Endothelin-1-mediated Brainstem Glial Activation Produces Asthmatic Airway Vagal Hypertonia Via Enhanced ATP-P2X4 Receptor Signaling in Sprague-Dawley Rats.

The occurrence of major asthma symptoms is largely attributed to airway vagal hypertonia, of which the central mechanisms remain unclear. This study tests the hypotheses that endothelin-1-mediated brainstem glial activation produces asthmatic airway vagal hypertonia via enhanced action of adenosine 5'-triphosphate on neuronal purinergic P2X4 receptors. A rat model of asthma was prepared using ovalbumin. Airway vagal tone was evaluated by the recurrent laryngeal discharge and plethysmographic measurement of pulmonary function. The changes in the brainstem were examined using ELISA, Western blot, luciferin-luciferase, quantitative reverse transcription-polymerase chain reaction, enzyme activity assay and immunofluorescent staining, respectively. The results showed that in the medulla of rats, endothelin receptor type B and P2X4 receptors were primarily expressed in astrocytes and neurons, respectively, and both of which, along with endothelin-1 content, were significantly increased after ovalbumin sensitization. Ovalbumin sensitization significantly increased recurrent laryngeal discharge, which was blocked by acute intracisternal injection of P2X4 receptor antagonist 5-BDBD, knockdown of brainstem P2X4 receptors, and chronic intraperitoneal injection of endothelin receptor type B antagonist BQ788, respectively. Ovalbumin sensitization activated microglia and astrocytes and significantly decreased ecto-5'-nucleotidase activity in the medulla, and all of which, together with the increase of medullary P2X4 receptor expression and decrease of pulmonary function, were reversed by chronic BQ788 treatment. These results demonstrated that in rats, allergic airway challenge activates both microglia and astrocytes in the medulla via enhanced endothelin-1/endothelin receptor type B signaling, which subsequently causes airway vagal hypertonia via augmented adenosine 5'-triphosphate/P2X4 receptor signaling in central neurons of airway vagal reflex.

Resection of the quadrangular lobule of the cerebellum to increase exposure of the cerebellomesencephalic fissure: an anatomical study with clinical correlation.

OBJECTIVE: The lateral aspect of the cerebellomesencephalic fissure frequently harbors vascular pathology and is a common surgical corridor used to access the pons tegmentum, as well as the cerebellum and its superior and middle peduncles. The quadrangular lobule of the cerebellum (QLC) represents an obstacle to reach these structures. The authors sought to analyze and compare exposure of the cerebellar interpeduncular region (CIPR) before and after QLC resection and provide a case series to evaluate its clinical applicability. METHODS: Forty-two sides of human brainstems were prepared with Klingler's method and dissected. The exposure area before and after resection of the QLC was measured and statistically studied. A case series of 59 patients who underwent QLC resection for the treatment of CIPR lesions was presented and clinical outcomes were evaluated at 1-year follow-up. RESULTS: The anteroposterior surgical corridor of the CIPR increased by 10.3 mm after resection of the QLC. The mean exposure areas were 42 mm2 before resection of the QLC and 159.6 mm2 after resection. In this series, ataxia, extrapyramidal syndrome, and akinetic mutism were found after surgery. However, all these cases resolved within 1 year of follow-up. Modified Rankin Scale score improved by 1 grade, on average. CONCLUSIONS: QLC resection significantly increased the exposure area, mainly in the anteroposterior axis. This surgical strategy appears to be safe and may help the neurosurgeon when operating on the lateral aspect of the cerebellomesencephalic fissure.

Outcomes of 2-SSRS plus bevacizumab therapy strategy for brainstem metastases (BSM) over 2 cm3: a multi-center study.

