seizures by up to 2 years. Two children had spontaneous hyperpnea preceding apnea during wakefulness with further background slowing. Video monitoring of 2 children revealed that episodic behavioral changes were not seizures. Ten of 12 sleep recordings had abnormal background activity with absent or rudimentary spindles. Normal activity occurred only in girls younger than 2 1/2 years of age. Epileptiform activity was markedly increased during sleep in 8 tracings in which both wakefulness and sleep were obtained. It was characterized by bilaterally independent and bisynchronous spike-and-wave activity, maximal in parasagittal areas. One patient had bursts of high-voltage slow-wave activity followed by attenuation. No apneic episodes were recorded during sleep. In Rett syndrome, electroencephalographic abnormalities include background slowing, centrally located short-duration spikes, and increased epileptiform activity during sleep. This activity commonly preceded clinical seizures in patients studied at initial presentation.

Valproic acid and thrombocytopenia in children: a case-controlled retrospective study.

Thrombocytopenia in association with valproic acid (VPA) therapy has been reported in patients of various ages with incidences ranging from 1 to 32%. To evaluate this association in a pediatric population, we retrospectively studied 167 children treated with VPA at our institution between 1989 and 1993. Ninety-one patients on VPA monotherapy and 76 on VPA polytherapy (VPA plus 1 to 3 other antiepileptic drugs) were compared with 92 age- and sex-matched control patients treated with antiepileptic drugs other than VPA. Study variables included patient age, most recent platelet count, VPA dose, dose/kg, and serum VPA level. Thrombocytopenia, defined as a platelet count < 200 x 10(3)/mm3, was present in 21.6% of the children treated with VPA (26.4% in those on VPA monotherapy and 15.8% in those on VPA polytherapy) but in only 5.4% of controls untreated with VPA. Serum VPA level was the highest risk factor for the development of thrombocytopenia in these patients (P = .0001) and greater age also independently predicted thrombocytopenia. The dose of VPA or dose/kg were not independent predictors of thrombocytopenia (P = .0025). The degree of thrombocytopenia was mild among these patients, reflected in the absence of significant difference in mean platelet count between the three groups and the absence of any bleeding complication or excessive bruising. We conclude from these findings that the risk for children developing severe thrombocytopenia with bleeding complications while taking VPA is low and that mild thrombocytopenia does not necessarily mandate discontinuing the drug. Because higher serum VPA levels do predict thrombocytopenia, platelet counts should be closely monitored after dose escalation in such patients.

Safety and efficacy of two pregabalin regimens for add-on treatment of partial epilepsy.

OBJECTIVE: To evaluate the efficacy, tolerability, and safety of two pregabalin regimens administered as adjunctive therapy to that of placebo in patients with medically refractory partial epilepsy. METHODS: A multicenter, double-blind, randomized, parallel-group, placebo-controlled trial was performed. Following a prospective 8-week baseline phase, patients were randomized to 12 weeks of double-blind treatment with placebo or pregabalin 600 mg/day administered twice daily (BID) or three times daily (TID). Primary efficacy was measured as change in seizure frequency from baseline of either pregabalin regimen compared with placebo. Secondary efficacy comparisons included the proportion of patients experiencing > or =50% reduction in seizure frequency (responder rate) and median percentage change from baseline in seizure frequency. Safety/tolerability assessments included adverse events (AEs), physical and neurologic examinations, and clinical laboratory evaluation. Efficacy and safety analyses were performed on the intent-to-treat (ITT) population. RESULTS: Pregabalin treatment resulted in seizure frequency reductions: 53% for pregabalin TID (p < or = 0.0001) and 44% for pregabalin BID (p < or = 0.0001) compared with a 1% increase for placebo. Responder rates were 49% for pregabalin TID and 43% for pregabalin BID compared with 9% for placebo (p < or = 0.001). Both pregabalin regimens were similar in efficacy and tolerability. The most common AEs were dizziness, somnolence, and ataxia. CONCLUSIONS: Pregabalin administered at 600 mg/day is safe, generally well tolerated, and efficacious as adjunctive therapy for the treatment of patients with partial seizures, with or without secondary generalizations. This dose can be administered on a twice daily or three times daily schedule with similar efficacy and tolerability results.

Generalized spike-waves, multiple loci, and clinical course in children with EEG features of benign epilepsy of childhood with centrotemporal spikes.

In 41 patients with EEG features of benign epilepsy of childhood with centrotemporal spikes (BECCT), we noted associated generalized spike-wave discharges (GSWD) in 14.6% and multiple independent sharp wave foci in 9.8%. The presence or absence of these EEG features was not predictive of the clinical course. The high incidence of GSWD in children with BECCT suggests a possible relation in the expression of these two EEG traits.

