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OBJECTIVE Magnetic resonance–guided focused ultrasound (MRgFUS) is an incisionless procedure capable of thermoablation through the focus of multiple acoustic beams. Although MRgFUS is currently approved for the treatment of tremor in adults, its safety and feasibility profile for intracranial lesions in the pediatric and young adult population remains unknown. METHODS The long-term outcomes of a prospective single-center, single-arm trial of MRgFUS at Nicklaus Children’s Hospital in Miami, Florida, are presented. Patients 15–22 years of age with centrally located lesions were recruited, clinically consistent with WHO grade I tumors that require surgical intervention. This cohort consisted of 4 patients with hypothalamic hamartoma (HH), and 1 patient with tuberous sclerosis complex harboring a subependymal giant cell astrocytoma (SEGA). RESULTS In each case, high-intensity FUS was used to target the intracranial lesion. Real-time MRI was used to monitor the thermoablations. Primary outcomes of interest were tolerability, feasibility, and safety of FUS. The radiographic ablation volume on intra- and postoperative MRI was also assessed. All 5 patients tolerated the procedure without any complications. Successful thermoablation was achieved in 4 of the 5 cases; the calcified SEGA was undertreated due to intratumor calcification, which prevented attainment of the target ablation temperature. The HHs underwent target tissue thermoablations that led to MR signal changes at the treatment site. For the patients harboring HHs, FUS thermoablations occurred without procedure-related complications and led to improvement in seizure control or hypothalamic hyperphagia. All 5 patients were discharged home on postoperative day 1 or 2, without any readmissions. There were no cases of hemorrhage, electrolyte derangement, endocrinopathy, or new neurological deficit in this cohort. CONCLUSIONS This experience demonstrates that FUS thermoablation of centrally located brain lesions in adolescents and young adults can be performed safely and that it provides therapeutic benefit for associated symptoms.

Objective: We describe a multicenter experience with vagus nerve stimulator implantation in pediatric patients with drug-resistant epilepsy. Our goal was to assess vagus nerve stimulation efficacy and identify potential predictors of favorable outcome. Methods: This is a retrospective study. Inclusion criteria: ≤18 years at time of vagus nerve stimulator implantation, at least 1 year of follow-up. All patients were previously found to be unsuitable for an excisional procedure. Favorable clinical outcome and effective vagus nerve stimulation therapy were defined as seizure reduction >50%. Outcome data were reviewed at 1, 2, 3, and 5 years after vagus nerve stimulator implantation. Fisher exact test and multiple logistic regression analysis were employed. Results: Eighty-nine patients met inclusion criteria. Responder rate (seizure frequency reduction >50%) at 1-year follow-up was 25.8% (4.5% seizure-free). At last follow-up, 31.5% had a favorable outcome and 5.2% were seizure free. The only factor significantly predicting favorable outcome was time to vagus nerve stimulator implantation, with the best outcome achieved when vagus nerve stimulator implantation was performed within 3 years of seizure onset. Implantation between 3 and 5 years after epilepsy onset correlated with better long-term seizure freedom (13.3% at T5). Overall, 65.2% of patients evidenced improved quality of life at last follow-up. However, 12.4% had adverse events, but most were mild and disappeared after 3-4 months. Conclusions: Early vagus nerve stimulator implantation within 5 years of seizure onset was the only predictor of favorable clinical outcome in pediatric patients. Improved quality of life and a low incidence of significant adverse events were observed.

Background: fMRI of mental phenomena is quite difficult to perform because lack of patient's cooperation or because the symptoms are stable. In some exceptional cases, however, fMRI and DTI are capable to provide insights on the anatomy of organic hallucinations. Methods: In this report we describe a 14-year-old boy with a left fronto-dorsal tumor who experienced chronic complex brief, frequent and repetitive complex visual and auditory hallucinations. His clinical picture included multiple and severe social and mood problems. During a presurgical fMRI mapping the patient complained of having the visual and auditory hallucinations. A block-design FMRI paradigm was obtained from the event timecourse. Deterministic DTI of the brain was obtained seeding the lesion as ROI. The patient underwent surgery and electrocorticography of the lesional area. Results: The fMRI of the hallucinations showed activation in the left inferior frontal gyrus (IFG) and the peri-lesional area. The tractography of the tumor revealed structural aberrant connectivity to occipital and temporal areas in addition to the expected connectivity with the IFG via the aslant fasciculus and homotopic contralateral areas. Intraoperative EEG demonstrated epileptic discharges in the tumor and neighboring areas. After resection, the patient's hallucinations stopped completely. He regained his normal social life and recover his normal mood. He remained asymptomatic for 90 days. Afterwards, hallucinations reappeared but with less intensity. Conclusions: To our knowledge, this is the first reported case of combined functional and structural connectivity imaging demonstrating brain regions participating in a network involved in the generation of complex auditory and visual hallucinations.

This paper presents a theoretical elaboration aimed to explain the correlation found between a new rs-fMRI modality and electrophysiology and nuclear medicine neuroimaging, performed to localize epileptogenic brain areas. We present in detail the clinical history, and electrophysiological and neuroimaging results of one child with intractable epilepsy, who was submitted for Phase-1 work-up as candidate for epilepsy surgery. The patient underwent a thorough workup including video-telemetry, ictal and interictal nuclear medicine imaging, resting-state fMRI, EEG-fMRI, intracranial electroencephalography (ECoG), deep electrode implantation, and resective surgery. Electrophysiology and neuroimaging findings were concordant with findings provided by the resting-state mean signal. The patient became seizure-free after the resection of the target area. A theoretical discussion is provided that considers the presence of a stable BOLD effect explaining the findings of the observed resting-state mean signal. This stable BOLD is linked to low regional metabolism usually present in the epileptogenic area during interictal periods, coupled with low oxygen extraction. Low oxygen extraction leaves more oxygen for the draining venule and consequently increases the BOLD signal.

