Add-On Deep Brain Stimulation versus Continued Vagus Nerve Stimulation for Childhood Epilepsy (ADVANCE): A Partially Randomized Patient Preference Trial.

Outcomes following vagus nerve stimulation (VNS) improve over years after implantation in children with drug-resistant epilepsy. The added value of deep brain stimulation (DBS) instead of continued VNS optimization is unknown. In a prospective, non-blinded, randomized patient preference trial of 18 children (aged 8-17 years) who did not respond to VNS after at least 1 year, add-on DBS resulted in greater seizure reduction compared with an additional year of VNS optimization (51.9% vs. 12.3%, p = 0.047). Add-on DBS also resulted in less bothersome seizures (p = 0.03), but no change in quality of life. DBS may be considered earlier for childhood epilepsy after non-response to VNS. ANN NEUROL 2024.

Differential pairing of transmembrane domain GxxxG dimerization motifs defines two HLA-DR MHC class II conformers.

MHC class II molecules function to present exogenous antigen-derived peptides to CD4 T cells to both drive T cell activation and to provide signals back into the class II antigen-presenting cell. Previous work established the presence of multiple GxxxG dimerization motifs within the transmembrane domains of MHC class II α and ß chains across a wide range of species and revealed a role for differential GxxxG motif pairing in the formation of two discrete mouse class II conformers with distinct functional properties (i.e., M1-and M2-paired I-Ak class II). Biochemical and mutagenesis studies detailed herein extend this model to human class II by identifying an anti-HLA-DR mAb (Tü36) that selectively binds M1-paired HLA-DR molecules. Analysis of the HLA-DR allele reactivity of the Tü36 mAb helped define other HLA-DR residues involved in mAb binding. In silico modeling of both TM domain interactions and whole protein structure is consistent with the outcome of biochemical/mutagenesis studies and provides insight into the possible structural differences between the two HLA-DR conformers. Cholesterol depletion studies indicate a role for cholesterol-rich membrane domains in the formation/maintenance of Tü36 mAb reactive DR molecules. Finally, phylogenetic analysis of the amino acid sequences of Tü36-reactive HLA-DR ß chains reveals a unique pattern of both Tü36 mAb reactivity and key amino acid polymorphisms. In total, these studies bring the paradigm M1/M2-paired MHC class II molecules to the human HLA-DR molecule and suggest that the functional differences between these conformers defined in mouse class II extend to the human immune system.

An augmented hybrid multibaseline and referenceless MR thermometry motion compensation algorithm for MRgHIFU hyperthermia.

PURPOSE: A hybrid principal component analysis and projection onto dipole fields (PCA-PDF) MR thermometry motion compensation algorithm was optimized with atlas image augmentation and validated. METHODS: Experiments were conducted on a 3T Philips MRI and Profound V1 Sonalleve high intensity focused ultrasound (high intensity focused ultrasound system. An MR-compatible robot was configured to induce motion on custom gelatin phantoms. Trials with periodic and sporadic motion were introduced on phantoms while hyperthermia was administered. The PCA-PDF algorithm was augmented with a predictive atlas to better compensate for larger sporadic motion. RESULTS: During periodic motion, the temperature SD in the thermometry was improved from 1 . 1 ± 0 . 1 $$ 1.1\pm 0.1 $$ to 0 . 5 ± 0 . 1 ∘ $$ 0.5\pm 0.{1}^{\circ } $$ C with both the original and augmented PCA-PDF application. For large sporadic motion, the augmented atlas improved the motion compensation from the original PCA-PDF correction from 8 . 8 ± 0 . 5 $$ 8.8\pm 0.5 $$ to 0 . 7 ± 0 . 1 ∘ $$ 0.7\pm 0.{1}^{\circ } $$ C. CONCLUSION: The PCA-PDF algorithm improved temperature accuracy to <1°C during periodic motion, but was not able to adequately address sporadic motion. By augmenting the PCA-PDF algorithm, temperature SD during large sporadic motion was also reduced to <1°C, greatly improving the original PCA-PDF algorithm.

Noninvasive release of tendons using MRI guided focused ultrasound: a hybrid therapy using long-pulse focused ultrasound followed by thermal ablation.

