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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.

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.

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.

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.

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.

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.

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.

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.

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.

Partial seizures in early postnatal life may be catastrophic and associated with poor long-term outcome. Epilepsy surgery can alleviate partial seizures in older children and adults, but there is little experience with surgical therapy in infancy apart from hemispheric epilepsy syndromes.We analyzed the results of cortical resection to treat medically refractory partial epilepsy in 31 children (16 boys, 15 girls) aged3 years (mean, 18.3 months). Subjects were included only if seizure relief was the primary indication for surgery.Follow-up of at least 1 year (mean, 4.6 years) in 26 patients revealed that 16 were seizure-free, 4 had90% seizure reduction, and 6 had90% reduction. There was no significant difference in seizure outcome between hemispherectomy/multilobar resections and lobar resections or temporal versus extratemporal resection. Seizure outcome was independent of the amount of cortex removed in nonlesional patients. Only the presence of a discrete lesion on preoperative neuroimaging correlated with a favorable outcome. Family perceptions of accelerated development in seizure-free patients were not confirmed on developmental assessment.We conclude that cortical resection often benefits very young children with catastrophic partial seizures, but does not guarantee enhanced neurological development. The location and extent of the excised cortex may not be critical as long as the entire epileptogenic region and lesion are removed.

Summary Purpose Variable predictors of postsurgical seizure outcome have been reported in children with tuberous sclerosis complex (TSC). We analyzed a large surgical series of pediatric TSC patients in order to identify prognostic factors crucial for selection of subjects for epilepsy surgery. Methods Thirty-three children with TSC who underwent excisional epilepsy surgery at Miami Children's Hospital were retrospectively reviewed. A total of 29 clinical, neuropsychological, electroencephalography (EEG), magnetic resonance imaging (MRI), and surgical variables were analyzed and related to seizure outcomes. Univariate Barnard's exact test, Wilcoxon's rank-sum test, and multivariate statistical Cox's model were used to examine the significance of associations between the variables and seizure outcome. Key Findings Eighteen patients (55%) have been seizure-free 2 years after (final) surgery; postoperative complications occurred in five subjects (15%). Complete removal of epileptogenic tissue detected by both MRI and intracranial EEG, regional scalp interictal EEG patterns, and agreement of interictal and ictal EEG localization were the most powerful predictors of seizure-free outcome. Other significant predictors included occurrence of regional scalp ictal EEG patterns, fewer brain regions affected by tubers, presence of preoperative hemiparesis, and one-stage surgery. Remaining factors such as age at seizure onset, incidence of infantile spasms or other seizure types, duration of epilepsy, seizure frequency, mental retardation, as well as types and extent of resections did not influence outcome. Significance Perioperative features rather than preoperative variables are the most important determinants of postsurgical seizure outcome in patients with TSC. Our findings may assist in the surgical management of these patients.

Summary Purpose To assess the predictive value of ictal single-photon emission computed tomography (SPECT) for outcome after excisional epilepsy surgery in a large population of children with focal cortical dysplasia (FCD). Methods One hundred seventy-three ictal SPECT studies in 106 children with histologically proven FCD were retrospectively analyzed. The extent and location of ictal hyperperfusion and completeness of surgical removal were assessed. Completeness of resection of epileptogenic regions defined by ictal SPECT, electroencephalography (EEG), and magnetic resonance imaging (MRI) were compared and correlated with postoperative seizure outcome. In addition, subcortical activation of the cerebellum, basal ganglia, and thalamus were analyzed. Key Findings The extent of hyperperfusion was focal or lobar in 58%, whereas multilobar activations occurred in only 32%; hemispheric or bilateral findings were rare. Favorable postsurgical seizure outcome was achieved in 67% patients with nonlocalized SPECT findings, 45% with nonresected ictal hyperperfusion, 36% with partially resected ictal hyperperfusion, and 86% when the zone of ictal hyperperfusion was completely resected (p = 0.000198). The favorable postsurgical outcome after complete removal of the SPECT hyperperfusion zone surpassed the 75% rate of seizure freedom in patients with removal of MRI/EEG-defined epileptogenic region. A similar predictive value of ictal SPECT for seizure outcome was found in nonoperated patients and subjects who were undergoing reoperation. Subcortical activation conferred no predictive value. Significance Ictal SPECT helps to define the epileptogenic zone in a high proportion of children with FCD undergoing surgical evaluation. Complete removal of both SPECT and MRI/EEG-defined regions is a strong predictor of surgical success and has important implications for surgical planning.

