Number of epilepsy surgeries has decreased despite an increase in pre-surgical evaluations at a tertiary pediatric epilepsy center in Ontario.

OBJECTIVE: A recent U.S. study reported that the number of epilepsy surgeries has remained stable or declined in recent years despite an increase in pre-surgical evaluation. This study aimed to evaluate trends in pre-surgical evaluation and epilepsy surgery from 2001 to 2019 and to determine whether these trends have changed in the later period (2014-2019) compared to earlier period (2001-2013). METHODS: This study evaluated trends in pre-surgical evaluation and epilepsy surgery at a tertiary pediatric epilepsy center. Children with drug resistant epilepsy who were evaluated for surgery were included. Clinical data, reasons for not undergoing surgery, and surgical characteristics of surgery patients were collected. Overall trends and trends in later period compared to earlier period for pre-surgical evaluation and epilepsy surgery were assessed. RESULTS: There were 1151 children who were evaluated for epilepsy surgery and 546 underwent surgery. There was an upward trend in pre-surgical evaluation in the earlier period (rate ratio [RR]=1.04 (95%CI:1.02-1.07), p<0.001) and the trajectory of presurgical evaluation in the later period was not significantly different to the earlier period (RR=1.00 [95%CI:0.95-1.06], p = 0.88). Among the reasons for not undergoing surgery, failure to localize the seizures occurred more frequently in later period than earlier period (22.6% vs. 17.1% respectively, p = 0.024). For number of surgeries, there was an upward trend between 2001 and 2013 (RR=1.08 [95%CI:1.05-1.11], p<0.001), and a decreasing trend in the later period compared to earlier period (RR=0.91 [95%CI:0.84-0.99], p = 0.029). CONCLUSION: Despite an increasing trend in pre-surgical evaluation, there was a decreasing trend in the number of epilepsy surgery in the later period as there was a larger proportion of patients in whom the seizures could not be localized. Trends in presurgical evaluation and epilepsy surgery will continue to evolve with introduction of technologies such as stereo-EEG and minimally invasive laser therapy.

Treatment with High-Dose Prednisolone in Vigabatrin-Refractory Infantile Spasms.

OBJECTIVES: This research aimed to study the short-term seizure outcomes following treatment with 8 mg/kg/day prednisolone in children with infantile spasms (IS) refractory to vigabatrin. We hypothesized that high-dose prednisolone may result in similar rates of electroclinical remission when compared to published ACTH rates. METHODS: All consecutive children with hypsarrhythmia or hypsarrhythmia variant on EEG with/without IS, who had been treated with vigabatrin as first-line anti-seizure medication (ASM) followed by high-dose oral prednisolone (8 mg/kg/day; maximum 60 mg/day) in cases who did not respond to vigabatrin, were included. Clinical and electroclinical response (ECR) at 2 weeks following initiation of treatment and adverse effects were assessed. RESULTS: Sixty-five children were included. A genetic etiology was seen in 38.5% cases. Complete ECR was seen in 30.8% (20/65) of the patients 2 weeks after vigabatrin. Complete ECR was noted in 77.8% (35/45) of the patients, 2 weeks after prednisolone initiation in children who failed vigabatrin, and this was sustained at 6 weeks in 66.7% (30/45) patients. Prednisolone was generally well tolerated. CONCLUSIONS: High-dose (8 mg/kg/day) oral prednisolone resulted in sustained complete ECR (at 6 weeks) in two-thirds of the children with hypsarrhythmia or hypsarrhythmia variant on EEG with/without parentally reported IS. It was generally well tolerated and found to be safe.

Early economic evaluation of MRI-guided laser interstitial thermal therapy (MRgLITT) and epilepsy surgery for mesial temporal lobe epilepsy.

