Long-term seizure outcomes after pediatric temporal lobectomy: does brain MRI lesion matter?

OBJECTIVE: There is emerging data that adults with temporal lobe epilepsy (TLE) without a discrete lesion on brain MRI have surgical outcomes comparable to those with hippocampal sclerosis (HS). However, pediatric TLE is different from its adult counterpart. In this study, the authors investigated if the presence of a potentially epileptogenic lesion on presurgical brain MRI influences the long-term seizure outcomes after pediatric temporal lobectomy. METHODS: Children who underwent temporal lobectomy between 2007 and 2015 and had at least 1 year of seizure outcomes data were identified. These were classified into lesional and MRI-negative groups based on whether an epilepsy-protocol brain MRI showed a lesion sufficiently specific to guide surgical decisions. These patients were also categorized into pure TLE and temporal plus epilepsies based on the neurophysiological localization of the seizure-onset zone. Seizure outcomes at each follow-up visit were incorporated into a repeated-measures generalized linear mixed model (GLMM) with MRI status as a grouping variable. Clinical variables were incorporated into GLMM as covariates. RESULTS: One hundred nine patients (44 females) were included, aged 5 to 21 years, and were classified as lesional (73%), MRI negative (27%), pure TLE (56%), and temporal plus (44%). After a mean follow-up of 3.2 years (range 1.2-8.8 years), 66% of the patients were seizure free for ≥ 1 year at last follow-up. GLMM analysis revealed that lesional patients were more likely to be seizure free over the long term compared to MRI-negative patients for the overall cohort (OR 2.58, p < 0.0001) and for temporal plus epilepsies (OR 1.85, p = 0.0052). The effect of MRI lesion was not significant for pure TLE (OR 2.64, p = 0.0635). Concordance of ictal electroencephalography (OR 3.46, p < 0.0001), magnetoencephalography (OR 4.26, p < 0.0001), and later age of seizure onset (OR 1.05, p = 0.0091) were associated with a higher likelihood of seizure freedom. The most common histological findings included cortical dysplasia types 1B and 2A, HS (40% with dual pathology), and tuberous sclerosis. CONCLUSIONS: A lesion on presurgical brain MRI is an important determinant of long-term seizure freedom after pediatric temporal lobectomy. Pediatric TLE is heterogeneous regarding etiologies and organization of seizure-onset zones with many patients qualifying for temporal plus nosology. The presence of an MRI lesion determined seizure outcomes in patients with temporal plus epilepsies. However, pure TLE had comparable surgical seizure outcomes for lesional and MRI-negative groups.

Vagus Nerve Stimulation for Electrographic Status Epilepticus in Slow-Wave Sleep.

BACKGROUND: Electrographic status epilepticus in slow sleep or continuous spike and waves during slow-wave sleep is an epileptic encephalopathy characterized by seizures, neurocognitive regression, and significant activation of epileptiform discharges during nonrapid eye movement sleep. There is no consensus on the diagnostic criteria and evidence-based optimal treatment algorithm for children with electrographic status epilepticus in slow sleep. PATIENT DESCRIPTION: We describe a 12-year-old girl with drug-resistant electrographic status epilepticus in slow wave sleep that was successfully treated with vagus nerve stimulation. Her clinical presentation, presurgical evaluation, decision-making, and course after vagus nerve stimulator implantation are described in detail. FINDINGS: After vagus nerve stimulator implantation, the girl remained seizure free for more than a year, resolved the electrographic status epilepticus in slow sleep pattern on electroencephalography, and exhibited significant cognitive improvement. CONCLUSION: Vagus nerve stimulation may be considered for electrographic status epilepticus in slow sleep.

A Site-Specific, Sustained-Release Drug Delivery System for Aneurysmal Subarachnoid Hemorrhage.

Nimodipine is the only drug approved for use by the Food and Drug Administration for improving outcome after aneurysmal subarachnoid hemorrhage (SAH). It has less than optimal efficacy, causes dose-limiting hypotension in a substantial proportion of patients, and is administered enterally 6 times daily. We describe development of site-specific, sustained-release nimodipine microparticles that can be delivered once directly into the subarachnoid space or cerebral ventricles for potential improvement in outcome of patients with aneurysmal SAH. Eight injectable microparticle formulations of nimodipine in poly(DL-lactide-co-glycolide) (PLGA) polymers of varying composition were tested in vitro, and 1 was advanced into preclinical studies and clinical application. Intracisternal or intraventricular injection of nimodipine-PLGA microparticles in rats and beagles demonstrated dose-dependent, sustained concentrations of nimodipine in plasma and cerebrospinal fluid for up to 29 days with minimal toxicity in the brain or systemic tissues at doses <2 mg in rats and 51 mg in beagles, which would be equivalent of up to 612-1200 mg in humans, based on scaling relative to cerebrospinal fluid volumes. Efficacy was tested in the double-hemorrhage dog model of SAH. Nimodipine-PLGA microparticles significantly attenuated angiographic vasospasm. This therapeutic approach shows promise for improving outcome after SAH and may have broader applicability for similar diseases that are confined to body cavities or spaces, are self-limited, and lack effective treatments.

