Correlation of Molecular Status with Preoperative Olfactory Function in Olfactory Groove Meningioma.

PURPOSE: The study aims to examine the possible correlation between genomic alterations and preoperative olfactory function in patients with olfactory groove meningioma (OGM), due to the frequent presence of olfactory impairment. METHODS: We utilised next-generation sequencing to analyse samples from 22 individuals with OGM in order to detect driver mutations. Tumour morphology was assessed using preoperative imaging, whereas olfactory function was examined using Sniffin' Sticks. RESULTS: In a study of 22 OGM patients, mutations were as follows: 10 with SMO/SUFU, 7 with AKT1, and 5 as wild type. Planum sphenoidale hyperostosis (PSH) was present in 75% of patients, showing significant variation by mutation (p = 0.048). Tumour volumes, averaging 25 cm3, significantly differed among groups. PSH negatively impacted olfaction, notably affecting odour threshold, discrimination, identification, and global olfactory performance score (TDI) (p values ranging from <0.001 to 0.003). Perifocal oedema was associated with lower TDI (p = 0.009) and altered threshold scores (p = 0.038). Age over 65 and female gender were linked to lower thresholds and discrimination scores (p = 0.037 and p = 0.019). CONCLUSION: The study highlights PSH and perifocal oedema's significant effect on olfactory function in OGM patients but finds no link between olfactory impairment and tumour mutations, possibly due to the small sample size. This suggests that age and gender affect olfactory impairment. Additional research with a larger group of participants is needed to explore the impact of OGM driver mutations on olfactory performance.

The Impact of Magnetic Resonance Imaging Findings in Predicting Neurological Status Pre- and Post-Treatment of Spinal Dural Arteriovenous Fistulas: A 22-Year Experience in a Neurovascular and Spine Center.

BACKGROUND: Successful treatment of spinal dural arteriovenous fistulas (SDAVF) requires prompt diagnosis with definitive fistula localization and non-delayed treatment. Magnetic resonance imaging (MRI) is used for the screening and follow-up of SDAVF, although the value of MRI signs such as myelopathy and flow voids is controversial. Therefore, we investigated the predictive value of MRI signs pre- and post-treatment and their correlation with the neurological status of SDAVF patients. METHODS: We retrospectively analyzed the clinical records of 81 patients who underwent surgical or endovascular treatment for SDAVF at our hospital between 2002 and 2023. A total of 41 SDAVF patients with follow-up MRI of 4.6 [2.9-6.5] months (median [interquartile range]) post-treatment and clinical follow-up of 3, 6, and 12 months were included. RESULTS: The extent of pretreatment myelopathy was seven [6-8] vertebral levels, with follow-up MRI showing no myelopathy in 70.7% of cases. The pretreatment flow voids extended over seven [4.5-10] vertebral levels and completely disappeared on follow-up MRI in 100% of cases. The modified Aminoff-Logue scale of disability (mALS) was four [2-7] pretreatment and two [0-4.5] at the third follow-up, with improvement in 65.9% of patients. The American Spinal Injury Association motor score (ASIA-MS) was 97 [88-100] pretreatment and 100 [95-100] at the third follow-up assessment, with 78% of patients improving. Pretreatment ASIA-MS correlated with the extent of myelopathy at admission (R2: 0.179; 95% CI: -0.185, -0.033; p = 0.006) but not with flow voids at admission, while pretreatment mALS showed no correlation with either MRI signs. The improvement in ASIA-MS and mALS between admission and the last follow-up showed no correlation with the extent of pretreatment myelopathy and flow voids or with pos-treatment MRI changes. The diagnostic sensitivity of magnetic resonance angiography (MRA) for localization of the fistula was 68.3% (28/41). CONCLUSIONS: The severity of the clinical condition in SDAVF patients has a multifactorial cause, whereby the ASIA-MS correlates with the extent of myelopathy pretreatment. MRI changes after treatment showed no correlation with the clinical outcome and cannot be used as a prognostic factor.

Diagnostic, clinical management, and outcomes in patients with spinal dural arteriovenous fistula.

