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OBJECTIVE The aim of this study was to assess the safety and efficacy of combined active responsive neurostimulation (RNS) and vagus nerve stimulation (VNS) therapies in pediatric patients with drug-resistant epilepsy. METHODS A single-center retrospective chart review was conducted on pediatric patients implanted with the RNS System with a concomitant active VNS System (VNS+RNS) between 2015 and 2021. Patients with at least 1 month of overlapping concomitant VNS and RNS treatment were included. Patients who had an RNS device implanted after 21 years of age, those who had responsive neurostimulators implanted after their VNS was inactivated, or those in whom the VNS battery died and was not replaced before RNS System implantation were excluded. RESULTS Seven pediatric VNS+RNS patients were identified, and their courses of treatment were evaluated. All patients tolerated concurrent VNS and RNS treatment well, no device-device interactions were identified, and no major treatment-related adverse effects were noted. The median follow-up after RNS System implantation was 1.2 years. By electroclinical criteria, all 7 patients achieved 75%–99% reductions in the frequency of disabling seizures after RNS System implantation. By patient and caregiver report, 2 patients (28.6%) had 75%–99% reductions in the frequency of their disabling seizures, 2 patients (28.6%) achieved 50%–74% reductions, 2 patients achieved 1%–24% reduction in frequency of disabling seizures, and 1 patient (14.3%) experienced a 1%–24% increase in seizure frequency. The available VNS magnet swipe data identified 2 patients with 75%–99% reductions in seizure frequency as measured by magnet swipes, one with 25%–49% reductions and the other with 1%–24% increases in seizure frequency as measured by magnet swipes. CONCLUSIONS This study demonstrated that RNS and VNS therapies can safely be used simultaneously in pediatric patients. RNS may potentially augment the therapeutic effects of VNS treatment. Patients in whom a response to VNS has been suboptimal should still be considered for RNS therapy.

Intraoperative neuromonitoring (IONM) has been used in neurosurgical procedures to assess patient safety and minimize risk of neurological deficit. However, its use in decompressive surgeries of Chiari malformation type I (CM-I) remains a topic of debate. Here we present the case of a 5-year-old girl who presented with acute right lower extremity monoplegia after accidental self-induced hyperflexion of the neck while playing. Imaging revealed 15 mm of tonsillar ectopia with cervical and upper thoracic spinal cord edema. She was taken to surgery for a suboccipital decompression with expansile duraplasty. IONM demonstrated improvement in motor evoked potentials during the decompression. Postoperatively, she had full recovery of strength and mobility. This is a case of acute weakness after mild trauma in the setting of previously asymptomatic CM-I that showed close correlation with IONM, clinical findings, and imaging. IONM during decompressive surgery for CM-I may be useful in patients who present acutely with cervical cord edema.

OBJECTIVE The authors of this study evaluated the safety and efficacy of stereotactic laser ablation (SLA) for the treatment of drug-resistant epilepsy (DRE) in children. METHODS Seventeen North American centers were enrolled in the study. Data for pediatric patients with DRE who had been treated with SLA between 2008 and 2018 were retrospectively reviewed. RESULTS A total of 225 patients, mean age 12.8 ± 5.8 years, were identified. Target-of-interest (TOI) locations included extratemporal (44.4%), temporal neocortical (8.4%), mesiotemporal (23.1%), hypothalamic (14.2%), and callosal (9.8%). Visualase and NeuroBlate SLA systems were used in 199 and 26 cases, respectively. Procedure goals included ablation (149 cases), disconnection (63), or both (13). The mean follow-up was 27 ± 20.4 months. Improvement in targeted seizure type (TST) was seen in 179 (84.0%) patients. Engel classification was reported for 167 (74.2%) patients; excluding the palliative cases, 74 (49.7%), 35 (23.5%), 10 (6.7%), and 30 (20.1%) patients had Engel class I, II, III, and IV outcomes, respectively. For patients with a follow-up ≥ 12 months, 25 (51.0%), 18 (36.7%), 3 (6.1%), and 3 (6.1%) had Engel class I, II, III, and IV outcomes, respectively. Patients with a history of pre-SLA surgery related to the TOI, a pathology of malformation of cortical development, and 2+ trajectories per TOI were more likely to experience no improvement in seizure frequency and/or to have an unfavorable outcome. A greater number of smaller thermal lesions was associated with greater improvement in TST. Thirty (13.3%) patients experienced 51 short-term complications including malpositioned catheter (3 cases), intracranial hemorrhage (2), transient neurological deficit (19), permanent neurological deficit (3), symptomatic perilesional edema (6), hydrocephalus (1), CSF leakage (1), wound infection (2), unplanned ICU stay (5), and unplanned 30-day readmission (9). The relative incidence of complications was higher in the hypothalamic target location. Target volume, number of laser trajectories, number or size of thermal lesions, or use of perioperative steroids did not have a significant effect on short-term complications. CONCLUSIONS SLA appears to be an effective and well-tolerated treatment option for children with DRE. Large-volume prospective studies are needed to better understand the indications for treatment and demonstrate the long-term efficacy of SLA in this population.