INTRODUCTION: Magnetic Resonance-guided Focused Ultrasound (MRgFUS) thermal ablation is an effective noninvasive ultrasonic therapy to disrupt in vivo porcine tendon but is prone to inducing skin burns. We evaluated the safety profile of a novel hybrid protocol that minimizes thermal spread by combining long-pulse focused ultrasound followed by thermal ablation. METHODS: In-vivo Achilles tendons (hybrid N = 15, thermal ablation alone N = 21) from 15 to 20 kg Yorkshire pigs were randomly assigned to 6 treatment groups in two studies. The first (N = 21) was ablation (600, 900, or 1200 J). The second (N = 15) was hybrid: pulsed FUS (13.5 MPa peak negative pressure) followed by ablation (600, 900, or 1200 J). Measurements of ankle range of motion, tendon temperature, thermal dose (240 CEM43), and assessment of skin burn were performed in both groups. RESULTS: Rupture was comparable between the two protocols: 1/5 (20%), 5/5 (100%) and 5/5 (100%) for hybrid protocol, compared to 2/7 (29%), 6/7 (86%) and 7/7 (100%) for the ablation-only protocol with energies of 600, 900, and 1200 J, respectively. The hybrid protocol produced lower maximum temperatures, smaller areas of thermal dose, fewer thermal injuries to the skin, and fewer full-thickness skin burns. The standard deviation for the area of thermal injury was also smaller for the hybrid protocol, suggesting greater predictability. CONCLUSION: This study demonstrated a hybrid MRgFUS protocol combining long-pulse FUS followed by thermal ablation to be noninferior and safer than an ablation-only protocol for extracorporeal in-vivo tendon rupture for future clinical application for noninvasive release of contracted tendon.

Seizure outcome of pediatric magnetic resonance-guided laser interstitial thermal therapy versus open surgery: A matched noninferiority cohort study.

OBJECTIVE: Minimally invasive magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) has been proposed as an alternative to open epilepsy surgery, to address concerns regarding the risk of open surgery. Our primary hypothesis was that seizure freedom at 1 year after MRgLITT is noninferior to open surgery in children with drug-resistant epilepsy (DRE). The secondary hypothesis was that MRgLITT has fewer complications and shorter hospitalization than surgery. The primary objective was to compare seizure outcome of MRgLITT to open surgery in children with DRE. The secondary objective was to compare complications and length of hospitalization of the two treatments. METHODS: This retrospective multicenter cohort study included children with DRE treated with MRgLITT or open surgery with 1-year follow-up. Exclusion criteria were corpus callosotomy, neurostimulation, multilobar or hemispheric surgery, and lesion with maximal dimension > 60 mm. MRgLITT patients were propensity matched to open surgery patients. The primary outcome was seizure freedom at 1 year posttreatment. The difference in seizure freedom was compared using noninferiority test, with noninferiority margin of -10%. The secondary outcomes were complications and length of hospitalization. RESULTS: One hundred eighty-five MRgLITT patients were matched to 185 open surgery patients. Seizure freedom at 1 year follow-up was observed in 89 of 185 (48.1%) MRgLITT and 114 of 185 (61.6%) open surgery patients (difference = -13.5%, one-sided 97.5% confidence interval = -23.8% to ∞, pNoninferiority  = .79). The lower confidence interval boundary of -23.8% was below the prespecified noninferiority margin of -10%. Overall complications were lower in MRgLITT compared to open surgery (10.8% vs. 29.2%, respectively, p < .001). Hospitalization was shorter for MRgLITT than open surgery (3.1 ± 2.9 vs. 7.2 ± 6.1 days, p < .001). SIGNIFICANCE: Seizure outcome of MRgLITT at 1 year posttreatment was inferior to open surgery. However, MRgLITT has the advantage of better safety profile and shorter hospitalization. The findings will help counsel children and parents on the benefits and risks of MRgLITT and contribute to informed decision-making on treatment options.

Outcomes following management of relapsed pediatric posterior fossa ependymoma in the molecular era.