Corpus callosotomy for childhood-onset drug-resistant epilepsy unresponsive to vagus nerve stimulation.

PURPOSE: Corpus callosotomy and vagus nerve stimulation are common palliative options for people with drug-resistant epilepsy when resective epilepsy surgery is not feasible. Because most of the published corpus callosotomy experience comes from a period before vagus nerve stimulation was approved and widely used, there is a paucity of data about efficacy of corpus callosotomy in patients with inadequate response to vagus nerve stimulation. METHODS: We report seven patients who had complete corpus callosotomy after an inadequate response to vagus nerve stimulation. At the time of surgery, these patients had failed a median of six antiseizure medications, three patients also had failed a trial of ketogenic diet, and all the patients had a vagus nerve stimulation implanted for a mean duration of 2.5 years with maximal tolerated settings. RESULTS: There was a decrease in total daily seizure frequency of 34.7% (± 94.7; median, 71.4%; interquartile range, 55.3) after corpus callosotomy at a mean follow-up of 2.6 years (± 1.4). One patient achieved complete seizure freedom and five patients had ≥ 50% reduction in seizure frequency. Six patients continued to have partial-onset seizures though the frequency was decreased. Drop attacks and tonic seizures stopped in all the patients. CONCLUSION: Seizure outcomes after corpus callosotomy in our series are most likely a result of complex dynamic interaction between the natural history of epilepsy, the effect of the surgery, ongoing vagus nerve stimulation modulation, and modification in antiseizure drugs. Our study supports the clinical decision to try corpus callosotomy in patients having nonlateralizing drug-resistant epilepsy with inadequate response to vagus nerve stimulation.

Increased levetiracetam clearance associated with a breakthrough seizure in a pregnant patient receiving once/day extended-release levetiracetam.

The use of levetiracetam for the treatment of epilepsy in women of childbearing age has increased as more evidence of teratogenicity of other broad-spectrum antiepileptic medications becomes available. Levetiracetam appears to be associated with a low incidence of major congenital malformations based on data from pregnancy registries. Major pregnancy-related changes in the pharmacokinetics of levetiracetam have been described in several case series, demonstrating a role for careful therapeutic drug monitoring of levetiracetam in pregnant patients. Extended-release levetiracetam provides a way to improve medication adherence in adults with epilepsy by allowing once/day dosing and may be considered for use in pregnancy to minimize the fluctuation of levetiracetam levels throughout the day, thus potentially minimizing dose-related adverse effects. In this case report, we describe a 16-year-old, compliant, pregnant patient who experienced subtherapeutic levetiracetam blood concentrations that occurred with use of extended-release levetiracetam. She experienced a breakthrough seizure with once/day dosing during her third trimester with low subsequent trough levels despite multiple dose increases. After changing to twice/day dosing of extended-release levetiracetam at delivery, the patient experienced no seizures and delivered a healthy infant without complications. This is the first case report, to our knowledge, to describe seizure breakthrough during pregnancy with an extended-release formulation of an antiepileptic medication. Pharmacokinetic changes associated with pregnancy may increase apparent clearance of extended-release formulations of levetiracetam, leading to periods of subtherapeutic blood or central nervous system concentrations. These changes support the important role of therapeutic monitoring of levetiracetam plasma concentrations to help maintain seizure control in women with epilepsy during pregnancy.

Acute postoperative seizures and long-term outcome following pediatric epilepsy surgery.

PURPOSE: Acute post-operative seizures (APOS) after epilepsy surgery, previously believed to be benign, are increasingly associated with poor long-term prognosis. Prior literature has focused primarily on adult temporal lobe epilepsy. This retrospective study aimed to identify the prevalence, prognostic significance and risk factors for APOS in pediatric epilepsy surgery at a single center. METHOD: Retrospective chart review of all children aged 0-21 years undergoing resective surgery for epilepsy between 2009 and 2012 at a single center. APOS were defined as seizures within 30 days of resection. Surgical outcome was determined, using a minimum of 12 months postoperative follow-up for inclusion. RESULTS: APOS, defined as a seizure within 30 days of resection, were identified in 50/112 (44%) of patients. APOS were a significant predictor of poor postoperative seizure outcome (ILAE 4-6); only 26% of those with APOS had a good outcome (ILAE 1-3), compared to 76% without APOS. Timing of postoperative seizure was not correlated with outcome. Most (54%) with APOS and good outcome had continued seizures between 14-30 days postoperatively. Patients with APOS after temporal (p=0.05) and extratemporal (p<0.001) resections had a significantly worse prognosis. APOS after hemispherectomy were not associated with a worse prognosis (p=0.22). Key risk factors for APOS include lack of ictal EEG lateralization to operated hemisphere/side of MRI abnormality. CONCLUSION: This study shows an association between APOS and poor outcome in both temporal and extratemporal pediatric epilepsy surgery. Findings support the expansion of APOS duration to 30 days.

