Effect of vigabatrin on seizure control and safety profile in different subgroups of children with epilepsy.

OBJECTIVE: To evaluate the efficacy and safety of vigabatrin in pediatric epilepsy. METHODS: We retrospectively reviewed patients with epilepsy treated with vigabatrin over a 2-year period at a pediatric tertiary center. We assessed the relationship between seizure frequency, etiology, vigabatrin dose, adverse events, medication discontinuation reasons, and electroencephalography (EEG) characteristics. RESULTS: One hundred three patients followed at Boston Children's Hospital were treated with vigabatrin and had complete medical records. Within the follow-up interval, 69 (67%) of 103 patients had discontinued vigabatrin therapy. Two patients (1.9%) died during therapy for unknown reasons. Median age at vigabatrin initiation was 8 months (interquartile range [IQR] 5-15). Median starting dose was 48.1 mg/kg per day (IQR 29.8-52.3) with a median target of 100 mg/kg (IQR 81.9-107.9). Median treatment duration was 12.1 months (n = 89, IQR 5.0-22.9) overall, and 13.3 months (IQR 5.2-23.2) for patients who discontinued vigabatrin. The most common reasons for discontinuation were controlled seizures in 31 (43.7%) of 71 and unsatisfactory therapeutic effect in 23 (32.4%) of 71. Median percent seizure reduction from baseline to first follow-up was 83.3% (IQR 27.4-99.8) and 96.7% (IQR 43.3-100) to last follow-up. Twenty-four (38.7%) of 62 patients with a follow-up posttreatment remained seizure-free. Four patients who had initially achieved seizure freedom relapsed. Patients with structural/metabolic etiology had greater median percent seizure reduction at first follow-up than patients with genetic etiology (98.7% vs. 61.4%, respectively, p = 0.001). Hypsarrhythmia resolved after therapy in 18 of 20 (90%, 95% confidence interval [CI] 70-97) patients with pretreatment hypsarrhythmia, and 2 patients presented with hypsarrhythmia posttreatment. Risk of having hypsarrhythmia was reduced by 32% (95% CI 14.9-49.1) posttreatment. SIGNIFICANCE: Vigabatrin is efficacious in all seizure types and resolved hypsarrhythmia in most patients. In this series with a median treatment duration of 12.1 months, vigabatrin had a good safety profile with a low rate of discontinuation due to nonophthalmologic and ophthalmologic adverse effects.

Reduced thalamic volume in patients with Electrical Status Epilepticus in Sleep.

PURPOSE: To test whether patients with Electrical Status Epilepticus in Sleep (ESES) and normal neuroimaging have a smaller thalamic volume than expected for age and for total brain volume. METHODS: Case-control study comparing three groups of subjects of 4-14 years of age and normal magnetic resonance imaging: 1) ESES patients, 2) patients with refractory epilepsy control group, and 3) healthy controls. Thalamic and total brain volumes were calculated using an algorithm for automatic segmentation and parcellation of magnetic resonance imaging. RESULTS: Eighteen ESES patients, 29 refractory epilepsy controls and 51 healthy controls were included. The median (p25-p75) age was 8.8 (7.5-10.3) years for ESES patients, 11 (7-12) years for healthy controls, and 9 (6.3-11.2) years for refractory epilepsy controls. After correcting for total brain volume and age, the left thalamus was not statistically significantly smaller in ESES patients than in healthy controls (p=0.077), in ESES patients than in refractory epilepsy controls (p=0.056); but the right thalamus was smaller in ESES patients than in healthy controls (p=0.044), and in ESES patients than in refractory epilepsy controls (p=0.033). CONCLUSION: Patients with ESES and normal magnetic resonance imaging have smaller relative thalamic volume controlling for age and total brain volume.

Clobazam higher-evening differential dosing as an add-on therapy in refractory epilepsy.

