Thalamic stereoelectroencephalography for neuromodulation target selection: Proof of concept and review of literature of pulvinar direct electrical stimulation.

In patients with drug-resistant epilepsy (DRE) who are not candidates for resective surgery, various thalamic nuclei, including the anterior, centromedian, and pulvinar nuclei, have been extensively investigated as targets for neuromodulation. However, the therapeutic effects of different targets for thalamic neuromodulation on various types of epilepsy are not well understood. Here, we present a 32-year-old patient with multifocal bilateral temporoparieto-occipital epilepsy and bilateral malformations of cortical development (MCDs) who underwent bilateral stereoelectroencephalographic (SEEG) recordings of the aforementioned three thalamic nuclei bilaterally. The change in the rate of interictal epileptiform discharges (IEDs) from baseline were compared in temporal, central, parietal, and occipital regions after direct electrical stimulation (DES) of each thalamic nucleus. A significant decrease in the rate of IEDs (33% from baseline) in the posterior quadrant regions was noted in the ipsilateral as well as contralateral hemisphere following DES of the pulvinar. A scoping review was also performed to better understand the current standpoint of pulvinar thalamic stimulation in the treatment of DRE. The therapeutic effect of neuromodulation can differ among thalamic nuclei targets and epileptogenic zones (EZs). In patients with multifocal EZs with extensive MCDs, personalized thalamic targeting could be achieved through DES with thalamic SEEG electrodes.

Intraoperative Integrated Diagnostic System for Malignant Central Nervous System Tumors.

PURPOSE: The 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors uses an integrated approach involving histopathology and molecular profiling. Because majority of adult malignant brain tumors are gliomas and primary CNS lymphomas (PCNSL), rapid differentiation of these diseases is required for therapeutic decisions. In addition, diffuse gliomas require molecular information on single-nucleotide variants (SNV), such as IDH1/2. Here, we report an intraoperative integrated diagnostic (i-ID) system to classify CNS malignant tumors, which updates legacy frozen-section (FS) diagnosis through incorporation of a qPCR-based genotyping assay. EXPERIMENTAL DESIGN: FS evaluation, including GFAP and CD20 rapid IHC, was performed on adult malignant CNS tumors. PCNSL was diagnosed through positive CD20 and negative GFAP immunostaining. For suspected glioma, genotyping for IDH1/2, TERT SNV, and CDKN2A copy-number alteration was routinely performed, whereas H3F3A and BRAF SNV were assessed for selected cases. i-ID was determined on the basis of the 2021 WHO classification and compared with the permanent integrated diagnosis (p-ID) to assess its reliability. RESULTS: After retrospectively analyzing 153 cases, 101 cases were prospectively examined using the i-ID system. Assessment of IDH1/2, TERT, H3F3AK27M, BRAFV600E, and CDKN2A alterations with i-ID and permanent genomic analysis was concordant in 100%, 100%, 100%, 100%, and 96.4%, respectively. Combination with FS and intraoperative genotyping assay improved diagnostic accuracy in gliomas. Overall, i-ID matched with p-ID in 80/82 (97.6%) patients with glioma and 18/19 (94.7%) with PCNSL. CONCLUSIONS: The i-ID system provides reliable integrated diagnosis of adult malignant CNS tumors.

Arteries Around the Superior Limiting Sulcus: Motor Complication Avoidance in Insular and Insulo-Opercular Surgery.

BACKGROUND AND OBJECTIVES: Insulo-opercular surgery can cause ischemic motor complications. A source of this is the arteries around the superior limiting sulcus (SLS), which reach the corona radiata, but the detailed anatomy remains unclear. To characterize arteries around the SLS including the long insular arteries (LIAs) and long medullary arteries, we classified them and examined their distribution in relation to the SLS, which helps reduce the risk of ischemia. METHODS: Twenty adult cadaveric hemispheres were studied. Coronal brain slices were created perpendicular to the SLS representing insular gyri (anterior short, middle short, posterior short, anterior long, and posterior long). The arteries within 10-mm proximity of the SLS that reached the corona radiata were excavated and classified by the entry point. RESULTS: A total of 122 arteries were identified. Sixty-three (52%), 20 (16%), and 39 (32%) arteries penetrated the insula (LIAs), peak of the SLS, and operculum (long medullary arteries), respectively. 100 and six (87%) arteries penetrated within 5 mm of the peak of the SLS. The arteries were distributed in the anterior short gyrus (19%), middle short gyrus (17%), posterior short gyrus (20%), anterior long gyrus (19%), and posterior long gyrus (25%). Seven arteries (5.7%) had anastomoses after they penetrated the parenchyma. CONCLUSION: Approximately 90% of the arteries that entered the parenchyma and reached the corona radiata were within a 5-mm radius of the SLS in both the insula and operculum side. This suggests that using the SLS as a landmark during insulo-opercular surgery can decrease the chance of ischemia.