Background: Infantile spasms is a rare disease characterized by distinct seizures and hypsarrhythmia. Adrenocorticotropic hormone (ACTH) is available as a natural product (repository corticotropin injection, [RCI]; Acthar® Gel) and as synthetic analogs. RCI is a naturally-sourced complex mixture of purified ACTH analogs and other pituitary peptides approved by the United States Food and Drug Administration as a monotherapy for the treatment of infantile spasms. RCI is commonly used in the United States. Outside the United States, synthetic analogs of ACTH—synthetic ACTH1-24 (tetracosactide) and synthetic ACTH1-39 (corticotropin carboxymethyl-cellulose [CCMC])—are used. The efficacy of RCI may differ from that of synthetic ACTH treatments based on the structure of peptide; however, no head-to-head clinical trials have compared the efficacy of RCI and synthetic ACTH treatments. Objective: A systematic review and indirect treatment comparison of clinical trials was conducted to assess the comparative efficacy of RCI and synthetic ACTH treatments in infantile spasms. Methods: A search was conducted in MEDLINE, EMBASE, and Cochrane databases through September 30, 2020. Relevant clinical trials on RCI or synthetic ACTH therapy and reporting either cessation of spasms or resolution of hypsarrhythmia, separately or as a combined outcome were included. A Bayesian indirect treatment comparison using a fixed-effects model was used for comparative efficacy. Results: Of 473 citations screened, 21 studies were reviewed qualitatively. In the indirect treatment comparison of six eligible clinical trial studies, the odds of achieving efficacy outcomes were five to eight times greater with RCI than with tetracosactide and 14 to 16 times greater than CCMC. This translated to a risk reduction of 10% to 14% and 40% to 50% with RCI versus tetracosactide and CCMC, respectively. For every two to five patients treated, RCI improved efficacy outcomes in one additional patient compared to synthetic ACTH (adjusted number needed-to-treat). Conclusions: Based on the available limited evidence, results suggest RCI may be more efficacious for infantile spasms than synthetic ACTH treatments. Our findings provide a blueprint to inform the design of future prospective studies for the treatment of infantile spasms., A systematic review and indirect treatment comparison of clinical trials was conducted to assess the comparative efficacy of RCI and synthetic ACTH treatments in infantile spasms.

Objective: We describe a multicenter experience with VNS implantation in pediatric patients with epileptic encephalopathy. Our goal was to assess VNS efficacy and identify potential predictors of favorable outcome. Methods: This was a retrospective study. Inclusion criteria were: ≤18 years at the time of VNS implantation and at least one year of follow-up. All patients were non-candidates for excisional procedures. Favorable clinical outcome and effective VNS therapy were defined as seizure reduction >50%. Outcome data were reviewed at one, two, three and five years after VNS implantation. Fisher's exact test, Kaplan-Meier and multiple logistic regression analysis were employed. Results: Twenty-seven patients met inclusion criteria. Responder rate (seizure frequency reduction ≥ 50%) at one-year follow-up was 25.9%, and 15.3% at last follow-up visit. The only variable significantly predicting favorable outcome was time to VNS implantation, with the best outcome achieved when VNS implantation was performed within five years of seizure onset (overall response rate of 83.3% at one year of follow-up and 100% at five years). In total, 63% of patients evidenced improved QOL at last follow-up visit. Only one patient exited the study due to an adverse event at two years from implantation. Significance: Early VNS implantation within five years of seizure onset was the only predictor of favorable clinical outcome in pediatric patients with epileptic encephalopathy. Improved QOL and a very low incidence of adverse events were observed.

ESES is a developmental epileptic disorder directly responsible for progressive encephalopathy and neurocognitive regression. The natural history, indications for surgical intervention, and predictors for favorable seizure and neuropsychological outcome remain unclear. We performed a retrospective review of children who underwent resective or disconnective surgery for ESES between January 2009 and July 2016 at a large tertiary pediatric center. Information on the patients' demographics, seizure semiology, radiographic and electrographic findings, and surgical management was collected. The primary outcome was seizure freedom at last follow-up visit, and secondary outcomes were neuropsychological improvement and electrographic ESES resolution. We identified 11 children who underwent surgery for ESES. The mean ages were 3.2 years for seizure onset, 7.1 years for formal ESES diagnosis, and 9.4 years for surgery. Seizure etiologies included cortical malformations (four patients), encephalomalacia and gliosis from prior hemorrhage or tumor resections (three patients), developmental porencephaly (one patient), and Rasmussen's encephalitis (one patient); the etiology was unknown in two children. Preoperatively, nine children had motor deficits, seven had speech and language delay, and three had visual field defects. All children had seizures and neuropsychological regression prior to surgical consideration. Focal cortical resections were performed in seven children, and hemispherectomies in four. Post-operatively, nine children experienced decreased seizure frequency, eight had neuropsychological improvement, and nine had resolution of electrographic ESES. Patients with poor surgical outcomes had more significant pre-operative comorbidities, in addition to bilateral ESES activity. In this case series, surgery for a carefully selected group of children with ESES is safe and feasible, yielding rates of seizure freedom and neuropsychological improvement that compare favorably with previous reports for antiepileptic drugs, benzodiazepines, and steroids. As we gain greater understanding into the management of ESES, surgery is an increasingly useful tool for patients with mild or moderate neurodevelopmental delay, focal epileptogenic foci, and hemi-ESES electrographic findings.

A more complete understanding of the epileptic aura represents an important challenge for localizing the epileptogenic zone and understanding brain networks. This review re-visits the localizing value of the epileptic aura, focusing on clinical pitfalls in epileptogenic zone detection and the importance of defining functional connectivity. We review the role of network node activation or alteration and its relationship to hub activation.

Background Patients with autism spectrum disorder and developmental delay or encephalopathy rarely demonstrate no or negligible hair and nail growth, suggesting a biotin-responsive clinical disorder. Methods A ten-year-old girl presented with features of autism spectrum disorder, isolated headaches, and episodes of headaches and limb shaking. Her medical history revealed that her hair and nails did not grow. Administration of biotin restored her nail and hair growth and improved intellectual ability and school performance. Her episodes of headaches, single limb shaking, and loss of consciousness responded to administration of acetazolamide, and her school performance and social skills further improved. Results A de novo c.1091 C > T, p.T364M pathogenic variant was found in the ATP1A2 gene by whole-exome sequencing, but a genetic etiology in the biotin-responsive metabolic pathways was not identified. Conclusions The combination of biotin and acetazolamide treatment was successful in restoring normal mental function and school performance. Poor or no clinical nail and hair growth in any child with a developmental delay-autism spectrum disorder presentation should be considered as evidence for a biotin-responsive genetic disorder even when exome testing is negative.

SummaryObjective Evaluate the seizure-reduction response and safety of brain-responsive stimulation in adults with medically intractable partial-onset seizures of neocortical origin. Methods Patients with partial seizures of neocortical origin were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2–6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset. Results There were 126 patients with seizures of neocortical onset. The average follow-up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty-six percent of patients experienced at least one seizure-free period of 6 months or longer and 14% experienced at least one seizure-free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices. Significance Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex.

Infants with West Syndrome and underlying structural pathology typically experience persistent symptomatic focal seizures and intellectual disability. We performed a retrospective case review of 84 patients with West Syndrome evaluated at one institution between 1990 and 2013. From this group we identified three patients with West syndrome and congenital hemiplegia who later developed genetic epilepsy features and had normal intellectual development. This outcome is highly unusual and raises important questions about the relationship and possible influence of genetic epilepsy in patients with pre-existent West Syndrome and brain injury.