Background: Evidence regarding the utilization and outcomes of endovascular thrombectomy (EVT) for pediatric ischemic stroke is limited, and justification for its use is largely based on extrapolation from clinical benefits observed in adults. Methods: Weighted discharge data from the National Inpatient Sample were queried to identify pediatric patients with ischemic stroke ( Results: Among 7365 pediatric patients with ischemic stroke identified, 190 (2.6%) were treated with EVT. Utilization significantly increased in the post-EVT clinical trial era (2016–2019; 1.7% versus 4.0%; P P P =0.830; adjusted hazard ratio, 1.01 [95% CI, 0.51–2.03]; P =0.972 for unfavorable outcome). Among patients with baseline National Institutes of Health Stroke Scale score >11 (75th percentile of scores in cohort), EVT-treated patients trended toward higher rates of favorable functional outcomes compared with those treated medically only (71.4% versus 55.6%; P =0.146). In a subcohort assessment of EVT-treated patients, those administered preceding thrombolytic therapy (n=79, 41.6%) trended toward higher rates of favorable functional outcomes (63.3% versus 49.5%; P =0.060). Conclusions: This cross-sectional evaluation of the clinical course and short-term outcomes of pediatric patients with ischemic stroke treated with EVT demonstrates that EVT is likely a safe modality which confers high rates of favorable functional outcomes.

We report the first quantitative systematic review of cerebrovascular disease in coronavirus disease 2019 (COVID-19) to provide occurrence rates and associated mortality. Through a comprehensive search of PubMed we identified 8 cohort studies, 5 case series, and 2 case reports of acute cerebrovascular disease in patients with confirmed COVID-19 diagnosis. Our first meta-analysis utilizing the identified publications focused on comorbid cerebrovascular disease in recovered and deceased patients with COVID-19. We performed 3 additional meta-analyses of proportions to produce point estimates of the mortality and incidence of acute cerebrovascular disease in COVID-19 patients. Patient's with COVID-19 who died were 12.6 times more likely to have a history of cerebrovascular disease. We estimated an occurrence rate of 2.6% (95% confidence interval, 1.2-5.4%) for acute cerebrovascular disease among consecutively admitted patients with COVID-19. While for those with severe COVID-19' we estimated an occurrence rate of 6.5% (95% confidence interval, 4.4-9.6%). Our analysis estimated a rate of 35.5% for in-hospital mortality among COVID-19 patients with concomitant acute cerebrovascular disease. This was consistent with a mortality rate of 34.0% which we obtained through an individual patient analysis of 47 patients derived from all available case reports and case series. COVID-19 patients with either acute or chronic cerebrovascular disease have a high mortality rate with higher occurrence of cerebrovascular disease in patients with severe COVID-19.

BACKGROUND AND PURPOSE: Embolization of the middle meningeal artery for treatment of refractory or recurrent chronic subdural hematomas has gained momentum during the past few years. Little has been reported on the use of the n-BCA liquid embolic system for middle meningeal artery embolization. We present the technical feasibility of using diluted n-BCA for middle meningeal artery embolization. MATERIALS AND METHODS: We sought to examine the safety and technical feasibility of the diluted n-BCA liquid embolic system for middle meningeal artery embolization. Patients with chronic refractory or recurrent subdural hematomas were prospectively enrolled from September 2019 to June 2020. The primary outcome was the safety and technical feasibility of the use of diluted n-BCA for embolization of the middle meningeal artery. The secondary end point was the efficacy in reducing hematoma volume. RESULTS: A total of 16 patients were prospectively enrolled. Concomitant burr-hole craniotomies were performed in 12 of the 16 patients. Two patients required an operation following middle meningeal artery embolization for persistent symptoms. The primary end point was met in 100% of cases in which there were no intra- or postprocedural complications. Distal penetration of the middle meningeal artery branches was achieved in all the enrolled cases. A 7-day post–middle meningeal artery embolization follow-up head CT demonstrated improvement (>50% reduction in subdural hematoma volume) in 9/15 (60%) patients, with 6/15 (40%) showing an unchanged or stable subdural hematoma. At day 21, available CT scans demonstrated substantial further improvement (>75% reduction in subdural hematoma volume). CONCLUSIONS: Embolization of the middle meningeal artery using diluted n-BCA and ethiodized oil (1:6) is safe and feasible from a technical standpoint. The use of a dextrose 5% bolus improves distal penetration of the glue.

OBJECTIVEPatients with shunted hydrocephalus often accumulate high levels of radiation over their lifetimes during evaluation of hardware integrity. Current practice involves the use of a series of conventional radiographs for this purpose. Newer low-dose EOS radiography is currently used to evaluate scoliosis but has not been explored to evaluate shunt integrity on a large scale. The goal of this study was to compare the quality of imaging using EOS low-dose radiography to conventional radiography to evaluate shunt tubing.METHODSA retrospective chart review was performed on 57 patients who previously had both conventional radiographs and low-dose EOS images of their cerebral shunt tubing from 2000 to 2018. Patient demographics (age, sex, type of shunt tubing, primary diagnosis) were collected. Conventional radiographic images and low-dose EOS images were independently analyzed by a neurosurgeon and neuroradiologist in three categories: image quality, delineation of shunt, and distinction of shunt compared to adjacent anatomy.RESULTSAll patients had shunted hydrocephalus due to spina bifida and Chiari type II malformation. Ratings of EOS and conventional radiographic images by both raters did not differ significantly in terms of image quality (rater 1, p = 0.499; rater 2, p = 0.578) or delineation of shunt (p = 0.107 and p = 0.256). Conventional radiographic images received significantly higher ratings than EOS on the ability to distinguish the shunt versus adjacent anatomy by rater 1 (p = 0.039), but not by rater 2 (p = 0.149). The overall score of the three categories combined was not significantly different between EOS and conventional radiography (rater 1, p = 0.818; rater 2, p = 0.186). In terms of cost, an EOS image was less costly than a conventional radiography shunt series ($236–$366 and $1300–$1547, respectively). The radiation dose was also lower for EOS images, with an effective dose of 0.086–0.140 mSv compared to approximately 1.6 mSv for a similar field of view with conventional radiography.CONCLUSIONSThe image quality of low-dose EOS radiography does not significantly differ from conventional radiography for the evaluation of cerebral shunts. In addition, EOS affords a much lower radiation dose and a lower cost.

