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The purpose of this study was to prospectively investigate the agreement between the epileptogenic zone(s) (EZ) localization by resting-state functional magnetic resonance imaging (rs-fMRI) and the seizure onset zone(s) (SOZ) identified by intracranial electroencephalogram (ic-EEG) using novel differentiating and ranking criteria of rs-fMRI abnormal independent components (ICs) in a large consecutive heterogeneous pediatric intractable epilepsy population without an a priori alternate modality informing EZ localization or prior declaration of total SOZ number. The EZ determination criteria were developed by using independent component analysis (ICA) on rs-fMRI in an initial cohort of 350 pediatric patients evaluated for epilepsy surgery over a 3-year period. Subsequently, these rs-fMRI EZ criteria were applied prospectively to an evaluation cohort of 40 patients who underwent ic-EEG for SOZ identification. Thirty-seven of these patients had surgical resection/disconnection of the area believed to be the primary source of seizures. One-year seizure frequency rate was collected postoperatively. Among the total 40 patients evaluated, agreement between rs-fMRI EZ and ic-EEG SOZ was 90% (36/40; 95% confidence interval [CI], 0.76–0.97). Of the 37 patients who had surgical destruction of the area believed to be the primary source of seizures, 27 (73%) rs-fMRI EZ could be classified as true positives, 7 (18%) false positives, and 2 (5%) false negatives. Sensitivity of rs-fMRI EZ was 93% (95% CI 78–98%) with a positive predictive value of 79% (95% CI, 63–89%). In those with cryptogenic localization-related epilepsy, agreement between rs-fMRI EZ and ic-EEG SOZ was 89% (8/9; 95% CI, 0.52–99), with no statistically significant difference between the agreement in the cryptogenic and symptomatic localization-related epilepsy subgroups. Two children with negative ic-EEG had removal of the rs-fMRI EZ and were seizure free 1 year postoperatively. Of the 33 patients where at least 1 rs-fMRI EZ agreed with the ic-EEG SOZ, 24% had at least 1 additional rs-fMRI EZ outside the resection area. Of these patients with un-resected rs-fMRI EZ, 75% continued to have seizures 1 year later. Conversely, among 75% of patients in whom rs-fMRI agreed with ic-EEG SOZ and had no anatomically separate rs-fMRI EZ, only 24% continued to have seizures 1 year later. This relationship between extraneous rs-fMRI EZ and seizure outcome was statistically significant (p = 0.01). rs-fMRI EZ surgical destruction showed significant association with postoperative seizure outcome. The pediatric population with intractable epilepsy studied prospectively provides evidence for use of resting-state ICA ranking criteria, to identify rs-fMRI EZ, as developed by the lead author (V.L.B.). This is a high yield test in this population, because no seizure nor particular interictal epilepiform activity needs to occur during the study. Thus, rs-fMRI EZ detected by this technique are potentially informative for epilepsy surgery evaluation and planning in this populatio...

Deep brain stimulation (DBS) has improved the prospects for many individuals with diseases affecting motor control, and recently it has shown promise for improving cognitive function as well. Several studies in individuals with Alzheimer disease and in amnestic rats have demonstrated that DBS targeted to the fimbria-fornix1-3, the region that appears to regulate hippocampal activity, can mitigate defects in hippocampus-dependent memory3-5. Despite these promising results, DBS has not been tested for its ability to improve cognition in any childhood intellectual disability disorder (IDD). IDDs are a pressing concern: they affect as much as 3% of the population and involve hundreds of different genes. We hypothesized that stimulating the neural circuits that underlie learning and memory might provide a more promising route to treating these otherwise intractable disorders than seeking to adjust levels of one molecule at a time. We therefore studied the effects of forniceal DBS in a well-characterized mouse model of Rett Syndrome (RTT), which is a leading cause of intellectual disability in females. Caused by mutations that impair the function of MeCP26, RTT appears by the second year of life, causing profound impairment in cognitive, motor, and social skills along with an array of neurological features7; RTT mice, which reproduce the broad phenotype of this disorder, also show clear deficits in hippocampus-dependent learning and memory and hippocampal synaptic plasticity8-11. Here we show that forniceal DBS in RTT mice rescued contextual fear memory as well as spatial learning and memory. In parallel, forniceal DBS restored in vivo hippocampal long-term potentiation (LTP) and hippocampal neurogenesis. These results indicate that forniceal DBS might mitigate cognitive dysfunction in RTT.

Summary Hypothalamic hamartomas (HHs) present a difficult medical problem, manifested by gelastic seizures, which are often medically intractable. Although existing techniques offer modest surgical outcomes with the potential for significant morbidity, the relatively novel technique of magnetic resonance imaging (MRI)–guided stereotactic laser ablation (SLA) offers a potentially safer, minimally invasive method with high efficacy for the HH treatment. We report here on 14 patients with medically refractory gelastic epilepsy who underwent stereotactic frame–based placement of an MR‐compatible laser catheter (1.6 mm diameter) through a 3.2‐mm twist drill hole. A U.S. Food and Drug Administration (FDA)–cleared laser surgery system (Visualase, Inc.) was utilized to ablate the HH, using real‐time MRI thermometry. Seizure freedom was obtained in 12 (86%) of 14 cases, with mean follow‐up of 9 months. There were no permanent surgical complications, neurologic deficits, or neuroendocrine disturbances. One patient had a minor subarachnoid hemorrhage that was asymptomatic. Most patients were discharged home within 1 day. SLA was demonstrated to be a safe and effective minimally invasive tool in the ablation of epileptogenic HH. Because use of SLA for HH is being adopted by other medical centers, further data will be acquired to help treat this difficult disorder.

