Development of an online calculator for the prediction of seizure freedom following pediatric hemispherectomy using the Hemispherectomy Outcome Prediction Scale (HOPS).

OBJECTIVES: Although hemispheric surgeries are among the most effective procedures for drug-resistant epilepsy (DRE) in the pediatric population, there is a large variability in seizure outcomes at the group level. A recently developed HOPS score provides individualized estimation of likelihood of seizure freedom to complement clinical judgement. The objective of this study was to develop a freely accessible online calculator that accurately predicts the probability of seizure freedom for any patient at 1-, 2-, and 5-years post-hemispherectomy. METHODS: Retrospective data of all pediatric patients with DRE and seizure outcome data from the original Hemispherectomy Outcome Prediction Scale (HOPS) study were included. The primary outcome of interest was time-to-seizure recurrence. A multivariate Cox proportional-hazards regression model was developed to predict the likelihood of post-hemispheric surgery seizure freedom at three time points (1-, 2- and 5- years) based on a combination of variables identified by clinical judgment and inferential statistics predictive of the primary outcome. The final model from this study was encoded in a publicly accessible online calculator on the International Network for Epilepsy Surgery and Treatment (iNEST) website (https://hops-calculator.com/). RESULTS: The selected variables for inclusion in the final model included the five original HOPS variables (age at seizure onset, etiologic substrate, seizure semiology, prior non-hemispheric resective surgery, and contralateral fluorodeoxyglucose-positron emission tomography [FDG-PET] hypometabolism) and three additional variables (age at surgery, history of infantile spasms, and magnetic resonance imaging [MRI] lesion). Predictors of shorter time-to-seizure recurrence included younger age at seizure onset, prior resective surgery, generalized seizure semiology, FDG-PET hypometabolism contralateral to the side of surgery, contralateral MRI lesion, non-lesional MRI, non-stroke etiologies, and a history of infantile spasms. The area under the curve (AUC) of the final model was 73.0%. SIGNIFICANCE: Online calculators are useful, cost-free tools that can assist physicians in risk estimation and inform joint decision-making processes with patients and families, potentially leading to greater satisfaction. Although the HOPS data was validated in the original analysis, the authors encourage external validation of this new calculator.

Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development.

Malformations of cortical development (MCD) are neurological conditions involving focal disruptions of cortical architecture and cellular organization that arise during embryogenesis, largely from somatic mosaic mutations, and cause intractable epilepsy. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat condition-related epilepsy. Here we report a genetic landscape from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation including in utero electroporation of mice and single-nucleus RNA sequencing. Genotype-phenotype correlation analysis elucidated specific MCD gene sets associated with distinct pathophysiological and clinical phenotypes. The unique single-cell level spatiotemporal expression patterns of mutated genes in control and patient brains indicate critical roles in excitatory neurogenic pools during brain development and in promoting neuronal hyperexcitability after birth.

Reversibility and developmental neuropathology of linear nevus sebaceous syndrome caused by dysregulation of the RAS pathway.

Linear nevus sebaceous syndrome (LNSS) is a neurocutaneous disorder caused by somatic gain-of-function mutations in KRAS or HRAS. LNSS brains have neurodevelopmental defects, including cerebral defects and epilepsy; however, its pathological mechanism and potentials for treatment are largely unclear. We show that introduction of KRASG12V in the developing mouse cortex results in subcortical nodular heterotopia and enhanced excitability, recapitulating major pathological manifestations of LNSS. Moreover, we show that decreased firing frequency of inhibitory neurons without KRASG12V expression leads to disrupted excitation and inhibition balance. Transcriptional profiling after destabilization domain-mediated clearance of KRASG12V in human neural progenitors and differentiating neurons identifies reversible functional networks underlying LNSS. Neurons expressing KRASG12V show molecular changes associated with delayed neuronal maturation, most of which are restored by KRASG12V clearance. These findings provide insights into the molecular networks underlying the reversibility of some of the neuropathologies observed in LNSS caused by dysregulation of the RAS pathway.

Preliminary Experience Suggests the Addition of Choroid Plexus Cauterization to Functional Hemispherectomy May Reduce Posthemispherectomy Hydrocephalus.