Background Aneurysmal ruptures typically cause subarachnoid bleeding with intraparenchymal and intraventricular extension. However, rare instances of acute aneurysmal ruptures present with concomitant, non-traumatic subdural hemorrhage (SDH). We explored the incidence and difference in outcomes of SDH with aneurysmal subarachnoid hemorrhage (aSAH) as compared with aSAH alone. Methods Retrospective cohort study from 2012 to 2015 from the National (Nationwide) Inpatient Sample (NIS) (20% stratified sample of all hospitals in the United States). NIS database (2012 to September 2015) queried to identify all patients presenting with aSAH. From this population, the patients with concomitant SDH were identified. Results A total of 10 075 patients with both cerebral aneurysms and aSAH were included. Of these, 335 cases of concomitant SDH and aSAH were identified. There was no significant change in the rate of SDH in aSAH over time. SDH with aSAH patients had a mortality of 24% compared with 12% (p=0.003) in the SAH only group, and only 16% were discharged home vs 37% (p=0.003) in the SAH group. Conclusions There is a 3.5% incidence of acute SDH in patients presenting with non-traumatic aSAH. Patients with SDH and aSAH have nearly double the mortality, higher rate of discharge to nursing home and rehabilitation, and a significantly lower rate of discharge to home and return to routine functioning. This information is useful in counseling and prognostication of patients with concomitant SDH and aSAH.

OBJECTIVETo determine resection margins near eloquent tissue, electrical cortical stimulation (ECS) mapping is often used with visual naming tasks. In recent years, auditory naming tasks have been found to provide a more comprehensive map. Differences in modality-specific language sites have been found in adult patients, but there is a paucity of research on ECS language studies in pediatric patients. The goals of this study were to evaluate word-finding distinctions between visual and auditory modalities and identify which cortical subregions most often contain critical language function in a pediatric population.METHODSTwenty-one pediatric patients with epilepsy or temporal lobe pathology underwent ECS mapping using visual (n = 21) and auditory (n = 14) tasks. Fisher’s exact test was used to determine whether the frequency of errors in the stimulated trials was greater than the patient’s baseline error rate for each tested modality and subregion.RESULTSWhile the medial superior temporal gyrus was a common language site for both visual and auditory language (43.8% and 46.2% of patients, respectively), other subregions showed significant differences between modalities, and there was significant variability between patients. Visual language was more likely to be located in the anterior temporal lobe than was auditory language. The pediatric patients exhibited fewer parietal language sites and a larger range of sites overall than did adult patients in previously published studies.CONCLUSIONSThere was no single area critical for language in more than 50% of patients tested in either modality for which more than 1 patient was tested (n > 1), affirming that language function is plastic in the setting of dominant-hemisphere pathology. The high rates of language function throughout the left frontal, temporal, and anterior parietal regions with few areas of overlap between modalities suggest that ECS mapping with both visual and auditory testing is necessary to obtain a comprehensive language map prior to epileptic focus or tumor resection.

OBJECTIVEDespite significant advances in diagnostic and surgical techniques, the surgical management of Chiari malformation type I (CM-I) with associated syringomyelia remains controversial, and the type of surgery performed is surgeon dependent. This study’s goal was to determine the feasibility of a prospective, multicenter, cohort study for CM-I/syringomyelia patients and to provide pilot data that compare posterior fossa decompression and duraplasty (PFDD) with and without tonsillar reduction.METHODSParticipating centers prospectively enrolled children suffering from both CM-I and syringomyelia who were scheduled to undergo surgical decompression. Clinical data were entered into a database preoperatively and at 1–2 weeks, 3–6 months, and 1 year postoperatively. MR images were evaluated by 3 independent, blinded teams of neurosurgeons and neuroradiologists. The primary endpoint was improvement or resolution of the syrinx.RESULTSEight clinical sites were chosen based on the results of a published questionnaire intended to remove geographic and surgeon bias. Data from 68 patients were analyzed after exclusions, and complete clinical and imaging records were obtained for 55 and 58 individuals, respectively. There was strong agreement among the 3 radiology teams, and there was no difference in patient demographics among sites, surgeons, or surgery types. Tonsillar reduction was not associated with > 50% syrinx improvement (RR = 1.22, p = 0.39) or any syrinx improvement (RR = 1.00, p = 0.99). There were no surgical complications.CONCLUSIONSThis study demonstrated the feasibility of a prospective, multicenter surgical trial in CM-I/syringomyelia and provides pilot data indicating no discernible difference in 1-year outcomes between PFDD with and without tonsillar reduction, with power calculations for larger future studies. In addition, the study revealed important technical factors to consider when setting up future trials. The long-term sequelae of tonsillar reduction have not been addressed and would be an important consideration in future investigations.

Cortical tubers associated with tuberous sclerosis complex (TSC) are potential epileptic foci that are often amenable to resective or ablative surgeries, and controlling seizures at a younger age may lead to improved functional outcomes. MRI-guided laser interstitial thermal therapy (MRgLITT) has become a popular minimally invasive alternative to traditional craniotomy. Benefits of MRgLITT include the ability to monitor the ablation in real time, a smaller incision, shorter hospital stay, reduced blood loss, and reduced postoperative pain. To place the laser probe for LITT, however, stereotaxy is required—which classically involves head fixation with cranial pins. This creates a relative minimum age limit of 2 years old because it demands a mature skull and fused cranial sutures. A novel technique is presented for the application of MRgLITT in a 6-month-old infant for the treatment of epilepsy associated with TSC. To the authors’ knowledge this is the youngest patient treated with laser ablation. The authors used a frameless navigation technique with a miniframe tripod system and intraoperative reference points. This technique expands the application of MRgLITT to younger patients, which may lead to safer surgical interventions and improved outcomes for these children.