Predictors of outcomes after surgery for medically intractable insular epilepsy: A systematic review and individual participant data meta-analysis.

Insular epilepsy (IE) is an increasingly recognized cause of drug-resistant epilepsy amenable to surgery. However, concerns of suboptimal seizure control and permanent neurological morbidity hamper widespread adoption of surgery for IE. We performed a systematic review and individual participant data meta-analysis to determine the efficacy and safety profile of surgery for IE and identify predictors of outcomes. Of 2483 unique citations, 24 retrospective studies reporting on 312 participants were eligible for inclusion. The median follow-up duration was 2.58 years (range, 0-17 years), and 206 (66.7%) patients were seizure-free at last follow-up. Younger age at surgery (≤18 years; HR = 1.70, 95% CI = 1.09-2.66, P = .022) and invasive EEG monitoring (HR = 1.97, 95% CI = 1.04-3.74, P = .039) were significantly associated with shorter time to seizure recurrence. Performing MR-guided laser ablation or radiofrequency ablation instead of open resection (OR = 2.05, 95% CI = 1.08-3.89, P = .028) was independently associated with suboptimal or poor seizure outcome (Engel II-IV) at last follow-up. Postoperative neurological complications occurred in 42.5% of patients, most commonly motor deficits (29.9%). Permanent neurological complications occurred in 7.8% of surgeries, including 5% and 1.4% rate of permanent motor deficits and dysphasia, respectively. Resection of the frontal operculum was independently associated with greater odds of motor deficits (OR = 2.75, 95% CI = 1.46-5.15, P = .002). Dominant-hemisphere resections were independently associated with dysphasia (OR = 13.09, 95% CI = 2.22-77.14, P = .005) albeit none of the observed language deficits were permanent. Surgery for IE is associated with a good efficacy/safety profile. Most patients experience seizure freedom, and neurological deficits are predominantly transient. Pediatric patients and those requiring invasive monitoring or undergoing stereotactic ablation procedures experience lower rates of seizure freedom. Transgression of the frontal operculum should be avoided if it is not deemed part of the epileptogenic zone. Well-selected candidates undergoing dominant-hemisphere resection are more likely to exhibit transient language deficits; however, the risk of permanent deficit is very low.

Is Hippocampal Resection Necessary for Low-Grade Epilepsy-Associated Tumors in the Temporal Lobe?

Low-grade epilepsy-associated tumors (LEATs) are common in the temporal lobe and can cause drug-resistant epilepsy. Complete resection of LEATs is sufficient for seizure relief. However, hippocampal resection might result in postoperative cognitive impairment. This study aimed to clarify the necessity of hippocampal resection for seizure and cognitive outcomes in patients with temporal lobe LEATs and a normal hippocampus. The study included 32 patients with temporal lobe LEATs and without hippocampal abnormalities. All patients underwent gross total resection as treatment for drug-resistant epilepsy at our tertiary epilepsy center from 2005 to 2020, followed by at least a 12-month follow-up period. Seizure and cognitive outcomes were compared between patients who underwent additional hippocampal resection (Resected group) and those who did not (Preserved group). Among the participants, 14 underwent additional hippocampal resection and 28 (87.5%) achieved seizure freedom irrespective of hippocampal resection. The seizure-free periods were not different between the two groups. Additional hippocampal resection resulted in a significantly negative impact on the postoperative verbal index. In conclusion, additional hippocampal resection in patients with temporal lobe LEATs without hippocampal abnormalities is unnecessary because lesionectomy alone results in good seizure control. Additional hippocampal resection may instead adversely affect the postoperative language function.

Impact of COVID-19 pandemic on epilepsy care in Japan: A national-level multicenter retrospective cohort study.

OBJECTIVE: The impact of the coronavirus disease 2019 (COVID-19) pandemic on epilepsy care across Japan was investigated by conducting a multicenter retrospective cohort study. METHODS: This study included monthly data on the frequency of (1) visits by outpatients with epilepsy, (2) outpatient electroencephalography (EEG) studies, (3) telemedicine for epilepsy, (4) admissions for epilepsy, (5) EEG monitoring, and (6) epilepsy surgery in epilepsy centers and clinics across Japan between January 2019 and December 2020. We defined the primary outcome as epilepsy-center-specific monthly data divided by the 12-month average in 2019 for each facility. We determined whether the COVID-19 pandemic-related factors (such as year [2019 or 2020], COVID-19 cases in each prefecture in the previous month, and the state of emergency) were independently associated with these outcomes. RESULTS: In 2020, the frequency of outpatient EEG studies (-10.7%, p<0.001) and cases with telemedicine (+2,608%, p=0.031) were affected. The number of COVID-19 cases was an independent associated factor for epilepsy admission (-3.75*10-3 % per case, p<0.001) and EEG monitoring (-3.81*10-3 % per case, p = 0.004). Further, the state of emergency was an independent factor associated with outpatient with epilepsy (-11.9%, p<0.001), outpatient EEG (-32.3%, p<0.001), telemedicine for epilepsy (+12,915%, p<0.001), epilepsy admissions (-35.3%; p<0.001), EEG monitoring (-24.7%: p<0.001), and epilepsy surgery (-50.3%, p<0.001). SIGNIFICANCE: We demonstrated the significant impact that the COVID-19 pandemic had on epilepsy care. These results support those of previous studies and clarify the effect size of each pandemic-related factor on epilepsy care.