Despite 2-staged stereotactic radiosurgery (2-SSRS) has been reported to provide patients with improved survival and limited toxicity, 2-SSRS for brainstem metastases (BSM) larger than 2 cm3 remains challenging. We tried to find out the effectiveness and safety of 2-SSRS plus bevacizumab therapy for BSMs over 2 cm3 and prognostic factors that related to the tumor local control. Patients that received 2-SSRS plus bevacizumab therapy from four gamma knife center were retrospectively studied from Jan 2014 to December 2023. Patients' domestic characteristics and the tumor features were evaluated before and after the treatment. Cox regression model was used to find out prognostic factors for tumor local control. 53 patients with 63 lesions received the therapy. The median peri-tumor edema volume greatly reduced at the end of therapy (P < 0.01), the median tumor volume dramatically reduced (P < 0.01) and patients' KPS score improved significantly (P < 0.05) 3 months after the therapy. Patients' median OS was 12.8 months. The tumor local control rate at 3, 6, and 12 months was 98.4%, 93.4%, and 85.2%. The incidence side effects were mainly oral and nasal hemorrhage (5.7%, 3/53), and radiation necrosis (13.2%, 7/53). Patients with primary lung adenocarcinoma, therapeutic dose over 12 Gy at second-stage SRS, primary peri-tumor edema volume less than 2.3 cm³, primary tumor volume less than 3.7 cm³ would enjoy longer tumor local control. These results suggested that 2-SSRS plus bevacizumab therapy was effective and safe for BSMs over 2 cm3. However, it is important for patients with BSM to receive early diagnosis and treatment to achieve good tumor local control.

Uraemic brainstem encephalopathy mimicking ocular myasthenia: a case report.

BACKGROUND: Uraemia causes a generalised encephalopathy as its most common neurological complication. Isolated brainstem uraemic encephalopathy is rare. We report a case of fatigable ptosis and complex ophthalmoplegia in brainstem uraemic encephalopathy. CASE PRESENTATION: A 22-year-old Sri Lankan man with end stage renal failure presented with acute onset diplopia and drooping of eyelids progressively worsening over one week. The patient had not complied with the prescribed renal replacement therapy which was planned to be initiated 5 months previously. On examination, his Glasgow coma scale score was 15/15, He had a fatigable asymmetrical bilateral ptosis. The ice-pack test was negative. There was a complex ophthalmoplegia with bilateral abduction failure and elevation failure of the right eye. The diplopia did not worsen with prolonged stare. The rest of the neurological examination was normal. Serum creatinine on admission was 21.81 mg/dl. The repetitive nerve stimulation did not show a decremental pattern. Magnetic resonance imaging (MRI) of the brain demonstrated diffuse midbrain and pontine oedema with T2 weighted/FLAIR hyperintensities. The patient was haemodialyzed on alternate days and his neurological deficits completely resolved by the end of the second week of dialysis. The follow up brain MRI done two weeks later demonstrated marked improvement of the brainstem oedema with residual T2 weighted/FLAIR hyperintensities in the midbrain. CONCLUSIONS: Uraemia may rarely cause an isolated brainstem encephalopathy mimicking ocular myasthenia, which resolves with correction of the uraemia.

Association of hemorrhage-to-treatment time with outcomes in patients with brainstem cavernous malformations: a nationwide cohort study.

BACKGROUND: Brainstem cavernous malformations (BSCMs) often present with haemorrhage, but the optimal timing for microsurgical intervention remains unclear. This study aims to explore how intervention timing relates to neurological outcomes in haemorrhagic BSCM patients undergoing microsurgery, offering insights for clinical decisions. METHODS: A total of 293 consecutive patients diagnosed with BSCMs, who underwent microsurgery were identified between March 2011 and January 2023 at two comprehensive centres in China, with a postoperative follow-up duration exceeding 6 months. Utilizing logistic regression models with restricted cubic splines, distinct time groups were identified. Subsequently, matching weight analysis compared these groups in terms of outcomes, new haemorrhage rates, cranial nerve deficits, and perioperative complications. The primary outcome was an unfavourable outcome, which was defined as a mRS score greater than 2 at the latest follow-up. RESULTS: Among the 293 patients, 48.5% were female, median age was (39.9±14.3) years, and median haemorrhage-to-treatment time was 42 days. Patients were categorized into acute (≤21 days), subacute (22-42 days), and delay (>42 days) intervention groups. After matching, 186 patients were analyzed. Adjusted analysis showed lower unfavourable outcome rates for acute [adjusted odds ratio (OR), 0.73; 95% CI, 0.65-0.82; P<0.001] and subacute (adjusted OR, 0.83; 95% CI, 0.72-0.95; P=0.007) groups compared to the delay group. Subacute intervention led to fewer cranial nerve deficits (adjusted OR, 0.76; 95% CI, 0.66-0.88, P<0.001). New haemorrhage incidence didn't significantly differ among groups. CONCLUSIONS: For haemorrhagic BSCMs patients, delayed microsurgical intervention that exceeded 42 days after a prior haemorrhage were associated with an increased risk of unfavourable neurological outcomes.

