Feasibility and safety of stereoelectroencephalography in young children.

PURPOSE: Stereoelectroencephalography (SEEG) is a diagnostic surgery that implants electrodes to identify areas of epileptic onset in patients with drug-resistant epilepsy (DRE). SEEG is effective in identifying the epileptic zone; however, placement of electrodes in very young children has been considered contraindicated due to skull thinness. The goal of this study was to evaluate if SEEG is safe and accurate in young children with thin skulls. METHODS: Four children under the age of two years old with DRE underwent SEEG to locate the region of seizure onset. Presurgical planning and placement of electrodes were performed using ROSA One Brain. Preoperative electrode plans were merged with postoperative CT scans to determine accuracy. Euclidean distance between the planned and actual trajectories was calculated using a 3D coordinate system at both the entry and target points for each electrode. RESULTS: Sixty-three electrodes were placed among four patients. Mean skull thickness at electrode entry sites was 2.34 mm. The mean difference between the planned and actual entry points was 1.12 mm, and the mean difference between the planned and actual target points was 1.73 mm. No significant correlation was observed between planned and actual target points and skull thickness (Pearson R = - 0.170). No perioperative or postoperative complications were observed. CONCLUSIONS: This study demonstrates that SEEG can be safe and accurate in children under two years of age despite thin skulls. SEEG should be considered for young children with DRE, and age and skull thickness are not definite contraindications to the surgery.

Myasthenia gravis in a pediatric patient with Lennox-Gastaut syndrome following responsive neurostimulation device implantation: illustrative case.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disorder in which the postsynaptic acetylcholine receptor of the neuromuscular junction is destroyed by autoantibodies. The authors report a case of MG in a pediatric patient who also suffered from Lennox-Gastaut syndrome (LGS) and is one of a limited number of pediatric patients who have undergone placement of a responsive neurostimulation (RNS) device (NeuroPace). OBSERVATIONS: A 17-year-old female underwent placement of an RNS device for drug-resistant epilepsy in the setting of LGS. Five months after device placement, the patient began experiencing intermittent slurred speech, fatigue, and muscle weakness. Initially, the symptoms were attributed to increased seizure activity and/or medication side effects. However, despite changing medications and RNS settings, no improvements occurred. Her antiacetylcholine receptor antibodies measured 62.50 nmol/L, consistent with a diagnosis of MG. The patient was then prescribed pyridostigmine and underwent a thymectomy, which alleviated most of her symptoms. LESSONS: The authors share the cautionary tale of a case of MG in a pediatric patient who was treated with RNS for intractable epilepsy associated with LGS. Although slurred speech, fatigue, muscle weakness, and other symptoms might stem from increased seizure activity and/or medication side effects, they could also be due to MG development.

Safety of vagus nerve stimulation and responsive neurostimulation used in combination for multifocal and generalized onset epilepsy in pediatric patients.

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.

Human cortical interneurons optimized for grafting specifically integrate, abort seizures, and display prolonged efficacy without over-inhibition.

Previously, we demonstrated the efficacy of human pluripotent stem cell (hPSC)-derived GABAergic cortical interneuron (cIN) grafts in ameliorating seizures. However, a safe and reliable clinical translation requires a mechanistic understanding of graft function, as well as the assurance of long-term efficacy and safety. By employing hPSC-derived chemically matured migratory cINs in two models of epilepsy, we demonstrate lasting efficacy in treating seizures and comorbid deficits, as well as safety without uncontrolled growth. Host inhibition does not increase with increasing grafted cIN densities, assuring their safety without the risk of over-inhibition. Furthermore, their closed-loop optogenetic activation aborted seizure activity, revealing mechanisms of graft-mediated seizure control and allowing graft modulation for optimal translation. Monosynaptic tracing shows their extensive and specific synaptic connections with host neurons, resembling developmental connection specificity. These results offer confidence in stem cell-based therapy for epilepsy as a safe and reliable treatment for patients suffering from intractable epilepsy.

Frailty Is Superior to Age for Predicting Readmission, Prolonged Length of Stay, and Wound Infection in Elective Otology Procedures.