Background: Spinal dural arteriovenous fistulas (SDAVFs) are rare spinal vascular malformations, but account for 70 to 80% of all spinal arteriovenous malformations. SDAVFs can be treated either surgically or endovascularly, with surgical treatment appearing to lead to higher closure rates. Our aim was to analyze the demographic data, diagnostic history, treatment characteristics and clinical short- and long-term outcomes. Methods: The medical records of 81 patients who underwent surgical (n = 70, 86.4%) and endovascular (n = 11, 13.6%) treatment for SDAVF at a university hospital between 2002 and 2023 were retrospectively analyzed. Results: SDAVF was observed more frequently in men than women (61, 75.3% vs. 20, 24.7%) with a mean age of 63.5 ± 12.7 years and a mean duration of symptoms to diagnosis of 12.0 ± 12.8 months. The most common first symptom was gait disturbance (36, 44.4%), followed by sensory disturbance (24, 29.6%). The location of the fistula point was most common in the lower thoracic region (36, 44.5%), followed by the lumbar region (23, 28.4%). Incomplete or failed occlusion of the fistula occurred in 8 patients (9.9%), with 6 patients (7.4%) undergoing further treatment either surgically or endovascularly. Treatment- or hospital-related complications were observed in 16 patients (19.8%). A single-level laminectomy was the most common approach (31, 44.3%), followed by single-level hemilaminectomy (28, 40.0%), and unilateral interlaminar fenestration (11, 15.7%). Back pain or radiculopathy was observed in 58% of patients (47/81) pre-treatment and had already decreased to 24.7% at hospital discharge (p < 0.001). No significant differences were observed in sensory disturbances (p = 0.681). The median of American Spinal Injury Association motor score (ASIA-MS) was 94 [82.5-100] at admission, 98 [86.5-100] at hospital discharge, 100 [90-100] at the first, second, and third follow-up (p = 0.019). The median modified Aminoff-Logue scale (mALS) was 5 [2-7] at admission, 3 [1-6] at hospital discharge, 2 [1-5] at the first follow-up, 2 [0.5-5] at the second follow-up and 2 [1-7] at the third follow-up (p = 0.006). Conclusions: SDAVF occurs predominantly in men in the 6th decade of life and can be safely and effectively treated surgically and endovascularly, improving symptoms such as pain and motor deficits, gait disturbances as well as bowel and bladder dysfunction, but not sensory disturbances.

The importance of considering competing risks in recurrence analysis of intracranial meningioma.

BACKGROUND: The risk of recurrence is overestimated by the Kaplan-Meier method when competing events, such as death without recurrence, are present. Such overestimation can be avoided by using the Aalen-Johansen method, which is a direct extension of Kaplan-Meier that accounts for competing events. Meningiomas commonly occur in older individuals and have slow-growing properties, thereby warranting competing risk analysis. The extent to which competing events are considered in meningioma literature is unknown, and the consequences of using incorrect methodologies in meningioma recurrence risk analysis have not been investigated. METHODS: We surveyed articles indexed on PubMed since 2020 to assess the usage of competing risk analysis in recent meningioma literature. To compare recurrence risk estimates obtained through Kaplan-Meier and Aalen-Johansen methods, we applied our international database comprising ~ 8,000 patients with a primary meningioma collected from 42 institutions. RESULTS: Of 513 articles, 169 were eligible for full-text screening. There were 6,537 eligible cases from our PERNS database. The discrepancy between the results obtained by Kaplan-Meier and Aalen-Johansen was negligible among low-grade lesions and younger individuals. The discrepancy increased substantially in the patient groups associated with higher rates of competing events (older patients with high-grade lesions). CONCLUSION: The importance of considering competing events in recurrence risk analysis is poorly recognized as only 6% of the studies we surveyed employed Aalen-Johansen analyses. Consequently, most of the previous literature has overestimated the risk of recurrence. The overestimation was negligible for studies involving low-grade lesions in younger individuals; however, overestimation might have been substantial for studies on high-grade lesions.

The importance of the bacterial spectrum in the clinical diagnostics and management of patients with spontaneous pyogenic spondylodiscitis and isolated spinal epidural empyema: a 20-year cohort study at a single spine center.