PURPOSE: The overall survival and prognostic factors for children with multiply recurrent posterior fossa ependymoma are not well understood. We aimed to assess prognostic factors associated with survival for relapsed pediatric posterior fossa ependymoma. METHODS: An institutional database was queried for children with a primary diagnosis of posterior fossa ependymoma from 2000 to 2019. Kaplan-Meier survival analysis and Cox-proportional hazard regression were used to assess the relationship between treatment factors and overall survival. RESULTS: There were 60 patients identified; molecular subtype was available for 56, of which 49 (87.5%) were PF-A and 7 (12.5%) were PF-B. Relapse occurred in 29 patients (48%) at a mean time of 24 months following primary resection. Median 50% survival was 12.3 years for all patients and 3.3 years following diagnosis of first relapsed disease. GTR was associated with significantly improved survival following primary resection (HR 0.373, 95% CI 0.14-0.96). Presence of recurrent disease was significantly associated with worse survival (p < 0.0001). At recurrent disease diagnosis, disseminated disease was a negative prognostic factor (HR 11.0 95% CI 2.7-44) while GTR at first relapse was associated with improved survival HR 0.215 (95% CI: 0.048-0.96, p = 0.044). Beyond first relapse, the impact of GTR was not significant on survival, though surgery compared to no surgery was favorable with HR 0.155 (95% CI: 0.04-0.59). CONCLUSIONS: Disseminated disease at recurrence and extent of resection for first relapsed disease were important prognostic factors. Surgery compared to no surgery was associated with improved survival for the multiply recurrent ependymoma cohort.

Time to dismiss boost? Outcomes of children with localized and metastatic germinoma.

PURPOSE: To determine long-term outcomes of a cohort of children with germinoma treated with chemotherapy and radiation therapy without primary tumor boost even in the absence of complete response to chemotherapy METHODS: This retrospective study analyzed the outcome of patients with germinoma consecutively diagnosed and treated at a tertiary care center from January 2000 to December 2021. MRIs were reviewed by two radiologists, blinded to patient data. Tumor location at diagnosis, tumor response to chemotherapy and at completion of radiation therapy and site of relapse were assessed. Tumor response was assessed radiologically by determining the tumor size and response on diffusion-weighted imaging, in addition to biochemical, cytological parameters and neurological status. RESULTS: Of 46 pediatric germinoma patients, 29 children (14 male; median age 12.8 years) received no primary tumor boost. Median follow-up was 63 months (range 9-187 months). Twenty-five children had localized disease and tumor location was suprasellar (n = 11), pineal (n = 10), bifocal (n = 3) and basal ganglia (n = 1) while 4 children had metastatic disease at presentation. All patients completed multi-agent chemotherapy followed by either ventricular irradiation (VI) (23.4 Gy) (n = 23), whole brain (WBI) (23.4 Gy) (n = 5) or craniospinal radiation (CSI) (23.4 Gy) (n = 1). Two children, who had localized disease at presentation and received VI after chemotherapy, relapsed 9 months and 32 months after completion of treatment respectively. No patient had a local relapse. Location of relapse was distant, outside (n = 1) and out- and inside (n = 1) the irradiation field. Five-year progression free survival (PFS) was 91% and overall survival (OS) was 100%. CONCLUSIONS: In this case series, excellent 5-year PFS and OS rates were achieved with chemotherapy followed by radiation therapy of 23.4 Gy delivered without primary tumor boost. No local relapse was observed despite omitting primary tumor boost in patients with localized and metastatic germinoma.

Noninvasive magnetic resonance-guided focused ultrasound for tendon disruption: an in vivo Animal study.