HSP90 Inhibition Overcomes Resistance to Molecular Targeted Therapy in BRAFV600E-mutant High-grade Glioma.

PURPOSE: Molecular targeted therapy using BRAF and/or MEK inhibitors has been applied to BRAFV600E-mutant high-grade gliomas (HGG); however, the therapeutic effect is limited by the emergence of drug resistance. EXPERIMENTAL DESIGN: We established multiple paired BRAFV600E-mutant HGG patient-derived xenograft models based on tissues collected prior to and at relapse after molecular targeted therapy. Using these models, we dissected treatment-resistant mechanisms for molecular targeted therapy and explored therapeutic targets to overcome resistance in BRAFV600E HGG models in vitro and in vivo. RESULTS: We found that, despite causing no major genetic and epigenetic changes, BRAF and/or MEK inhibitor treatment deregulated multiple negative feedback mechanisms, which led to the reactivation of the MAPK pathway through c-Raf and AKT signaling. This altered oncogenic signaling primarily mediated resistance to molecular targeted therapy in BRAFV600E-mutant HGG. To overcome this resistance mechanism, we performed a high-throughput drug screening to identify therapeutic agents that potently induce additive cytotoxicity with BRAF and MEK inhibitors. We discovered that HSP90 inhibition combined with BRAF/MEK inhibition coordinately deactivated the MAPK and AKT/mTOR pathways, and subsequently induced apoptosis via dephosphorylation of GSK3ß (Ser9) and inhibition of Bcl-2 family proteins. This mediated potent cytotoxicity in vitro and in vivo in refractory models with acquired resistance to molecular targeted therapy. CONCLUSIONS: The combination of an HSP90 inhibitor with BRAF or MEK inhibitors can overcome the limitations of the current therapeutic strategies for BRAFV600E-mutant HGG.

Epilepsy surgery in children under 3 years of age: surgical and developmental outcomes.

OBJECTIVE: Pediatric epilepsy surgery is known to be effective, but early surgery in infancy is not well characterized. Extensive cortical dysplasia, such as hemimegalencephaly, can cause refractory epilepsy shortly after birth, and early surgical intervention is indicated. However, the complication rate of early pediatric surgery is significant. In this study, the authors assessed the risk-benefit balance of early pediatric epilepsy surgery as relates to developmental outcomes. METHODS: This is a retrospective descriptive study of 75 patients who underwent their first curative epilepsy surgery at an age under 3 years at the authors' institution between 2006 and 2019 and had a minimum 1-year follow-up of seizure and developmental outcomes. Clinical information including surgical complications, seizure outcomes, and developmental quotient (DQ) was collected from medical records. The effects of clinical factors on DQ at 1 year after surgery were evaluated. RESULTS: The median age at surgery was 6 months, peaking at between 3 and 4 months. Operative procedures included 27 cases of hemispherotomy, 19 cases of multilobar surgery, and 29 cases of unilobar surgery. Seizure freedom was achieved in 82.7% of patients at 1 year and in 71.0% of patients at a mean follow-up of 62.8 months. The number of antiseizure medications (ASMs) decreased significantly after surgery, and 19 patients (30.6%) had discontinued their ASMs by the last follow-up. Postoperative complications requiring cerebrospinal fluid (CSF) diversion surgery, such as hydrocephalus and cyst formation, were observed in 13 patients (17.3%). The mean DQ values were 74.2 ± 34.3 preoperatively, 60.3 ± 23.3 at 1 year after surgery, and 53.4 ± 25.1 at the last follow-up. Multiple regression analysis revealed that the 1-year postoperative DQ was significantly influenced by preoperative DQ and postoperative seizure freedom but not by the occurrence of any surgical complication requiring CSF diversion surgery. CONCLUSIONS: Early pediatric epilepsy surgery has an acceptable risk-benefit balance. Seizure control after surgery is important for postoperative development.

