To investigate the association between chemical markers (triglyceride, C-reactive protein (CRP), and inflammation markers) and perfusion markers (relative cerebral vascular reserve (rCVR)) with moyamoya disease progression and complication types. A total of 314 patients diagnosed with moyamoya disease were included. Triglyceride and CRP levels were assessed and categorized based on Korean guidelines for dyslipidemia and CDC/AHA guidelines, respectively. Perfusion markers were evaluated using Diamox SPECT. Cox proportional hazard analysis was performed to examine the relationship between these markers and disease progression, as well as complication types (ischemic stroke, hemorrhagic stroke, and rCVR deterioration). Elevated triglyceride levels (≥ 200) were significantly associated with higher likelihood of end-point events (HR: 2.292, CI 1.00-4.979, P = 0.03). Severe decreased rCVR findings on Diamox SPECT were also significantly associated with end-point events (HR: 3.431, CI 1.254-9.389, P = 0.02). Increased CRP levels and white blood cell (WBC) count were significantly associated with moyamoya disease progression. For hemorrhagic stroke, higher triglyceride levels were significantly associated with end-point events (HR: 5.180, CI 1.355-19.801, P = 0.02). For ischemic stroke, severe decreased rCVR findings on Diamox SPECT (HR: 5.939, CI 1.616-21.829, P < 0.01) and increased CRP levels (HR: 1.465, CI 1.009-2.127, P = 0.05) were significantly associated with end-point events. Elevated triglyceride, CRP, and inflammation markers, as well as decreased rCVR, are potential predictors of moyamoya disease progression and complication types. Further research is warranted to understand their role in disease pathophysiology and treatment strategies.

Background: This study evaluates the effectiveness of Therapeutic Hypothermia (TH) in treating poor-grade aneurysmal subarachnoid hemorrhage (SAH), focusing on functional outcomes, mortality, and complications such as vasospasm, delayed cerebral ischemia (DCI), and hydrocephalus.Methods: Adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, a comprehensive literature search was conducted across multiple databases, including Medline, Embase, and Cochrane Central, up to November 2023. Nine studies involving 368 patients were selected based on eligibility criteria focusing on TH in poor-grade SAH patients. Data extraction, bias assessment, and evidence certainty were systematically performed.Results: The primary analysis of unfavorable outcomes in 271 participants showed no significant difference between the TH and standard care groups (risk ratio [RR], 0.87). However, a significant reduction in vasospasm was observed in the TH group (RR, 0.63) among 174 participants. No significant differences were found in DCI, hydrocephalus, and mortality rates in the respective participant groups.Conclusions: TH did not significantly improve primary unfavorable outcomes in poor-grade SAH patients. However, the reduction in vasospasm rates indicates potential specific benefits. The absence of significant findings in other secondary outcomes and mortality highlights the need for further research to better understand TH's role in treating this patient population.

Neuro-critically ill patients face unique challenges in nutritional support due to varying metabolic and energy demands arising from clinical situations such as elevated intracranial pressure, trauma, stroke, epilepsy, targeted temperature management (TTM), and pharmacological interventions. Despite these challenges, there is a lack of systematic reviews addressing their specific needs. This study conducts a systematic review and narrative synthesis of the existing literature on nutritional support for neuro-critical patients, focusing on amino acids that act as neurotransmitters or their precursors. We examined nutritional requirements and timing in patients with stroke and traumatic brain injury, as well as energy and metabolic demands during TTM, a common therapeutic intervention in neuro-critical care. Our review aims to clarify uncertainties surrounding amino acid provision in neuro-critical patients and provide up-to-date recommendations on nutritional support for those with elevated intracranial pressure and undergoing TTM, serving as a foundation for future research and evidence-based guideline development. Key findings include the potential benefits of branched-chain amino acids (BCAAs) in neuro-critical care, the roles of methionine and serine, the significance of arginine in vascular constriction, the controversial role of glutamate in nutrition, and the potential benefits of selenium supplementation. We also discussed special considerations in nutritional support for neuro-critical patients, such as changes in energy demand, the influence of sedation on energy demand, and metabolism changes during TTM. Our review highlights the need for a better understanding of the unique metabolic requirements of neuro-critical patients and the development of evidence-based guidelines for optimal nutritional support in this population.