Epileptiform abnormalities during sleep in Rett syndrome.

We recorded all-night electroencephalograms (EEGs)/polysomnograms on 2 consecutive nights from 4 children (ages 4-11 years) with Rett syndrome. The first 10 sec of each 60 sec epoch were analyzed with counts of left and right hemisphere spikes and correlated with sleep stage. Spike counts were lowest during wakefulness. Spikes were most frequent over parasagittal regions during all sleep stages and varied from 0.28 +/- 0.03 to 40.4 +/- 0.7 (mean +/- S.E.M.) spikes/hemisphere/min. Spike counts were 51-109% higher during NREM sleep than during REM sleep. In 3 of 4 subjects, spikes were most frequent during light NREM sleep. Spikes increased in frequency during the second half of the night. We conclude that in Rett syndrome, epileptiform activity is maximally expressed in stage 1-2 NREM sleep and during the early morning hours. Sleep EEG features may be useful in the diagnosis of Rett syndrome.

Increased seizures after discontinuing carbamazepine: results from the gabapentin monotherapy trial.

Studies in patients with epilepsy undergoing telemetry evaluation for surgery have suggested that discontinuation of carbamazepine (CBZ) is associated with increased seizures. The period of observation in that setting, however, was limited to a few days. The authors reviewed the occurrence of seizures in patients with epilepsy who had all their antiepileptic medications discontinued during an 8-week period, converted to gabapentin monotherapy, and observed for 26 weeks as part of the gabapentin trial #945-082. Two hundred and seventy-five patients were enrolled. Kaplan-Meier estimates of time to exit for all patients showed that 18% of patients previously treated with CBZ completed the study as compared with 30% of the patients receiving other antiepileptic medications. Increase in the frequency of seizures was maximal in the 2 weeks following CBZ discontinuation. Seizures increased both in frequency and severity but no new seizure types were observed. The findings in this study show that removal of CBZ is associated with increased frequency of seizures in patients with a previous history of epilepsy with incompletely controlled seizures. The period of maximal increase was the first 2 weeks after CBZ discontinuation.

Asymmetric hypsarrhythmia: clinical electroencephalographic and radiological findings.

Twenty-six children (16 boys and 10 girls) with hypsarrhythmia and infantile spasms (IS) were studied at the University of Michigan EEG Laboratory in a 4-year period. Six (2 boys, 4 girls), had asymmetric hypsarrhythmia with a preponderance of both slowing and epileptiform activity over one hemisphere. All 6 had the symptomatic form of IS, 4 with dysplastic conditions, 1 with porencephaly from a cerebral infarct, and 1 with hypoxicischemic encephalopathy. Five children had focal abnormalities on either physical examination or imaging studies. Four had the highest amplitude slowing and most epileptiform activity ipsilateral to the lesion, in 1, it was contralateral. Asymmetric hypsarrhythmia constituted 23% of cases with hypsarrhythmia examined at our EEG laboratory. The significant success in surgical therapy for some children with IS indicates the importance of identifying focal hemispheric abnormalities even if they are not apparent clinically. EEG may suggest focal changes not detected clinically or radiologically.

Carbamazepine-induced tics.

A variety of movement disorders are known to occur in association with carbamazepine (CBZ) therapy in adults and children, but development of tics has been described infrequently and only in patients with underlying Tourette's syndrome or other movement disorders. We report 3 children with epilepsy who developed facial motor tics after initiation of CBZ for complex partial seizures. All 3 had documented CBZ blood levels in the therapeutic range at the time, and none had other symptoms or signs of clinical intoxication. Neurologic examinations were normal in 2 and showed developmental delay of expressive language in the third. Brain imaging was normal in all. After development of the tics in 2, CBZ was continued at the same or higher dose, and the tics abated and then ceased spontaneously < or = 6 months. In the third child, the tics ceased after CBZ discontinuation. These cases demonstrate that CBZ can induce simple motor tics in children. These idiosyncratic reactions may be transient and do not always necessitate drug discontinuation.

Dose-response trial of pregabalin adjunctive therapy in patients with partial seizures.