Single-Institutional Experience of Chronic Intracranial Electroencephalography Based on the Combined Usage of Subdural and Depth Electrodes.

Implantation of subdural electrodes on the brain surface is still widely performed as one of the "gold standard methods" for the presurgical evaluation of epilepsy. Stereotactic insertion of depth electrodes to the brain can be added to detect brain activities in deep-seated lesions to which surface electrodes are insensitive. This study tried to clarify the efficacy and limitations of combined implantation of subdural and depth electrodes in intractable epilepsy patients. Fifty-three patients with drug-resistant epilepsy underwent combined implantation of subdural and depth electrodes for long-term intracranial electroencephalography (iEEG) before epilepsy surgery. The detectability of early ictal iEEG change (EIIC) were compared between the subdural and depth electrodes. We also examined clinical factors including resection of MRI lesion and EIIC with seizure freedom. Detectability of EIIC showed no significant difference between subdural and depth electrodes. However, the additional depth electrode was useful for detecting EIIC from apparently deep locations, such as the insula and mesial temporal structures, but not in detecting EIIC in patients with ulegyria (glial scar). Total removal of MRI lesion was associated with seizure freedom. Depth electrodes should be carefully used after consideration of the suspected etiology to avoid injudicious usage.

IDH-Mutant Astrocytoma With Chromosome 19q13 Deletion Manifesting as an Oligodendroglioma-Like Morphology.

Partial deletions in chromosomes 1p and 19q are found in a subset of astrocytic tumors; however, it remains unclear how these alterations affect their histological features and prognosis. Herein, we present 3 cases of isocitrate dehydrogenase (IDH)-mutant astrocytoma with chromosome 19q13 deletion. In the first case, the primary tumor harbored an IDH1 mutation with chromosome 1p/19q partial deletions, which covered 19q13 and exhibited a durable initial response to radiotherapy and temozolomide (TMZ) treatment. However, the tumor lost the chromosome 1p/19q partial deletions at recurrence and became resistant to TMZ. Histologically, an oligodendroglioma-like feature was found in the primary tumor but not in the recurrent tumor. Capicua transcriptional repressor (CIC), located on 19q13, was less expressed in the primary tumor but was highly expressed in the recurrent tumor. Similar histological findings were observed in 2 other astrocytic tumors with IDH1 or IDH2 mutations. These tumors also had chromosome 19q13 deletion, including the CIC gene, weakly expressed CIC, and oligodendroglioma-like morphology. These tumors recurred at 6 and 32 months, respectively. These findings suggest that IDH-mutant astrocytoma with chromosome 19q13 partial deletion, including the CIC gene, may induce an oligodendroglioma-like phenotype, but the clinical prognosis may not be similar to that of genetically defined oligodendroglioma.

Superficial siderosis and nonobstructive hydrocephalus due to subependymoma in the ventricle: An illustrative case report.

Background: Intraventricular tumors can generally result in obstructive hydrocephalus as they grow. Rarely, however, some intraventricular tumors develop superficial siderosis (SS) and trigger hydrocephalus, even though the tumor has hardly grown. Here, we present an illustrative case of SS and nonocclusive hydrocephalus caused by subependymoma of the lateral ventricles. Case Description: A 78-year-old man with an intraventricular tumor diagnosed 7 years ago had been suffering from gait disturbance for 2 years. He also developed cognitive impairment. Intraventricular tumors showed little growth on annual magnetic resonance imaging (MRI). MRI T2-star weighted images (T2*WI) captured small intratumoral hemorrhages from the beginning of the follow-up. Three years before, at the same time as the onset of ventricular enlargement, T2*WI revealed low intensity in the whole tumor and cerebral surface. Subsequent follow-up revealed that this hemosiderin deposition had spread to the brain stem and cerebellar surface, and the ventricles had expanded further. Cerebrospinal fluid (CSF) examination revealed xanthochromia. The tumor was completely removed en bloc. Histopathological findings were consistent with those of subependymoma. Although CSF findings improved, SS and hydrocephalus did not improve. Therefore, the patient underwent a lumboperitoneal shunt for CSF diversion after tumor resection. Conclusion: Some intraventricular tumors cause SS and nonobstructive hydrocephalus due to microbleeding, even in the absence of tumor growth. T2*WI and, if necessary, timely CSF examination can allow identification of presymptomatic SS. This follow-up strategy may provide a favorable course by facilitating early intervention in patients with intraventricular lesions, not just subependymomas.

Verbal and memory deficits caused by aphasic status epilepticus after resection of a left temporal lobe glioma.