Fully endoscopic approach for resection of brainstem cavernous malformations: a systematic review of the literature.

BACKGROUND: Brainstem cavernous malformations (BCMs) are benign lesions that typically have an acute onset and are associated with a high rate of morbidity. The selection of the optimal surgical approach is crucial for obtaining favorable outcomes, considering the different anatomical locations of various brainstem lesions. Endoscopic surgery is increasingly utilized in treating of BCMs, owing to its depth illumination and panoramic view capabilities. For intra-axial ventral BCMs, the best surgical options are endoscopic endonasal approaches, following the "two-point method. For cavernous hemangiomas on the dorsal side of the brainstem, endoscopy proves valuable by providing enhanced visualization of the operative field and minimizing the need for brain retraction. METHODS: In this review, we gathered data on the fully endoscopic approach for the resection of BCMs, and outlined technical notes and tips. Total of 15 articles were included in this review. The endoscopic endonasal approach was utilized in 19 patients, and the endoscopic transcranial approach was performed in 3 patients. RESULTS: The overall resection rate was 81.8% (18/22). Among the 19 cases of endoscopic endonasal surgery, postoperative cerebrospinal fluid (CSF) leakage occurred in 5 cases, with lesions exceeding 2 cm in diameter in 3 patients with postoperative CSF rhinorrhea. Among the 20 patients with follow-up data, 2 showed no significant improvement after surgery, whereas the remaining 18 patients showed significant improvement compared to their admission symptoms. CONCLUSIONS: This systematic literature review demonstrates that a fully endoscopic approach is a safe and effective option for the resection of BCMs. Further, it can be considered an alternative to conventional craniotomy, particularly when managed by a neurosurgical team with extensive experience in endoscopic surgery, addressing these challenging lesions.

Brainstem control of vocalization and its coordination with respiration.

Phonation critically depends on precise controls of laryngeal muscles in coordination with ongoing respiration. However, the neural mechanisms governing these processes remain unclear. We identified excitatory vocalization-specific laryngeal premotor neurons located in the retroambiguus nucleus (RAmVOC) in adult mice as being both necessary and sufficient for driving vocal cord closure and eliciting mouse ultrasonic vocalizations (USVs). The duration of RAmVOC activation can determine the lengths of both USV syllables and concurrent expiration periods, with the impact of RAmVOC activation depending on respiration phases. RAmVOC neurons receive inhibition from the preBötzinger complex, and inspiration needs override RAmVOC-mediated vocal cord closure. Ablating inhibitory synapses in RAmVOC neurons compromised this inspiration gating of laryngeal adduction, resulting in discoordination of vocalization with respiration. Our study reveals the circuits for vocal production and vocal-respiratory coordination.

Gender-related variation expressions of neuroplastin TRAF6, GluA1, GABA(A) receptor, and PMCA in cortex, hippocampus, and brainstem in an experimental epilepsy model.

Epileptic seizures are seen as a result of changing excitability balance depending on the deterioration in synaptic plasticity in the brain. Neuroplastin, and its related molecules which are known to play a role in synaptic plasticity, neurotransmitter activities that provide balance of excitability and, different neurological diseases, have not been studied before in epilepsy. In this study, a total of 34 Sprague-Dawley male and female rats, 2 months old, weighing 250-300 g were used. The epilepsy model in rats was made via pentylenetetrazole (PTZ). After the completion of the experimental procedure, the brain tissue of the rats were taken and the histopathological changes in the hippocampus and cortex parts and the brain stem were investigated, as well as the immunoreactivity of the proteins related to the immunohistochemical methods. As a result of the histopathological evaluation, it was determined that neuron degeneration and the number of dilated blood vessels in the hippocampus, frontal cortex, and brain stem were higher in the PTZ status epilepticus (SE) groups than in the control groups. It was observed that neuroplastin and related proteins TNF receptor-associated factor 6 (TRAF6), Gamma amino butyric acid type A receptors [(GABA(A)], and plasma membrane Ca2+ ATPase (PMCA) protein immunoreactivity levels increased especially in the male hippocampus, and only AMPA receptor subunit type 1 (GluA1) immunoreactivity decreased, unlike other proteins. We believe this may be caused by a problem in the mechanisms regulating the interaction of neuroplastin and GluA1 and may cause problems in synaptic plasticity in the experimental epilepsy model. It may be useful to elucidate this mechanism and target GluA1 when determining treatment strategies.