OBJECTIVE: To determine the predictive ability of the 5-point modified frailty index relative to age in elective otology patients. STUDY DESIGN: Retrospective database analysis. SETTING: Multicenter, national database of surgical patients. PATIENTS: We selected all elective surgical patients who received tympanoplasty, tympanomastoidectomy, mastoidectomy, revision mastoidectomy, and cochlear implant procedures from 2016 to 2019 from the National Surgical Quality Improvement database. INTERVENTIONS: Therapeutic. MAIN OUTCOME MEASURES: Readmission rates, discharge disposition, reoperation rates, and extended length of hospital stay. RESULTS: Utilizing receiver operating characteristics with area under the curve (AUC) analysis, nonrobust status was determined to be a superior predictor relative to age of readmission (AUC = 0.628 [p < 0.001] versus AUC = 0.567 [p = 0.047], respectively) and open wound infection relative to age (AUC = 0.636 [p = 0.024] versus AUC = 0.619 [p = 0.048], respectively). Nonrobust otology patients were more likely to have dyspnea at rest and an American Society of Anesthesiology score higher than 2 before surgery (odds ratios, 13.304 [95% confidence interval, 2.947-60.056; p < 0.001] and 7.841 [95% confidence interval, 7.064-8.704; p < 0.001], respectively). CONCLUSION: Nonrobust status was found to be a useful predictor of readmission and prolonged length of stay in patients undergoing elective otology procedures, which generally have low complication rate. Given the aging population and corresponding increase in otology disease, it is important to use age-independent risk stratification measures. Frailty may provide a useful risk stratification tool to select surgical candidates within the aging population.

Cervical fusion for adult patients with atlantoaxial rotatory subluxation.

Background: Atlantoaxial rotatory subluxation (AARS) is a rare injury of the C1/C2 junction. It is often associated with trauma in adults. Treatment may depend on the duration of symptoms and clinical presentation, but there is no consensus regarding the ideal management of these injuries. Our objective is to ascertain the prevalence of neurological deficit, complications, and outcomes of patients diagnosed with AARS undergoing cervical fusion (CF) versus those treated without CF. Methods: The 2016-2019 National Inpatient Sample (NIS) was queried using International Classification of Diseases, 10th revision (ICD-10) for adult patients with C1/C2 subluxation. Patients undergoing CF were defined through ICD-10 procedure codes. Baseline health and acute illness severity was calculated using the 11-point modified frailty index (mFI-11). Presenting characteristics, treatment complications, and outcomes were evaluated of CF vs. non-CF patients. Results: Of 990 adult patients with AARS, 720 were treated without CF and 270 were treated with CF. CF patients were more often myelopathic. Patients that had undergone CF treatment were negatively associated with having had extensive trauma. Patients undergoing CF experienced significantly longer length of stay (LOS), increased healthcare resource utilization, and decreased inpatient mortality. Sepsis had a negative association with patients that underwent CF treatment while pneumonia had a positive association. Conclusions: Adult patients undergoing CF for AARS demonstrated an increase in healthcare resource utilization but also a significant decrease in mortality. Extent of acute injury appears to have a strong influence on decision making for CF. Further study of decision making for treatment of this rare injury in adults is warranted.

Characteristics of Patients Selected for Surgical Treatment of Spinal Meningioma.

BACKGROUND: Spinal meningiomas are benign extra-axial tumors that can present with neurological deficits. Treatment partly depends on the degree of disability as there is no agreed-upon patient selection algorithm at present. We aimed to elucidate general patient selection patterns in patients undergoing surgery for spinal meningioma. METHODS: Data for patients with spinal tumors admitted between 2016 and 2019 were extracted from the U.S. Nationwide Inpatient Sample. We identified patients with a primary diagnosis of spinal meningioma (using International Classification of Disease, 10th revision codes) and divided them into surgical and nonsurgical treatment groups. Patient characteristics were evaluated for intergroup differences. RESULTS: Of 6395 patients with spinal meningioma, 5845 (91.4%) underwent surgery. Advanced age, nonwhite race, obesity, diabetes mellitus, chronic renal failure, and anticoagulant/antiplatelet use were less prevalent in the surgical group (all P < 0.001). The only positive predictor of surgical treatment was elective admission status (odds ratio, 3.166; P < 0.001); negative predictors were low income, Medicaid insurance, anxiety, obesity, and plegia. Patients with bowel-bladder dysfunction, plegia, or radiculopathy were less likely to undergo surgical treatment. The surgery group was less likely to experience certain complications (deep vein thrombosis, P < 0.001; pulmonary embolism, P = 0.002). Increased total hospital charges were associated with nonwhite race, diabetes, depression, obesity, myelopathy, plegia, and surgery. CONCLUSIONS: Patients treated surgically had a decreased incidence of complications, comorbidities, and Medicaid payer status. A pattern of increased utilization of health care resources and spending was also observed in the surgery group. The results indicate a potentially underserved population of patients with spinal meningioma.