Mannitol, derived from mannose sugar, is crucial in treating patients with elevated intracranial pressure (ICP). Its dehydrating properties at the cellular and tissue levels increase plasma osmotic pressure, which is studied for its potential to reduce ICP through osmotic diuresis. While clinical guidelines support mannitol use in these cases, the best approach for its application continues to be debated. Important aspects needing further investigation include: 1) bolus administration versus continuous infusion, 2) ICP-based dosing versus scheduled bolus, 3) identifying the optimal infusion rate, 4) determining the appropriate dosage, 5) establishing fluid replacement plans for urinary loss, and 6) selecting monitoring techniques and thresholds to assess effectiveness and ensure safety. Due to the lack of adequate high-quality prospective research data, a comprehensive review of recent studies and clinical trials is crucial. This assessment aims to bridge the knowledge gap, improve understanding of effective mannitol use in elevated ICP patients, and provide insights for future research. In conclusion, this review aspires to contribute to the ongoing discourse on mannitol application. By integrating the latest findings, this review will offer valuable insights into the function of mannitol in decreasing ICP, thereby informing better therapeutic approaches and enhancing patient outcomes.

To investigate the association between chemical markers (triglyceride, C-reactive protein (CRP), and inflammation markers) and perfusion markers (relative cerebral vascular reserve (rCVR)) with moyamoya disease progression and complication types. A total of 314 patients diagnosed with moyamoya disease were included. Triglyceride and CRP levels were assessed and categorized based on Korean guidelines for dyslipidemia and CDC/AHA guidelines, respectively. Perfusion markers were evaluated using Diamox SPECT. Cox proportional hazard analysis was performed to examine the relationship between these markers and disease progression, as well as complication types (ischemic stroke, hemorrhagic stroke, and rCVR deterioration). Elevated triglyceride levels (≥ 200) were significantly associated with higher likelihood of end-point events (HR: 2.292, CI 1.00-4.979, P = 0.03). Severe decreased rCVR findings on Diamox SPECT were also significantly associated with end-point events (HR: 3.431, CI 1.254-9.389, P = 0.02). Increased CRP levels and white blood cell (WBC) count were significantly associated with moyamoya disease progression. For hemorrhagic stroke, higher triglyceride levels were significantly associated with end-point events (HR: 5.180, CI 1.355-19.801, P = 0.02). For ischemic stroke, severe decreased rCVR findings on Diamox SPECT (HR: 5.939, CI 1.616-21.829, P < 0.01) and increased CRP levels (HR: 1.465, CI 1.009-2.127, P = 0.05) were significantly associated with end-point events. Elevated triglyceride, CRP, and inflammation markers, as well as decreased rCVR, are potential predictors of moyamoya disease progression and complication types. Further research is warranted to understand their role in disease pathophysiology and treatment strategies.

Background: This study evaluates the effectiveness of Therapeutic Hypothermia (TH) in treating poor-grade aneurysmal subarachnoid hemorrhage (SAH), focusing on functional outcomes, mortality, and complications such as vasospasm, delayed cerebral ischemia (DCI), and hydrocephalus.Methods: Adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, a comprehensive literature search was conducted across multiple databases, including Medline, Embase, and Cochrane Central, up to November 2023. Nine studies involving 368 patients were selected based on eligibility criteria focusing on TH in poor-grade SAH patients. Data extraction, bias assessment, and evidence certainty were systematically performed.Results: The primary analysis of unfavorable outcomes in 271 participants showed no significant difference between the TH and standard care groups (risk ratio [RR], 0.87). However, a significant reduction in vasospasm was observed in the TH group (RR, 0.63) among 174 participants. No significant differences were found in DCI, hydrocephalus, and mortality rates in the respective participant groups.Conclusions: TH did not significantly improve primary unfavorable outcomes in poor-grade SAH patients. However, the reduction in vasospasm rates indicates potential specific benefits. The absence of significant findings in other secondary outcomes and mortality highlights the need for further research to better understand TH's role in treating this patient population.