BACKGROUND: MRI-guided laser interstitial thermal therapy (MRgLITT) is a new minimally invasive treatment for temporal lobe epilepsy (TLE), with limited effectiveness data. It is unknown if the cost savings associated with shorter hospitalization could offset the high equipment cost of MRgLITT. We examined the cost-utility of MRgLITT versus surgery for TLE from healthcare payer perspective, and the value of additional research to inform policy decision on MRgLITT. METHODS: We developed a microsimulation model to evaluate quality adjusted life years (QALYs), costs, and incremental cost-effectiveness ratio (ICER) of MRgLITT versus surgery in TLE, assuming life-time horizon and 1.5% discount rate. Model inputs were derived from the literature. We conducted threshold and sensitivity analyses to examine parameter uncertainties, and expected value of partial perfect information analyses to evaluate the expected monetary benefit of eliminating uncertainty on probabilities associated with MRgLITT. RESULTS: MRgLITT yielded 0.08 more QALYs and cost $7,821 higher than surgery, with ICER of $94,350/QALY. Influential parameters that could change model outcomes include probabilities of becoming seizure-free from disabling seizures state and returning to disabling seizures from seizure-free state 5 years after surgery and MRgLITT, cost of MRgLITT disposable equipment, and utilities of disabling seizures and seizure-free states of surgery and MRgLITT. The cost-effectiveness acceptability curve showed surgery was preferred in more than 50% of iterations. The expected monetary benefit of eliminating uncertainty for probabilities associated with MRgLITT was higher than for utilities associated with MRgLITT. CONCLUSIONS: MRgLITT resulted in more QALYs gained and higher costs compared to surgery in the base-case. The model was sensitive to variations in the cost of MRgLITT disposable equipment. There is value in conducting more research to reduce uncertainty on the probabilities and utilities of MRgLITT, but priority should be given to research focusing on improving the precision of estimates on effectiveness of MRgLITT.

Systematic review and network meta-analysis of resective surgery for mesial temporal lobe epilepsy.

OBJECTIVE: To evaluate the effectiveness of anterior temporal lobectomy (ATL) versus selective amygdalohippocampectomy (SAH) on seizure-free outcome in patients with temporal lobe epilepsy, using both direct and indirect evidence from the literature. METHODS: MEDLINE, Embase and Cochrane databases were searched for original research articles and systematic reviews comparing ATL versus SAH, and ATL or SAH versus medical management (MM). The outcome was seizure freedom at 12 months of follow-up or longer. Direct pairwise meta-analyses were conducted, followed by a random-effect Bayesian network meta-analysis (NMA) combining direct and indirect evidence. RESULTS: Twenty-eight articles were included (18 compared ATL vs SAH, 1 compared ATL vs SAH vs MM, 8 compared ATL vs MM, and 1 compared SAH vs MM). Direct pairwise meta-analyses showed no significant differences in seizure-free outcome of ATL versus SAH (OR 1.14, 95% CI 0.93 to 1.39; p=0.201), but the odds of seizure-free outcome were higher for ATL versus MM (OR 29.16, 95% CI 10.44 to 81.50; p<0.00001), and SAH versus MM (OR 28.42, 95% CI 10.17 to 79.39; p<0.00001). NMA also showed that the odds of seizure-free outcome were no different in ATL versus SAH (OR 1.15, 95% credible interval (CrI) 0.84-1.15), but higher for ATL versus MM (OR 27.22, 95% CrI 15.38-27.22), and SAH versus MM (OR 23.57, 95% CrI 12.67-23.57). There were no significant differences between direct and indirect comparisons (all p>0.05). CONCLUSION: Direct evidence, indirect evidence and NMA did not identify a difference in seizure-free outcome of ATL versus SAH.

"Saved by the Bell": Near SUDEP during intracranial EEG monitoring.

SUDEP is the sudden unexpected death of a person with epilepsy, when no structural or toxicological cause of death can be found. The majority of witnessed cases are reported to be preceded by a convulsive seizure and postictal hypoventilation. Here, we report an 8-year-old girl with drug-resistant focal seizures secondary to a focal cortical dysplasia type IIb. While undergoing invasive intracranial monitoring with subdural and depth electrodes, she had a clinical apnea event recorded on video, followed by bradycardia, which required resuscitation. Her intracranial electroencephalogram (EEG) during the event showed diffuse slowing and attenuation of cortical activity, with bradycardia that responded to positive pressure ventilation with oxygen. This near SUDEP event was not preceded by either an electroclinical or electrographic seizure. This is the first report of a witnessed, near-SUDEP event during intracranial monitoring. It emphasizes the fact that near-SUDEP can occur without a preceding seizure.

Diagnostic evaluation and surgical management of pediatric insular epilepsy utilizing magnetoencephalography and invasive EEG monitoring.