Stereotactic frame-based biopsy of infratentorial lesions via the suboccipital-transcerebellar approach with the Zamorano-Duchovny stereotactic system-a retrospective analysis of 79 consecutive cases.

OBJECTIVE: Lesions of the posterior fossa (brainstem and cerebellum) are challenging in diagnosis and treatment due to the fact that they are often located eloquently and total resection is rarely possible. Therefore, frame-based stereotactic biopsies are commonly used to asservate tissue for neuropathological diagnosis and further treatment determination. The aim of our study was to assess the safety and diagnostic success rate of frame-based stereotactic biopsies for lesions in the posterior fossa via the suboccipital-transcerebellar approach. METHODS: We performed a retrospective database analysis of all frame-based stereotactic biopsy cases at our institution since 2007. The aim was to identify all surgical cases for infratentorial lesion biopsies via the suboccipital-transcerebellar approach. We collected clinical data regarding outcomes, complications, diagnostic success, radiological appearances, and stereotactic trajectories. RESULTS: A total of n = 79 cases of stereotactic biopsies for posterior fossa lesions via the suboccipital-transcerebellar approach (41 female and 38 male) utilizing the Zamorano-Duchovny stereotactic system were identified. The mean age at the time of surgery was 42.5 years (± 23.3; range, 1-87 years). All patients were operated with intraoperative stereotactic imaging (n = 62 MRI, n = 17 CT). The absolute diagnostic success rate was 87.3%. The most common diagnoses were glioma, lymphoma, and inflammatory disease. The overall complication rate was 8.7% (seven cases). All patients with complications showed new neurological deficits; of those, three were permanent. Hemorrhage was detected in five of the cases having complications. The 30-day mortality rate was 7.6%, and 1-year survival rate was 70%. CONCLUSIONS: Our data suggests that frame-based stereotactic biopsies with the Zamorano-Duchovny stereotactic system via the suboccipital-transcerebellar approach are safe and reliable for infratentorial lesions bearing a high diagnostic yield and an acceptable complication rate. Further research should focus on the planning of safe trajectories and a careful case selection with the goal of minimizing complications and maximizing diagnostic success.

Focused ultrasound-mediated blood-brain barrier opening is safe and feasible with moderately hypofractionated radiotherapy for brainstem diffuse midline glioma.

BACKGROUND: Diffuse midline glioma (DMG) is a pediatric tumor with dismal prognosis. Systemic strategies have been unsuccessful and radiotherapy (RT) remains the standard-of-care. A central impediment to treatment is the blood-brain barrier (BBB), which precludes drug delivery to the central nervous system (CNS). Focused ultrasound (FUS) with microbubbles can transiently and non-invasively disrupt the BBB to enhance drug delivery. This study aimed to determine the feasibility of brainstem FUS in combination with clinical doses of RT. We hypothesized that FUS-mediated BBB-opening (BBBO) is safe and feasible with 39 Gy RT. METHODS: To establish a safety timeline, we administered FUS to the brainstem of non-tumor bearing mice concurrent with or adjuvant to RT; our findings were validated in a syngeneic brainstem murine model of DMG receiving repeated sonication concurrent with RT. The brainstems of male B6 (Cg)-Tyrc-2J/J albino mice were intracranially injected with mouse DMG cells (PDGFB+, H3.3K27M, p53-/-). A clinical RT dose of 39 Gy in 13 fractions (39 Gy/13fx) was delivered using the Small Animal Radiation Research Platform (SARRP) or XRAD-320 irradiator. FUS was administered via a 0.5 MHz transducer, with BBBO and tumor volume monitored by magnetic resonance imaging (MRI). RESULTS: FUS-mediated BBBO did not affect cardiorespiratory rate, motor function, or tissue integrity in non-tumor bearing mice receiving RT. Tumor-bearing mice tolerated repeated brainstem BBBO concurrent with RT. 39 Gy/13fx offered local control, though disease progression occurred 3-4 weeks post-RT. CONCLUSION: Repeated FUS-mediated BBBO is safe and feasible concurrent with RT. In our syngeneic DMG murine model, progression occurs, serving as an ideal model for future combination testing with RT and FUS-mediated drug delivery.

[Brain Stem and Para-Brain Stem Lesions].