Summary: The relation between hyperventilation (HV)-induced high-amplitude rhythmical slowing (HIHARS) and altered responsiveness without generalized spike and wave activity has not been clearly defined. To test whether altered responsiveness is a nonspecific physiologic response rather than a symptom of generalized epilepsy, we assessed verbal recall ability and motor response testing in 12 healthy nonepileptic children (mean age 9.6 years). Both tasks were administered as a baseline before HV, during HV but before onset of EEG slowing, and during HIHARS. Verbal recall and motor responsiveness remained unchanged during baseline and HV before onset of slowing. During HIHARS, all children exhibited impaired verbal recall (p

To define the contribution of the EEG evaluation in children with seizures and Sturge-Weber syndrome, we reviewed EEG data in 14 radiologically confirmed cases. Thirteen exhibited marked voltage attenuation that was localized to the region of the cerebral angiomatosis. Polymorphic slowing occurred ipsilateral to the lesion in six patients and was bilateral in six. By contrast, interictal spikes were evident in only two patients and did not always correlate with the angiomatosis. Seizures were captured in four patients and consistently revealed ictal discharges only at the periphery of the lesion. These findings indicate that abnormalities of EEG background rather than interictal spikes are consistently present early in the course of Sturge-Weber syndrome and correlate with the region of angiomatosis.

Dominant mesial temporal lobe resection for pharmacoresistant epilepsy is frequently associated with verbal memory impairment. More-extensive lesioning improves seizure outcome, but further compromises memory. A better understanding of ipsilateral neural structures and networks for verbal memory could improve selectivity of surgical ablation, thereby holding promise for seizure-freedom without memory impairment.

Children with medically resistant temporal lobe seizures that persist into adolescence often experience psychosocial deterioration and medical morbidity. It is therefore especially important to evaluate the contribution of surgical therapy in preadolescent children. We describe our experience with temporal lobectomy in 16 children less than 12 years (mean age 7 years) who had intractable seizures of temporal lobe origin. Structural lesions were identified on neuroimaging studies in 11 patients. In all patients, the standard anterior temporal lobectomy was tailored according to the extent of the lesion and epileptogenic field. At follow-up, 11 children were seizure-free, three were 90% improved, one was 50% improved, and one was unchanged. Neuropathological abnormalities were identified in virtually all children. Prenatally acquired abnormalities of neurogenesis were the most common, whereas mesial temporal sclerosis was found in only two children. We conclude that tailored temporal lobectomy in the first decade of life is highly beneficial in carefully selected children with medically refractory seizures.

There are no reports of an association between obsessive-compulsive disorder and cingulate epilepsy in childhood. We report the behavioral, cognitive, and EEG findings in a young girl with medically resistant seizures and severe obsessive-compulsive symptomatology. Her Scalp EEG and neuropsychological test scores suggested right frontal lobe dysfunction. The intractability of her seizures and progressive intellectual and psychosocial deterioration prompted evaluation for excisional surgery. Intracranial EEG recording demonstrated a focal seizure origin in the right anterior cingulate gyrus. Cingulotomy resulted in freedom from seizures and significant improvement in her obsessive-compulsive symptoms.

Excisional surgery achieves seizure freedom in a large proportion of children with intractable lesional epilepsy, but the outcome for children without a focal lesion on MRI is less clear. We report the outcome of a cohort predominantly of children with nonlesional intractable partial epilepsy undergoing resective surgery.We studied 102 patients with nonlesional intractable partial epilepsy who underwent excisional surgery. The epileptogenic region was identified by integrating clinical exam and video-EEG data complemented by ictal SPECT (n = 40), PET (n = 10), extraoperative subdural monitoring (n = 80), and electrocorticography (n = 22). All patients had follow-up greater than 2 years, 76 patients had 5-year follow-up, and 43 patients had 10-year follow-up.A total of 66 resections were unilobar; 36 were multilobar. One patient died of causes unrelated to seizures or surgery. At 2-year follow-up, 44 of 101 patients were seizure-free, 15 experienced90% reduction, 17 had50% reduction, and 25 were unchanged. At 5-year follow-up, 35 of 76 patients were seizure-free, 12 experienced90% reduction, 12 had50% reduction, and 17 were unchanged. At 10-year follow-up, 16 of 43 patients were seizure-free, 13 experienced90% reduction, 7 had50% reduction, and 7 were unchanged. Outcomes correlated with the presence of convergent focal interictal spikes (p0.005) on the scalp EEG and completeness of resection (p0.0005).Our findings demonstrate that excisional surgery is successful in the majority of children with nonlesional partial epilepsy. A multimodal integrative approach can minimize the size of resection and alleviate the need for invasive EEG monitoring. Focal interictal spikes and completeness of resection predict good outcome. The benefits of surgery are long-lasting.