INTRODUCTION: The diagnosis and surgical management of pediatric patients with insular epilepsy is challenging due to variable and indistinct seizure semiology arising within the insular cortex. In addition, surgical approaches are associated with potential morbidity given the regional neurosurgical and vascular anatomy. Our institutional experience in evaluation and surgical management of insular epilepsy patients is presented. Diagnostic evaluation, surgical treatment and seizures outcomes are highlighted. METHODS: The institutional database for all pediatric surgical epilepsy patients was reviewed over a period of 15 years (2000-2015). Study subjects were defined as patients who had undergone surgical resection of the epileptogenic zone involving the insular cortex. Diagnostic imaging, electrophysiological studies and surgical records were assessed. RESULTS: Six (n = 6) patients with insular epilepsy were identified with a mean follow up of 2.8 years (range: 0.8-6.8 years). Mean age at surgical resection was 9.5 ±â€¯2.5 years (range: 2.5-16 years). Majority of patients (n = 4/6, 67%) underwent more than 1 surgical procedure. Magnetoencephalography (MEG) identified insular cortex involvement presurgically in all cases. MEG cluster localization was useful in guiding invasive EEG monitoring in 5 patients and was concordant with identification of epileptogenic zone through intracranial monitoring in all 5 patients. Surgical resection of the epileptogenic zone, as delineated through MEG spike sources and invasive EEG monitoring, was associated with favorable seizure outcome in 4 of 6 patients (67%; Engel Class I). Cortical dysgenesis was identified on histopathology in 4 cases. CONCLUSION: Diagnostic evaluation through invasive and noninvasive electrophysiological studies is critical to identify pediatric patients with insular epilepsy. Our findings suggest that MEG may help with identifying the epileptogenic zone within the insular cortex, which could be confirmed with invasive intracranial monitoring.

Predictive coding: A contemporary view on the burden of normality and forced normalization in individuals undergoing epilepsy surgery.

Following epilepsy surgery, a good psychosocial outcome is not necessarily contingent on a good seizure outcome. Increasingly, it is believed that "successful" surgery is a combination of both an acceptable and expected seizure status as well as the individual's perception of improvements in quality of life (QOL). The factors that create this optimal outcome remain an ongoing area of research in the epilepsy community. That being said, there have been some major breakthroughs in observing and understanding poor outcomes seen in a subset of postoperative patients with epilepsy. Characteristics of burden of normality and forced normalization are two phenomena that have been evident in cases of poor postoperative outcomes. In this review, we provide a summary of research and concepts used to explain these poor QOL outcomes for a seemingly successful surgery and suggest a contemporary view in understanding the mechanism of forced normalization through understanding the brain as a predictive organ. Using such a predictive coding model together with recommendations of other studies, we suggest the crucial need for a preoperative intervention addressing patient predictions and expectations to optimize on the benefits achievable through epilepsy surgery.

Microscopic and macroscopic infarct complicating pediatric epilepsy surgery.

OBJECTIVE: There is some suggestion that microscopic infarct could be associated with invasive monitoring, but it is unclear if the microscopic infarct is also visible on imaging and associated with neurologic deficits. The aims of this study were to assess the rates of microscopic and macroscopic infarct and other major complications of pediatric epilepsy surgery, and to determine if these complications were higher following invasive monitoring. METHODS: We reviewed the epilepsy surgery data from a tertiary pediatric center, and collected data on microscopic infarct on histology and macroscopic infarct on postoperative computed tomography (CT) or magnetic resonance imaging (MRI) done one day after surgery and major complications. RESULTS: Three hundred fifty-two patients underwent surgical resection and there was one death. Forty-two percent had invasive monitoring. Thirty patients (9%) had microscopic infarct. Univariable analyses showed that microscopic infarct was higher among patients with invasive monitoring relative to no invasive monitoring (20% vs. 0.5%, respectively, p < 0.001). Eighteen patients (5%) had macroscopic infarct on CT or MRI. Univariable analysis showed no significant difference in macroscopic infarct between invasive monitoring and no invasive monitoring (8% vs. 3%, respectively, p = 0.085). One patient with microscopic infarct had transient right hemiparesis, and two with both macroscopic and microscopic infarct had unexpected persistent neurologic deficits. Thirty-two major complications (9.1%) were reported, with no difference in major complications between invasive monitoring and no invasive monitoring (10% vs. 7%, p = 0.446). In the multivariable analysis, invasive monitoring increased the odds of microscopic infarct (odds ratio [OR] 15.87, p = 0.009), but not macroscopic infarct (OR 2.6, p = 0.173) or major complications (OR 1.4, p = 0.500), after adjusting for age at surgery, sex, age at seizure onset, operative type, and operative location. SIGNIFICANCE: Microscopic infarct was associated with invasive monitoring, and none of the patients had permanent neurologic deficits. Macroscopic infarct was not associated with invasive monitoring, and two patients with macroscopic infarct had persistent neurologic deficits.