OBJECTIVE Seizure onset in the insular cortex as a cause of refractory epilepsy is underrepresented in the pediatric population, possibly due to difficulties localizing seizure onset in deep anatomical structures and limited surgical access to the insula, a complex anatomical structure with a rich overlying vascular network. Insular seizure semiology may mimic frontal, temporal, or parietal lobe semiology, resulting in false localization, incomplete resection, and poor outcome. METHODS The authors retrospectively reviewed the records of all pediatric patients who underwent insular cortical resections for intractable epilepsy at Miami Children's Hospital from 2009 to 2015. Presurgical evaluation included video electroencephalography monitoring and anatomical/functional neuroimaging. All patients underwent excisional procedures utilizing intraoperative electrocorticography or extraoperative subdural/depth electrode recording. RESULTS Thirteen children (age range 6 months–16 years) with intractable focal epilepsy underwent insular-opercular resection. Seven children described symptoms that were suggestive of insular seizure origin. Discharges on scalp EEG revealed wide fields. Four patients were MRI negative (i.e., there were no insular or brain abnormalities on MRI), 4 demonstrated insular signal abnormalities, and 5 had extrainsular abnormalities. Ten patients had insular involvement on PET/SPECT. All patients underwent invasive investigation with insular sampling; in 2 patients resection was based on intraoperative electrocorticography, whereas 11 underwent surgery after invasive EEG monitoring with extraoperative monitoring. Four patients required an extended insular resection after a failed initial surgery. Postoperatively, 2 patients had transient hemiplegia. No patients had new permanent neurological deficits. At the most recent follow-up (mean 43.8 months), 9 (69%) children were seizure free and 1 had greater than 90% seizure reduction. CONCLUSIONS Primary insular seizure origin should be considered in children with treatment-resistant focal seizures that are believed to arise within the perisylvian region based on semiology, widespread electrical field on scalp EEG, or insular abnormality on anatomical/functional neuroimaging. There is a reasonable chance of seizure freedom in this group of patients, and the surgical risks are low.

Summary Objective The aim of this study was to investigate the utility of three-dimensional electroencephalography source imaging (3D-ESI) with low-resolution electroencephalographic data in the pediatric noninvasive presurgical evaluation, and to compare the findings with positron emission tomography (PET) and ictal single-photon emission computed tomography (iSPECT). Methods We retrospectively selected 60 patients from a database of 594 patients who underwent excisional surgery for drug-resistant epilepsy. Patients were

The long-term efficacy and safety of responsive direct neurostimulation was assessed in adults with medically refractory partial onset seizures.All participants were treated with a cranially implanted responsive neurostimulator that delivers stimulation to 1 or 2 seizure foci via chronically implanted electrodes when specific electrocorticographic patterns are detected (RNS System). Participants had completed a 2-year primarily open-label safety study (n = 65) or a 2-year randomized blinded controlled safety and efficacy study (n = 191); 230 participants transitioned into an ongoing 7-year study to assess safety and efficacy.The average participant was 34 (±11.4) years old with epilepsy for 19.6 (±11.4) years. The median preimplant frequency of disabling partial or generalized tonic-clonic seizures was 10.2 seizures a month. The median percent seizure reduction in the randomized blinded controlled trial was 44% at 1 year and 53% at 2 years (p0.0001, generalized estimating equation) and ranged from 48% to 66% over postimplant years 3 through 6 in the long-term study. Improvements in quality of life were maintained (p0.05). The most common serious device-related adverse events over the mean 5.4 years of follow-up were implant site infection (9.0%) involving soft tissue and neurostimulator explantation (4.7%).The RNS System is the first direct brain responsive neurostimulator. Acute and sustained efficacy and safety were demonstrated in adults with medically refractory partial onset seizures arising from 1 or 2 foci over a mean follow-up of 5.4 years. This experience supports the RNS System as a treatment option for refractory partial seizures.This study provides Class IV evidence that for adults with medically refractory partial onset seizures, responsive direct cortical stimulation reduces seizures and improves quality of life over a mean follow-up of 5.4 years.

Localization of the epileptogenic zone (EZ) is challenging in children with tuberous sclerosis complex (TSC). We sought to ascertain whether brain MRI could identify the EZ in TSC patients independent of the clinical and diagnostic data.Presurgical MRI's of 34 children with TSC who underwent epilepsy surgery at Miami Children's Hospital were retrospectively reevaluated by experts blinded to all other data. Changes typical of TSC (tubers, calcifications, cystic changes) and abnormalities of the perituberal cortex typical of focal cortical dysplasia (FCD) (increased cortical thickness, abnormal gyration, transmantle change, gray/white matter junction blurring) were identified and their localization was compared with the resection site. Sensitivity, specificity and accuracy of individual MRI features to localize the EZ were determined and statistically compared between postoperatively seizure-free and non-seizure-free patients as well as clusters of features typical of FCD and TSC.MRI alone correctly localized the resection cavity in all 19 postoperatively seizure-free patients and 12 of 15 non-seizure-free subjects. Sensitivity, specificity and accuracy of MRI features typical of FCD to localize EZ (90%, 96% and 96%, respectively) were superior to those typical of TCS (79%, 75% and 75%, p0.0001). Increased cortical thickness and abnormal gyral formation outside tubers occurred only in the resection site. Resection sites were better predicted by MRI in seizure-free than in non-seizure-free patients.Thorough MRI evaluation identifies the EZ in a significant proportion of TSC patients. Epileptogenic regions were mostly characterized by "FCD-like" changes outside cortical tubers. The findings may have important practical consequences for surgical planning in TSC.

Nearly one third of patients with epilepsy become medically intractable, and the likelihood of achieving seizure freedom decreases with each additional medication trial. For appropriately chosen patients, epilepsy surgery affords the opportunity to achieve seizure freedom and potentially wean off medications. Epilepsy surgery, as with medical management, is not without adverse effects; to counsel patients wisely, practitioners need to understand the advantages and disadvantages of both. Randomized controlled trials in temporal lobe epilepsy reveal that epilepsy surgery achieves superior outcome compared to continued medical management. Although seizure freedom is the ultimate goal of any therapy, it represents a single outcome measure among a variety of other domains that affect patient welfare. It is imperative that providers understand the patient variables that affect these outcome measures and how these measures impact each other. Because the data comparing surgical therapy versus medical management for refractory epilepsy are limited, we review the available evidence comparing outcomes beyond seizure freedom including quality of life, cognition, psychosocial function, mortality, and financial costs.