Objective: Postoperative resting-state functional magnetic resonance imaging (MRI) in children with intractable epilepsy has not been quantified in relation to seizure outcome. Therefore, its value as a biomarker for epileptogenic pathology is not well understood. Methods: In a sample of children with intractable epilepsy who underwent prospective resting-state seizure onset zone (SOZ)-targeted epilepsy surgery, postoperative resting-state functional MRI (rs-fMRI) was performed 6 to 12 months later. Graded normalization of the postoperative resting-state SOZ was compared to seizure outcomes, patient, surgery, and anatomical MRI characteristics. Results: A total of 64 cases were evaluated. Network-targeted surgery, followed by postoperative rs-fMRI normalization was significantly (p < 0.001) correlated with seizure reduction, with a Spearman rank correlation coefficient of 0.83. Of 39 cases with postoperative rs-fMRI SOZ normalization, 38 (97%) became completely seizure free. In contrast, of the 25 cases without complete rs-fMRI SOZ normalization, only 3 (5%) became seizure free. The accuracy of rs-fMRI as a biomarker predicting seizure freedom is 94%, with 96% sensitivity and 93% specificity. Interpretation: Among seizure localization techniques in pediatric epilepsy, network-targeted surgery, followed by postoperative rs-fMRI normalization, has high correlation with seizure freedom. This study shows that rs-fMRI SOZ can be used as a biomarker of the epileptogenic zone, and postoperative rs-fMRI normalization is a biomarker for SOZ quiescence.

High-frequency oscillations in local field potentials recorded with intracranial EEG are putative biomarkers of seizure onset zones in epileptic brain. However, localized 80-500 Hz oscillations can also be recorded from normal and non-epileptic cerebral structures. When defined only by rate or frequency, physiological high-frequency oscillations are indistinguishable from pathological ones, which limit their application in epilepsy presurgical planning. We hypothesized that pathological high-frequency oscillations occur in a repetitive fashion with a similar waveform morphology that specifically indicates seizure onset zones. We investigated the waveform patterns of automatically detected high-frequency oscillations in 13 epilepsy patients and five control subjects, with an average of 73 subdural and intracerebral electrodes recorded per patient. The repetitive oscillatory waveforms were identified by using a pipeline of unsupervised machine learning techniques and were then correlated with independently clinician-defined seizure onset zones. Consistently in all patients, the stereotypical high-frequency oscillations with the highest degree of waveform similarity were localized within the seizure onset zones only, whereas the channels generating high-frequency oscillations embedded in random waveforms were found in the functional regions independent from the epileptogenic locations. The repetitive waveform pattern was more evident in fast ripples compared to ripples, suggesting a potential association between waveform repetition and the underlying pathological network. Our findings provided a new tool for the interpretation of pathological high-frequency oscillations that can be efficiently applied to distinguish seizure onset zones from functionally important sites, which is a critical step towards the translation of these signature events into valid clinical biomarkers.awx374media15721572971001.

Object The most common cause of cervical spine arthrodesis in the pediatric population is instability related to congenital or traumatic pathology. Instrumenting the cervical spine can be challenging given smaller anatomical structures, less ossified bone, and future growth potential and development. Studies in adult patients have suggested that using screw constructs results in improved outcomes with lower rates of instrumentation failure. However, the pediatric literature is limited to small retrospective series. Based on a review of the literature and their own patient series, the authors report that instrumenting the pediatric cervical spine with screw constructs may be safer and more effective than using wiring techniques. Methods The authors reviewed the existing pediatric cervical spine arthrodesis literature and contributed 31 of their own cases from September 1, 2007, to January 1, 2011. They reviewed 204 abstracts from January 1, 1966, to December 31, 2010, and 80 manuscripts with 883 total patients were included in the review. They recorded demographic, radiographic, and outcomes data—as well as surgical details—with a focus on fusion rates and complications. Patients were then grouped into categories based upon the procedure performed: 1) patients who underwent fusions bridging the occipitocervical junction and 2) patients who underwent fusion of the cervical spine that did not include the occiput, thus including atlantoaxial and subaxial fusions. Patients were further subdivided according to the type of instrumentation used—some had posterior cervical fusion with wiring (with or without rod implantation); others had posterior cervical fusion with screws. Results The entire series comprised 914 patients with a mean age of 8.30 years. Congenital abnormalities were encountered most often (in 55% of cases), and patients had a mean follow-up of 32.5 months. From the entire cohort, 242 patients (26%) experienced postsurgical complications, and 50 patients (5%) had multiple complications. The overall fusion rate was 94.4%. For occipitocervical fusions (N = 285), both screw and wiring groups had very high fusion rates (99% and 95%, respectively, p = 0.08). However, wiring was associated with a higher complication rate. From a sample of 252 patients, 14% of those treated with screw instrumentation had complications, compared with 50% of patients treated with wiring (p < 0.05). In cervical fusions not involving the occipitocervical junction (N = 181), screw constructs had a 99% fusion rate, whereas wire instrumentation only had an 83% fusion rate (p < 0.05). Similarly, patients who underwent screw fixation had a lower complication profile (15%) when compared with those treated with wiring constructs (54%, p < 0.05). Conclusions The results of this study are limited by variations in construct design, use of orthoses, follow-up duration, and newer adjuvant products promoting fusions. However, a literature review and the authors' own series of pediatric cases suggest that instrumentation of the cervical spine in children may be safer and more efficacious using screw constructs rather than wiring techniques.

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