Total intravenous anesthesia affecting spike sources of magnetoencephalography in pediatric epilepsy patients: focal seizures vs. non-focal seizures.

PURPOSE: Magnetoencephalography (MEG) provides source localization of interictal spikes. This study evaluated the inhibitory effects of propofol on MEG spike sources (MEGSSs) among different types of seizures in patients who underwent two separate MEG studies with and without total intravenous anesthesia (TIVA) using propofol. METHODS: We studied 19 children (1-14 years; mean, 6.2 years) who had MEG with and without TIVA. TIVA was administered using propofol (0.03-0.06 mg/kg/min) to record MEG with simultaneous EEG. We analyzed number of spikes of MEG and MEGSSs comparing MEG studies done with and without TIVA. RESULTS: Seizures were divided into nine focal seizure (FS) with/without secondary generalization, five epileptic spasm (ES), and five generalized seizure (GS). TIVA significantly decreased the number of MEG spikes/min (from 4.5 to 2.0) in five FS without secondary generalization (p<0.05). The number of MEG spikes/min was significantly lower (1.9) in FS than that in non-FS (ES+GS, 6.1) (p<0.01). MEGSSs without TIVA were clustered in 15 patients (6FS; 4ES; 5GS), scattered in four (3FS; 1ES). MEG under TIVA showed clusters in 10 patients (1FS; 4ES; 5GS), scatters in three (2FS; 1ES) and no MEGSS in six patients with FS. Under TIVA, nine (90%) of ten patients with non-FS showed MEGSSs clusters compared to one (11%) of nine patients with FS (p<0.01). CONCLUSIONS: Reduction of MEGSSs occurred in patients with FS under TIVA. Diffuse/generalized spikes in non-FS are not affected by TIVA. Propofol may decrease focal spikes in the epileptic cortex in FS. Cortical hyperexcitability in non-FS group would be stronger or more extensive than that in the FS group of patients.

Source localization of interictal spike-locked neuromagnetic oscillations in pediatric neocortical epilepsy.

OBJECTIVE: To evaluate the utility of an event-related beamforming (ERB) algorithm in source localization of interictal discharges. METHODS: We analyzed interictal magnetoencephalography data in 35 children with intractable neocortical epilepsy. We used a spatiotemporal beamforming method to estimate the spatial distribution of source power in individual interictal spikes. We compared ERB results to source localization using the equivalent current dipole model and to the seizure onset zones on intracranial EEG. RESULTS: Focal beamformer localization was observed in 66% of patients and multifocal in the remaining 34%. ERB localized within 2 cm of the equivalent current dipole cluster centroid in 77% of the patients. ERB localization was concordant with the seizure onset zone on intracranial EEG at the gyral level in 69% of patients. Focal ERB localization area was included in the resection margin in 22/23 patients. However, focal ERB localization was not statistically associated with better surgical outcome. CONCLUSIONS: ERB can be used for source localization of interictal spikes and can be predictive of the ictal onset zone in a subset of patients with neocortical epilepsy. SIGNIFICANCE: These results support the utility of beamformer source localization as a fast semi-automated method for source localization of interictal spikes and planning the surgical strategy.

A randomized controlled trial of flunarizine as add-on therapy and effect on cognitive outcome in children with infantile spasms.

PURPOSE: Cognitive impairment is observed commonly in children with a history of infantile spasms (IS). The goal of this study was to prospectively examine the effect on cognitive outcome of a neuroprotective agent used as adjunctive therapy during treatment of the spasms. METHODS: In a randomized controlled trial, patients received a standardized therapy plus flunarizine or placebo. The standardized treatment consisted of vigabatrin as first-line therapy. Nonresponders were switched to intramuscular synthetic adrenocorticotropic hormone (sACTH depot) after 2 weeks and, if necessary, to topiramate after two additional weeks. The Vineland Adaptive Behavior Scale (VABS) and Bayley Scales of Infant Development (BSID) were used as outcome measures 24 months after the intervention. KEY FINDINGS: Sixty-eight of 101 children diagnosed over 3 years in seven centers in Canada received either adjunctive flunarizine or placebo. Sixty-five of the 68 children (96%) became spasm-free within 8 weeks and no late relapse occurred. Bayley and Vineland results were available at baseline and at 24 months in 45 children. There was no significant difference in the BSID developmental quotient between the flunarizine- and placebo-treated children at baseline (44.3 ± 35.5 vs. 30.9 ± 29.8; p = 0.18) or 24 months later (56.9 ± 33.3 vs. 46 ± 34.2; p = 0.29). However, the 10 flunarizine-treated children with no identified etiology had a better outcome than the eight controls at 24 months on both the Vineland Scale (84.1 ± 11.3 vs. 72.3 ± 9.8; p = 0.03) and the Bayley Scale (87.6 ± 14.7 vs. 69.9 ± 25.3; p = 0.07). SIGNIFICANCE: Our study failed to demonstrate a protective effect of flunarizine on cognitive outcome in a cohort of children with IS. An analysis of subgroups suggested that flunarizine may further improve cognitive outcome in children with no identified etiology.