OBJECTIVE Postoperative hydrocephalus occurs in one-third of children after posterior fossa tumor resection. Although models to predict the need for CSF diversion after resection exist for preoperative variables, it is unknown which postoperative variables predict the need for CSF diversion. In this study, the authors sought to determine the clinical and radiographic predictors for CSF diversion in children following posterior fossa tumor resection. METHODS This was a retrospective cohort study involving patients ≤ 18 years of age who underwent resection of a primary posterior fossa tumor between 2000 and 2018. The primary outcome was the need for CSF diversion 6 months after surgery. Candidate predictors for CSF diversion including age, race, sex, frontal occipital horn ratio (FOHR), tumor type, tumor volume and location, transependymal edema, papilledema, presence of postoperative intraventricular blood, and residual tumor were evaluated using a best subset selection method with logistic regression. RESULTS Of the 63 included patients, 26 (41.3%) had CSF diversion at 6 months. Patients who required CSF diversion had a higher median FOHR (0.5 vs 0.4) and a higher percentage of postoperative intraventricular blood (30.8% vs 2.7%) compared with those who did not. A 0.1-unit increase in FOHR or intraventricular blood was associated with increased odds of CSF diversion (OR 2.9 [95% CI 1.3–7.8], p = 0.02 and OR 20.2 [95% CI 2.9–423.1], p = 0.01, respectively) with an overfitting-corrected concordance index of 0.68 (95% CI 0.56–0.80). CONCLUSIONS The preoperative FOHR and postoperative intraventricular blood were significant predictors of the need for permanent CSF diversion within 6 months after posterior fossa tumor resection in children.

INTRODUCTION There are increasing reports of a pediatric multi-system inflammatory syndrome associated with coronavirus disease 2019 (COVID-19) that presents with varying clinical features, but includes features of Kawasaki disease or toxic shock syndrome. Symptoms include fever, rash, abdominal pain, vomiting, and diarrhea. Many patients present without any respiratory symptoms and testing for SARS-CoV-2 is often negative. METHODS A retrospective chart review was performed. RESULTS A 7-year-old previously healthy male presented with 3 days of fevers up to 102.4F, headaches, abdominal pain, and intractable vomiting. Both parents had tested positive for SARS-CoV-2 four weeks prior. Nasopharyngeal swab tested positive for SARS-CoV-2 RNA. Echocardiogram was normal. CT venogram of his head was negative for any pathology. He developed severe neck pain and persistent headache during his hospitalization. Soon after receiving hydroxychloroquine, he developed a facial rash and altered mental status with episodes of aphasia, agitation, and pinpoint pupils. He then became unresponsive with left gaze deviation. A non-contrast head CT and CT angiography were negative. He was given levetiracetam and cefazolin and transferred to the pediatric intensive care unit. An electroencephalogram (EEG) showed no epileptiform activity. Over the following 7 hours, the EEG demonstrated left frontotemporal slowing, which progressed into a loss of fast activity over the right hemisphere with increased delta activity in the left hemisphere, then abruptly changed to generalized voltage attenuation.He rapidly lost brainstem reflexes, developing fixed and dilated pupils. Repeat CT scan revealed diffuse cerebral edema with loss of gray-white differentiation. Lab results then were consistent with severe inflammation. An intracranial pressure monitor revealed pressures greater than 76 mmHg. His exam soon became consistent with brain death. Pathologic evaluation showed diffuse cerebral edema with perivascular mononuclear infiltrates. CONCLUSION The cause of this pediatric multi-system inflammatory syndrome is unclear and the mechanism by which SARS-CoV-2 affects the nervous system is unknown. Pediatric patients with COVID-19 and neurologic symptoms should be closely monitored as they can rapidly decline due to fulminant cerebral edema.

Coronavirus disease 2019 (COVID-19) is associated with a high inflammatory burden that can induce severe respiratory disease among other complications; vascular and neurological damage has emerged as a key threat to COVID-19 patients. Risk of severe infection and mortality increases with age, male sex, and comorbidities including cardiovascular disease, hypertension, obesity, diabetes, and chronic pulmonary disease. We review clinical and neuroradiological findings in five patients with COVID-19 who suffered severe neurological disease and illustrate the pathological findings in a 7-year-old boy with COVID-19-induced encephalopathy whose brain tissue sample showed angiocentric mixed mononuclear inflammatory infiltrate. We summarize the structural and functional properties of the virus including the molecular processes that govern the binding to its membrane receptors and cellular entry. In addition, we review clinical and experimental evidence in patients and animal models that suggests coronaviruses enter into the central nervous system (CNS), either via the olfactory bulb or through hematogenous spread. We discuss suspected pathophysiological mechanisms including direct cellular infection and associated recruitment of immune cells and neurovirulence, at least in part, mediated by cytokine secretion. Moreover, contributing to the vascular and neurological injury, coagulopathic disorders play an important pathogenic role. We survey the molecular events that contribute to the thrombotic microangiopathy. We describe the neurological complications associated with COVID-19 with a focus on the potential mechanisms of neurovascular injury. Our thesis is that following infection, three main pathophysiological processes-inflammation, thrombosis, and vascular injury-are responsible for the neurological damage and diverse pathology seen in COVID-19 patients.