Objective: To determine the most important factors influencing neuropsychological performance in children with intractable epilepsy due to focal cortical dysplasia and the nature of the interaction among significant variables. Methods: Surgical patients with histologically verified focal cortical dysplasia were retrospectively evaluated to determine the impact of histopathology, extent of lobar involvement, hemispheric laterality, age at onset, and duration of epilepsy on cognitive functioning. A composite neuropsychological variable was obtained by transforming data from 5 major cognitive domains using principal components analysis. Multiple regression was used to examine the unique contributions of predictor variables on composite cognition and Full Scale IQ. Data were qualitatively evaluated for nonstatistical trends. Results: Poor cognitive outcomes were associated with early age at onset of epilepsy (AOE) and widespread dysplastic involvement. Extent of dysplasia and AOE together accounted for 35% of Full Scale IQ variance, and 21% of composite cognitive performance. Each factor contributed independently to cognitive dysfunction. Conclusions: Early AOE disrupts critical periods of development and leads to poor cognitive outcome, but children with multilobar dysplasia are likely to have diminished cognitive skills regardless of AOE. Later AOE is not expected to mitigate deficits because of widespread pathology, nor would a localized lesion be likely to mollify the developmental deficits resulting from early AOE.

Aims. To assess the localizing value of ictal SPECT in very young epilepsy surgery candidates when cerebral haemodynamic responses are known to be immature. Methods. We retrospectively studied 13 infants with intractable focal epilepsy caused by focal cortical dysplasia (FCD). Completeness of resection of the (1) ictal SPECT hyperperfusion zone and (2) cerebral cortex with prominent ictal and interictal abnormalities on intracranial EEG (ECoG or long-term invasive monitoring) and the MRI lesion, when present, were correlated with postoperative seizure outcome. Results. All five patients with complete resection of the ictal SPECT hyperperfusion zone were seizure-free compared to only one of eight patients with incomplete or no excision of hyperperfusion zones (p=0.00843). Similar results were noted for the MRI/iEEG-defined epileptogenic region; five of six patients with complete removal were seizure-free, whereas only one of seven incompletely resected patients was seizure-free (p=0.02914). All four patients who underwent complete resection of both regions were seizure-free compared to none of the six with incomplete resection (p=0.01179). Conclusion. Despite age-related differences in cerebral perfusion, ictal SPECT provides useful localization data in infants with FCD. Complete resection of the hyperperfused regions is a strong predictor of favourable outcome. The added information may alleviate the need for invasive EEG evaluations in some patients.

The pharmacotherapy of epilepsy in children must account for a number of specific issues. The nature of epileptic disorders found in children differs from that in adults. For example, epilepsies of childhood are more likely to be developmentally or genetically based than those found in adults. Children also differ from adults in indications for antiepileptic drugs. Indeed, some types of childhood epilepsy do not require specific pharmacological treatment since prognosis is often excellent without therapy. This is especially true for children who are neurologically nonnal and those with benign epilepsy syndromes that have a characteristic electroclinical presentation, such as febrile seizures. In contrast, children with evidence of brain damage or those with serious epilepsy syndromes must be treated promptly.Once it has been decided that treatment is necessary, the choice of treatment should be based on a comparison of efficacy and tolerability of individual antiepileptic agents. The spectrum of toxicity is often different in younger patients from that in adults, and adverse effects that are acceptable in adults may be cause for discontinuation of therapy in children. Intellectual, cognitive and behavioural toxicity are particularly unacceptable.Establishing sustained therapeutic serum concentrations in children also requires specific attention. Rapid gastrointestinal transit times and interactions with milk and infant formulas may pose special management problems. Toxic metabolites of antiepileptic drugs are frequently produced in children. This can lead to drug hypersensitivity and other possible conditions, such as valproic acid (sodium valproate)-induced hepatotoxicity.Unless specific paediatric data are obtained, recommendations for the treatment of epilepsies in children will continue to be based on studies in adults and on anecdotal observations. Given the high prevalence and significant morbidity of childhood epilepsies, further studies of treatments are urgently needed.

SummaryObjective This study investigates whether a combined rotating dipole (RD) and moving dipole (MD) solution enhances three-dimensional electroencephalography (EEG) source imaging (3D-ESI) localization in magnetic resonance imaging (MRI)–negative pediatric patients with focal cortical dysplasia (FCD). Methods We retrospectively selected 14 MRI-negative patients with FCD from a cohort of 60 pediatric patients previously used to evaluate the diagnostic utility of 3D-ESI in epilepsy surgery. Patients were younger than 18 years at time of surgery and had at least 1 year of outcome data. RD and MD models were constructed for each interictal spike or sharp wave, and it was determined whether each inverse algorithm localized within the surgical resection cavity (SRC). We also compared the 3D-ESI findings and surgical outcome with positron emission tomography (PET) and ictal single photon emission computed tomography (iSPECT). Results RD analyses revealed a high concordance with the SRC (78.6%), particularly for temporal lobe resection (100.0%), and showed superior localization compared to PET and iSPECT, with the highest correlation in FCD type I and temporal lobe resection. Furthermore, the RD method was superior to iSPECT in FCD type II cases and to PET in extratemporal resections. RD and MD results were comparable, but in 18.2% of patients with FCD type I with localizing RDs, the MD solution was only partially within the SRC; in all of these patients 3D-ESI also correlated with superior surgical outcome compared to PET and iSPECT, especially when RD and MD solutions were analyzed together. Significance 3D-ESI in MRI-negative cases showed superior localization compared to iSPECT or PET, especially in FCD type I and temporal lobe epilepsy, and correlated with superior surgical outcome compared to iSPECT and PET at 1 year and 2 years postoperatively, especially when RD and MD solutions were analyzed together. These findings suggest that 3D-ESI based on a combined RD-MD solution improves surgical accuracy in MRI-negative patients with FCD.

Summary Purpose: Medically refractory epilepsy caused by cortical tubers resulting from tuberous sclerosis complex (TSC) often requires surgical intervention. The locations of cortical tubers generally are determined by preoperative magnetic resonance imaging (MRI). In this pilot study, we explored the feasibility of using the optical characteristics of cortical tubers as a potential means to guide their resection intraoperatively. Methods: Optical characteristics of normal cortex and cortical tubers were measured intraoperatively using diffuse reflectance spectroscopy in three children undergoing epilepsy surgery for drug-resistant seizures. Unique diffuse reflectance spectroscopic features of cortical tubers were identified and their physiologic associations determined. Key Findings: Diffuse reflectance spectra revealed several features that distinguish cortical tubers from normal cortex. In tubers, diffuse reflectance intensities at oxy- and deoxyhemoglobin isobestic points, like 500, 530, and 570 nm, were consistently higher than those in normal cortex. According to the profile of diffuse reflectance spectra from 520–580 nm, hemoglobin oxygenation in tubers often was lower than in normal cortex. Significance: Albeit preliminary, our findings suggest that the optical characteristics of cortical tubers differ from intervening normal cortex, likely reflecting the lower cerebral blood volumes and reduced hemoglobin oxygenation of cortical tubers. The results of this study can be used to design biomedical instruments that aid tuberectomies.