BACKGROUND: Cerebral hemispherectomy can effectively treat unihemispheric epilepsy. However, posthemispherectomy hydrocephalus (PHH), a serious life-long complication, remains prevalent, requiring careful considerations in technique selection and postoperative management. In 2016, we began incorporating open choroid plexus cauterization (CPC) into our institution's hemispherectomy procedure in an attempt to prevent PHH. OBJECTIVE: To determine whether routine CPC prevented PHH without exacerbating hemispherectomy efficacy or safety. METHODS: A retrospective review of consecutive patients who underwent hemispherectomy for intractable epilepsy between 2011 and 2021 was performed. Multivariate logistic regression was used to identify factors independently associated with PHH requiring cerebrospinal fluid (CSF) shunting. RESULTS: Sixty-eight patients were included in this study, of whom 26 (38.2%) underwent CPC. Fewer patients required CSF shunting in the CPC group (7.7% vs 28.7%, P = .033) and no patients who underwent de novo hemispherectomy with CPC developed PHH. Both cohorts experienced seizure freedom (65.4% vs 59.5%, P = .634) and postoperative complications, including infection (3.8% vs 2.4%, P = .728), hemorrhage (0.0% vs 2.4%, P = .428), and revision hemispherectomy (19.2% vs 14.3%, P = .591) at similar rates. Patients without CPC had greater odds of developing PHH requiring CSF shunting (odds ratio = 8.36, P = .026). The number needed to treat with CPC to prevent an additional case of PHH was 4.8, suggesting high effectiveness. CONCLUSION: Preventing PHH is critical. Our early experience demonstrated that routinely incorporating CPC into hemispherectomy effectively prevents PHH without causing additional complications, especially in first-time hemispherectomies. A multicenter randomized controlled trial with long-term follow-up is required to corroborate the findings of our single-institutional case series and determine whether greater adoption of this technique is justified.

Brain molecular mechanisms in Rasmussen encephalitis.

OBJECTIVE: This study was undertaken to identify molecular mechanisms in brain tissue of Rasmussen encephalitis (RE) when compared to people with non-RE epilepsy (PWE) and control cases using whole exome sequencing (WES), RNAseq, and proteomics. METHODS: Frozen brain tissue (ages = 2-19 years) was obtained from control autopsy (n = 14), surgical PWE (n = 10), and surgical RE cases (n = 27). We evaluated WES variants in RE associated with epilepsy, seizures, RE, and human leukocyte antigens (HLAs). Differential expression was evaluated by RNAseq (adjusted p < .05) and label-free quantitative mass spectrometry (false discovery rate < 5%) in the three groups. RESULTS: WES revealed no common pathogenic variants in RE, but several rare and likely deleterious variants of unknown significance (VUS; ANGPTL7/MTOR, SCN1A, FCGR3B, MTOR) and more common HLA VUS in >25% of RE cases (HLA-DRB1, HLA-DQA2), all with allele frequency < 5% in the general population. RNAseq in RE versus PWE (1516 altered transcripts) revealed significant activation of crosstalk between dendritic and natural killer cells (p = 7.94 × 10-6 , z = 2.65), in RE versus control (7466 transcripts) neuroinflammation signaling activation (p = 6.31 × 10-13 , z = 5.07), and in PWE versus control (945 transcripts) phagosome formation activation (p = 2.00 × 10-13 , z = 5.61). Proteomics detected fewer altered targets. SIGNIFICANCE: In RE, we identified activated immune signaling pathways and immune cell type annotation enrichment that suggest roles of the innate and adaptive immune responses, as well as HLA variants that may increase vulnerability to RE. Follow-up studies could evaluate cell type density and subregional localization associated with top targets, clinical history (neuropathology, disease duration), and whether modulating crosstalk between dendritic and natural killer cells may limit disease progression.

A molecular interactome of the glioblastoma perivascular niche reveals integrin binding sialoprotein as a mediator of tumor cell migration.

Glioblastoma (GBM) is characterized by extensive microvascular hyperproliferation. In addition to supplying blood to the tumor, GBM vessels also provide trophic support to glioma cells and serve as conduits for migration into the surrounding brain, promoting recurrence. Here, we enrich CD31-expressing glioma vascular cells (GVCs) and A2B5-expressing glioma tumor cells (GTCs) from primary GBM and use RNA sequencing to create a comprehensive molecular interaction map of the secreted and extracellular factors elaborated by GVCs that can interact with receptors and membrane molecules on GTCs. To validate our findings, we utilize functional assays, including a hydrogel-based migration assay and in vivo mouse models to demonstrate that one identified factor, the little-studied integrin binding sialoprotein (IBSP), enhances tumor growth and promotes the migration of GTCs along the vasculature. This perivascular niche interactome will serve as a resource to the research community in defining the potential functions of the GBM vasculature.