Premature fusion of the cranial sutures can lead to significant neurocognitive, developmental, and esthetic consequences, especially if not corrected within the first year of life. This study aimed to identify the drivers of delayed cranial vault reconstruction (CVR) and its impact on complication and 30-day readmission rates among craniosynostosis patients.The medical records of all children who underwent CVR for craniosynostosis between 2005 and 2017 at an academic institution were retrospectively reviewed. A delay in operation was defined by surgery performed12 months of age. Patient demographics, comorbidities, perioperative complication rates, and 30-day readmission rates were collected.A total of 96 patients underwent primary CVR, with 79 (82.3%) patients undergoing nondelayed surgery and 17 (17.7%) patients undergoing surgery12 months of age. Children undergoing delayed surgery were significantly more likely to be non-White (P 0.0001), have Medicaid insurance (P = 0.023), and have a non-English primary language (P 0.005). There was increased incidence of developmental disability identified at first consult (no-delay: 3.9% vs delay: 41.2%, P 0.0001) and increased intracranial pressure (no-delay: 6.3% vs delay: 29.4%, P 0.005) among children undergoing delayed surgery. The delayed cohort had a significantly higher unplanned 30-day readmission rate (no-delay: 0.0% vs delay: 5.9%, P = 0.03).Our study suggests that craniosynostosis patients who are non-White, have a non-English primary language, and have Medicaid insurance are at risk for delayed primary surgery, which may lead to increased 30-day readmission. Interventions are necessary to reduce craniosynostosis patients' barriers to care to minimize the sequelae associated with delayed surgery.

Chronic injury to the brain from seizure activity is associated with decreased language skills in pediatric patients, as measured on neuropsychological tests for language function and academic achievement. This makes the study of language in patients with epilepsy clinically necessary. Functional magnetic resonance imaging and direct electrical cortical stimulation have been used to evaluate aspects of cortical language processing in healthy adults and in adults with epilepsy or other neurological insults. Results of these studies help to locate cortical language areas that are involved with modality-specific language processing (visual naming, auditory naming, sentence-completion, and repetition) and the neuroplasticity of language areas in the setting of neurological injury and reorganization. A better understanding of language processing contributes to a more efficient and efficacious electrical cortical stimulation mapping of language areas for patients with intractable epilepsy who are undergoing preresection evaluation. Most of the current literature on localization and reorganization of cortical language areas in the setting of epilepsy concerns the adult patient population, whereas the literature on pediatric patients is substantially lacking in comparison. This article reviews the conclusions drawn thus far from Wada, magnetoencephalography, functional magnetic resonance imaging, and electrical cortical stimulation language studies on types of language reorganization seen in pediatric patients with intractable temporal lobe epilepsy and the clinical factors associated with reorganization, and proposes future directions of research to further the academic and clinical understanding of language processing in pediatric patients.

OBJECTIVE Medically refractory epilepsy is a debilitating disorder that is particularly challenging to treat in patients who have already failed a surgical resection. Evidence regarding outcomes of further epilepsy surgery is limited to small case series and reviews. Therefore, our group performed the first quantitative meta-analysis of the literature from the past 30 years to assess for rates and predictors of successful reoperations. METHODS A PubMed search was conducted for studies reporting outcomes of repeat epilepsy surgery. Studies were excluded if they reported fewer than five eligible patients or had average follow-ups < 1 year, and patients were excluded from analysis if they received a nonresective intervention. Outcomes were stratified by each variable of interest, and quantitative meta-analysis was performed to generate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS Seven hundred eighty-two patients who received repeat resective epilepsy surgery from 36 studies were included. Engel I outcome was observed in 47% (n = 369) of patients. Significant predictors of seizure freedom included congruent over noncongruent electrophysiology data (OR = 3.6, 95% CI = 1.6-8.2), lesional over nonlesional epilepsy (OR = 3.2, 95% CI = 1.9-5.3), and surgical limitations over disease-related factors associated with failure of the first surgery (OR = 2.6, 95% CI = 1.3-5.3). Among patients with at least one of these predictors, seizure freedom was achieved in 58%. Conversely, the use of invasive monitoring was associated with worse outcome (OR = 0.4, 95% CI = 0.2-0.9). Temporal lobe over extratemporal/multilobe resection (OR = 1.5, 95% CI = 0.8-3.0) and abnormal over normal preoperative magnetic resonance imaging (OR = 1.9, 95% CI = 0.6-5.4) showed nonsignificant trends toward seizure freedom. SIGNIFICANCE This analysis supports considering further resection in patients with intractable epilepsy who continue to have debilitating seizures after an initial surgery, especially in the context of factors predictive of a favorable outcome.

Fulminant idiopathic intracranial hypertension (FIIH) is a subtype of idiopathic intracranial hypertension (IIH) characterized by rapid, severe, progressive vision loss. Surgical intervention is often performed either as a cerebrospinal fluid (CSF) shunt procedure or an optic nerve sheath fenestration or, at times, both. These surgical procedures carry a significant risk of morbidity and failure. We present 2 patients in whom a temporary lumbar drain was successfully used in the management of medically undertreated pediatric FIIH, and circumvented the need for surgical intervention.