PURPOSE: Clobazam treatment tailored to the timing of patient's seizures may improve seizure control. We aim to describe the safety and efficacy of higher-evening differential dose of clobazam as add-on therapy in patients with night-time/early morning seizures. METHOD: Differential dosing with higher evening dosing was started based on a high proportion of seizures (>80%) at nighttime (6p.m. to 6a.m.). Differential dosing was defined as providing more than 50% of the total daily dose of clobazam after 6p.m. RESULTS: Twenty-seven patients were treated with clobazam differential dosing as an add-on therapy. The median age was 9.1 years, with 11 (40.7%) females and median of the first follow-up was 2.7 months. Patients with differential dosing tolerated a higher median total clobazam dose of 0.8mg/kg/d at first follow-up, as compared to 0.6mg/kg/d in controls. In differential dose, the median percentage of the total clobazam dose administered in the evening was 66.7%. Differential dose patients exhibited a median seizure reduction of 75% as compared to 50% in controls (p<0.005). Patients with generalized seizures benefited the most from differential dosing with a 77.5% median seizure reduction, as compared to 50% in controls (p=0.017). CONCLUSION: Higher-evening differential dose of clobazam improved seizure control in patients with predominantly nighttime and early-morning seizures. Chronotherapy tailored to the patients' seizure susceptibility patterns may improve care in epilepsy patients as differential dosing may allow for higher overall treatment doses at times of greatest seizure susceptibility without increased side effects at other times.

Autonomic changes following generalized tonic clonic seizures: An analysis of adult and pediatric patients with epilepsy.

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is the most common cause of mortality directly related to epilepsy. Its incidence is higher in adult patients and its pathophysiology remains poorly understood, but likely involves autonomic dysregulation following generalized tonic clonic seizures (GTCS). In the current study, we aimed to analyze post-ictal autonomic changes following GTCS in adult and pediatric patients. METHODS: Patients admitted to the epilepsy monitoring unit were prospectively recruited, and wore an electrodermal activity (EDA) wrist sensor that continuously measured sympathetic activity while being monitored with EEG and EKG electrodes. Peri-ictal EDA parameters were assessed as a measure of sympathetic activity. Peri-ictal parasympathetic activity was determined through the high frequency component (HF) analysis of heart rate variability (HRV). The duration of post-ictal generalized EEG suppression (PGES) was also documented. RESULTS: Twenty patients with GTCS were included in the study on whom 30 GTCS were recorded. PGES duration strongly correlated with age (r=0.62, p=0.004) and measures of the EDA response. After controlling for PGES duration, we found pediatric patients had greater sympathetic activation measured as log rising portion of the area under the curve of the EDA response (ß=+0.67, p=0.034) and a higher degree of vagal suppression measured as maximal percentage change of HF power (ß=-12.65, p=0.0036). CONCLUSION: Sympathetic activity can be measured in the peri-ictal period, and directly correlates with PGES duration. Age is a significant determinant of the sympathetic and parasympathetic response following a GTCS; given the same PGES duration, pediatric patients demonstrate stronger sympathetic activation and higher vagal suppression. However, the increase in PGES duration with age and the associated autonomic dysregulation may provide clues as to why there is a variable vulnerability to SUDEP across age groups.

Seizure detection, seizure prediction, and closed-loop warning systems in epilepsy.

Nearly one-third of patients with epilepsy continue to have seizures despite optimal medication management. Systems employed to detect seizures may have the potential to improve outcomes in these patients by allowing more tailored therapies and might, additionally, have a role in accident and SUDEP prevention. Automated seizure detection and prediction require algorithms which employ feature computation and subsequent classification. Over the last few decades, methods have been developed to detect seizures utilizing scalp and intracranial EEG, electrocardiography, accelerometry and motion sensors, electrodermal activity, and audio/video captures. To date, it is unclear which combination of detection technologies yields the best results, and approaches may ultimately need to be individualized. This review presents an overview of seizure detection and related prediction methods and discusses their potential uses in closed-loop warning systems in epilepsy.

Comparison of risk factors for pediatric convulsive status epilepticus when defined as seizures ≥ 5 min versus seizures ≥ 30 min.