Incomplete resection of the epileptogenic zone (EZ) is the most important predictor of poor outcome after resective surgery for intractable epilepsy. We analyzed the contribution of preoperative and perioperative variables including MRI and EEG data as predictors of seizure-free (SF) outcome after incomplete resection.We retrospectively reviewed patients18 years of age with incomplete resection for epilepsy with 2 years of follow-up. Fourteen preoperative and perioperative variables were compared in SF and non-SF (NSF) patients. We compared lesional patients, categorized by reason for incompleteness, to lesional patients with complete resection. We analyzed for effect of complete EEG resection on SF outcome in patients with incompletely resected MRI lesions and vice versa.Eighty-three patients with incomplete resection were included with 41% becoming SF. Forty-eight lesional patients with complete resection were included. Thirty-eight percent (57/151) of patients with incomplete resection and 34% (47/138) with complete resection were excluded secondary to lack of follow-up or incomplete records. Contiguous MRI lesions were predictive of seizure freedom after incomplete resection. Fifty-seven percent of patients incomplete by MRI alone, 52% incomplete by EEG alone, and 24% incomplete by both became SF compared to 77% of patients with complete resection (p = 0.0005).Complete resection of the MRI- and EEG-defined EZ is the best predictor of seizure freedom, though patients incomplete by EEG or MRI alone have better outcome compared to patients incomplete by both. More than one-third of patients with incomplete resection become SF, with contiguous MRI lesions a predictor of SF outcome.

Purpose Anecdotal reports have described cortical malformations in epileptic patients with Sturge-Weber syndrome (SWS). No data are available regarding the prevalence and significance of this association. Methods We reviewed retrospectively the clinical profile, preoperative magnetic resonance imaging (MRI) studies, and pathology reports of all patients with SWS and medically intractable epilepsy evaluated in our epilepsy surgery program between 1979 and 2006. Results Twelve patients (male/female = 7/5) were identified. Mean age at seizure onset was 11.1 +/- 16.7 months. Seizures occurred daily in seven patients and weekly in five patients. A facial port-wine stain was noted in 10 cases. Eleven patients evidenced developmental delay and eight were hemiparetic. Eight patients underwent excisional surgery for epilepsy (mean age 10.3 +/- 6.5 year), including hemispherectomy (n = 4) and focal cortical resection (n = 4). Tissue was available for neuropathology in six operated cases and revealed polymicrogyria (n = 3) and cortical dysplasia (n = 4). Polymicrogyria was associated with cortical dysplasia in one child. Brain MRIs were reviewed in 10 of 12 patients and were consistent with cortical malformations in all cases. Conclusions We conclude that cortical malformations are frequent in patients with medically intractable epilepsy and Sturge-Weber-syndrome and may be the primary cause of epilepsy.

Cortical malformations are highly epileptogenic lesions associated with complex, unanticipated, and often aberrant electrophysiologic and functional relationships. These relationships are inextricably linked to widespread cortical networks subserving eloquent functions, particularly language and motor ability. Cytomegalic neurons but not balloon cells in Palmini type 2 dysplastic cortex are intrinsically hyperexcitable and contribute to local epileptogenesis and functional responsiveness. However, there is much evidence that focal cortical dysplasia is rarely a localized or even regional process, and is a functionally, electrophysiologically, and ultimately clinically integrated neural network disorder. Not surprisingly, malformed cortex is implicated in cognitive dysfunction, particularly disturbances of linguistic processing. An understanding of these relationships is critical for successful epilepsy surgery. Gains in surgical prognosis rely on multiple diagnostic modalities to delineate complex anatomic, electrophysiologic, and functional relationships in magnetic resonance imaging (MRI)-negative patients with rates of seizure-freedom roughly comparable to lesional patients.

Background: Focal cortical dysplasia (FCD) is recognized as the major cause of focal intractable epilepsy in childhood. Various factors influencing postsurgical seizure outcome in pediatric patients with FCD have been reported. Objective: To analyze different variables in relation to seizure outcome in order to identify prognostic factors for selection of pediatric patients with FCD for epilepsy surgery. Methods: A cohort of 149 patients with histologically confirmed mild malformations of cortical development or FCD with at least 2 years of postoperative follow-up was retrospectively studied; 113 subjects had at least 5 years of postoperative follow-up. Twenty-eight clinical, EEG, MRI, neuropsychological, surgical, and histopathologic parameters were evaluated. Results: The only significant predictor of surgical success was completeness of surgical resection, defined as complete removal of the structural MRI lesion (if present) and the cortical region exhibiting prominent ictal and interictal abnormalities on intracranial EEG. Unfavorable surgical outcomes are mostly caused by overlap of dysplastic and eloquent cortical regions. There were nonsignificant trends toward better outcomes in patients with normal intelligence, after hemispherectomy and with FCD type II. Other factors such as age at seizure onset, duration of epilepsy, seizure frequency, associated pathologies including hippocampal sclerosis, extent of EEG and MRI abnormalities, as well as extent and localization of resections did not influence outcome. Twenty-five percent of patients changed Engel9s class of seizure outcome after the second postoperative year. Conclusions: The ability to define and fully excise the entire region of dysplastic cortex is the most powerful variable influencing outcome in pediatric patients with focal cortical dysplasia.

Objective Focal cortical dysplasia (FCD) is the most frequent pathological finding in pediatric epilepsy surgery patients. Several histopathological types of FCD are distinguished. The aim of the study was to define distinctive features of FCD subtypes. Methods We retrospectively reviewed clinical, electroencephalographic, magnetic resonance imaging, neuropsychological, and surgical variables, and seizure outcome data in 200 children. Cortical malformations were histopathologically confirmed in all patients, including mild malformation of cortical development type II (mMCD) in 36, FCD type Ia in 55, FCD type Ib in 39, FCD type IIa in 35, and FCD type IIb in 35 subjects. Results Perinatal risk factors were more frequent in mMCD/FCD type I than FCD type II. Children with FCD type IIb had more localized ictal electroencephalographic patterns and magnetic resonance imaging changes. Increased cortical thickness, abnormal gyral/sulcal patterns, gray/white matter junction blurring, and gray matter signal abnormality in fluid-attenuated inversion recovery and T2-weighted sequences occurred more often in FCD type II, were infrequent in FCD type I, and rare in mMCD. Lobar hypoplasia/atrophy was common in FCD type I. Hippocampal sclerosis was most frequent in FCD type I. Neuropsychological testing demonstrated no significant differences between the groups. There was a trend toward better surgical outcomes in FCD type II compared with FCD type I patients. Interpretation Different histopathological types of mMCD/FCD have distinct clinical and imaging characteristics. The ability to predict the subtype before surgery could influence surgical planning. Invasive electroencephalographic study should be considered when mMCD/FCD type I is expected based on noninvasive tests. Ann Neurol 2008;63:758–769