Objective: To determine the current best practice for treatment of infantile spasms in children. Methods: Database searches of MEDLINE from 1966 and EMBASE from 1980 and searches of reference lists of retrieved articles were performed. Inclusion criteria were the documented presence of infantile spasms and hypsarrhythmia. Outcome measures included complete cessation of spasms, resolution of hypsarrhythmia, relapse rate, developmental outcome, and presence or absence of epilepsy or an epileptiform EEG. One hundred fifty-nine articles were selected for detailed review. Recommendations were based on a four-tiered classification scheme. Results: Adrenocorticotropic hormone (ACTH) is probably effective for the short-term treatment of infantile spasms, but there is insufficient evidence to recommend the optimum dosage and duration of treatment. There is insufficient evidence to determine whether oral corticosteroids are effective. Vigabatrin is possibly effective for the short-term treatment of infantile spasm and is possibly also effective for children with tuberous sclerosis. Concerns about retinal toxicity suggest that serial ophthalmologic screening is required in patients on vigabatrin; however, the data are insufficient to make recommendations regarding the frequency or type of screening. There is insufficient evidence to recommend any other treatment of infantile spasms. There is insufficient evidence to conclude that successful treatment of infantile spasms improves the long-term prognosis. Conclusions: ACTH is probably an effective agent in the short-term treatment of infantile spasms. Vigabatrin is possibly effective.

Summary: Purpose: Children with tuberous sclerosis complex (TSC) benefit from excisional surgery if seizures can be localized to a single tuber. We evaluated the role of noninvasive studies to localize the epileptogenic tuber/region (ET/R) and the outcome of focal resection. Methods: We identified 21 children with TSC, ages 3 months to 15 years (mean 4.8 years). All had video-(electroencephalogram) EEG and magnetic resonance imaging (MRI) scans, and 18 also had ictal single photon emission-computed tomography (SPECT) studies. An ET/R was localized in 17 patients. Thirteen patients underwent resection guided by intraoperative electrocorticography (n = 7) or subdural monitoring (n = 6). Results: Interictal EEG revealed a principal spike focus (PSF) that corresponded to the ET/R in 14 children. In seven, PSFs occurred in rhythmic runs. PSFs were not observed remote from the ET/R. Focal polymorphic slowing and attenuation occurred in the region of the PSF in 11 patients. Sixteen patients demonstrated an ictal focus corresponding to the ET/R. Ictal SPECT revealed focal hyperperfusion correlating with the ET/R in 10 patients. Although the MRIs in all children revealed multiple tubers, the ET/R corresponded to a large discrete tuber in 8 patients and a calcified tuber in 13 patients. Patchy calcified tubers were also seen elsewhere in six patients. At a mean follow-up of 26 months, 9 of the 13 children who underwent surgery were seizure-free, one had greater than 75% reduction in seizures, two were unchanged, and one was lost to follow-up. New seizures developed in one child from a contralateral tuber. Conclusions: Surgical resection of an ET/R alleviates seizures in most children with TSC and intractable epilepsy. The scalp EEG and MRI help define the ET/R and improve case selection when ictal SPECT is nonlocalizing.

Purpose Lamotrigine (LTG) is an antiepileptic drug (AED) recently released in several countries. It is effective for a variety of seizure types in adults and children both as an add-on agent and in monotherapy, and is generally well tolerated. This report reviews the apparent risk factors for rash associated with LTG to determine whether and how the risk of serious rash can be minimized in practice. Methods The panel of experts reviewed all published and unpublished data related to the incidence and risk factors for serious rash with LTG. Results An allergic skin reaction occurs in approximately 10% of patients, usually in the first 8 weeks. Rashes leading to hospitalization, including Stevens-Johnson syndrome and hypersensitivity syndrome, occurred in approximately one of 300 adults and one of 100 children in clinical trials and appeared to be increased with overrapid titration when starting therapy and with concurrent valproate (VPA). Conclusions Recommendations are made for both minimizing the likelihood of serious rash and for management of rash in patients taking LTG. Risk of serious rash may possibly be lessened by strict adherence to manufacturer's dosing guidelines, particularly in patients who are at higher risk: those on concurrent VPA and in the pediatric population.

Epilepsy syndromes occupy an important position in the current nosology of the epilepsies, describing and classifying seizure disorders with shared clinical and EEG features. Increasingly, this schema is being refined as new information becomes available and our understanding of etiology and presentation of each syndrome widens. Advances in neuroimaging and neurogenetics have been particularly important and are likely to fundamentally change our concepts of syndrome classification. At present, the International League Against Epilepsy classification of epilepsy syndromes according to presumed localization (partial, generalized, undetermined) and etiology (idiopathic, cryptogenic, symptomatic). In clinical practice, it is often useful to conceptualize epilepsy syndromes according to their usual age at presentation, which greatly facilitates syndrome identification in new patients and recognizes the age-related expression of many childhood epilepsies. Definitional problems exist for many pediatric epilepsy syndromes, particularly the epileptic encephalopathies of early infancy, the benign epilepsies of infancy and childhood, the myoclonic epilepsies of infancy and early childhood, and the idiopathic generalized epilepsies of childhood and adolescence. It is likely that further input from the fields of molecular genetics and neuroimaging will enable the classification of epilepsies to become more etiologically oriented and disease specific.