Responsive Neurostimulation Targeting the Anterior, Centromedian and Pulvinar Thalamic Nuclei and the Detection of Electrographic Seizures in Pediatric and Young Adult Patients.

Background: Responsive neurostimulation (RNS System) has been utilized as a treatment for intractable epilepsy. The RNS System delivers stimulation in response to detected abnormal activity, via leads covering the seizure foci, in response to detections of predefined epileptiform activity with the goal of decreasing seizure frequency and severity. While thalamic leads are often implanted in combination with cortical strip leads, implantation and stimulation with bilateral thalamic leads alone is less common, and the ability to detect electrographic seizures using RNS System thalamic leads is uncertain. Objective: The present study retrospectively evaluated fourteen patients with RNS System depth leads implanted in the thalamus, with or without concomitant implantation of cortical strip leads, to determine the ability to detect electrographic seizures in the thalamus. Detailed patient presentations and lead trajectories were reviewed alongside electroencephalographic (ECoG) analyses. Results: Anterior nucleus thalamic (ANT) leads, whether bilateral or unilateral and combined with a cortical strip lead, successfully detected and terminated epileptiform activity, as demonstrated by Cases 2 and 3. Similarly, bilateral centromedian thalamic (CMT) leads or a combination of one centromedian thalamic alongside a cortical strip lead also demonstrated the ability to detect electrographic seizures as seen in Cases 6 and 9. Bilateral pulvinar leads likewise produced reliable seizure detection in Patient 14. Detections of electrographic seizures in thalamic nuclei did not appear to be affected by whether the patient was pediatric or adult at the time of RNS System implantation. Sole thalamic leads paralleled the combination of thalamic and cortical strip leads in terms of preventing the propagation of electrographic seizures. Conclusion: Thalamic nuclei present a promising target for detection and stimulation via the RNS System for seizures with multifocal or generalized onsets. These areas provide a modifiable, reversible therapeutic option for patients who are not candidates for surgical resection or ablation.

Intraoperative navigation in surgical management of traumatic spine injury: a propensity score matching analysis.

BACKGROUND: Traumatic spinal injury (TSI) can lead to severe morbidity and significant health care resource utilization. Intraoperative navigation (ION) systems have been shown to improve outcomes in some populations. However, controversy about the benefit of ION remains. To our knowledge, there is no large database analysis studying the outcomes of ION on TSI patients. Here we hope to compare complications and outcomes in patients with TSI undergoing spinal fusion of 3 or more levels with or without the use of ION. METHODS: The 2015-2019 National Surgical Quality Improvement Program (NSQIP) database was queried for cases of posterior spinal instrumentation of 3 or more levels. This population was then selected for postoperative diagnosis consistent with TSI. The effect of prolonged operative time was analyzed for all patients. Propensity score matching analysis was performed to create ION case and non-ION control groups. Baseline demographic characteristics, complications, and outcome data were collected and compared between ION and non-ION groups. RESULTS: A total of 1,034 patients were included in the propensity matched analysis. Among comorbidities, only obesity was significantly more likely in the non-ION group. There was no difference in case complexity between the two groups. ION was associated with higher incidence of prolonged operative time but was a negative independent predictor for sepsis. Prolonged operative time was a significant independent predictor for pulmonary embolism and requirement of transfusion in all patients. Discharge to home, readmission, and reoperation rates did not differ between TSI patients with or without ION. CONCLUSIONS: Use of ION during posterior spinal fusion of 3 or more levels in TSI patients is not associated with worse outcomes. Prolonged operative time, rather than ION, appears to have a higher influence on the rate of complications in this population. Evaluation of ION in the context of specific populations and pathology is warranted to optimize its use.