BACKGROUND: Nonconvulsive status epilepticus (NCSE) is induced by common neurosurgical conditions, for example, trauma, stroke, tumors, and surgical interventions in the brain. The aggressiveness of the treatment for NCSE depends on its neurological prognosis. Aphasic status epilepticus (ASE) is a subtype of focal NCSE without consciousness impairment. The impact of ASE on neurological prognosis is poorly documented. We describe a case of postoperative ASE resulting in verbal and memory deficits. CASE DESCRIPTION: A 54-year-old, right-handed man with focal impaired awareness seizures underwent partial resection for a left temporal lobe tumor. No neurological deficits were observed immediately after surgery. Three days later, however, a focal to bilateral tonic-clonic seizure (FBTCS) occurred, followed by aphasia. Electroencephalography revealed 1.5 Hz left-sided periodic discharges. He was diagnosed with ASE. Multiple anti-seizure drugs were ineffective for the resolution of the patient's verbal disturbance. Nine days after the FBTCS, deep sedation with intravenous anesthetics was performed and the ASE stopped. Thereafter, his symptoms gradually improved. However, the prolonged ASE resulted in verbal and memory deficits. Automated hippocampal volumetry revealed an approximate decrease of 20% on the diseased side on magnetic resonance imaging 3 months after surgery. CONCLUSION: Prolonged ASE can induce verbal and memory deficits. Early intervention with intravenous anesthetics is required to obtain a favorable neurological prognosis.

A Hyperactive RelA/p65-Hexokinase 2 Signaling Axis Drives Primary Central Nervous System Lymphoma.

Primary central nervous system lymphoma (PCNSL) is an isolated type of lymphoma of the central nervous system and has a dismal prognosis despite intensive chemotherapy. Recent genomic analyses have identified highly recurrent mutations of MYD88 and CD79B in immunocompetent PCNSL, whereas LMP1 activation is commonly observed in Epstein-Barr virus (EBV)-positive PCNSL. However, a lack of clinically representative preclinical models has hampered our understanding of the pathogenic mechanisms by which genetic aberrations drive PCNSL disease phenotypes. Here, we establish a panel of 12 orthotopic, patient-derived xenograft (PDX) models from both immunocompetent and EBV-positive PCNSL and secondary CNSL biopsy specimens. PDXs faithfully retained their phenotypic, metabolic, and genetic features, with 100% concordance of MYD88 and CD79B mutations present in PCNSL in immunocompetent patients. These models revealed a convergent functional dependency upon a deregulated RelA/p65-hexokinase 2 signaling axis, codriven by either mutated MYD88/CD79B or LMP1 with Pin1 overactivation in immunocompetent PCNSL and EBV-positive PCNSL, respectively. Notably, distinct molecular alterations used by immunocompetent and EBV-positive PCNSL converged to deregulate RelA/p65 expression and to drive glycolysis, which is critical for intracerebral tumor progression and FDG-PET imaging characteristics. Genetic and pharmacologic inhibition of this key signaling axis potently suppressed PCNSL growth in vitro and in vivo. These patient-derived models offer a platform for predicting clinical chemotherapeutics efficacy and provide critical insights into PCNSL pathogenic mechanisms, accelerating therapeutic discovery for this aggressive disease. SIGNIFICANCE: A set of clinically relevant CNSL xenografts identifies a hyperactive RelA/p65-hexokinase 2 signaling axis as a driver of progression and potential therapeutic target for treatment and provides a foundational preclinical platform. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/23/5330/F1.large.jpg.

Cognitive and developmental outcomes after pediatric insular epilepsy surgery for focal cortical dysplasia.

OBJECTIVE: Cognitive risk associated with insular cortex resection is not well understood. The authors reviewed cognitive and developmental outcomes in pediatric patients who underwent resection of the epileptogenic zone involving the insula. METHODS: A review was conducted of 15 patients who underwent resective epilepsy surgery involving the insular cortex for focal cortical dysplasia, with a minimum follow-up of 12 months. The median age at surgery was 5.6 years (range 0.3-13.6 years). Developmental/intelligence quotient (DQ/IQ) scores were evaluated before surgery, within 4 months after surgery, and at 12 months or more after surgery. Repeated measures multivariate ANOVA was used to evaluate the effects on outcomes of the within-subject factor (time) and between-subject factors (resection side, anterior insular resection, seizure control, and antiepileptic drug [AED] reduction). RESULTS: The mean preoperative DQ/IQ score was 60.7 ± 22.8. Left-side resection and anterior insular resection were performed in 9 patients each. Favorable seizure control (International League Against Epilepsy class 1-3) was achieved in 8 patients. Postoperative motor deficits were observed in 9 patients (permanent in 6, transient in 3). Within-subject changes in DQ/IQ were not significantly affected by insular resection (p = 0.13). Postoperative changes in DQ/IQ were not significantly affected by surgical side, anterior insular resection, AED reduction, or seizure outcome. Only verbal function showed no significant changes before and after surgery and no significant effects of within-subject factors. CONCLUSIONS: Resection involving the insula in children with impaired development or intelligence can be performed without significant reduction in DQ/IQ, but carries the risk of postoperative motor deficits.