Summary: The spikes in benign rolandic epilepsy (BRE) typically involve both the central and midtemporal regions as recorded on standard EEG montages, but the seizures are characterized by sensorimotor manifestations that are rarely referable to the temporal lobe. To study this apparent disparity, we evaluated the field distribution of interictal spikes in 33 BRE patients using closely spaced electrodes (AEEGS 1990) arranged over perisylvian cortex. None of the 33 patients showed maximum negativity in the midtemporal regions (T3/T4). Instead, maximum negativity was evident in the high central region (C3/C4) in 10 children (30.3%) and in the low central region (C5/C6) in 23 (69.7%). Hand involvement was significantly frequent (50%) in the high central group, and drooling with oromotor involvement was a distinctive symptom (65.2%) in the low central group. Our findings indicate that the spikes in patients with BRE are exclusively suprasylvian in origin and correlate with two electroclinical subgroups.

Summary: During the course of a seizure, subdural recordings often show secondary areas which develop in-dependent electrographic sequences that may outlast the primary seizure sequence. We reviewed the subdural data on 8 patients with intraictal secondarily activated foci (ISF). In 6 patients, ISFs were documented to be capable of generating independent seizures; ISF seizures occurred during the initial subdural monitoring period in 3, but became ictal generators only after excision of the primary focus in the other 3. Prominent interictal abnormalities were observed at the ISFs in 5 of 8 patients. The ISF in 1 patient correlated with the structural lesion on magnetic resonance imaging (MRI) scan. We believe that ISFs have significant epileptogenicity and should be re-sected when possible. ReSUMe Pendant l'tvolution d'une crise, des enregistrements sousduraux revelent frequemment des zones secondaires qui dtveloppent des stquences electrographiques indtpendantes qui peuvent durer plus longtemps que la stquence critique primaire. Les auteurs ont revu les donntes sousdurales obtenues chez 8 patients presentant des foyers secondairement activts pendant les crises. Chez 6 patients, ils ont pu prouver que ces foyers ttaient capables de gtnerer des crises indtpendantes; ces crises survenaient pendant la periodes de monitorage sousdural initiale chez 3 patients, mais les foyers ne sont devenus des gtntrateurs de crises qu'apres l'excision du foyer primaire chez les autres 3 patients. Des anomalies intercritiques evidentes etaient observees au niveau de ces foyers chez 5 des 18 patients. Chez 1 patient, ce foyer etait corrCle avec une Iesion structurelle sur l'IRM. Les auteurs pensent que ces foyers actives secondairement pendant les crises presentent une epileptogenicite significative et devraient etre reseques lorsque cela est possible. RESUMEN Durante el curso de un ataque, los registros subdurales con frecuencia revelan Areas secundarias que desarrollan secuencias electrograficas independientes que pueden sobrepasar la frecuencia del ataque primario. Se revisa la informacion subdural en 8 pacientes con focos intraictales secundariamente activados (ISF). En 6 pacientes, los ISF fueron capaces de generar ataques independientes; los ataques ISF ocurrieron durante el period0 inicial de monitorizacion subdural en 3 casos pero se convirtieron en generadores ictales solamente desputs de la excision quirurgica del foco primario en los otros 3 casos. Se observaron anomalias interictales llamativas en los ISFs en 5 de 8 pacientes. Los ISF en 1 enfermo correlacionaron con una lesion estructural en la Resonancia MagnCtica. Los autores estiman que los ISFs poseen una epileptogenicidad significativa y deben ser extirpados siempre que sea posible. ZUSAMMENFASSUNG Wahrend des Verlaufs von Anfallen zeigen subdurale Ableitungen haufig sekundar betroffene Areale, die unabhangig elektroencephalographische Veranderung entwickeln und die primare Anfallsentladung uberdauern. Wir untersuchten die subdural erhobenen Daten von 8 Patienten mit intraictal, sekundar aktivierten Foci (ISF). Bei 6 Patienten erwiesen sich die ISF's als in der Lage befindlich, selbstandige Anaalle auszulosen. Bei 3 Patienten hatten die ISF Anfalle wahrend des initialen subduralen Monitorings auf. Nach Exision des primaren Fokus generierte sie bei 3 Kindern Anfalle. Deutliche ictale Veranderungen in den ISF's Konnten bei 5 von 8 Patienten beobachtet werden. Bei einem Patienten korrilierte der ISF mit einer strukturellen Lasion im MRI. Daraus schliepen wir, dap ISF signifikant epileptisch sind und deshalb wenn maglich ebenfalls resiziert werden sollten.