Human Astrocytes Exhibit Tumor Microenvironment-, Age-, and Sex-Related Transcriptomic Signatures.

Astrocytes are critical for the development and function of synapses. There are notable species differences between human astrocytes and commonly used animal models. Yet, it is unclear whether astrocytic genes involved in synaptic function are stable or exhibit dynamic changes associated with disease states and age in humans, which is a barrier in understanding human astrocyte biology and its potential involvement in neurologic diseases. To better understand the properties of human astrocytes, we acutely purified astrocytes from the cerebral cortices of over 40 humans across various ages, sexes, and disease states. We performed RNA sequencing to generate transcriptomic profiles of these astrocytes and identified genes associated with these biological variables. We found that human astrocytes in tumor-surrounding regions downregulate genes involved in synaptic function and sensing of signals in the microenvironment, suggesting involvement of peritumor astrocytes in tumor-associated neural circuit dysfunction. In aging, we also found downregulation of synaptic regulators and upregulation of markers of cytokine signaling, while in maturation we identified changes in ionic transport with implications for calcium signaling. In addition, we identified subtle sexual dimorphism in human cortical astrocytes, which has implications for observed sex differences across many neurologic disorders. Overall, genes involved in synaptic function exhibit dynamic changes in the peritumor microenvironment and aging. These data provide powerful new insights into human astrocyte biology in several biologically relevant states that will aid in generating novel testable hypotheses about homeostatic and reactive astrocytes in humans.SIGNIFICANCE STATEMENT Astrocytes are an abundant class of cells playing integral roles at synapses. Astrocyte dysfunction is implicated in a variety of human neurologic diseases. Yet our knowledge of astrocytes is largely based on mouse studies. Direct knowledge of human astrocyte biology remains limited. Here, we present transcriptomic profiles of human cortical astrocytes, and we identified molecular differences associated with age, sex, and disease state. We found that peritumor and aging astrocytes downregulate genes involved in astrocyte-synapse interactions. These data provide necessary insight into human astrocyte biology that will improve our understanding of human disease.

Functional cognitive and language outcomes after cerebral hemispherectomy for hemimegalencephaly.

OBJECTIVE: Hemispheric surgeries are an effective treatment option to control seizures for children with hemimegalencephaly (HME); however, not enough is known about their cognitive outcomes. This study aimed to delineate the cognitive and language outcomes after hemispherectomy for HME and identify the clinical characteristics associated with cognition and language. METHODS: Data came from the Global Pediatric Epilepsy Surgery Registry, a patient-driven web-based registry for epilepsy surgery. We focused on children's functional status, assessed through parent-reports of cognitive and language skills. Parents also reported on their satisfaction with surgery, their child's quality of life, and various demographic, clinical, and surgery characteristics. RESULTS: Parents of 45 children (40% female) participated. Children were aged 2.6 (SD 6.5) months at seizure onset, 10.8 (SD 12.7) months at hemispherectomy, and 8.7 (SD 4.8) years at follow-up, at which point 68% were seizure-free. We found that at follow-up, 43% had average or mildly impaired cognition, 26% could speak age appropriately, and 21% had satisfactory reading skills. A total of 55%, 43%, and 17% of children first babbled, spoke their first words, and started speaking in sentences at an age-appropriate period, respectively. Children who had undergone a right hemisphere resection and those who were older at epilepsy onset were more likely to have better cognitive and language outcomes. SIGNIFICANCE: Children with HME have delayed language milestones and continue to require significant language and literacy support long-term after cerebral hemispherectomy.

Comparison of the real-world effectiveness of vertical versus lateral functional hemispherotomy techniques for pediatric drug-resistant epilepsy: A post hoc analysis of the HOPS study.