PURPOSE: Surgical resection of the tendon is an effective treatment for severe contracture. Magnetic Resonance-guided Focused Ultrasound (MRgFUS) is a non-invasive ultrasonic therapy which produces a focal increase in temperature, subsequent tissue ablation and disruption. We evaluated MRgFUS as a clinically translatable treatment modality to non-invasively disrupt in vivo porcine tendons. MATERIAL AND METHODS: In vivo Achilles tendons (n = 28) from 15-20kg Yorkshire pigs (n = 16) were randomly assigned to 4 treatment groups of 600, 900, 1200 and 1500 J. Pretreatment range of motion (ROM) of the ankle joint was measured with the animal under general anesthesia. Following MRgFUS treatment, success of tendon rupture, ROM increase, temperature, thermal dosage, skin burn, and histology analyses were performed. RESULTS: Rupture success was found to be 29%, 86%, 100% and 100% for treatment energies of 600, 900, 1200 and 1500 J respectfully. ROM difference at 90° flexion showed a statistically significant change in ROM between 900 J and 1200 J from 16° to 27°. There was no statistical significance between other groups, but there was an increase in ROM as more energy was delivered in the treatment. For each of the respective treatment groups, the maximal temperatures were 58.4 °C, 63.3 °C, 67.6 °C, and 69.9 °C. The average areas of thermal dose measured were 24.3mm2, 53.2mm2, 77.8mm2 and 91.6mm2. The average areas of skin necrosis were 5.4mm2, 21.8mm2, 37.2mm2, and 91.4mm2. Histologic analysis confirmed tissue ablation and structural collagen fiber disruption. CONCLUSIONS: This study demonstrated that MRgFUS is able to disrupt porcine tendons in vivo without skin incisions.

Preservation of endocrine function after Ommaya reservoir insertion in children with cystic craniopharyngioma.

INTRODUCTION: Children with craniopharyngiomas (CP) can experience significant morbidities caused by extensive surgery and/or radiation. Ommaya reservoir insertion (ORI) into cystic CP represents a minimally invasive approach allowing immediate decompression and aims to avoid additional injuries. The purpose of this study was to determine the surgical outcome and relevance of upfront ORI (± intracystic treatment) for preservation of endocrine function. METHODS: We performed a retrospective chart review of children with CP treated at the Hospital for Sick Children between 01/01/2000 and 15/01/2020. Endocrine function was reviewed at the time of initial surgery and throughout follow-up. New endocrinological deficits related to the index procedure were defined as immediate failure (IF), whereas postoperative duration of endocrinological stability (ES) was analyzed using the Kaplan-Meier method. The rate of IF and ES was compared between the treatment groups. RESULTS: Seventy-nine patients were included and had a median age of 8.3 years (range 2.1-18.0 years); 31 were males. Fifty-three patients with upfront surgical treatment, including 29 ORI and 24 gross total or partial resections had sufficient endocrinological follow-up data. Endocrine dysfunction occurring immediately after the index procedure (IF) was observed in 15 patients (62.5%) in the resection group compared to two patients (6.8%) in the ORI group, odds ratio: 0.05 (CI: 0.01-0.26, p < 0.0001). Excluding those with immediate endocrinological deficits, mean ES after ORI was 19.4 months (CI: 11.6-34.2), compared to 13.4 months (CI:10.6-NA) after surgical resection. CONCLUSIONS: Endocrine function was preserved in patients with upfront ORI (± intracystic treatment), which was confirmed as a minimally invasive procedure with an overall low morbidity profile.

Building the ecosystem for pediatric neuro-oncology care in Pakistan: Results of a 7-year long twinning program between Canada and Pakistan.

BACKGROUND: Low- and middle-income countries sustain the majority of pediatric cancer burden, with significantly poorer survival rates compared to high-income countries. Collaboration between institutions in low- and middle-income countries and high-income countries is one of the ways to improve cancer outcomes. METHODS: Patient characteristics and effects of a pediatric neuro-oncology twinning program between the Hospital for Sick Children in Toronto, Canada and several hospitals in Karachi, Pakistan over 7 years are described in this article. RESULTS: A total of 460 patients were included in the study. The most common primary central nervous system tumors were low-grade gliomas (26.7%), followed by medulloblastomas (18%), high-grade gliomas (15%), ependymomas (11%), and craniopharyngiomas (11.7%). Changes to the proposed management plans were made in consultation with expert physicians from the Hospital for Sick Children in Toronto, Canada. On average, 24% of the discussed cases required a change in the original management plan over the course of the twinning program. However, a decreasing trend in change in management plans was observed, from 36% during the first 3.5 years to 16% in the last 3 years. This program also led to the launch of a national pediatric neuro-oncology telemedicine program in Pakistan. CONCLUSIONS: Multidisciplinary and collaborative efforts by experts from across the world have aided in the correct diagnosis and treatment of children with brain tumors and helped establish local treatment protocols. This experience may be a model for other low- and middle-income countries that are planning on creating similar programs.