Neurosurgical management of frontal lobe epilepsy in children.

OBJECT: Pediatric frontal lobe epilepsy (FLE) remains a challenging condition for neurosurgeons and epileptologists to manage. Postoperative seizure outcomes remain far inferior to those observed in temporal lobe epilepsies, possibly due to inherent difficulties in delineating and subsequently completely resecting responsible epileptogenic regions. In this study, the authors review their institutional experience with the surgical management of FLE and attempt to find predictors that may help to improve seizure outcome in this population. METHODS: All surgically treated cases of intractable FLE from 1990 to 2008 were reviewed. Demographic information, preoperative and intraoperative imaging and electrophysiological investigations, and follow-up seizure outcome were assessed. Inferential statistics were performed to look for potential predictors of seizure outcome. RESULTS: Forty patients (20 male, 20 female) underwent surgical management of FLE during the study period. Patients were an average of 5.6 years old at the time of FLE onset and 11.7 years at the time of surgery; patients were followed for a mean of 40.25 months. Most patients displayed typical FLE semiology. Twenty-eight patients had discrete lesions identified on MRI. Eight patients underwent 2 operations. Cortical dysplasia was the most common pathological diagnosis. Engel Class I outcome was obtained in 25 patients (62.5%), while Engel Class II outcome was observed in 5 patients (12.5%). No statistically significant predictors of outcome were found. CONCLUSIONS: Control of FLE remains a challenging problem. Favorable seizure outcome, obtained in 62% of patients in this series, is still not as easily obtained in FLE as it is in temporal lobe epilepsy. While no statistically significant predictors of seizure outcome were revealed in this study, patients with FLE continue to require extensive workup and investigation to arrive at a logical and comprehensive neurosurgical treatment plan. Future studies with improved neuroimaging and advanced invasive monitoring strategies may well help define factors for success in this form of epilepsy that is difficult to control.

Prospective preliminary analysis of the development of autism and epilepsy in children with infantile spasms.

The objective of this study was to compare the efficacy of corticotropin (ACTH) versus vigabatrin in treating infantile spasms and to determine which medication has a more favorable long-term outcome in terms of cognitive function, evolution of epilepsy, and incidence of autism. Patients with infantile spasms were included in the study if they were 3 to 16 months old, had hypsarrhythmia, and had no previous treatment with vigabatrin or corticosteroids. Patient evaluation included electroencephalographic and psychometric measures before and after treatment. Patients were stratified based on etiology (idiopathic or symptomatic) and sex and then randomized between the ACTH and vigabatrin treatment groups. Each of the treatment groups received either ACTH or vigabatrin for 2 weeks. At the end of 2 weeks of treatment, patients were considered responders if spasms and hypsarrhythmia resolved. Nonresponders were crossed over and treated with the alternate drug. Nine patients were included in the study. Three patients received ACTH, one of whom was a responder. Six patients received vigabatrin, three of whom were responders. The five nonresponders received both therapies. All patients had some degree of developmental plateau or regression before the initiation of treatment. Four patients with idiopathic infantile spasms showed improved cognitive function following treatment. The remaining five patients remained significantly delayed. Five patients with symptomatic infantile spasms had epilepsy following treatment; three of them were in the autistic spectrum. The small number of infants in this pilot study is insufficient to determine which of the two drugs is more effective. However, the following trends were identified: vigabatrin may be more effective for patients with symptomatic infantile spasms; patients with idiopathic infantile spasms tend to have a better cognitive outcome; and patients with symptomatic infantile spasms tend to develop both epilepsy and autism.