Neuro-critically ill patients face unique challenges in nutritional support due to varying metabolic and energy demands arising from clinical situations such as elevated intracranial pressure, trauma, stroke, epilepsy, targeted temperature management (TTM), and pharmacological interventions. Despite these challenges, there is a lack of systematic reviews addressing their specific needs. This study conducts a systematic review and narrative synthesis of the existing literature on nutritional support for neuro-critical patients, focusing on amino acids that act as neurotransmitters or their precursors. We examined nutritional requirements and timing in patients with stroke and traumatic brain injury, as well as energy and metabolic demands during TTM, a common therapeutic intervention in neuro-critical care. Our review aims to clarify uncertainties surrounding amino acid provision in neuro-critical patients and provide up-to-date recommendations on nutritional support for those with elevated intracranial pressure and undergoing TTM, serving as a foundation for future research and evidence-based guideline development. Key findings include the potential benefits of branched-chain amino acids (BCAAs) in neuro-critical care, the roles of methionine and serine, the significance of arginine in vascular constriction, the controversial role of glutamate in nutrition, and the potential benefits of selenium supplementation. We also discussed special considerations in nutritional support for neuro-critical patients, such as changes in energy demand, the influence of sedation on energy demand, and metabolism changes during TTM. Our review highlights the need for a better understanding of the unique metabolic requirements of neuro-critical patients and the development of evidence-based guidelines for optimal nutritional support in this population.

Mannitol, derived from mannose sugar, is crucial in treating patients with elevated intracranial pressure (ICP). Its dehydrating properties at the cellular and tissue levels increase plasma osmotic pressure, which is studied for its potential to reduce ICP through osmotic diuresis. While clinical guidelines support mannitol use in these cases, the best approach for its application continues to be debated. Important aspects needing further investigation include: 1) bolus administration versus continuous infusion, 2) ICP-based dosing versus scheduled bolus, 3) identifying the optimal infusion rate, 4) determining the appropriate dosage, 5) establishing fluid replacement plans for urinary loss, and 6) selecting monitoring techniques and thresholds to assess effectiveness and ensure safety. Due to the lack of adequate high-quality prospective research data, a comprehensive review of recent studies and clinical trials is crucial. This assessment aims to bridge the knowledge gap, improve understanding of effective mannitol use in elevated ICP patients, and provide insights for future research. In conclusion, this review aspires to contribute to the ongoing discourse on mannitol application. By integrating the latest findings, this review will offer valuable insights into the function of mannitol in decreasing ICP, thereby informing better therapeutic approaches and enhancing patient outcomes.