A simulation study to investigate the use of concentric tube robots for epilepsy surgery.

PURPOSE: Patients with pharmacoresistant refractory epilepsy may require epilepsy surgery to prevent future seizure occurrences. Conventional surgery consists of a large craniotomy with straight rigid tools with associated outcomes of morbidity, large tissue resections, and long post-operative recovery times. Concentric tube robots have recently been developed as a promising application to neurosurgery due to their nonlinear form and small diameter. The authors present a concept study to explore the feasibility of performing minimally invasive hemispherotomy with concentric tube robots. METHODS: A model simulation was used to achieve the optimal design and surgical path planning parameters of the concentric tube robot for corpus callosotomy and temporal lobectomy. A single medial burr hole was chosen to access the lateral ventricles for both white matter disconnections. RESULTS: The concentric tube robot was able to accurately reach the designated surgical paths on the corpus callosum and the temporal lobe. CONCLUSION: In a model simulation, the authors demonstrated the feasibility of performing corpus callosotomy and temporal lobectomy using concentric tube robots. Further advancements in the technology may increase the applicability of this technique for epilepsy surgery to better patient outcomes.

Moderate procedural confidence improvement following hands-on practice using the hemispherectomy simulator.

INTRODUCTION: Pediatric hemispherectomy is a technically demanding procedure with significant risk. There are relatively few opportunities for surgeon trainees to gain confidence in this nuanced surgery solely through traditional apprenticeship prior to independent practice. Surgeon confidence has been linked to better intraoperative performance and surgical simulation has, according to literature, resulted in improved surgeon confidence. This manuscript measures the effect of epilepsy simulation on the procedural confidence of neurosurgical trainees as a marker of future improved intraoperative performance. METHODS: Eleven neurosurgery residents and fellows were allowed to practice on a novel hemispherectomy simulator. Pre- and post-simulation procedural confidence was measured using a 10-item questionnaire, with total scores ranging from 10 (least confident) to 50 (most confident). Matched pair t-testing was performed to determine participant mean difference between the pre- and post-procedural data sets. RESULTS: The assessment tool bore a high reliability coefficient (Cronbach's α = 0.93). The procedural confidence of all the study participants increased following simulation (p value < 0.001). The overall mean increase in confidence was 7.2 ± 4.0 (mean ± standard deviation), 7.5 ± 4.7 among fellows and 6.8 ± 3.6 among residents. Procedural confidence values were higher among the fellows (26.9 ± 8.1) compared to the residents (19.0 ± 7.4). This difference in means was statistically significant (p value 0.03). A positive association was calculated between the perceived confidence and the postgraduate year of training (p value 0.005, r = 0.57). CONCLUSION: The hemispherectomy simulator moderately improves perceived confidence among neurosurgical trainees and may augment pre-operative surgical practice opportunities.

Timing of Temporizing Neurosurgical Treatment in Relation to Shunting and Neurodevelopmental Outcomes in Posthemorrhagic Ventricular Dilatation of Prematurity: A Meta-analysis.

OBJECTIVE: To determine the relationship between timing of initiation of temporizing neurosurgical treatment and rates of ventriculoperitoneal shunt (VPS) and neurodevelopmental impairment in premature infants with post-hemorrhagic ventricular dilatation (PHVD). STUDY DESIGN: We searched MEDLINE, EMBASE, CINAHL, Web of Science, the Cochrane Database of Systematic Reviews, and the Cochrane Center Register of Controlled Trials for studies that reported on premature infants with PHVD who underwent a temporizing neurosurgical procedure. The timing of the temporizing neurosurgical procedure, gestational age, birth weight, outcomes of conversion to VPS, moderate-to-severe neurodevelopmental impairment, infection, temporizing neurosurgical procedure revision, and death at discharge were extracted. RESULTS: Sixty-two full-length articles and 6 conference abstracts (n = 2533 patients) published through November 2020 were included. Pooled rate for conversion to VPS was 60.5% (95% CI, 54.9-65.8), moderate-severe neurodevelopmental impairment 34.8% (95% CI, 27.4-42.9), infection 8.2% (95% CI, 6.7-10.1), revision 14.6% (95% CI, 10.4-20.1), and death 12.9% (95% CI, 10.2-16.4). The average age at temporizing neurosurgical procedure was 24.2 ± 11.3 days. On meta-regression, older age at temporizing neurosurgical procedure was a predictor of conversion to VPS (P < .001) and neurodevelopmental impairment (P < .01). Later year of publication predicted increased survival (P < .01) and external ventricular drains were associated with more revisions (P = .001). Tests for heterogeneity reached significance for all outcomes and a qualitative review showed heterogeneity in the study inclusion and diagnosis criteria for PHVD and initiation of temporizing neurosurgical procedure. CONCLUSIONS: Later timing of temporizing neurosurgical procedure predicted higher rates of conversion to VPS and moderate-severe neurodevelopmental impairment. Outcomes were often reported relative to the number of patients who underwent a temporizing neurosurgical procedure and the criteria for study inclusion and the initiation of temporizing neurosurgical procedure varied across institutions. There is need for more comprehensive outcome reporting that includes all infants with PHVD regardless of treatment.