OBJECTIVE: This study was undertaken to determine whether the vertical parasagittal approach or the lateral peri-insular/peri-Sylvian approach to hemispheric surgery is the superior technique in achieving long-term seizure freedom. METHODS: We conducted a post hoc subgroup analysis of the HOPS (Hemispheric Surgery Outcome Prediction Scale) study, an international, multicenter, retrospective cohort study that identified predictors of seizure freedom through logistic regression modeling. Only patients undergoing vertical parasagittal, lateral peri-insular/peri-Sylvian, or lateral trans-Sylvian hemispherotomy were included in this post hoc analysis. Differences in seizure freedom rates were assessed using a time-to-event method and calculated using the Kaplan-Meier survival method. RESULTS: Data for 672 participants across 23 centers were collected on the specific hemispherotomy approach. Of these, 72 (10.7%) underwent vertical parasagittal hemispherotomy and 600 (89.3%) underwent lateral peri-insular/peri-Sylvian or trans-Sylvian hemispherotomy. Seizure freedom was obtained in 62.4% (95% confidence interval [CI] = 53.5%-70.2%) of the entire cohort at 10-year follow-up. Seizure freedom was 88.8% (95% CI = 78.9%-94.3%) at 1-year follow-up and persisted at 85.5% (95% CI = 74.7%-92.0%) across 5- and 10-year follow-up in the vertical subgroup. In contrast, seizure freedom decreased from 89.2% (95% CI = 86.3%-91.5%) at 1-year to 72.1% (95% CI = 66.9%-76.7%) at 5-year to 57.2% (95% CI = 46.6%-66.4%) at 10-year follow-up for the lateral subgroup. Log-rank test found that vertical hemispherotomy was associated with durable seizure-free progression compared to the lateral approach (p = .01). Patients undergoing the lateral hemispherotomy technique had a shorter time-to-seizure recurrence (hazard ratio = 2.56, 95% CI = 1.08-6.04, p = .03) and increased seizure recurrence odds (odds ratio = 3.67, 95% CI = 1.05-12.86, p = .04) compared to those undergoing the vertical hemispherotomy technique. SIGNIFICANCE: This pilot study demonstrated more durable seizure freedom of the vertical technique compared to lateral hemispherotomy techniques. Further studies, such as prospective expertise-based observational studies or a randomized clinical trial, are required to determine whether a vertical approach to hemispheric surgery provides superior long-term seizure outcomes.

Clonally Focused Public and Private T Cells in Resected Brain Tissue From Surgeries to Treat Children With Intractable Seizures.

Using a targeted transcriptomics approach, we have analyzed resected brain tissue from a cohort of 53 pediatric epilepsy surgery cases, and have found that there is a spectrum of involvement of both the innate and adaptive immune systems as evidenced by the differential expression of immune-specific genes in the affected brain tissue. The specimens with the highest expression of immune-specific genes were from two Rasmussen encephalitis cases, which is known to be a neuro-immunological disease, but also from tuberous sclerosis complex (TSC), focal cortical dysplasia, and hemimegalencephaly surgery cases. We obtained T cell receptor (TCR) Vß chain sequence data from brain tissue and blood from patients with the highest levels of T cell transcripts. The clonality indices and the frequency of the top 50 Vß clonotypes indicated that T cells in the brain were clonally restricted. The top 50 Vß clonotypes comprised both public and private (patient specific) clonotypes, and the TCR Vß chain third complementarity region (CDR3) of the most abundant public Vß clonotype in each brain sample was strikingly similar to a CDR3 that recognizes an immunodominant epitope in either human cytomegalovirus or Epstein Barr virus, or influenza virus A. We found that the frequency of 14 of the top 50 brain Vß clonotypes from a TSC surgery case had significantly increased in brain tissue removed to control recurrent seizures 11 months after the first surgery. Conversely, we found that the frequency in the blood of 18 of the top 50 brain clonotypes from a second TSC patient, who was seizure free, had significantly decreased 5 months after surgery indicating that T cell clones found in the brain had contracted in the periphery after removal of the brain area associated with seizure activity and inflammation. However, the frequency of a public and a private clonotype significantly increased in the brain after seizures recurred and the patient underwent a second surgery. Combined single cell gene expression and TCR sequencing of brain-infiltrating leukocytes from the second surgery showed that the two clones were CD8 effector T cells, indicating that they are likely to be pathologically relevant.