Dear Editor, Glioblastoma (GBM), the most aggressive malignant tumour, is increasingly treated with immunotherapy.1-3 The stimulator of interferon genes (STING) pathway4 is key to tumour immunity and a studied target for immunotherapy.5 This study explores the immune landscape of GBM, focusing on spatial relationships between tumour-associated immune cells (TAICs)6 and STING-expressing cells, uncovering patterns linked to prognosis. We studied 14 recurrent GBM patients using protein composition and Gene Ontology (GO) analysis and analyzed immune pathways in 69 newly diagnosed GBM patients undergoing standard therapy. Spatial analysis of cells was performed using QuPath, CytoMAP, and R, as illustrated in Figure 1A. From our proteomic analysis, we identified protein groups with marked upregulation in patients with favourable responses. A total of 99 proteins were highly upregulated in the favourable group, while 170 were more pronounced in the unfavourable group (Figure 1B). Clusters of downregulated and upregulated proteins were identified using the Benjamini-Hochberg False Discovery Rate. The expression of TMEM173, the gene encoding STING, was significantly elevated in the favourable group, as measured by protein expression using a mass spectrometer. The results were represented as an abundance ratio, and statistical significance was confirmed using the adjusted p-value. (Figure 1C). GO analysis showed that upregulated proteins in the favourable group were mainly linked to immune response activation. (Figure 1D). Pathways such as ‘regulation of innate immune response’ and ‘phagocytic respiratory burst’ were strongly linked to innate immune activation (Figure 1E). Additionally, pathways like ‘cell surface receptor signalling in immune response’, ‘T cell migration’ and ‘positive regulation of T cell receptor signalling’ were significantly linked to immune response activation (Figure 1F). p-Values were transformed to -log10 for statistical significance, with values above 1.3 considered significant. Table S1 provides the GO categories associated with immune response activation. We used multiplex immunohistochemistry (IHC) to analyze immune cell distribution and protein markers in the TME. Markers included CD4+ (helper T cells), CD8+ (cytotoxic T cells), CD11c+ (dendritic cells), TCRγ/δ+ (γ/δ T cells), ATRX+ (tumour cells) and DAPI+ (nuclei), with STING as a primary marker of interest. We explored correlations between immune cell populations identified by multiplex IHC and patient survival (Figure 2A). Tumour specimens were stained with multiplex immunofluorescence, and a pathologist selected regions of interest (ROIs), which were scanned at high magnification and analyzed with markers including ATRX, CD8, STING, DAPI, CD4, CD11c and TCRγ/δ. (Figure 2B). Multiplex IHC enabled analysis of cell interactions in the tumour microenvironment, quantifying marker expression and its impact on prognosis. Correlation analysis between marker expression and overall survival (OS) revealed a significant positive correlation between STING+ cell count and OS (R = 0.256, p = .036) (Figure 2C). No other markers showed a statistically significant correlation with OS. Linear regression analysis showed an increase in OS with higher STING+ cell counts (β = 0.481, p = .036) (Figure 2D). Table S2 summarizes linear regression results for each marker and OS. When adjusted for progression-free survival (PFS), increased STING+ cell counts were significantly linked to improved OS (β = 0.302, p = .025, R2 = 0.692) (Figure 2G). Table S3 details the results of the analysis correlating cell counts with OS, adjusted for PFS. Comparing patients with high and low STING expression revealed that only the patient with low STING expression experienced recurrence 1.5 years after surgery (Figure 2E). Using QuPath, cell coordinates and phenotypes were mapped for spatial analysis in R. Visualization showed that the patient without GBM recurrence had a higher number of STING-expressing cells (Figure 2F). These results show that multiplex IHC enables visual comparison of TME cell composition differences between patients with favourable and unfavourable outcomes. The STING pathway affects the TME by modulating immunosuppressive and immunoproliferative conditions through T cells and dendritic cells, influencing tumour progression based on the context.7 This study analyzed spatial interactions of STING+ cells, which are present in hematopoietic, endothelial, epithelial, and fibroblast cells.8 STING-expressing endothelial cells play a key role in promoting immune responses driven by macrophages and help in T cell recruitment across blood vessels.9 In the brain's microvascular structure, which comprises the blood-brain barrier (BBB), type I interferons secreted by endothelial cells enhance immune responses, impacting tumour immunity.10 This study specifically targets STING+CD4−CD8−CD11c−ATRX−TCRγ/δ− cells, which are likely endothelial cells forming the BBB. We measured mean distances from STING+ cells to ATRX+ cells, TCRγ/δ+ cells, CD4+ cells, CD8+ cells and CD11c+ cells (Figure 3A). The correlation analysis between STING expression and immune markers in our study was conducted using an unsupervised approach. This method allowed us to identify natural patterns and relationships within the data without introducing potential biases from predefined categories or labels. From the patient group, we selected individuals with favourable or poor OS outcomes and generated positional plots of surgical samples (Figure 3B). ROIs chosen by the pathologist were further examined at high magnification, with cell coordinates derived from these plots. Voronoi diagrams were used for selected ROIs to merge clusters and simplify visual representation (Figure 3B). Patients with high STING expression showed CD4+ cells near STING+ cells and few CD11c+ cells, while low STING expression patients had CD11c+ cells near STING+ cells and scarce CD4+ cells (Figure 3B). Notably, the patient with a close spatial relationship between CD4+ and STING+ cells had a favourable prognosis, with an OS of 3371 days, whereas the patient with CD11c+ cells near STING+ cells had a poor prognosis, with an OS of 108 days. The chord diagram showed a significant link between OS and the mean distances from STING+ cells to CD4+ and CD11c+ cells (Figure 3C). Correlation analysis demonstrated a significant negative correlation between the distance from STING+ cells to CD4+ cells and OS (R = -0.089, p = .047). Conversely, a positive correlation between the distance from STING+ cells to CD11c+ cells and OS was also identified (R = 0.342, p = .042) (Figure 3D). Linear regression confirmed that shorter distances between STING+ and CD4+ cells were linked to lower OS (p = .047) (Figure 3E). Likewise, greater distances between STING+ and CD11c+ cells were associated with increased OS (p = .042) (Figure 3F). These findings indicate a potential association between the spatial relationships of STING+ cells and nearby immune cells and survival outcomes in GBM patients. In particular, closer proximity between STING+ cells and CD4+ cells showed a trend toward improved survival, while greater distance between STING+ cells and CD11c+ cells appeared to correlate with better outcomes (Figure 3G). Given STING's dual roles in tumour promotion and inhibition, these spatial interactions may contribute to shaping the immune microenvironment in a nuanced manner. Hanwool Jeon: Conceptualization, methodology, formal analysis, data curation, funding acquisition and writing and editing; Hayeong Kang: Conceptualization, methodology, formal analysis, data curation and writing and editing; Jihyun Im: Validation, visualization, formal analysis, data curation and writing and editing; Suin Jo: Methodology, validation, visualization, data curation and writing and editing; Hyunchul Jung: Resources; Moinay Kim: Resources; Jae Hyun Kim: Resources; Jeong Hoon Kim: Resources; Chang-Ki Hong: Resources; Young-Hoon Kim: Resources; Sang Woo Song: Resources; Jinha Park: Methodology and data curation; Sang-Yeob Kim: Methodology, data curation, supervision and writing and editing, Seungjoo Lee: Conceptualization, methodology, investigation, validation, formal analysis, data curation, resources, supervision, funding acquisition and writing and editing. We thank the Clinical Proteomics Core, and the Laboratory of Animal Research at the ConveRgence mEDIcine research center (CREDIT) at Asan Medical Center for their equipment, services, and expertise. The authors declare no conflict of interest. This research was supported by a grant from the Basic Science Research Program, funded by the Korean government's Ministry of Science and ICT (MSIT) (2022R1A2C2011941), Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHID), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: RS-2024-00438911) to Seungjoo Lee. Additionally, support was provided by the Health Fellowship Foundation and the Korean government's Ministry of Science and ICT (2022R1C1C2002698) to Hanwool Jeon. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