Epilepsy surgery in infants up to 3 months of age: Safety, feasibility, and outcomes: A multicenter, multinational study.

OBJECTIVE: Drug-resistant epilepsy (DRE) during the first few months of life is challenging and necessitates aggressive treatment, including surgery. Because the most common causes of DRE in infancy are related to extensive developmental anomalies, surgery often entails extensive tissue resections or disconnection. The literature on "ultra-early" epilepsy surgery is sparse, with limited data concerning efficacy controlling the seizures, and safety. The current study's goal is to review the safety and efficacy of ultra-early epilepsy surgery performed before the age of 3 months. METHODS: To achieve a large sample size and external validity, a multinational, multicenter retrospective study was performed, focusing on epilepsy surgery for infants younger than 3 months of age. Collected data included epilepsy characteristics, surgical details, epilepsy outcome, and complications. RESULTS: Sixty-four patients underwent 69 surgeries before the age of 3 months. The most common pathologies were cortical dysplasia (28), hemimegalencephaly (17), and tubers (5). The most common procedures were hemispheric surgeries (48 procedures). Two cases were intentionally staged, and one was unexpectedly aborted. Nearly all patients received blood products. There were no perioperative deaths and no major unexpected permanent morbidities. Twenty-five percent of patients undergoing hemispheric surgeries developed hydrocephalus. Excellent epilepsy outcome (International League Against Epilepsy [ILAE] grade I) was achieved in 66% of cases over a median follow-up of 41 months (19-104 interquartile range [IQR]). The number of antiseizure medications was significantly reduced (median 2 drugs, 1-3 IQR, p < .0001). Outcome was not significantly associated with the type of surgery (hemispheric or more limited resections). SIGNIFICANCE: Epilepsy surgery during the first few months of life is associated with excellent seizure control, and when performed by highly experienced teams, is not associated with more permanent morbidity than surgery in older infants. Thus surgical treatment should not be postponed to treat DRE in very young infants based on their age.

Cutting Edge: Core Binding Factor ß Is Required for Group 2 Innate Lymphoid Cell Activation.

Group 2 innate lymphoid cells (ILC2) are tissue-resident, long-lived innate effector cells implicated in allergy and asthma. Upon activation, mature ILC2 rapidly secrete large amounts of type-2 cytokines and other effector molecules. The molecular pathways that drive ILC2 activation are not well understood. In this study, we report that the transcriptional controller core binding factor ß (CBFß) is required for ILC2 activation. Deletion or inhibition of CBFß did not impair the maintenance of ILC2 at homeostasis but abolished ILC2 activation during allergic airway inflammation. Treatment with CBFß inhibitors prevented ILC2-mediated airway hyperresponsiveness in a mouse model of acute Alternaria allergen inhalation. CBFß promoted expression of key ILC2 genes at both transcriptional and translational levels. CBF transcriptional complex directly bound to Il13 and Vegfa promoters and enhancers, and controlled gene transcription. CBFß further promoted ribosome biogenesis and enhanced gene translation in activated ILC2. Together, these data establish an essential role for CBFß in ILC2 activation.

Surgical targeting of large hypothalamic hamartomas and seizure-freedom following MR-guided laser interstitial thermal therapy.