PURPOSE: To identify risk factors (RF) of pediatric convulsive status epilepticus (SE) and to determine whether defining SE as seizures ≥ 5 min (SE5) or seizures ≥ 30 min (SE30) would modify the risk factors identified. METHODS: Retrospective case-control study. We included patients 1 month to 21 years of age at the time of convulsive SE. We compared the characteristics of patients with SE (cases) versus those without SE (controls) using two different seizure duration thresholds: 5 min and 30 min. RESULTS: 1062 patients (54% males) were enrolled. The median (p25-p75) age at the episode was 6.4 (2.8-11.8) years. 444 (41.8%) patients had SE5 and 149 (14%) patients had SE30. On univariate analysis, risk factors for SE were not markedly different when considering a 5 or 30 min threshold. Compared to their respective controls patients with both SE5 and SE30 were younger at the age of seizure onset and at the age of SE, were on more antiepileptic drugs (AEDs) at baseline, had a higher rate of changes in AEDs in the three months prior to the episode, were more likely to have developmental delay at baseline, and a higher mortality rate. A higher baseline seizure frequency, and a higher increase in seizure frequency prior to the index episode were seen only in SE5. CONCLUSION: This series identifies RF which predict convulsive SE in pediatric patients. These RF are similar when considering a 5 min or a 30 min threshold for the definition of SE.

Treatment for continuous spikes and waves during sleep (CSWS): survey on treatment choices in North America.

OBJECTIVE: Current literature does not allow an evidence-based approach to the treatment of continuous spikes and waves during sleep (CSWS). The aim of this study was to describe treatment choices made by clinicians caring for patients with CSWS in North America. METHODS: A 24-question survey on treatment choices for CSWS was distributed to the members of the American Epilepsy Society (AES). The survey presented a clinical vignette of CSWS. The questions addressed treatment choices for that clinical scenario. Surveys were self-administered and collected using an online survey website (www.surveymonkey.com). RESULTS: Two-hundred thirty-two surveys were completed. Prominent sleep-potentiated spiking was considered to warrant treatment by 81% of respondents. The proportion of patients in whom cognitive improvement occurs when sleep-potentiated spiking is effectively treated is in >75% of patients (according to 16% of respondents), in 25-75% of patients (according to 52% of respondents), in <25% of patients (according to 20% of respondents), and no or unclear cognitive changes (according to 12% of respondents). The preferred first choice to reduce sleep-potentiated epileptiform activity was high-dose benzodiazepines (47%), valproate (26%), and corticosteroids (15%). The preferred second-choice was valproate (26%), high-dose benzodiazepines (24%), and corticosteroids (23%). Among high-dose benzodiazepines, the preferred one was diazepam 1 mg/kg for one night followed by 0.5 mg/kg/day. The preferred dose of valproate was 30-49 mg/kg/day. Among corticosteroids the preferred choice was oral prednisone 2 mg/kg/day. The most commonly considered endpoints of treatment efficacy were (in decreasing order): response of epileptiform activity in electroencephalography (EEG), cognitive function, and seizure reduction. Results were consistent among respondents with different levels of training and clinical experience. There were differences in conceptualization and treatment approaches between pediatric and adult neurologists. SIGNIFICANCE: Most clinicians considered that prominent sleep-potentiated epileptiform activity should be treated. There was no agreement on best treatment, but potential candidates included high-dose benzodiazepines, valproate, levetiracetam, and corticosteroids.

Clobazam: effect on frequency of seizures and safety profile in different subgroups of children with epilepsy.