Purpose Gliomatosis cerebri (GC) is a rare neoplastic disorder that may present as intractable epilepsy during early life. We report our experience regarding the evaluation and the surgical treatment of epilepsy in this population. Methods All children evaluated between 1990 and 2006 for surgery of epilepsy (n = 741) with pathologically proven GC were selected. Results We identified four male children with age at seizure onset ranging from 4 months to 11 years. Two had hemiparesis and one child with infantile spasms was developmentally delayed. Seizures occurred daily (n = 3) or monthly (n = 1). Ictal semiology was consistent with psychomotor seizures (n = 1), partial motor seizures (n = 2), and asymmetric epileptic spasms (n = 1). Surgery was symptomatic and aimed at debulking and controlling the epilepsy. Procedure was individually tailored based on the presurgical evaluation. Brain MRI revealed widespread hemispheric involvement (n = 3) or infiltration of the temporal lobe and basal ganglia (n = 1). Two patients were initially misdiagnosed as hemispheric cortical dysplasia and hemimegalencephaly. Scalp EEG was nonlocalizing in two cases, showed a right temporal focus in one case, and was not performed in one case. Interictal SPECT in one patient revealed widespread hemispheric hypoperfusion. Three cases were resected under ECoG guidance after a mean delay of 11 months after seizure onset. Following functional hemispherectomy (n = 1) or focal cortical resection (n = 2), all children were alive and seizure free with a mean follow-up of 48 months (2-5 years). No unexpected complication was reported. One nonoperated case was alive but still seizing after 15 months follow-up. Chemotherapy was associated in three cases. Conclusions GC is a rare cause of medically resistant epilepsy that may present in early life. The lack of a discrete lesion may lead to diagnostic uncertainty, especially in infancy. Epilepsy surgery is an effective therapy that can improve quality of life.

This study evaluated language organization in children with intractable epilepsy caused by temporal lobe focal cortical dysplasia (FCD) alone or dual pathology (temporal lobe FCD and hippocampal sclerosis, HS). We analyzed clinical, neurological, fMRI, neuropsychological, and histopathologic data in 46 pediatric patients with temporal lobe lesions who underwent excisional epilepsy surgery. The frequency of atypical language representation was similar in both groups, but children with dual pathology were more likely to be left-handed. Atypical receptive language cortex correlated with lower intellectual capacity, verbal abstract conceptualization, receptive language abilities, verbal working memory, and a history of status epilepticus but did not correlate with higher seizure frequency or early seizure onset. Histopathologic substrate had only a minor influence on neuropsychological status. Greater verbal comprehension deficits were noted in children with atypical receptive language representation, a risk factor for cognitive morbidity.

Performing epilepsy surgery on children with non-lesional brain MRI often results in large lobar or multilobar resections. The aim of this study was to determine if smaller resections result in a comparable rate of seizure freedom.We reviewed 25 children who had undergone focal corticectomies restricted to one aspect of a single lobe or the insula at our institution within a 5.5-year period. Data collected in the comprehensive non-invasive pre-surgical evaluation (including scalp video-EEG, volumetric MRI, functional MRI, EEG source localization, and SPECT and PET), as well as from invasive recordings performed in each patient, was reviewed. Data from each functional modality was identified as convergent or divergent with the epileptogenic zone using image coregistration. Specific biomarkers (from extra-operative and invasive testing) previously indicated to be indicative of focal epileptogenicity were used to further tailor each resection to an epileptogenic epicentre. Tissue pathology and postoperative outcomes were obtained from all 25 patients.Two years postoperatively, 15/25 (60%) children were seizure-free, three (12%) experienced90% reduction in seizure frequency, two (8%) had a 50-90% reduction in seizure frequency, and the remaining five (20%) had no change in seizure burden. There was no significant difference in outcome based on numerous pre- and postoperative factors including location of resection, the number of preoperative functional tests providing convergent data, and tissue pathology.In MRI-negative children with focal epilepsy, an epileptogenic epicentre within a larger epileptogenic zone can be identified when specific biomarkers are recognized on non-invasive and invasive testing. When such children undergo resection of a small, well-defined epileptogenic epicentre, favourable outcomes can be achieved.

Our inability to adequately treat many patients with refractory epilepsy caused by focal cortical dysplasia (FCD), surgical inaccessibility and failures are significant clinical drawbacks. The targeting of physiologic features of epileptogenesis in FCD and colocalizing functionality has enhanced completeness of surgical resection, the main determinant of outcome. Electroencephalography (EEG)-functional magnetic resonance imaging (fMRI) and magnetoencephalography are helpful in guiding electrode implantation and surgical treatment, and high-frequency oscillations help defining the extent of the epileptogenic dysplasia. Ultra high-field MRI has a role in understanding the laminar organization of the cortex, and fluorodeoxyglucose-positron emission tomography (FDG-PET) is highly sensitive for detecting FCD in MRI-negative cases. Multimodal imaging is clinically valuable, either by improving the rate of postoperative seizure freedom or by reducing postoperative deficits. However, there is no level 1 evidence that it improves outcomes. Proof for a specific effect of antiepileptic drugs (AEDs) in FCD is lacking. Pathogenic mutations recently described in mammalian target of rapamycin (mTOR) genes in FCD have yielded important insights into novel treatment options with mTOR inhibitors, which might represent an example of personalized treatment of epilepsy based on the known mechanisms of disease. The ketogenic diet (KD) has been demonstrated to be particularly effective in children with epilepsy caused by structural abnormalities, especially FCD. It attenuates epigenetic chromatin modifications, a master regulator for gene expression and functional adaptation of the cell, thereby modifying disease progression. This could imply lasting benefit of dietary manipulation. Neurostimulation techniques have produced variable clinical outcomes in FCD. In widespread dysplasias, vagus nerve stimulation (VNS) has achieved responder rates >50%; however, the efficacy of noninvasive cranial nerve stimulation modalities such as transcutaneous VNS (tVNS) and noninvasive (nVNS) requires further study. Although review of current strategies underscores the serious shortcomings of treatment-resistant cases, initial evidence from novel approaches suggests that future success is possible.