Surgeries for brainstem lesions and adjacent areas needs meticulous manipulation in the profoundly deep surgical field. Moreover, it is associated with a high risk of complications pertinent to resection. The opportunity for a surgeon to amass extensive surgical experience in these lesions is limited. Additionally, the reduced tissue mobility in the brainstem, compared to other lesions, makes selecting the optimal surgical approach critical. Preoperative simulation is pivotal in surmounting these challenges. However, the limitations of preoperative simulations should be recognized in accurately depicting diminutive vessels and cranial nerves around the brainstem. Incorporating intraoperative anatomical observations and data from intraoperative monitoring into a surgical strategy is imperative. Here, we present three cases in which we believe preoperative simulation was effective; a cavernous hemangioma of the brainstem, trochlear schwannoma, and diffuse midline glioma in the pons.

A brainstem-hypothalamus neuronal circuit reduces feeding upon heat exposure.

Empirical evidence suggests that heat exposure reduces food intake. However, the neurocircuit architecture and the signalling mechanisms that form an associative interface between sensory and metabolic modalities remain unknown, despite primary thermoceptive neurons in the pontine parabrachial nucleus becoming well characterized1. Tanycytes are a specialized cell type along the wall of the third ventricle2 that bidirectionally transport hormones and signalling molecules between the brain's parenchyma and ventricular system3-8. Here we show that tanycytes are activated upon acute thermal challenge and are necessary to reduce food intake afterwards. Virus-mediated gene manipulation and circuit mapping showed that thermosensing glutamatergic neurons of the parabrachial nucleus innervate tanycytes either directly or through second-order hypothalamic neurons. Heat-dependent Fos expression in tanycytes suggested their ability to produce signalling molecules, including vascular endothelial growth factor A (VEGFA). Instead of discharging VEGFA into the cerebrospinal fluid for a systemic effect, VEGFA was released along the parenchymal processes of tanycytes in the arcuate nucleus. VEGFA then increased the spike threshold of Flt1-expressing dopamine and agouti-related peptide (Agrp)-containing neurons, thus priming net anorexigenic output. Indeed, both acute heat and the chemogenetic activation of glutamatergic parabrachial neurons at thermoneutrality reduced food intake for hours, in a manner that is sensitive to both Vegfa loss-of-function and blockage of vesicle-associated membrane protein 2 (VAMP2)-dependent exocytosis from tanycytes. Overall, we define a multimodal neurocircuit in which tanycytes link parabrachial sensory relay to the long-term enforcement of a metabolic code.

Immune Checkpoint Inhibitor-Associated Kelch-Like Protein-11 IgG Brainstem Encephalitis.

OBJECTIVES: Kelch-like protein-11 (KLHL11)-IgG is associated with rhombencephalitis and seminoma. It has not previously been described as a neurologic immune checkpoint inhibitor (ICI)-related adverse event (nirAE) or in association with esophageal adenocarcinoma. METHODS: We describe a 61-year-old man with metastatic esophageal adenocarcinoma treated with folinic acid, fluorouracil, oxaliplatin (FOLFOX), and nivolumab, who subsequently developed diplopia, vertigo, and progressive gait ataxia after 8 weeks of treatment. RESULTS: Owing to a concern for ICI-associated myasthenia gravis, nivolumab was held and he was treated with prednisone and pyridostigmine. EMG showed no neuromuscular junction dysfunction, and acetylcholine-receptor antibodies were negative. Brain MRI was unrevealing. Murine brain tissue immunofluorescence assay revealed KLHL11-IgG in both serum and CSF, confirmed by cell-based assay. Tumor histopathology demonstrated poorly differentiated, highly proliferative adenocarcinoma with increased mitotic figures and cytoplasmic KLHL11 immunoreactivity. He was initiated on 6 months of cyclophosphamide in addition to FOLFOX for post-ICI-associated KLHL11-IgG rhombencephalitis. DISCUSSION: We report KLHL11-IgG rhombencephalitis associated with poorly differentiated esophageal cancer as a novel nirAE. Tumor staining revealed KLHL11 immunoreactivity, supporting a cancer-antigen-driven ICI-associated paraneoplastic syndrome. Recognition of novel nirAEs can expedite treatment and potentially prevent progressive neurologic disability.

VEGF expression disparities in brainstem motor neurons of the SOD1G93A ALS model: Correlations with neuronal vulnerability.