BACKGROUND: Clobazam has been used in clinical practice as an adjunctive treatment for diverse seizure types and epilepsy syndromes. We evaluated the efficacy and safety of clobazam in a large sample of patients with refractory epilepsy at a tertiary pediatric center. METHODS: We retrospectively reviewed patients treated with clobazam between January 2001 and July 2013 who had a follow-up visit at least one month after starting clobazam. Response was defined as ≥50% reduction in seizure frequency compared with baseline seizure frequency during the 3 months before the introduction of clobazam. We examined the relationship between dose range and response rate. RESULTS: Four-hundred twenty-five patients were prescribed clobazam, of whom 300 (median age 9.1 years, interquartile range 4.7-13.3 years) had follow-up data greater than 1 month. Median follow-up was 5 months (interquartile range 3-11 months). Response to treatment with clobazam was observed in 203 of 300 (67.7%) patients, of whom 84 (28%) became seizure-free. The median starting dose was 0.2 (interquartile range 0.13-0.33) mg/kg/day with a target dose of 0.48 (0.26-0.80) mg/kg/day. Twenty-seven (9%) patients discontinued clobazam, 16 (59.3%) because adverse effects, 10 (37%) because of a lack of efficacy, and one (3.7%) because of a combination of adverse effects and lack of efficacy. The most common adverse effects were tiredness in 44 of 300 (14.6%) and mood or behavioral changes in 23 (7.7%). CONCLUSIONS: Clobazam is a well-tolerated antiepileptic drug with good response rates in pediatric patients with refractory epilepsy.

Chronic sazetidine-A maintains anxiolytic effects and slower weight gain following chronic nicotine without maintaining increased density of nicotinic receptors in rodent brain.

Chronic nicotine administration increases the density of brain α4ß2* nicotinic acetylcholine receptors (nAChRs), which may contribute to nicotine addiction by exacerbating withdrawal symptoms associated with smoking cessation. Varenicline, a smoking cessation drug, also increases these receptors in rodent brain. The maintenance of this increase by varenicline as well as nicotine replacement may contribute to the high rate of relapse during the first year after smoking cessation. Recently, we found that sazetidine-A (saz-A), a potent partial agonist that desensitizes α4ß2* nAChRs, does not increase the density of these receptors in brain at doses that decrease nicotine self-administration, increase attention in rats, and produce anxiolytic effects in mice. Here, we investigated whether chronic saz-A and varenicline maintain the density of nAChRs after their up-regulation by nicotine. In addition, we examined the effects of these drugs on a measure of anxiety in mice and weight gain in rats. After increasing nAChRs in the rodent brain with chronic nicotine, replacing nicotine with chronic varenicline maintained the increased nAChR binding, as well as the α4ß2 subunit proteins measured by western blots. In contrast, replacing nicotine treatments with chronic saz-A resulted in the return of the density of nAChRs to the levels seen in saline controls. Nicotine, saz-A and varenicline each demonstrated anxiolytic effects in mice, but only saz-A and nicotine attenuated the gain of weight over a 6-week period in rats. These findings suggest that apart from its modest anxiolytic and weight control effects, saz-A, or drugs like it, may be useful in achieving long-term abstinence from smoking.

Expression of FMS-like tyrosine kinase 3 ligand by oncolytic herpes simplex virus type I prolongs survival in mice bearing established syngeneic intracranial malignant glioma.

BACKGROUND: Glioblastoma is a fatal brain tumor in needing urgent effective therapy. Treatments with both oncolytic viruses and immunotherapy have shown preclinical efficacy and clinical promise. We sought to exploit possible synergies between oncolytic herpes simplex virus type 1 (oHSV-1) infection of intracranial gliomas and delivery of immune-stimulating fms-like tyrosine kinase 3 ligand (Flt3L) by engineering a herpes vector to express the cytokine. OBJECTIVE: To construct an oHSV-1 vector that expresses high levels of Flt3L and examine its antiglioma efficacy in an immunocompetent murine model. METHODS: G47Δ and a bacterial artificial chromosome system were used to generate a novel oHSV-1, termed G47Δ-Flt3L, expressing Flt3L. Cytokine expression was confirmed, and G47Δ-Flt3L was injected intratumorally into established intracranial CT-2A gliomas in syngeneic C57/Bl6 mice. Animals were followed for survival and assessed by the Kaplan-Meier method. RESULTS: G47Δ-Flt3L expressed high levels of Flt3L in culture. Expression of Flt3L affected neither viral replication nor had a cytotoxic effect on CT2A glioma cells. Direct inoculation into intracerebral CT2A glioma cells resulted in high levels of detectable Flt3L in mouse blood and was superior to parental G47Δ in prolonging survival in glioma-bearing animals. CONCLUSION: Treatment with G47Δ-Flt3L improves survival of glioma-bearing mice.