OBJECTIVEThis study aimed to assess the safety and efficacy of MR-guided stereotactic laser ablation (SLA) therapy in the treatment of pediatric brain tumors.METHODSData from 17 North American centers were retrospectively reviewed. Clinical, technical, and radiographic data for pediatric patients treated with SLA for a diagnosis of brain tumor from 2008 to 2016 were collected and analyzed.RESULTSA total of 86 patients (mean age 12.2 ± 4.5 years) with 76 low-grade (I or II) and 10 high-grade (III or IV) tumors were included. Tumor location included lobar (38.4%), deep (45.3%), and cerebellar (16.3%) compartments. The mean follow-up time was 24 months (median 18 months, range 3–72 months). At the last follow-up, the volume of SLA-treated tumors had decreased in 80.6% of patients with follow-up data. Patients with high-grade tumors were more likely to have an unchanged or larger tumor size after SLA treatment than those with low-grade tumors (OR 7.49, p = 0.0364). Subsequent surgery and adjuvant treatment were not required after SLA treatment in 90.4% and 86.7% of patients, respectively. Patients with high-grade tumors were more likely to receive subsequent surgery (OR 2.25, p = 0.4957) and adjuvant treatment (OR 3.77, p = 0.1711) after SLA therapy, without reaching significance. A total of 29 acute complications in 23 patients were reported and included malpositioned catheters (n = 3), intracranial hemorrhages (n = 2), transient neurological deficits (n = 11), permanent neurological deficits (n = 5), symptomatic perilesional edema (n = 2), hydrocephalus (n = 4), and death (n = 2). On long-term follow-up, 3 patients were reported to have worsened neuropsychological test results. Pre-SLA tumor volume, tumor location, number of laser trajectories, and number of lesions created did not result in a significantly increased risk of complications; however, the odds of complications increased by 14% (OR 1.14, p = 0.0159) with every 1-cm3 increase in the volume of the lesion created.CONCLUSIONSSLA is an effective, minimally invasive treatment option for pediatric brain tumors, although it is not without risks. Limiting the volume of the generated thermal lesion may help decrease the incidence of complications.

Background/Aims: We performed a morphometric analysis of Chiari I malformations to look for predictors of cervical syrinx formation. Methods: Eighteen patients with Chiari I malformation and associated cervical syrinx and 16 patients with Chiari I malformation without associated cervical syrinx were included in the study. Chiari I size was obtained from the radiology report; foramen magnum diameter, cerebellar volume, posterior fossa volume and intracranial volume were calculated using OsiriX software, and average measurements were compared between the two groups. Results and Conclusion: Patients with Chiari I with syrinx had an average tonsillar descent of 13.03 ± 5.31 mm compared to 9.25 ± 3.31 mm in the Chiari I without syrinx group (p < 0.05). Patients with Chiari I and syrinx also showed increased cerebellar crowding with a higher cerebellar volume to posterior fossa volume ratio; however, this difference was not significant (0.83 vs. 0.81; p = 0.1872). No difference between groups was found in posterior fossa volume, intracranial volume and foramen magnum diameter. Therefore, only Chiari I size based on the extent of tonsillar herniation was found to be a determinant of cervical syrinx formation.

BACKGROUND Certain intrauterine risk factors are known to increase the risk of premature cranial suture fusion and may cause complications during birth. Some of these risk factors may be modifiable. Therefore, the authors sought to characterize the institutional patterns of prenatal risk factors and perinatal complications in nonsyndromic craniosynostosis patients compared to normal births from the surrounding area to identify areas for possible intervention or prevention. METHODS The medical records of all infants with nonsyndromic craniosynostosis and full birth records born at Duke University Health System from 2006 to 2017 were retrospectively reviewed. Maternal comorbidities, prenatal risk factors, and perinatal complications were collected. The North Carolina State Center for Health Statistics was queried for perinatal statistics from Durham county and the Northeastern Perinatal Care Region to represent a control cohort of normal births from the same time period and region. The primary outcome investigated was the incidence of prenatal risk factors and complications at birth associated with premature fusion of cranial sutures. RESULTS Eighty births with nonsyndromic craniosynostosis were included in this study. The majority of these patients were males (61.7%) and born via cesarean section (55.0%). Intrauterine growth restriction occurred in 10.0% and head trauma during delivery occurred in 2.5%. Twinning (14.8% vs 3.6%, P

OBJECTIVEIn children, the repair of skull defects arising from decompressive craniectomy presents a unique set of challenges. Single-center studies have identified different risk factors for the common complications of cranioplasty resorption and infection. The goal of the present study was to determine the risk factors for bone resorption and infection after pediatric cranioplasty.METHODSThe authors conducted a multicenter retrospective case study that included all patients who underwent cranioplasty to correct a skull defect arising from a decompressive craniectomy at 13 centers between 2000 and 2011 and were less than 19 years old at the time of cranioplasty. Prior systematic review of the literature along with expert opinion guided the selection of variables to be collected. These included: indication for craniectomy; history of abusive head trauma; method of bone storage; method of bone fixation; use of drains; size of bone graft; presence of other implants, including ventriculoperitoneal (VP) shunt; presence of fluid collections; age at craniectomy; and time between craniectomy and cranioplasty.RESULTSA total of 359 patients met the inclusion criteria. The patients’ mean age was 8.4 years, and 51.5% were female. Thirty-eight cases (10.5%) were complicated by infection. In multivariate analysis, presence of a cranial implant (primarily VP shunt) (OR 2.41, 95% CI 1.17–4.98), presence of gastrostomy (OR 2.44, 95% CI 1.03–5.79), and ventilator dependence (OR 8.45, 95% CI 1.10–65.08) were significant risk factors for cranioplasty infection. No other variable was associated with infection.Of the 240 patients who underwent a cranioplasty with bone graft, 21.7% showed bone resorption significant enough to warrant repeat surgical intervention. The most important predictor of cranioplasty bone resorption was age at the time of cranioplasty. For every month of increased age the risk of bone flap resorption decreased by 1% (OR 0.99, 95% CI 0.98–0.99, p < 0.001). Other risk factors for resorption in multivariate models were the use of external ventricular drains and lumbar shunts.CONCLUSIONSThis is the largest study of pediatric cranioplasty outcomes performed to date. Analysis included variables found to be significant in previous retrospective reports. Presence of a cranial implant such as VP shunt is the most significant risk factor for cranioplasty infection, whereas younger age at cranioplasty is the dominant risk factor for bone resorption.