Hemispherectomy Outcome Prediction Scale: Development and validation of a seizure freedom prediction tool.

OBJECTIVE: To develop and validate a model to predict seizure freedom in children undergoing cerebral hemispheric surgery for the treatment of drug-resistant epilepsy. METHODS: We analyzed 1267 hemispheric surgeries performed in pediatric participants across 32 centers and 12 countries to identify predictors of seizure freedom at 3 months after surgery. A multivariate logistic regression model was developed based on 70% of the dataset (training set) and validated on 30% of the dataset (validation set). Missing data were handled using multiple imputation techniques. RESULTS: Overall, 817 of 1237 (66%) hemispheric surgeries led to seizure freedom (median follow-up = 24 months), and 1050 of 1237 (85%) were seizure-free at 12 months after surgery. A simple regression model containing age at seizure onset, presence of generalized seizure semiology, presence of contralateral 18-fluoro-2-deoxyglucose-positron emission tomography hypometabolism, etiologic substrate, and previous nonhemispheric resective surgery is predictive of seizure freedom (area under the curve = .72). A Hemispheric Surgery Outcome Prediction Scale (HOPS) score was devised that can be used to predict seizure freedom. SIGNIFICANCE: Children most likely to benefit from hemispheric surgery can be selected and counseled through the implementation of a scale derived from a multiple regression model. Importantly, children who are unlikely to experience seizure control can be spared from the complications and deficits associated with this surgery. The HOPS score is likely to help physicians in clinical decision-making.

Long-Term Patient-Reported Outcomes of Visual Field Defects and Compensatory Mechanisms in Patients After Cerebral Hemispherectomy.

BACKGROUND: In cases of intractable epilepsy resistant to drug therapy, hemispherectomy is often the only treatment option to mitigate seizures; however, the true long-term subjective visual outcomes are relatively unexplored. In this study, we sought to determine and characterize patient-reported visual function years after hemispherectomy. METHODS: This was an observational study conducted on a large cohort of children with seizure disorder treated with cerebral hemispherectomy. An online survey was sent to parents with questions to assess subjective visual function with a variety of questions from presence of visual field defects after hemispherectomy, to improvement over time, compensatory mechanisms used, and development of strabismus. RESULTS: This survey was emailed to 248 parents of previously evaluated children who agreed to be re-surveyed, 48 (20%) of which responded. The average age at hemispherectomy was approximately 5 (±4) years, and the average time after hemispherectomy was 7 (±5) years. Thirty-nine patients (81%) were seizure-free after 1 surgery and 85% (n = 41) were seizure-free after ≥1 surgeries. Thirty-four (71%) experienced a visual field defect after surgery, but 25 (52%) experienced subjective improvement over time. Thirty-eight (79%) used compensatory mechanisms, such as head tilting, with 16 (33%) patients experiencing subjective improvement over time. Twenty-seven (56%) patients experienced a decrease in visual acuity after surgery with 12 (25%) experiencing subjective improvement over time. CONCLUSION: In a large cohort examining patient-reported visual outcomes years after hemispherectomy, most patients experienced strabismus and/or visual field defects. However, more than half reported improvements and compensatory mechanisms (exotropic strabismus and ipsilateral esotropic strabismus) over time, presumably to enhance visual field function. By exploring subjective visual and cognitive function, this paper uniquely characterizes patient-reported improvements over time, and provides motivation for larger longitudinal studies using more quantitative measures of visual function and improvement after hemispherectomy.

Effect of Gene Mutation on Seizures in Surgery for Tuberous Sclerosis Complex.

BACKGROUND: Tuberous sclerosis complex (TSC) is a rare genetic disorder that commonly leads to drug-resistant epilepsy in affected patients. This study aimed to determine whether the underlying genetic mutation (TSC1 vs. TSC2) predicts seizure outcomes following surgical treatments for epilepsy. METHODS: We retrospectively assessed TSC patients using the TSC Natural History Database core registry. Data review focused on outcomes in patients treated with surgical resection or vagus nerve stimulation. RESULTS: A total of 42 patients with a TSC1 mutation, and 145 patients with a TSC2 mutation, were identified. We observed a distinct clinical phenotype: children with TSC2 mutations tended to be diagnosed with TSC at a younger age than those with a TSC1 mutation (p < 0.001), were more likely to have infantile spasms (p < 0.001), and to get to surgery at a later age (p = 0.003). Among this TSC2 cohort, seizure control following resective epilepsy surgery was achieved in less than half (47%) the study sample. In contrast, patients with TSC1 mutations tended to have more favorable postsurgical outcomes; seizure control was achieved in 66% of this group. CONCLUSION: TSC2 mutations result in a more severe epilepsy phenotype that is also less responsive to resective surgery. It is important to consider this distinct clinical disposition when counseling families preoperatively with respect to seizure freedom. Larger samples are required to better characterize the independent effects of genetic mutation, infantile spasms, and duration of epilepsy as they relate to seizure control following resective or neuromodulatory epilepsy surgery.