BACKGROUND: Large hypothalamic hamartomas (HH) are often associated with difficult-to-treat, refractory seizures. Although magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) has emerged as a useful tool to treat these challenging lesions, postoperative outcomes are variable and potentially related to differences in surgical targeting. PURPOSE: We sought to identify differences in the anatomic localization of laser ablations that either did or did not result in seizure freedom. METHODS: Four children who underwent MRgLITT for large HH (3 seizure-free and 1 not seizure-free) were included in the analysis. Ablation volumes were segmented, normalized, and overlaid on a high-resolution hypothalamic atlas. For each lesion, the size, spatial extent, and degree of overlap with key hypothalamic nuclei and surrounding brain regions were computed and compared between ablations that did and did not result in seizure freedom. RESULTS: Ablation masks that resulted in seizure freedom were smaller and located more centrally than the ablation mask that did not. In addition, ablation masks that resulted in seizure freedom overlapped with regions including the paraventricular nucleus, the posterior hypothalamus and the zona incerta, fornix, and mammillothalamic tract, whereas the single non-seizure-free ablation did not. CONCLUSION: Differences in the size, position, and anatomical localization of ablation volumes may be a potential contributor to the variability in postoperative outcomes of large HH treated with MRgLITT. A novel, high-resolution MRI atlas of the hypothalamus identifies a number of regions at the interface of large HH that are preferentially disconnected in seizure-free patients. This method of anatomical localization not only serves as a potential clinical tool for surgical targeting but may also provide novel insights into the mechanisms of epileptogenesis in hypothalamic hamartomas.

Traumatic atlanto-occipital dislocation in children: is external immobilization an option?

OBJECT: Traumatic atlanto-occipital dislocation (AOD) is a relatively uncommon traumatic cervical spine injury characterized by disruption and instability of the atlanto-occipital joint. At many centers, management of pediatric AOD includes occipitocervical arthrodesis, but whether external immobilization without surgery is a viable treatment option for some pediatric patients is unknown. To answer this question, we analyzed our outcomes of pediatric AOD at the Hospital for Sick Children. METHODS: We performed a retrospective chart review of all children with clinical and radiographic evidence of traumatic AOD. A total of 10 patients met criteria for traumatic AOD: 8 were treated with external immobilization alone and 2 were treated with occipitocervical arthrodesis. RESULTS: Eight patients were treated exclusively with 3 months of halo immobilization. Two patients were treated with occipitocervical instrumentation and arthrodesis. No patient undergoing halo immobilization required subsequent operative fusion. CONCLUSION: Halo immobilization is a safe, viable, and definitive treatment option for the selected children with AOD.

Fetal Surgery for Open Spina Bifida in Canada: Initial Results.

OBJECTIVE: Fetal myelomeningocele closure results in better infant outcomes than postnatal closure at the cost of potential prematurity and maternal morbidity. Our aim is to describe the setup of a fetal myelomeningocele closure program in Canada and document its outcomes. METHODS: We conducted a retrospective review of all open fetal myelomeningocele closure surgeries performed at the Ontario Fetal Centre in its first 3 years of operation (2017-2020). Maternal and fetal baseline characteristics, surgical details, pregnancy outcomes, and infant follow-up until 1 year of age were recorded. RESULTS: Twenty-seven women underwent fetal myelomeningocele closure surgery, 10 of whom (37%) resided outside of Ontario. Mean gestational age at surgery was 25.0 ± 0.7 weeks. All surgeries were technically uncomplicated and no fetal deaths occurred. There was a significant negative correlation between increasing experience and skin-to-skin surgical time (R²â€¯= 0.36; P = 0.001). Of the 26 patients who have delivered, 4 (15.4%) experienced preterm prelabour rupture of membranes. Mean gestational age at delivery was 34.9±3.0 weeks. All but 1 patient delivered by cesarean. Maternal complications occurred in 9 women (34.6%). There were no maternal deaths, but 3 (11.5%) infant deaths. Of the 14 surviving infants who have reached at least 1 year of age, 5 (35.7%) underwent ventriculo-peritoneal shunting. Of the 9 infants who have not yet reached 1 year of age, 3 (33.3%) underwent endoscopic third ventriculostomy and none underwent shunting. CONCLUSION: Fetal open spina bifida closure can be performed in Canada, with results similar to those reported by other international expert centres. Long-term follow-up is ongoing.