OBJECTIVE Somatic variants are a recognized cause of epilepsy-associated focal malformations of cortical development (MCD). We hypothesized that somatic variants may underlie a wider range of focal epilepsy, including nonlesional focal epilepsy (NLFE). Through genetic analysis of brain tissue, we evaluated the role of somatic variation in focal epilepsy with and without MCD. METHODS We identified somatic variants through high-depth exome and ultra-high-depth candidate gene sequencing of DNA from epilepsy surgery specimens and leukocytes from 18 individuals with NLFE and 38 with focal MCD. RESULTS We observed somatic variants in 5 cases in SLC35A2, a gene associated with glycosylation defects and rare X-linked epileptic encephalopathies. Nonsynonymous variants in SLC35A2 were detected in resected brain, and absent from leukocytes, in 3 of 18 individuals (17%) with NLFE, 1 female and 2 males, with variant allele frequencies (VAFs) in brain-derived DNA of 2 to 14%. Pathologic evaluation revealed focal cortical dysplasia type Ia (FCD1a) in 2 of the 3 NLFE cases. In the MCD cohort, nonsynonymous variants in SCL35A2 were detected in the brains of 2 males with intractable epilepsy, developmental delay, and magnetic resonance imaging suggesting FCD, with VAFs of 19 to 53%; Evidence for FCD was not observed in either brain tissue specimen. INTERPRETATION We report somatic variants in SLC35A2 as an explanation for a substantial fraction of NLFE, a largely unexplained condition, as well as focal MCD, previously shown to result from somatic mutation but until now only in PI3K-AKT-mTOR pathway genes. Collectively, our findings suggest a larger role than previously recognized for glycosylation defects in the intractable epilepsies. Ann Neurol 2018.

Idiopathic intracranial hypertension (IIH), formerly known as pseudotumor cerebri, is a disease of elevated intracranial pressure that is thought to develop due to impaired CSF absorption related to elevated venous sinus pressure in the setting of increased intraabdominal and thoracic pressures. Symptoms can be disabling and, if left untreated, can lead to permanent visual loss. Previous treatments directed toward vision preservation include CSF diversion through shunting and optic nerve sheath fenestration. Recently, attention has been turned toward surgical weight loss strategies as an alternative to shunt treatment. The authors present a report of 3 patients with adolescent-onset IIH that was treated at the authors’ institution (Duke University) in whom bariatric surgery was pursued successfully. The patients had previously undergone CSF shunting at ages 12, 15, and 23 years. They were shunt dependent for a collective average of 3.3 years prior to bariatriwc surgery. All patients reported “low-pressure” or postural headaches after bariatric surgery that correlated with dramatic reduction in their weight. Two of the 3 patients had their shunts removed and continued to be shunt free 1.5 years later at last follow-up; the third patient remained shunt dependent with the pressure set at 200 mm H2O. Given the significant complications inherent to multiple shunt revisions, earlier intervention for weight loss, including bariatric surgery, in these patients might have prevented complications and the associated health care burden. The authors recommend a multidisciplinary approach for IIH treatment with early consideration for weight loss interventions in select patients.

Objective To assess the impact of age at referral on treatment options in craniosynostosis and to identify risk factors for referral delays in this population. Study design A retrospective cohort study was performed on patients with an abnormal head shape diagnosis treated at a single academic medical center between January 1, 2004 and January 1, 2014. Newly diagnosed patients with craniosynostosis were identified and referral patterns were examined. A multivariate logistic regression model was used to identify risk factors associated with the range of ages at initial referral. Results A total of 477 patients were evaluated at our institution, 197 of whom were subsequently diagnosed with craniosynostosis. The median age at initial appointment was 5.6 months (mean 8.2 months). Only 28% of children were referred within 3 months of birth. Patients referred within 3 months of birth were less likely to have had preappointment imaging than those patients referred slightly later (OR 2.53, CI 1.07-5.98, P = .035). Several variables were associated with referral after 12 months of age including multiple suture involvement (OR 4.21, CI 1.06-16.68, P = .041), minority race (OR 4.96, CI 1.91-12.9, P ≤ .0001), and referral by a nonpediatrician (OR 6.9, CI 1.73-27.49, P = .006). Conclusions Obtaining imaging before referral to a specialist for abnormal head shape was associated with a delay in evaluation and potentially increases radiation exposure and limits treatment options in patients with craniosynostosis. In addition, children from minority groups, children referred from someone other than a pediatrician's office, and those with multiple suture craniosynostosis are at increased risk of delayed referral. Further studies into the cause of these delays are warranted.

Glioblastoma (GBM) is the most common brain cancer and is highly lethal in both adults and children. 2-methoxyestradiol (2ME2) is a microtubule inhibitor that potently inhibits HIF1α, GBM angiogenesis and tumor growth in preclinical models. In patients, 2ME2 exhibits low toxicity and promising but inconsistent efficacy. Given its preclinical potency and its tolerability in patients, we sought to determine whether 2ME2 therapy could be enhanced by addressing resistance via combination therapy, and with biomarkers to identify responsive glioma subgroups. We demonstrate that the PTEN-PI3K axis regulates HIF1α in glioma models. We utilized isogenic-pairs of glioma cell lines, deficient in PTEN or stably reconstituted with PTEN, to determine the role of PTEN in 2ME2 sensitivity in vitro and in vivo. Chou-Talalay synergy studies reveal significant synergy when a pan-PI3K inhibitor is combined with 2ME2. This synergistic activity was correlated with a synergistic suppression of HIF1α accumulation under hypoxic conditions in glioma models. In vivo, 2ME2 markedly inhibited tumor-induced angiogenesis and significantly reduced tumor growth only in a PTEN reconstituted GBM models in both subcutaneous and orthotopic intracranial mouse models. Collectively, these results: (1) suggest that PTEN status predicts sensitivity to 2ME2 and (2) justify exploration of 2ME2 combined with pan-PI3K inhibitors for the treatment of this intractable brain cancer.