Recurrent limbic seizures do not cause hippocampal neuronal loss: A prolonged laboratory study.

PURPOSE: It remains controversial whether neuronal damage and synaptic reorganization found in some forms of epilepsy are the result of an initial injury and potentially contributory to the epileptic condition or are the cumulative affect of repeated seizures. A number of reports of human and animal pathology suggest that at least some neuronal loss precedes the onset of seizures, but there is debate over whether there is further damage over time from intermittent seizures. In support of this latter hypothesis are MRI studies in people that show reduced hippocampal volumes and cortical thickness with longer durations of the disease. In this study we addressed the question of neuronal loss from intermittent seizures using kindled rats (no initial injury) and rats with limbic epilepsy (initial injury). METHODS: Supragranular mossy fiber sprouting, hippocampal neuronal densities, and subfield area measurements were determined in rats with chronic limbic epilepsy (CLE) that developed following an episode of limbic status epilepticus (n = 25), in kindled rats (n = 15), and in age matched controls (n = 20). To determine whether age or seizure frequency played a role in the changes, CLE and kindled rats were further classified by seizure frequency (low/high) and the duration of the seizure disorder (young/old). RESULTS: Overall there was no evidence for progressive neuronal loss from recurrent seizures. Compared with control and kindled rats, CLE animals showed increased mossy fiber sprouting, decreased neuronal numbers in multiple regions and regional atrophy. In CLE, but not kindled rats: 1) Higher seizure frequency was associated with greater mossy fiber sprouting and granule cell dispersion; and 2) greater age with seizures was associated with decreased hilar densities, and increased hilar areas. There was no evidence for progressive neuronal loss, even with more than 1000 seizures. CONCLUSION: These findings suggest that the neuronal loss associated with limbic epilepsy precedes the onset of the seizures and is not a consequence of recurrent seizures. However, intermittent seizures do cause other structural changes in the brain, the functional consequences of which are unclear.

Novel tonometer device distinguishes brain stiffness in epilepsy surgery.

Complete surgical resection of abnormal brain tissue is the most important predictor of seizure freedom following surgery for cortical dysplasia. While lesional tissue is often visually indiscernible from normal brain, anecdotally, it is subjectively stiffer. We report the first experience of the use of a digital tonometer to understand the biomechanical properties of epilepsy tissue and to guide the conduct of epilepsy surgery. Consecutive epilepsy surgery patients (n = 24) from UCLA Mattel Children's Hospital were recruited to undergo intraoperative brain tonometry at the time of open craniotomy for epilepsy surgery. Brain stiffness measurements were corrected with abnormalities on neuroimaging and histopathology using mixed-effects multivariable linear regression. We collected 249 measurements across 30 operations involving 24 patients through the pediatric epilepsy surgery program at UCLA Mattel Children's Hospital. On multivariable mixed-effects regression, brain stiffness was significantly associated with the presence of MRI lesion (ß = 32.3, 95%CI 16.3-48.2; p < 0.001), severity of cortical disorganization (ß = 19.8, 95%CI 9.4-30.2; p = 0.001), and recent subdural grid implantation (ß = 42.8, 95%CI 11.8-73.8; p = 0.009). Brain tonometry offers the potential of real-time intraoperative feedback to identify abnormal brain tissue with millimeter spatial resolution. We present the first experience with this novel intraoperative tool for the conduct of epilepsy surgery. A carefully designed prospective study is required to elucidate whether the clinical application of brain tonometry during resective procedures could guide the area of resection and improve seizure outcomes.

Epilepsy surgery for Rasmussen encephalitis: the UCLA experience.