Amyotrophic lateral sclerosis (ALS) is a rare neuromuscular disease characterized by severe muscle weakness mainly due to degeneration and death of motor neurons. A peculiarity of the neurodegenerative processes is the variable susceptibility among distinct neuronal populations, exemplified by the contrasting resilience of motor neurons innervating the ocular motor system and the more vulnerable facial and hypoglossal motor neurons. The crucial role of vascular endothelial growth factor (VEGF) as a neuroprotective factor in the nervous system is well-established since a deficit of VEGF has been related to motoneuronal degeneration. In this study, we investigated the survival of ocular, facial, and hypoglossal motor neurons utilizing the murine SOD1G93A ALS model at various stages of the disease. Our primary objective was to determine whether the survival of the different brainstem motor neurons was linked to disparate VEGF expression levels in resilient and susceptible motor neurons throughout neurodegeneration. Our findings revealed a selective loss of motor neurons exclusively within the vulnerable nuclei. Furthermore, a significantly higher level of VEGF was detected in the more resistant motor neurons, the extraocular ones. We also examined whether TDP-43 dynamics in the brainstem motor neuron of SOD mice was altered. Our data suggests that the increased VEGF levels observed in extraocular motor neurons may potentially underlie their resistance during the neurodegenerative processes in ALS in a TDP-43-independent manner. Our work might help to better understand the underlying mechanisms of selective vulnerability of motor neurons in ALS.

Inflammatory lesions of the brainstem: Keys for the diagnosis by MRI.

OBJECTIVE: To describe the magnetic resonance imaging (MRI) findings for the most common inflammatory and immune-mediated diseases that involve the brainstem. CONCLUSION: Inflammatory lesions involving the brainstem are associated with a wide range of autoimmune, infectious, and paraneoplastic syndromes, making the differential diagnosis complex. Being familiar with these entities, their clinical characteristics, and their manifestations on MRI, especially the number of lesions, their shape and extension, and their appearance in different sequences, is useful for orienting the radiological diagnosis.

The effectiveness of diffusion kurtosis imaging metrics for distinguishing between brainstem glioma and cerebellar medulloblastoma.

Background: In some clinical situations, distinguishing between cerebellar medulloblastoma and brainstem glioma is important. We assessed whether diffusion kurtosis imaging (DKI) metrics could be used to distinguish cerebellar medulloblastomas from brainstem gliomas in children. Patients and methods: This prospective study was approved by the institutional review board. Seventy patients were separated into two groups according to eventual diagnosis: brainstem glioma (n = 30) and cerebellar medulloblastoma (n = 40). Both groups underwent brain magnetic resonance imaging (MRI), including DKI. The Kurtosis value for the tumor region and the ratio between Kurtosis values between the tumor and the normal parenchyma (rKurtosis) were compared between groups using the Mann-Whitney U test. Receiver operating characteristic curve analysis and the Youden's Index were applied to identify a cutoff value for distinguishing between the two tumor types, and the area under the curve (AUC), sensitivity, and specificity for the selected cutoff value were calculated. Results: Compared with brainstem gliomas, cerebellar medulloblastomas had significantly higher Kurtosis and rKurtosis values (p < 0.05). Medulloblastoma could be differentiated from brainstem gliomas using a Kurtosis value of 0.91 or an rKurtosis value of 0.90, both of which achieved 100% sensitivity, 96.7% specificity, and AUC values of 0.990. Conclusions: DKI measurements can contribute to distinguishing between cerebellar medulloblastoma and brainstem glioma in children.

Brain and Brain Stem Necrosis After Reirradiation for Recurrent Childhood Primary Central Nervous System Tumors: A PENTEC Comprehensive Review.