Summary Objective To report the feasibility, safety, and clinical outcomes of an exploratory study of MR-guided Laser Interstitial Thermal Therapy (MRgLITT) as a minimally invasive surgical procedure for the ablation of epileptogenic foci in children with drug-resistant, lesional epilepsy. Methods Retrospective chart review of all MRgLITT procedures at a single tertiary care center. All procedures were performed using a U.S. Food and Drug Administration (FDA)–cleared surgical laser ablation system (Visualase Thermal Therapy System). Predefined clinical and surgical variables were extracted from archived medical records. Results Seventeen patients underwent 19 MRgLITT procedures from May 2011 to January 2014. Mean age at seizure onset was 7.1 years (range 0.1–14.8 years). Mean age at surgery was 15.3 years (range 5.9–20.6 years). Surgical substrates were mixed but mainly composed of focal cortical dysplasia (n = 11). Complications occurred in four patients. Average length of hospitalization postsurgery was 1.56 days. Mean follow-up was 16.1 months (n = 16; range 3.5–35.9 months). Engel class I outcome was achieved in seven patients (7/17; 41%), Engel class II in one (1/17; 6%), Engel class III in three (3/17; 18%), and Engel class IV in six (6/17; 35%). Three patients (3/8; 38%) with class I and II outcomes and five patients (5/9; 56%) with class III and IV outcomes had at least one prior resection. Fisher's exact test was not statistically significant for the association between Engel class outcome and previous resection (p = 0.64). Significance This study provides descriptive results regarding the use of MRgLITT in a mixed population of pediatric, lesional, drug-resistant epilepsy cases. The ability to classify case-specific outcomes and reduce technical complications is anticipated as experience develops. Further multicenter, prospective studies are required to delineate optimal candidates for MRgLITT, and larger cohorts are needed to more accurately define outcome and complication rates.

Summary Objective There are limited data on the indications for the use of chronic invasive electroencephalography (EEG) monitoring (IEM) for pediatric epilepsy surgery. Methods We retrospectively studied 102 children who underwent intracranial monitoring to map critical cortex, localize the epileptogenic region, or resolve divergent findings. We assessed IEM utility based on changes to the resection plan following analysis of noninvasive data. Results IEM was judged useful in 87% of cases and had greatest utility for resolving discordant data and localizing extratemporal and multilobar epileptogenic zones. IEM data were least useful for seizure onset in the temporal lobe and had little utility for direct cortical stimulation mapping unless functional magnetic resonance imaging (fMRI) revealed atypical language representation or the epileptogenic zone was in proximity to critical cortex. Significance IEM utility was demonstrated for a majority of cases with well-defined indications. The method of assessing utility will facilitate multicentric studies toward developing future consensus and practice guidelines.

Seizure outcomes in children are typically assessed using the Engel classification system. However, they may be reported at variable duration of follow-up, often a wide range in individual studies. Completeness of resection is the major predictor of seizure freedom for all epilepsy cases; otherwise, positive and negative predictors depend on specific presurgical, surgical, and postsurgical variables. Lobar seizure-free outcomes are variable: frontal (33.7–66 %), insular (about 80 %), occipital (30–69.2 %), parietal (40–82 %), and temporal (63.2–85 %) in the longer term from data available. Rates of seizure freedom in temporal lobe epilepsy (TLE) are better than for extratemporal lobe epilepsy (ETLE) and comparable to adult rates. Hemidisconnection outcomes range from 41 to 83 % which is better than for tailored multilobar approaches. For seizure foci not amenable to focal resection, corpus callosotomy (CC) remains a potential treatment option for children with atonic seizures. Early decisions should be made about weaning of medication to determine which children require antiepileptic drugs (AEDs) in the longer term.

The Commission on Neurosurgery of the International League Against Epilepsy (ILAE) formed the Pediatric Epilepsy Surgery Subcommission in 1998 and charged it with formulating guidelines and recommendations for epilepsy surgery in childhood. Also endorsed by the Commission on Paediatrics, the following document is the consensus agreement after a meeting of 32 individuals from 12 countries in 2003. The panel agreed that insufficient class 1 evidence exists to recommend practice guidelines at this time. Instead, the panel generated criteria concerning the unique features of pediatric epilepsy patients to justify dedicated resources for specialty pediatric surgical centers, suggested guidelines for physicians for when to refer children with refractory epilepsy, and recommendations on presurgical evaluation and postoperative assessments. The panel also outlined areas of agreement and disagreement on which future research and consensus meetings should focus attention to generate practice guidelines and criteria for pediatric epilepsy surgery centers.

Objective: To determine if epilepsy surgery is effective in improving the quality of life (QOL) of children with intractable seizures using the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE). Methods: The authors conducted a prospective study of the families of 35 children with intractable epilepsy who underwent epilepsy surgery. Parents completed the QOLCE preoperatively and again 6 to 18 months after surgery. At both assessment dates parents indicated the severity of their child’s seizures during the past 6 months and the frequency of their child’s seizures during the past 4 weeks on Likert-type scales. Children were split into two groups according to surgery outcome: seizure free vs persistent seizures. Statistical analyses were conducted to determine if children rendered seizure free showed a greater improvement in QOL compared to those with persistent seizures postoperatively. Results: Greater improvement in QOL was documented for children rendered seizure free vs children with persistent seizures. This was significant for the overall QOLCE QOL score and subscales assessing cognitive, social, emotional, behavioral, and physical domains of life. Conclusions: Epilepsy surgery improves the quality of life of children rendered seizure free. Families can be counseled preoperatively of the potential benefits of surgery beyond seizure reduction.

Organogenesis throughout childhood affects almost every aspect of pediatric pharmacotherapy. The antiepileptic drugs (AEDs) are particularly impacted since most elimination rates are diminished for the first 6 months of infancy, but quickly attain and supersede adult values. When children enter a hypermetabolic stage, large doses of AEDs may be necessary to maintain effective serum concentrations. Medication noncompliance is frequently confused as hypermetabolism, since both present with low serum drug concentrations. Amazingly, noncompliance among children with chronic illness approaches a similar incidence to that reported in the adult population. It is obviously important to include this in the differential diagnosis of the etiology of subtherapeutic serum AED concentrations. Maturational differences also affect gastrointestinal drug absorption. Intestinal transit time and absorptive surface area are both diminished in young children. Drug delivery systems suitable in adults may not deliver the total dosage in children. Differences in the composition of body compartments and protein binding can alter the volume of drug distribution and, consequently, serum concentrations. In addition to pathophysiologic changes, there is evidence to suggest differences between a mature and immature brain. These differences include quantitative and qualitative responses to neurotransmitters. Hence, it is understandable why seizure semiology is different in children compared with adults. This constellation of factors contributes to the challenges of caring for children with epilepsy.

The preoperative evaluation of patients with suspected cortical dysplasia involves detailed neurologic and neuropsychologic evaluations, electroencephalography, and comprehensive neuroimaging and functional studies. The goal is to identify a focal region of seizure onset and to assess for motor impairments, speech and language difficulties, or developmental delay. Although the electroencephalogram abnormalities in cortical dysplasia are nonspecific, they typically include unusual high-amplitude (slowing and focal) activity. The association of cortical dysplasia with cardiovascular, dermatologic, and other systemic disorders is discussed.