OBJECTIVE: Rasmussen encephalitis (RE) is a rare inflammatory neurological disorder typically involving one hemisphere and resulting in drug-resistant epilepsy and progressive neurological decline. Here, the authors present seizure outcomes in children who underwent epilepsy surgery for RE at a single institution. METHODS: The records of consecutive patients who had undergone epilepsy surgery for RE at the UCLA Mattel Children's Hospital between 1982 and 2018 were retrospectively reviewed. Basic demographic information, seizure history, procedural notes, and postoperative seizure and functional outcome data were analyzed. RESULTS: The cohort included 44 patients, 41 of whom had sufficient data for analysis. Seizure freedom was achieved in 68%, 48%, and 22% of the patients at 1, 5, and 10 years, respectively. The median time to the first seizure for those who experienced seizure recurrence after surgery was 39 weeks (IQR 11-355 weeks). Anatomical hemispherectomy, as compared to functional hemispherectomy, was independently associated with a longer time to postoperative seizure recurrence (HR 0.078, p = 0.03). There was no statistically significant difference in postoperative seizure recurrence between patients with complete hemispherectomy and those who had less-than-hemispheric surgery. Following surgery, 68% of the patients could ambulate and 84% could speak regardless of operative intervention. CONCLUSIONS: A large proportion of RE patients will have seizure relapse after surgery, though patients with anatomical hemispherectomies may have a longer time to postoperative seizure recurrence. Overall, the long-term data in this study suggest that hemispheric surgery can be seen as palliative treatment for seizures rather than a cure for RE.

Paroxysmal Discharges in Tissue Slices From Pediatric Epilepsy Surgery Patients: Critical Role of GABAB Receptors in the Generation of Ictal Activity.

In the present study, we characterized the effects of bath application of the proconvulsant drug 4-aminopyridine (4-AP) alone or in combination with GABAA and/or GABAB receptor antagonists, in cortical dysplasia (CD type I and CD type IIa/b), tuberous sclerosis complex (TSC), and non-CD cortical tissue samples from pediatric epilepsy surgery patients. Whole-cell patch clamp recordings in current and voltage clamp modes were obtained from cortical pyramidal neurons (CPNs), interneurons, and balloon/giant cells. In pyramidal neurons, bath application of 4-AP produced an increase in spontaneous synaptic activity as well as rhythmic membrane oscillations. In current clamp mode, these oscillations were generally depolarizing or biphasic and were accompanied by increased membrane conductance. In interneurons, membrane oscillations were consistently depolarizing and accompanied by bursts of action potentials. In a subset of balloon/giant cells from CD type IIb and TSC cases, respectively, 4-AP induced very low-amplitude, slow membrane oscillations that echoed the rhythmic oscillations from pyramidal neurons and interneurons. Bicuculline reduced the amplitude of membrane oscillations induced by 4-AP, indicating that they were mediated principally by GABAA receptors. 4-AP alone or in combination with bicuculline increased cortical excitability but did not induce seizure-like discharges. Ictal activity was observed in pyramidal neurons and interneurons from CD and TSC cases only when phaclofen, a GABAB receptor antagonist, was added to the 4-AP and bicuculline solution. These results emphasize the critical and permissive role of GABAB receptors in the transition to an ictal state in pediatric CD tissue and highlight the importance of these receptors as a potential therapeutic target in pediatric epilepsy.

Pathological high frequency oscillations associate with increased GABA synaptic activity in pediatric epilepsy surgery patients.