BRAF V600E mutation mediates FDG-methionine uptake mismatch in polymorphous low-grade neuroepithelial tumor of the young.

We present a case of a 14-year old boy with tumor-associated refractory epilepsy. Positron emission tomography imaging demonstrated a region with heterogeneous high 11C-methionine uptake and a region with homogenous low 18F-fluorodeoxyglucose uptake within the tumor. Histopathological and genomic analyses confirmed the tumor as BRAF V600E-mutated polymorphous low-grade neuroepithelial tumor of the young (PLNTY). Within the high-methionine-uptake region, we observed increased protein levels of L-type amino acid transporter 1 (LAT1), a major transporter of methionine; c-Myc; and constituents of the mitogen-activated protein kinase (MAPK) pathway. We also found that LAT1 expression was linked to the BRAF V600E mutation and subsequent activation of MAPK signaling and c-Myc. Pharmacological and genetic inhibition of the MAPK pathway suppressed c-Myc and LAT1 expression in BRAF V600E-mutated PLNTY and glioblastoma cells. The BRAF inhibitor dabrafenib moderately suppressed cell viability in PLNTY. Collectively, our results indicate that BRAF V600E mutation-activated MAPK signaling and downstream c-Myc induces specific metabolic alterations in PLNTY, and may represent an attractive target in the treatment of the disease.

Incision Edge "Lifting Method" in Cerebral Bypass Surgery: A Novel Optional Technique for Narrow or Thin Recipient Arteries.

BACKGROUND: Cerebral bypass surgery, such as the superficial temporal artery-middle cerebral artery bypass, is one of the essential procedures for cerebral revascularization. However, very narrow or thin blood vessels will increase the risk of anastomotic problems, such as occurs in Moyamoya disease. For such vessels, we have devised a "lifting method" in the recipient arteriotomy. In the present study, we have introduced this novel optional technique and evaluated its effects. METHODS: The lifting method is a procedure of lifting the incision edge of a linear incision on the recipient vessel to widen the ostium. We attempted the lifting method in 23 consecutive patients (41 arteries) and, as a historical control, compared the results with those from the conventional method in 25 consecutive patients (37 arteries) for the previous 3 years. We compared patient age, years of surgical experience, recipient vessel diameter, anastomotic events, and final patency. As a subanalysis, the same evaluations were performed separately for patients with Moyamoya disease. Furthermore, the time required for the lifting procedure was measured retrospectively. RESULTS: The incidence of anastomotic events with the conventional method was 13.5% overall and 19% in those with Moyamoya disease. No adverse events occurred with the lifting method (P < 0.05). No statistically significant differences were found for the other factors, including final patency between the 2 groups. The time required for the lifting procedure averaged 1 minute, 15 seconds. CONCLUSIONS: Use of the lifting method widens and secures the ostium in a recipient vessel and greatly facilitates operability. We have found it to be a foolproof method enabling safe and reliable anastomosis even with narrow or thin vessels.

Efficacy of relaxin for cisplatin-induced testicular dysfunction and epididymal spermatotoxicity.

BACKGROUND: Cisplatin (CP) is an extremely effective anticancer agent widely used to treat various cancer types, however, the potential side effects include testicular dysfunction. This study was to investigate, using a rat model of CP-induced testicular dysfunction, the protective effects of relaxin (RLN) against oxidative stress, testicular function, histological damage, spermatogenesis, germ-cell apoptosis, and sperm output, and to explore the usefulness of RLN as a potential protective drug for use with CP in chemotherapeutic treatments. METHODS: Sprague-Dawley male rats were used, which were divided into three groups: sham control, CP, and CP + RLN. Porcine RLN (500 ng/h) or saline was infused for 5 days using an implanted osmotic mini-pump following intraperitoneal injection of CP (6 mg/kg). RLN dose was chosen based on previous studies showing that it resulted in serum relaxin levels comparable to those in rats at the middle of pregnancy. At 5 days after CP administration, samples were collected and assessment of testicular histopathology, germ-cell apoptosis, oxidative stress, lipid peroxidation, and sperm quality was performed as main measures. RESULTS: The testicular CP model showed reduced testis weight and significantly decreased spermatogenesis scores. Additionally, CP administration induced a 4.6-fold increase in the apoptotic index associated with a significant increase in oxidative stress and upregulation of pro-apoptotic Casp3 and downregulation of anti-apoptotic Bcl2 levels, resulting in a marked reduction in sperm concentration. However, RLN administration caused a significant reduction in CP-mediated damage by attenuating oxidative stress and cell apoptosis. RLN administration efficiently scavenged ROS via the activation of SOD, CAT, and GPx and upregulation of GSH to prevent lipid peroxidation and decreased apoptosis by altering Bcl2 and Casp3 expression, thereby reducing histopathological damage and restoring spermatogenesis. Furthermore, RLN ameliorated attenuated sperm motility in the cauda epididymis resulting from CP treatment. CONCLUSIONS: This study clearly indicates that RLN exerts a protective effect against CP-induced testicular damage through attenuation of oxidative stress and suppression of apoptosis. Our findings suggest RLN as a potentially efficacious drug for use with cisplatin chemotherapy in order to ameliorate CP-induced side effects and testicular injury adversely affecting spermatogenesis, sperm quality, and oxidative-stress parameters.