The molecular mechanism unraveling why a particular type of pediatric brain tumor (pBT) behaves so differently from child to child or genetic/epigenetic changes in the mitochondrial genome vary from tumor to tumor is not clearly understood. Despite the identification of mitochondrial DNA (mtDNA) mutations in different types of pBT, the contribution of mitochondrial dysfunction-related genes or proteins that are selectively up- or down-regulated in pBT of different types has not been comprehensively examined. In the present study, we combined a 2D DIGE approach with protein identification using MALDI-TOF MS and LC–MS/MS, coupled with mtDNA genomics to screen brain samples for discovering changes in protein expression, and mtDNA sequence variation and mtDNA copy number in the disease states. Two-dimensional gel electrophoresis-based differential proteomic analysis of the brain tumors showed that 116 proteins were found to be up- or down-regulated in brain tumors. Some of the proteins up-regulated in tumors compared to controls were dihydropyrimidinase-like 2; glial fibrillary acidic protein isoform 2; phosphoserine aminotransferase isoform 1; Sirt2 histone deacetylase; and C10orf2 protein, mitochondrial DNA helicase. Proteins down-regulated in brain tumors compared to controls were heat shock protein 90 kDa beta, BiP; guanine nucleotide binding protein (G protein), beta polypeptide 2-like 1, isoform CRA_d; histone H2B.1; neurofilament, light polypeptide 68 kDa; Annexin I; and RAN. These differentially expressed proteins may provide useful information for developing molecular markers of diagnostic or prognostic value. To investigate further the role of mitochondrial dysfunction, we examined the effects of mtDNA copy number, oxidative damage, and mtDNA variants as independent or combined risk factors for the development of pBTs. Bayesian network and mechanistic hierarchical structure Markov Chain Monte Carlo (MCMC) modeling were used to analyze the relationship between these variables. The combined effects of G3196, 9952A, 10006G, 100398G, oxidative mtDNA damages, and mtDNA copy number increased the probability of developing brain tumors in female children by 51 times more when compared to normal incidence of pediatric brain tumors. Comparison of mechanistic structure models also supported the finding that female children who have the wild type allele G3196, variant allele 9952A, variant allele 10006G, variant allele10398A, and high mtDNA copy number had increased probability of developing pediatric brain tumors. Estimation of nuclear genes controlling mitochondrial biogenesis and development of brain, cortical dysplasia, and the effect of the environment using MCMC method showed that these latent variables had a very significant contribution in the development of pediatric brain tumors. Together, these results suggest that mitochondrial genome and tumor proteome are important contributors to brain tumor risk in children, and findings from this study may guide the prospects for targeting mitochondria for therapeutic treatment of childhood brain tumor.

Despite that mutations in mitochondrial DNA (mtDNA) have been associated with major epilepsy syndromes, the role of mtDNA instability and mitochondrial dysfunction in epileptogenesis has not been comprehensively examined. In the present study, we investigated the role of mtDNA copy number, oxidative damage, and mtDNA variants as independent or combined risk factors for the development of intractable childhood epilepsy. We analyzed mtDNA copy number and oxidative damage by quantitative polymerase chain reaction (PCR), and mtDNA variants by dot blot in brain tissue specimens collected from 21 pediatric intractable epilepsy patients and 11 non-epileptic patients. Bayesian network and mechanistic hierarchical structure Markov chain Monte Carlo (MCMC) modeling were used to analyze the relationship between these variables. The combined effects of oxidative mtDNA damages and mtDNA copy number produced more significant correlation with epilepsy than that of mtDNA copy number alone with epilepsy. Epilepsy patients showed significant correlations with mtDNA single nucleotide polymorphisms (SNPs) — A1555G, G3196A, T3197C, G9952A, A10006G, A10398G, cortical dysplasia status, oxidative mtDNA damage and relative mtDNA copy number. Comparison of 12 mechanistic structure models suggested that female children who have the wild type allele 10398A and variant allele 9952A, and high mtDNA copy number and oxidative stress have increased probability of developing intractable epilepsy. Estimation of nuclear genes controlling mitochondrial biogenesis, cortical dysplasia, and the effect of the environment using MCMC method showed that these latent variables had a very significant contribution in the development of intractable epilepsy. These data suggest that mitochondrial genetics play a significant role in the pathogenesis of epilepsy in children, and findings of this study may guide the prospects for targeting mitochondria for therapeutic treatment of childhood intractable epilepsy.

Summary Children with intractable epilepsy benefit from early surgical treatment when possible to reduce long-term morbidity. Issues for transition are variable according to type and timing of surgery, and the outcome. When surgery is successful, cognitive and behavioral improvements may not be apparent for several years. The value of continuing antiepileptic drug (AED) treatment after successful surgery remains unclear, and the adjustment to a life without seizures may be challenging.

Many patients who were once considered inoperable are candidates for a wide variety of surgical procedures. This trend is particularly striking at pediatric centers that serve patients with diverse forms of epilepsy that compromise development. Newer diagnostic techniques, including structural and functional imaging, EEG monitoring, and surgical technology, can provide a complete representation of the etiology and expression of the epileptic focus, including accurate cortical localization. This review focuses on several forms of epilepsy that, until recently, were not regarded to be surgically amenable. The adverse seizure and neurobehavioral prognosis in patients with these disorders provides the justification to search for innovative treatments. With more sophisticated tools for preoperative evaluation and an expanding knowledge base, it is likely that the number of surgical candidates will continue to increase in the future.

Malformations of cortical development (MCD) account for a high proportion of medically resistant partial seizures in children and figure prominently in pediatric surgical series. In contrast to the results of epilepsy surgery for postnatally acquired lesions, seizure freedom in patients with MCD is less certain owing to difficulties in defining the epileptic zone, and fully excising the epileptogenic cortex. The authors present evidence that, compared with postnatally acquired lesions such as those due to tumors or trauma, focal epileptogenesis associated with MCD is best conceptualized as a disorder of widespread and patchy disturbance of cortical networks. This developmental perspective implies that the epileptogenic region in MCD is rarely discrete even in patients with focal anatomic lesions, and may include remote cortical or subcortical areas. Preoperative investigative protocols based on this model have improved surgical results, but outcome remains far from optimal and further progress in understanding the complex developmentally based features of MCD is required.

Disorders of cortical development form a spectrum of lesions produced by insults to the developing neocortex. These conditions typically first manifest in childhood with epilepsy, developmental delay, and focal neurologic signs. Although the clinical and electrophysiologic findings are often nonspecific, high-resolution magnetic resonance imaging facilitates diagnosis during life, and assists in delineating specific clinical syndromes. While many patients are dysmorphic and severely affected by mental retardation and epilepsy, some have normal or near-normal cognitive function and no seizures. Molecular studies of dysplastic cortex are providing new insights into the basic mechanisms of brain function and development, while pathologic analysis of tissue removed at surgery is helping to define epileptic circuitry. Treatment of the epilepsy associated with cortical dysplasia is often frustrating, but surgical approaches based on accurately defining epileptogenic regions are proving increasingly successful. Genetic diagnosis is important for accurate counseling of families. (J Child Neurol 1999;14:759-771).