Pathological high-frequency oscillations (HFOs), specifically fast ripples (FRs, >250 Hz), are pathognomonic of an active epileptogenic zone. However, the origin of FRs remains unknown. Here we explored the correlation between FRs recorded with intraoperative pre-resection electrocorticography (ECoG) and spontaneous synaptic activity recorded ex vivo from cortical tissue samples resected for the treatment of pharmacoresistant epilepsy. The cohort included 47 children (ages 0.22-9.99 yr) with focal cortical dysplasias (CD types I and II), tuberous sclerosis complex (TSC) and non-CD pathologies. Whole-cell patch clamp recordings were obtained from pyramidal neurons and interneurons in cortical regions that were positive or negative for pathological HFOs, defined as FR band oscillations (250-500 Hz) at ECoG. The frequency of spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and IPSCs, respectively) was compared between HFO+ and HFO- regions. Regardless of pathological substrate, regions positive for FRs displayed significantly increased frequencies of sIPSCs compared with regions negative for FRs. In contrast, the frequency of sEPSCs was similar in both regions. In about one third of cases (n = 17), pacemaker GABA synaptic activity (PGA) was observed. In the vast majority (n = 15), PGA occurred in HFO+ areas. Further, fast-spiking interneurons displayed signs of hyperexcitability exclusively in HFO+ areas. These results indicate that, in pediatric epilepsy patients, increased GABA synaptic activity is associated with interictal FRs in the epileptogenic zone and suggest an active role of GABAergic interneurons in the generation of pathological HFOs. Increased GABA synaptic activity could serve to dampen excessive excitability of cortical pyramidal neurons in the epileptogenic zone, but it could also promote neuronal network synchrony.

Etiology and Age Modifies Subjective Visual Function After Cerebral Hemispherectomy.

BACKGROUND: Cerebral hemispherectomy is typically used to treat patients with pharmacoresistant epilepsy. Visual-related outcomes are relatively unstudied in this population, aside from the knowledge that patients develop a complete homonymous hemianopia contralateral to the side of the hemispherectomy. The purpose of this study was to determine and characterize parent-reported functional visual, oculomotor, and postural changes in a large population of patients following cerebral hemispherectomy. METHODS: An online survey was sent to parents of children who had undergone hemispherectomy for seizure control. Families were recruited by the Brain Recovery Project: Childhood Epilepsy Surgery Foundation. Parent-reported subjective visual function was assessed by the presence of peripheral field defects, ocular misalignment and anomalous head posture. RESULTS: A total of 196 (12.5%) participants responded. Postoperative follow-up was 92±78 months (range: 1-382). Ninety-three percent of parents reported the child had difficulties with peripheral vision. Torticollis was present postoperatively in 122 (62%) patients. Strabismus was noted in 93 (49%). Fifty-five (59%) of the strabismus patients demonstrated exotropia with the majority of exotropia patients demonstrating the exo-deviated eye in the direction contralateral to the hemispherectomy (74.5%). Both torticollis and strabismus were most frequently seen immediately after surgery. Sixty-six patients (34%) underwent strabismus treatment. Patients with younger age of seizure onset, younger age of surgery, and certain epilepsy etiologies (hemimegencephaly, Sturge-Weber syndrome) were more likely to develop strabismus and torticollis. CONCLUSIONS: Torticollis and strabismus are common after hemispherectomy and appear to be influenced by etiology and age at surgery. Preoperative discussion with parents and patients regarding those compensatory mechanisms is recommended, and postoperative ophthalmologic assessments are also encouraged.

Physical Growth of the Contralateral Cerebrum is Preserved After Hemispherotomy in Childhood.

BACKGROUND: Hemispherotomy can be an effective treatment for refractory childhood epilepsy. However, the extent of postoperative brain development after hemispherotomy remains incompletely understood. This study aims to provide an anatomic foundation in assessing development of the contralateral hemisphere, by measuring volumetric growth after hemispherotomy. METHODS: Eleven patients with hemimegalencephaly, Rasmussen's encephalitis, and cerebral infarction who underwent hemispherotomy before age 12 years, an immediate preoperative magnetic resonance imaging, and at least three years of follow-up magnetic resonance imagings were retrospectively analyzed. The volume of the contralateral hemisphere was measured before and after surgery. Growth curves were compared with those of healthy individuals from an open database. The growth rate relative to the healthy individuals ("catch-up rate") was calculated. RESULTS: A positive volumetric growth of the contralateral hemisphere was observed across all pathologies. The hemimegalencephaly subgroup underwent hemispherotomy at the earliest time and had the largest postoperative growth rate, which exceeded that of healthy individuals. The Rasmussen subgroup underwent surgery at the second earliest time and had an intermediate growth rate, which was similar to that of healthy individuals. The infarction subgroup underwent surgery at the latest time and had the slowest growth rate, which was less than that of healthy individuals. CONCLUSIONS: The contralateral hemisphere continues to increase in volume after hemispherotomy in childhood. Further studies with a larger sample size and correlation with cognitive outcomes may aid in characterizing the prognosis after hemispherotomy.