Hydrocephalus treatment in patients with craniosynostosis: an analysis from the Hydrocephalus Clinical Research Network prospective registry.

OBJECTIVE: Hydrocephalus may be seen in patients with multisuture craniosynostosis and, less commonly, single-suture craniosynostosis. The optimal treatment for hydrocephalus in this population is unknown. In this study, the authors aimed to evaluate the success rate of ventriculoperitoneal shunt (VPS) treatment and endoscopic third ventriculostomy (ETV) both with and without choroid plexus cauterization (CPC) in patients with craniosynostosis. METHODS: Utilizing the Hydrocephalus Clinical Research Network (HCRN) Core Data Project (Registry), the authors identified all patients who underwent treatment for hydrocephalus associated with craniosynostosis. Descriptive statistics, demographics, and surgical outcomes were evaluated. RESULTS: In total, 42 patients underwent treatment for hydrocephalus associated with craniosynostosis. The median gestational age at birth was 39.0 weeks (IQR 38.0, 40.0); 55% were female and 60% were White. The median age at first craniosynostosis surgery was 0.6 years (IQR 0.3, 1.7), and at the first permanent hydrocephalus surgery it was 1.2 years (IQR 0.5, 2.5). Thirty-three patients (79%) had multiple different sutures fused, and 9 had a single suture: 3 unicoronal (7%), 3 sagittal (7%), 2 lambdoidal (5%), and 1 unknown (2%). Syndromes were identified in 38 patients (90%), with Crouzon syndrome being the most common (n = 16, 42%). Ten patients (28%) received permanent hydrocephalus surgery before the first craniosynostosis surgery. Twenty-eight patients (67%) underwent VPS treatment, with the remaining 14 (33%) undergoing ETV with or without CPC (ETV ± CPC). Within 12 months after initial hydrocephalus intervention, 14 patients (34%) required revision (8 VPS and 6 ETV ± CPC). At the most recent follow-up, 21 patients (50%) required a revision. The revision rate decreased as age increased. The overall infection rate was 5% (VPS 7%, 0% ETV ± CPC). CONCLUSIONS: This is the largest prospective study reported on children with craniosynostosis and hydrocephalus. Hydrocephalus in children with craniosynostosis most commonly occurs in syndromic patients and multisuture fusion. It is treated at varying ages; however, most patients undergo surgery for craniosynostosis prior to hydrocephalus treatment. While VPS treatment is performed more frequently, VPS and ETV are both reasonable options, with decreasing revision rates with increasing age, for the treatment of hydrocephalus associated with craniosynostosis.

Coordinating Tissue Regeneration Through Transforming Growth Factor-ß Activated Kinase 1 Inactivation and Reactivation.

Aberrant wound healing presents as inappropriate or insufficient tissue formation. Using a model of musculoskeletal injury, we demonstrate that loss of transforming growth factor-ß activated kinase 1 (TAK1) signaling reduces inappropriate tissue formation (heterotopic ossification) through reduced cellular differentiation. Upon identifying increased proliferation with loss of TAK1 signaling, we considered a regenerative approach to address insufficient tissue production through coordinated inactivation of TAK1 to promote cellular proliferation, followed by reactivation to elicit differentiation and extracellular matrix production. Although the current regenerative medicine paradigm is centered on the effects of drug treatment ("drug on"), the impact of drug withdrawal ("drug off") implicit in these regimens is unknown. Because current TAK1 inhibitors are unable to phenocopy genetic Tak1 loss, we introduce the dual-inducible COmbinational Sequential Inversion ENgineering (COSIEN) mouse model. The COSIEN mouse model, which allows us to study the response to targeted drug treatment ("drug on") and subsequent withdrawal ("drug off") through genetic modification, was used here to inactivate and reactivate Tak1 with the purpose of augmenting tissue regeneration in a calvarial defect model. Our study reveals the importance of both the "drug on" (Cre-mediated inactivation) and "drug off" (Flp-mediated reactivation) states during regenerative therapy using a mouse model with broad utility to study targeted therapies for disease. Stem Cells 2019;37:766-778.