PURPOSE: Reirradiation is increasingly used in children and adolescents/young adults (AYA) with recurrent primary central nervous system tumors. The Pediatric Normal Tissue Effects in the Clinic (PENTEC) reirradiation task force aimed to quantify risks of brain and brain stem necrosis after reirradiation. METHODS AND MATERIALS: A systematic literature search using the PubMed and Cochrane databases for peer-reviewed articles from 1975 to 2021 identified 92 studies on reirradiation for recurrent tumors in children/AYA. Seventeen studies representing 449 patients who reported brain and brain stem necrosis after reirradiation contained sufficient data for analysis. While all 17 studies described techniques and doses used for reirradiation, they lacked essential details on clinically significant dose-volume metrics necessary for dose-response modeling on late effects. We, therefore, estimated incidences of necrosis with an exact 95% CI and qualitatively described data. Results from multiple studies were pooled by taking the weighted average of the reported crude rates from individual studies. RESULTS: Treated cancers included ependymoma (n = 279 patients; 7 studies), medulloblastoma (n = 98 patients; 6 studies), any CNS tumors (n = 62 patients; 3 studies), and supratentorial high-grade gliomas (n = 10 patients; 1 study). The median interval between initial and reirradiation was 2.3 years (range, 1.2-4.75 years). The median cumulative prescription dose in equivalent dose in 2-Gy fractions (EQD22; assuming α/ß value = 2 Gy) was 103.8 Gy (range, 55.8-141.3 Gy). Among 449 reirradiated children/AYA, 22 (4.9%; 95% CI, 3.1%-7.3%) developed brain necrosis and 14 (3.1%; 95% CI, 1.7%-5.2%) developed brain stem necrosis with a weighted median follow-up of 1.6 years (range, 0.5-7.4 years). The median cumulative prescription EQD22 was 111.4 Gy (range, 55.8-141.3 Gy) for development of any necrosis, 107.7 Gy (range, 55.8-141.3 Gy) for brain necrosis, and 112.1 Gy (range, 100.2-117 Gy) for brain stem necrosis. The median latent period between reirradiation and the development of necrosis was 5.7 months (range, 4.3-24 months). Though there were more events among children/AYA undergoing hypofractionated versus conventionally fractionated reirradiation, the differences were not statistically significant (P = .46). CONCLUSIONS: Existing reports suggest that in children/AYA with recurrent brain tumors, reirradiation with a total EQD22 of about 112 Gy is associated with an approximate 5% to 7% incidence of brain/brain stem necrosis after a median follow-up of 1.6 years (with the initial course of radiation therapy being given with conventional prescription doses of ≤2 Gy per fraction and the second course with variable fractionations). We recommend a uniform approach for reporting dosimetric endpoints to derive robust predictive models of late toxicities following reirradiation.

Brainstem nuclei responsive to cystometry in both endometriosis and cystitis rat models: C-fos immunohistochemistry study.

PURPOSE: Although the co-occurrence of interstitial cystitis (IC) and endometriosis (ENDO) is remarkably high, the exact pathophysiology for this co-occurrence is unknown. The convergence of the inputs from the involved structures to the same neuronal centers may suggest neuronal hyperexcitability as a mechanism for this co-occurrence. METHODS: The present study aimed to investigate the association between IC and ENDO, by studying the changes in brainstem responses to cystometry in a rat model of ENDO and cyclophosphamide (CYP)-induced IC using c-fos immunohistochemistry. RESULTS: Following cystometry the brainstem areas that had significant increase in c-fos expression in ENDO alone included: periaqueductal gray (PAG) nuclei, dorsal raphe nucleus, raphe obscurus nucleus, kolliker- Fuse areas, and area postrema. However, the brainstem areas that had increased significantly in the c-fos expression in the ENDO and CYP treated animals included: gigantocellular nucleus, lateral paragigantocellular nucleus, caudoventrolateral nucleus, rostroventrolateral/caudoventrolateral nucleus, lateral reticular nucleus, locus coeruleus, lateral PAG, raphe pallidus nucleus, raphe magnus nucleus, rostroventrolateral nucleus, dorsal motor nucleus of vagus, and solitary tract nucleus. Whereas only lateral parabrachial nucleus showed significant increase in c-fos expression in CYP treated animals alone. CONCLUSIONS: The results of the present study demonstrate the overlap of brainstem nuclei that are excited by urinary bladder under ENDO and IC conditions. The pattern of hyperexcitability of the brainstem nuclei may help in understating the pathophysiology of IC and ENDO conditions.

Intraoperative Neurophysiologic Monitoring and Mapping in Children Undergoing Brainstem Surgery.

SUMMARY: Intraoperative neurophysiologic monitoring during surgery for brainstem lesions is a challenge for intraoperative neurophysiologists and surgeons. The brainstem is a small structure packed with vital neuroanatomic networks of long and short pathways passing through the brainstem or originating from it. Many central pattern generators exist within the brainstem for breathing, swallowing, chewing, cardiovascular regulation, and eye movement. During surgery around the brainstem, these generators need to be preserved to maintain their function postoperatively. This short review presents neurophysiologic and neurosurgical experiences of brainstem surgery in children.