CONTEXTE: Le cis platine (CP) est un agent anticancéreux extrêmement efficace largement utilisé pour traiter divers types de cancer. Parmi les effets secondaires potentiels associés aux traitements par CP on compte le dysfonctionnement des testicules. Le propos de ce manuscrit est d'étudier, à l'aide d'un modèle rat de dysfonctionnement testiculaire induit par la prise de CP, l'action protectrice de la relaxine (RLN) contre les effets délétères dus au CP lesquels incluent le stress oxydant, la perte de fonction testiculaire, les dommages histologiques au testicule, l'apoptose des cellules germinales et la baisse de la qualité des spermatozoïdes. L'objectif est d'explorer l'utilité de la RLN comme médicament protecteur potentiel à utiliser avec le CP dans les traitements chimiothérapeutiques. MÉTHODES: Des rats mâles Sprague-Dawley ont été utilisés. Trois groupes : contrôle, CP, et CP + RLN ont été comparés. Après une injection intrapéritonéale de CP (6mg/kg), de la RLN porcine (500 ng/h) ou du sérum physiologique a été perfusé pendant 5 jours en utilisant une mini-pompe osmotique implantée. La dose de RLN a été choisie en fonction d'études antérieures qui avaient montré qu'elle entraînait des taux sériques de RLN comparables à ceux de rats en milieu de la gestation. Cinq jours après l'administration de la CP, des échantillons ont été prélevés afin d'évaluer l'histopathologie, l'apoptose des cellules germinales, le stress oxydant, la peroxydation des lipides et les paramètres spermatiques. RÉSULTATS: Le groupe CP a montré une réduction du poids des testicules et une diminution significative des scores de spermatogenèse. De plus, l'administration de CP a entraîné une augmentation de l'apoptose de 4,6 fois associée à une augmentation significative du stress oxydant, de la régulation à la hausse de la Caspase 3 pro-apoptotique et à la baisse de Bcl2 anti-apoptotique conduisant in fine à une réduction marquée de la concentration en spermatozoïdes. La RLN a ainsi significativement corrigée les effets négatifs du CP en atténuant le stress oxydant et l'apoptose. La RLN a permis d'éliminer efficacement les ROS via l'activation de la triade enzymatique anti-oxydante superoxyde dismutase (SOD)/catalase (CAT)/glutathion peroxydase (GPx) et via la régulation à la hausse du GSH prévenant ainsi la lipopéroxydation. La RLN a par ailleurs diminué les atteintes histopathologiques testiculaires préservant la spermatogenèse. En parallèle, la RLN a amélioré la mobilité spermatique des spermatozoïdes prélevés dans la queue de l'épididyme. CONCLUSIONS: Cette étude montre clairement que la RLN exerce un effet protecteur contre les lésions testiculaires par l'atténuation du stress oxydant et la suppression de l'apoptose induite par le CP. Nos résultats suggèrent que la RLN est un médicament potentiellement pertinent à utiliser afin de diminuer les effets secondaires induits par le CP sur la fonction testiculaire et sur les spermatozoïdes lors de la chimiothérapie cancéreuse.

Visualization of AMPA receptors in living human brain with positron emission tomography.

Although aberrations in the number and function of glutamate AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors are thought to underlie neuropsychiatric disorders, no methods are currently available for visualizing AMPA receptors in the living human brain. Here we developed a positron emission tomography (PET) tracer for AMPA receptors. A derivative of 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetamide radiolabeled with 11C ([11C]K-2) showed specific binding to AMPA receptors. Our clinical trial with healthy human participants confirmed reversible binding of [11C]K-2 in the brain according to Logan graphical analysis (UMIN000020975; study design: non-randomized, single arm; primary outcome: dynamics and distribution volumes of [11C]K-2 in the brain; secondary outcome: adverse events of [11C]K-2 during the 4-10 d following dosing; this trial met prespecified endpoints). In an exploratory clinical study including patients with epilepsy, we detected increased [11C]K-2 uptake in the epileptogenic focus of patients with mesial temporal lobe epilepsy, which was closely correlated with the local AMPA receptor protein distribution in surgical specimens from the same individuals (UMIN000025090; study design: non-randomized, single arm; primary outcome: correlation between [11C]K-2 uptake measured with PET before surgery and AMPA receptor protein density examined by biochemical study after surgery; secondary outcome: adverse events during the 7 d following PET scan; this trial met prespecified endpoints). Thus, [11C]K-2 is a potent PET tracer for AMPA receptors, potentially providing a tool to examine the involvement of AMPA receptors in neuropsychiatric disorders.