We report a rare and diagnostically challenging case of a 39-year-old male patient who presented with symptoms of dizziness and headaches, without any focal neurological symptoms. Initial imaging stud- ies suggested a germ cell tumor, and an endoscopic biopsy led to a preliminary diagnosis of a pineal parenchymal tumor of intermediate differentiation. However, histological evaluation following surgical resection revealed the final diagnosis to be an ectopic pituitary neuroendocrine tumor (PitNET), a con- dition that is exceedingly rare. Ectopic PitNETs are uncommon tumors that develop outside the normal anatomical location of the pituitary gland. Their atypical presentation often leads to misdiagnosis as other intracranial neoplasms. This case highlights the diagnostic challenges posed by ectopic PitNETs and contributes to the limited literature on this rare condition. It underscores the importance of main- taining a broad differential diagnosis in patients presenting with atypical intracranial neoplasms

Background: Serum calcium and magnesium levels are a key factor of the coagulation cascade and may potentially contribute to the pathophysiology of intracerebral hemorrhage (ICH) expansion. The aim of this study was to attain and sustain target levels of serum calcium and magnesium for three days following admission. Methods: A single-blind, prospective, multicenter randomized study was conducted from 2019 to 2022 years, enrolling acute ICH patients aged 18–80 years, with radiological diagnosis and without surgical intervention. Participants were randomly assigned in a 1:1 ratio to either the study group or the control group. In the study group, the target serum levels of calcium (9–10.2 mg/dL) and magnesium (2–3 mg/dL) were actively achieved and maintained for a duration of 3 days following admission. The primary outcome was the expansion of ICH volume within the first 3 days between the study group and the control groups. Results: After implementing inclusion/exclusion criteria, 105 of 354 patients remained in the study. There were no significant differences in ICH volume on hospital days 2 and 3 between the groups. Admission factors including Glasgow coma scale score, hemoglobin level, ICH volume, and spot sign showed significant correlations in multivariate analysis. On the third day of hospitalization, admission serum magnesium levels showed a significant correlation with ICH expansion, whereas calcium levels did not. Conclusion: Admission serum magnesium levels were found to correlate with hematoma expansion in patients with acute ICH. While magnesium itself may not be a direct therapeutic target, it could serve as a valuable indicator for identifying potential therapeutic strategies aimed at preventing ICH volume increase. Trial Registration: Clinical Research Information Service Identifier: KCT0004427