Activated microglia cause metabolic disruptions in developmental cortical interneurons that persist in interneurons from individuals with schizophrenia.

The mechanisms by which prenatal immune activation increase the risk for neuropsychiatric disorders are unclear. Here, we generated developmental cortical interneurons (cINs)-which are known to be affected in schizophrenia (SCZ) when matured-from induced pluripotent stem cells (iPSCs) derived from healthy controls (HCs) and individuals with SCZ and co-cultured them with or without activated microglia. Co-culture with activated microglia disturbed metabolic pathways, as indicated by unbiased transcriptome analyses, and impaired mitochondrial function, arborization, synapse formation and synaptic GABA release. Deficits in mitochondrial function and arborization were reversed by alpha lipoic acid and acetyl-L-carnitine treatments, which boost mitochondrial function. Notably, activated-microglia-conditioned medium altered metabolism in cINs and iPSCs from HCs but not in iPSCs from individuals with SCZ or in glutamatergic neurons. After removal of activated-microglia-conditioned medium, SCZ cINs but not HC cINs showed prolonged metabolic deficits, which suggests that there is an interaction between SCZ genetic backgrounds and environmental risk factors.

Large-Scale Generation and Characterization of Homogeneous Populations of Migratory Cortical Interneurons from Human Pluripotent Stem Cells.

During development, cortical interneurons (cINs) are generated from the ventral telencephalon, robustly migrate to the dorsal telencephalon, make local synaptic connections, and critically regulate brain circuitry by inhibiting other neurons. Thus, their abnormality is associated with various brain disorders. Human pluripotent stem cell (hPSC)-derived cINs can provide unlimited sources with which to study the pathogenesis mechanism of these disorders as well as provide a platform to develop novel therapeutics. By employing spinner culture, we could obtain a >10-fold higher yield of cIN progenitors compared to conventional culture without affecting their phenotype. Generated cIN spheres can be maintained feeder-free up to 10 months and are optimized for passaging and cryopreservation. In addition, we identified a combination of chemicals that synchronously matures generated progenitors into SOX6+KI67- migratory cINs and extensively characterized their maturation in terms of metabolism, migration, arborization, and electrophysiology. When transplanted into mouse brains, chemically matured migratory cINs generated grafts that efficiently disperse and integrate into the host circuitry without uncontrolled growth, making them an optimal cell population for cell therapy. Efficient large-scale generation of homogeneous migratory cINs without the need of feeder cells will play a critical role in the full realization of hPSC-derived cINs for development of novel therapeutics.

Early Palliative Care for Patients With Brain Metastases Decreases Inpatient Admissions and Need for Imaging Studies.

BACKGROUND: Early encounters with palliative care (PC) can influence health-care utilization, clinical outcome, and cost. AIM: To study the effect of timing of PC encounters on brain metastasis patients at an academic medical center. SETTING/PARTICIPANTS: All patients diagnosed with brain metastases from January 2013 to August 2015 at a single institution with inpatient and/or outpatient PC records available for review (N = 145). DESIGN: Early PC was defined as having a PC encounter within 8 weeks of diagnosis with brain metastases; late PC was defined as having PC after 8 weeks of diagnosis. Propensity score matched cohorts of early (n = 46) and late (n = 46) PC patients were compared to control for differences in age, gender, and Karnofsky Performance Status (KPS) at diagnosis. Details of the palliative encounter, patient outcomes, and health-care utilization were collected. RESULTS: Early PC versus late PC patients had no differences in baseline KPS, age, or gender. Early PC patients had significantly fewer number of inpatient visits per patient (1.5 vs 2.9; P = .004), emergency department visits (1.2 vs 2.1; P = .006), positron emission tomography/computed tomography studies (1.2 vs 2.7, P = .005), magnetic resonance imaging scans (5.8 vs 8.1; P = .03), and radiosurgery procedures (0.6 vs 1.3; P < .001). There were no differences in overall survival (median 8.2 vs 11.2 months; P = .2). Following inpatient admissions, early PC patients were more likely to be discharged home (59% vs 35%; P = .04). CONCLUSIONS: Timely PC consultations are advisable in this patient population and can reduce health-care utilization.