Antiretroviral drug content in products from developing countries.

Generic and brand name antiretroviral drugs are becoming increasingly available in developing countries. We analyzed 6 antiretroviral medications from 4 international sources for drug content. The active ingredient in tested drug products was within 15% of the labeled amount (range, -12% to +15%) for drugs that were properly stored.

Detection of nevirapine in plasma using thin-layer chromatography.

BACKGROUND: Nevirapine (NVP) is widely prescribed in resource-poor settings to pregnant women for treatment and prevention of HIV infection. High rates of misreported adherence, however, have compelled clinicians to find alternative methods to ensure systemic drug exposure. This report describes a fast, inexpensive thin-layer chromatography (TLC) method to detect the presence of NVP in human plasma. METHODS: Human plasma was spiked with various concentrations of NVP. NVP was subsequently isolated using solid-phase extraction and visualized with TLC. Clinical samples with NVP concentrations predetermined by high-performance liquid chromatography were used to validate the TLC method. RESULTS: NVP was detected at concentrations as low as 60 ng/mL. The lower limit of detection was set at 100 ng/mL due to the clear spot definition at this concentration. The turnaround time for assay results averages several hours, and costs associated with the assay are considerably below standard drug quantitation techniques. CONCLUSION: TLC provides a rapid, sensitive, and economical tool to qualitatively measure NVP in plasma. This method offers clinicians in resource-poor settings an alternative approach for measuring adherence, particularly in developing-world regions where NVP use is common and there is an immediate need to prevent mother-to-child HIV transmission.

Simultaneous determination of nine antiretroviral compounds in human plasma using liquid chromatography.

A rapid, sensitive and specific high-performance liquid chromatographic (HPLC) method using UV detection was developed for the determination of nine antiretroviral compounds commonly found in plasma from patients receiving antiretroviral therapy. Analytes include indinavir, saquinavir, ritonavir, amprenavir, lopinavir, delavirdine, efavirenz, nelfinavir and its M8 metabolite. Analytes were isolated from plasma using tert.-butyl methyl ether and separation achieved via reversed-phase liquid chromatography on a C(8) column with a gradient mobile phase. Detection at 210 nm provided adequate sensitivity. Limit of quantification is 50 ng/ml and all analytes demonstrated linearity across 50-10000 ng/ml from a single 200-microliter plasma sample. Recovery from plasma was consistently high (>80%). This novel HPLC methodology allows us to simultaneously determine plasma concentrations of nine antiretrovirals, including lopinavir, in HIV-infected patients on a single HPLC system.

Effect of Seville orange juice and grapefruit juice on indinavir pharmacokinetics.

Considerable interpatient variability in indinavir pharmacokinetics, possibly due in part to variable metabolism of the drug through intestinal cytochrome P450 (CYP) 3A4, may contribute to poor virologic response in certain individuals with HIV infection. The purpose of this study was to characterize the influence of intestinal CYP3A4 modulation with grapefruit juice and Seville orange juice on indinavir pharmacokinetics. In an open-label, three-period crossover study, 13 healthy volunteers received indinavir 800 mg every 8 hours for 1 day and a single 800 mg dose the next morning. The last two indinavir doses were taken with 8 ounces of Seville orange juice, single-strength grapefruit juice, or water (control). Plasma samples were collected at time 0 (predose) and at 0.5, 1, 2, 3, 4, and 5 hours after the last indinavir dose. Concentration-time data were analyzed using noncompartmental methods. Coadministration of Seville orange juice and indinavir resulted in a statistically significant increase in indinavir t(max) (1.87 [1.65-2.22] vs. 1.25 [1.03-1.60] h; p < 0.05) without altering other pharmacokinetic parameter values. Grapefruit juice administration did not result in any changes in indinavir pharmacokinetics. Modulation of intestinal CYP3A4 by grapefruit juice and Seville orange juice did not alter the systemic availability of indinavir. The contribution of presystemic metabolism to indinavir interpatient variability appears to be small.