The use of epilepsy surgery in various medically resistant epilepsies is well established. For patients with intractable pediatric epilepsy, the role of intracranial electrodes, resective surgery, hemispherectomy, corpus callosotomy, neurostimulation, and multiple subpial transections continues to be very effective in select cases. Newer treatment and diagnostic methods include laser thermal ablation, minimally invasive surgeries, stereo electroencephalography, electrocorticography, and other emerging techniques. This article will review the established and emerging surgical therapies for severe pediatric epilepsies, their respective indications and overall efficacy.

Inflammatory pseudotumor (IP) is a benign process that most commonly occurs in the lung and orbit. Extension into the central nervous system is extremely rare, and primary intraventricular lesions of the lateral ventricles are even more infrequent with only 2 cases reported in pediatric patients to date. Here, the authors present an unusual case of IP occurring in a 16-year-old female presenting with a 2-week history of progressive headaches and vomiting, without focal neurological deficits or radiographic evidence of hydrocephalus. The patient underwent left parietal craniotomy and complete resection of the tumor, with no signs of recurrence at 3-month follow-up. Although the rarity of intraventricular IP in pediatric patients can make its initial identification difficult, IP should be considered as a potential diagnosis in this population wherein good outcomes may be achieved following surgical resection.

Object Hypothermia has been extensively evaluated in the management of traumatic brain injury (TBI), but no consensus as to its effectiveness has yet been reached. Explanatory hypotheses include a possible confounding effect of the neuroprotective benefits by adverse systemic effects. To minimize the systemic effects, the authors evaluated a selective cerebral cooling system, the CoolSystem Discrete Cerebral Hypothermia System (a “cooling cap”), in the management of TBI. Methods A prospective randomized controlled clinical trial was conducted at Grady Memorial Hospital, a Level I trauma center. Adults admitted with severe TBI (Glasgow Coma Scale [GCS] score ≤ 8) were eligible. Patients assigned to the treatment group received the cooling cap, while those in the control group did not. Patients in the treatment group were treated with selective cerebral hypothermia for 24 hours, then rewarmed over 24 hours. Their intracranial and bladder temperatures, cranial-bladder temperature gradient, Glasgow Outcome Scale (GOS) and Functional Independence Measure (FIM) scores, and mortality rates were evaluated. The primary outcome was to establish a cranial-bladder temperature gradient in those patients with the cooling cap. The secondary outcomes were mortality and morbidity per GOS and FIM scores. Results The cohort comprised 25 patients (12 in the treatment group, 13 controls). There was no significant intergroup difference in demographic data or median GCS score at enrollment (treatment group 3.0, controls 3.0; p = 0.7). After the third hour of the study, the mean intracranial temperature of the treatment group was significantly lower than that of the controls at all time points except Hours 4 (p = 0.08) and 6 (p = 0.08). However, the target intracranial temperature of 33°C was achieved in only 2 patients in the treatment group. The mean intracranial-bladder temperature gradient was not significant for the treatment group (p = 0.07) or the controls (p = 0.67). Six (50.0%) of 12 patients in the treatment group and 4 (30.8%) of 13 in the control group died (p = 0.43). The medians of the maximum change in GOS and FIM scores during the study period (28 days) for both groups were 0. There was no significant difference in complications between the groups (p value range 0.20–1.0). Conclusions The cooling cap was not effective in establishing a statistically significant cranial-bladder temperature gradient or in reaching the target intracranial temperature in the majority of patients. No significant difference was achieved in mortality or morbidity between the 2 groups. As the technology currently stands, the Discrete Cerebral Hypothermia System cooling cap is not beneficial for the management of TBI. Further refinement of the equipment available for the delivery of selective cranial cooling will be needed before any definite conclusions regarding the efficacy of discrete cerebral hypothermia can be reached.

Angiogenesis is tightly regulated by opposing mechanisms in mammalian cells and is controlled by the angiogenic switch. Other review articles have described a central role for the PTEN/PI-3 kinase/AKT signaling node in the coordinate control of cell division, tumor growth, apoptosis, invasion and cellular metabolism [1, 2]. In this review, we focus on literature that supports the PTEN/PI-3 kinase/AKT signaling node as a major control point for the angiogenic switch in both the on and off positions. We also discuss the rationale for designing small molecule drugs that target the PTEN/PI-3 kinase/AKT signaling node for therapeutic intervention. Our hypothesis is that, instead of inhibiting one cell surface receptor, such as VEGFR2 with bevacizumab (Avastin®), thereby leaving a significant number of receptors free to pulse angiogenic signals, a more effective strategy may be to regulate signaling through an intercept node where redundant cell surface receptor signals converge to transmit important signaling events within the cell. This therapeutic configuration brings coordinate control over multiple cell surface receptors in concert with a physiologic response which may combine arrest of cell cycle progression with growth inhibition and the induction of genes involved in specialized functions such as movement, which are all required for the complex process of angiogenesis to occur in a temporal-spatial paradigm.