Transient water-electrolyte disturbance after hemispherotomy in young infants with epileptic encephalopathy.

PURPOSE: This study aimed to elucidate the clinical features of water-electrolyte disturbance (WED) as a sequela of hemispherotomy. METHODS: We performed a retrospective chart review to identify the clinical features of diabetes insipidus (DI) as a complication in < 12-month-old patients who underwent hemispherectomy or hemispherotomy for severe epilepsy between 2007 and 2018. Central DI was diagnosed if a patient developed polyuria (urine output > 5 mL/kg/h), abnormally high serum osmolality (> 300 mOsm/kg), high serum sodium level (> 150 mEq/L), either abnormally low urine specific gravity (< 1.005) or low urine osmolality (< 300 mOsm/kg) or both, and effective control of polyuria with arginine vasopressin (AVP). The clinical course of post-hemispherotomy WED, complications other than WED, and seizure outcomes were analyzed. RESULTS: The review identified that 3 of 23 infants developed WED. All patients developed polyuria within 2 days after surgery, with high serum osmolality and hypotonic urine; AVP was effective in treating these symptoms. The clinical course was compatible with central DI. Two patients subsequently developed hyponatremia in a biphasic or triphasic manner. All patients had multiple seizures that were probably related to WED. Two patients developed asymptomatic cerebral sinovenous thrombosis, possibly because of the surgical procedure and dehydration; anticoagulant treatment was provided. All patients were treated for WED for up to 2 months and had no residual pituitary dysfunction. CONCLUSION: Systemic complications other than intracranial ones can occur in patients who have undergone hemispherotomy. Perioperative systemic management of young infants undergoing this procedure should include careful water and electrolyte balance monitoring.

Is intracranial electroencephalography useful for planning resective surgery in intractable epilepsy with ulegyria?

OBJECTIVE: Intractable epilepsy patients with ulegyria could be candidates for resective surgery. Complete resection of ulegyria in the epileptogenic hemisphere is associated with favorable seizure outcome, although the risk of postoperative functional deficits is higher. The authors evaluated the extent of resection and postsurgical outcomes in epilepsy patients with ulegyria who underwent intracranial electroencephalography (iEEG) monitoring prior to resection to clarify the efficacy of iEEG-guided partial resection of ulegyria. METHODS: Ten consecutive epilepsy patients with ulegyria (7 males and 3 females, age range at surgery 7-34 years) underwent iEEG prior to resective surgery between 2011 and 2017 with a minimum follow-up of 12 months (range 12-72 months). The diagnosis of ulegyria was based on the typical pattern of cortical atrophy especially at the bottom of the sulcus on MRI. An iEEG study was indicated after comprehensive preoperative evaluations, including high-field MRI, long-term video-EEG, magnetoencephalography, and FDG-PET. The resection planning was based on iEEG analysis. Total lesionectomy was not always performed, as preservation of cortical function was prioritized. RESULTS: Ulegyria was seen in the occipital and/or parietal lobe in 9 patients and bilaterally in 5 patients. Ictal EEG onset involved the temporal neocortex in 6 patients. Intracranial electrodes were implanted unilaterally in all except 1 patient with bilateral lesions. The extent of MRI lesion was covered by the electrodes. Seizure onset zones (SOZs) and irritative zones (IZs) were identified in all patients. SOZs and IZs were completely resected in 8 patients but were only partially removed in the remaining 2 patients because the eloquent cortices and the epileptogenic zones overlapped. Ulegyria of the epileptogenic side was totally resected in 1 patient. Seizure freedom was achieved in 4 patients, including 3 after partial lesionectomy. Extended resection of the temporal neocortex was performed in 4 patients, although postoperative seizure freedom was achieved only in 1 of these patients. Visual field deficit was seen in 4 patients. Three of 5 patients with bilateral lesions achieved seizure freedom after unilateral resective surgery. CONCLUSIONS: Intracranial EEG-guided partial lesionectomy provides a reasonable chance of postoperative seizure freedom with a lower risk of functional deficits. Patients with bilateral ulegyria should not be excluded from consideration as surgical candidates.