BACKGROUND: Pregabalin is an alpha(2)-delta ligand that has anxiolytic, analgesic, and anticonvulsant properties. OBJECTIVE: To establish the efficacy, safety, and tolerability of pregabalin administered twice-daily (BID) without dose titration as adjunctive treatment in patients with partial seizures and to confirm the dose-response relationship. METHODS: This 76-center, double-blind, randomized, placebo-controlled, parallel-group study consisted of an 8-week baseline and a 12-week double-blind phase. Patients with refractory partial seizures on one to three antiepileptic drugs were randomly assigned to one of five treatment groups (placebo or 50, 150, 300, and 600 mg/d pregabalin, all administered BID). Efficacy was assessed using seizure frequency reduction and responder rate (> or =50% seizure reduction from baseline). Pharmacokinetic parameters were estimated. RESULTS: A total of 453 patients were included in the intent-to-treat analysis. The median baseline seizure rate was 10 per month. Seizure frequency reductions from baseline were 7% (placebo; n = 100), 12% (50 mg/d; n = 88), 34% (150 mg/d; n = 86), 44% (300 mg/d; n = 90), and 54% (600 mg/d; n = 89). Responder rates (> or =50% seizure reduction) were 14% (placebo), 15% (50 mg/d), 31% (150 mg/d), 40% (300 mg/d), and 51% (600 mg/d). Discontinuation rates due to adverse events were 5% (placebo), 7% (50 mg/d), 1% (150 mg/d), 14% (300 mg/d), and 24% (600 mg/d). The 150-, 300-, and 600-mg/d pregabalin groups were associated with greater reductions in seizures (p < or = 0.0001) and greater responder rates compared with the placebo group (p < or = 0.006). There was a favorable dose-response trend for both seizure reductions (p < or = 0.0001) and responder rate (p < or = 0.001). CONCLUSION: Adjunctive therapy with pregabalin 150, 300, and 600 mg/d, given in twice-daily doses without titration, is significantly effective and well tolerated in the treatment of patients with partial seizures as demonstrated in patients with refractory partial seizures.

Altered excitatory and inhibitory amino acid receptor binding in hippocampus of patients with temporal lobe epilepsy.

We examined binding to excitatory amino acid and inhibitory amino acid receptors in frozen hippocampal sections prepared from surgical specimens resected from 8 individuals with medically refractory temporal lobe epilepsy. The excitatory receptors studied included N-methyl-D-aspartate (NMDA), strychnine-insensitive glycine, phencyclidine, and quisqualate. The inhibitory receptors studied were gamma-aminobutyric acid type A (GABAA) and benzodiazepine. Excitatory and inhibitory amino acid receptor binding were differentially altered in the patients with temporal lobe epilepsy in comparison to 8 age-comparable autopsy control subjects, and changes in receptor binding were regionally selective in four areas. Binding to phencyclidine receptors associated with the NMDA channel was reduced by 35 to 70% in all regions in the hippocampi of the patients. In contrast, binding to the NMDA recognition site and its associated glycine modulatory site was elevated by 20 to 110% in the cornu ammonis (CA) 1 area and dentate gyrus of the hippocampus of the patients. Binding to these sites was unaffected in area CA4. Binding to the quisqualate-type excitatory amino acid receptor was unchanged in all regions except the stratum lacunosum moleculare CA1, where it was increased by 63%. GABAA and benzodiazepine receptor binding was reduced by 20 to 60% in CA1 and CA4, but unchanged in dentate gyrus. The data indicate that excitatory and inhibitory amino acid receptors are altered in the hippocampus of patients with temporal lobe epilepsy.

Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of pregabalin in the treatment of postherpetic neuralgia (PHN). METHODS: The authors conducted a multicenter, parallel-group, double-blind, placebo-controlled, 8-week, randomized clinical trial in PHN, defined as pain for 3 or more months following herpes zoster rash healing. Patients (n = 173) were randomized to treatment with pregabalin or placebo. Patients randomized to pregabalin received either 600 mg/day (creatinine clearance > 60 mL/min) or 300 mg/day (creatinine clearance 30 to 60 mL/min). The primary efficacy measure was the mean of the last seven daily pain ratings. Secondary endpoints included additional pain ratings, sleep interference, quality of life, mood, and patient and clinician ratings of global improvement. RESULTS: Pregabalin-treated patients had greater decreases in pain than patients treated with placebo (endpoint mean scores 3.60 vs 5.29, p = 0.0001). Pain was significantly reduced in the pregabalin-treated patients after the first full day of treatment and throughout the study, and significant improvement on the McGill Pain Questionnaire total, sensory, and affective pain scores was also found. The proportions of patients with >or=30% and >or=50% decreases in mean pain scores were greater in the pregabalin than in the placebo group (63% vs 25% and 50% vs 20%, p = 0.001). Sleep also improved in patients treated with pregabalin compared to placebo (p = 0.0001). Both patients and clinicians were more likely to report global improvement with pregabalin than placebo (p = 0.001). Given the maximal dosage studied, pregabalin had acceptable tolerability compared to placebo despite a greater incidence of side effects, which were generally mild to moderate in intensity. CONCLUSIONS: Treatment of PHN with pregabalin is safe, efficacious in relieving pain and sleep interference, and associated with greater global improvement than treatment with placebo.