BACKGROUND: Personalized clinical management of spondylodiscitis (SD) and isolated spinal epidural empyema (ISEE) is challenging due to limited evidence of microbiologic findings and their clinical impact during the clinical course of the disease. We aimed to characterize clinico-microbiological and imaging phenotypes of SD and ISEE to provide useful insights that could improve outcomes and potentially modify guidelines. METHODS: We performed chart review and collected data on the following parameters: bacterial antibiogram-resistogram, type of primary spinal infection, location of spinal infection, source of infection, method of detection, clinical complications (sepsis, septic embolism, and endocarditis), length of hospital and intensive care unit (ICU) stay, relapse rate, and disease-related mortality in patients with proven pyogenic SD and ISEE treated surgically in a university hospital in Germany between 2002 and 2022. RESULTS: We included data from 187 patients (125 SD, 66.8% and 62 ISEE, 33.2%). Gram-positive bacteria (GPB) were overall more frequently detected than gram-negative bacteria (GNB) (GPB: 162, 86.6% vs. GNB: 25, 13.4%, p < 0.001). Infective endocarditis was caused only by GPB (GPB: 23, 16.5% vs. GNB: 0, 0.0%, p = 0.046). Methicillin-susceptible Staphylococcus aureus was the most frequently isolated strain (MSSA: n = 100, 53.5%), occurred more frequently in the cervical spine compared to other bacteria (OB) (MSSA: 41, 41.0% vs. OB: 18, 20.7%, p = 0.004) and was most frequently detected in patients with skin infection as the primary source of infection (MSSA: 26, 40.6% vs. OB: 11, 16.7%, p = 0.002). Streptococcus spp. and Enterococcus spp. (SE: n = 31, 16.6%) were more often regarded as the cause of endocarditis (SE: 8, 27.6% vs. OB: 15, 11.4%, p = 0.037) and were less frequently detected in intraoperative specimens (SE: 19, 61.3% vs. OB: 138, 88.5%, p < 0.001). Enterobacterales (E: n = 20, 10.7%) were identified more frequently in urinary tract infections (E: 9, 50.0% vs. OB: 4, 3.6%, p < 0.001). Coagulase-negative Staphylococci (CoNS: n = 20, 10.7%) were characterized by a lower prevalence of sepsis (CoNS: 4, 20.0% vs. OB: 90, 53.9%, p = 0.004) and were more frequently detected in intraoperative specimens (CoNS: 20, 100. 0% vs. OB: 137, 82.0%, p = 0.048). Moreover, CoNS-associated cases showed a shorter length of ICU stay (CoNS: 2 [1-18] days vs. OB: 6 [1-53] days, median [interquartile range], p = 0.037), and occurred more frequently due to foreign body-associated infections (CoNS: 8, 61.5% vs. OB: 15, 12.8%, p = 0.008). The presence of methicillin-resistant Staphylococcus aureus (MRSA) prolonged hospital stay by 56 [24-58] days and ICU stay by 16 [1-44] days, whereas patients with Pseudomonas aeruginosa spent only 20 [18-29] days in the hospital and no day in the ICU 0 [0-5] days. CONCLUSIONS: Our retrospective cohort study identified distinct bacterial-specific manifestations in pyogenic SD and ISEE regarding clinical course, neuroanatomic targets, method of pathogen detection, and sources of infection. The clinico-microbiological patterns varied depending on the specific pathogens.

Genetic characterization and mutational profiling of foramen magnum meningiomas: a multi-institutional study.

OBJECTIVE: Foramen magnum (FM) meningiomas pose significant surgical challenges and have high morbidity and mortality rates. This study aimed to investigate the distribution of clinically actionable mutations in FM meningiomas and identify clinical characteristics associated with specific mutational profiles. METHODS: The authors conducted targeted next-generation sequencing of 62 FM meningiomas from three international institutions, covering all relevant meningioma genes (AKT1, KLF4, NF2, POLR2A, PIK3CA, SMO, TERT promoter, and TRAF7). Patients with a radiation-induced meningioma or neurofibromatosis type 2 (NF2) were excluded from the study. Additionally, patient and tumor characteristics, including age, sex, radiological features, and tumor location, were retrospectively collected and evaluated. RESULTS: The study cohort consisted of 46 female and 16 male patients. Clinically significant driver mutations were detected in 58 patients (93.5%). The most commonly observed alteration was TRAF7 mutations (26, 41.9%), followed by AKT1E17K mutations (19, 30.6%). Both mutations were significantly associated with an anterolateral tumor location relative to the brainstem (p = 0.0078). NF2 mutations were present in 11 cases (17.7%) and were associated with posterior tumor location, in contrast to tumors with TRAF7 and AKT1E17K mutations. Other common mutations in FM meningiomas included POLR2A mutations (8, 12.9%; 6 POLR2AQ403K and 2 POLR2AH439_L440del), KLF4K409Q mutations (7, 11.3%), and PIK3CA mutations (4, 6.5%; 2 PIK3CAH1047R and 2 PIK3CAE545K). POLR2A and KLF4 mutations exclusively occurred in female patients and showed no significant association with specific tumor locations. All tumors harboring AKT1E17K and POLR2A mutations displayed meningothelial histology. Ten tumors exhibited intratumoral calcification, which was significantly more frequent in NF2-mutant compared with AKT1-mutant FM meningiomas (p = 0.047). CONCLUSIONS: These findings provide important insights into the molecular genetics and clinicopathological characteristics of FM meningiomas. The identification of specific genetic alterations associated with tumor location, volume, calcification, histology, and sex at diagnosis may have implications for personalized treatment strategies in the future.

Development of a bleeding scale and hemostasis algorithm in cranial neurosurgery.

Effective hemostasis is crucial in neurosurgery as anatomical and functional considerations reduce tolerance for any bleeding. The classification of bleeding severities is a necessary step to enable neurosurgeons to counteract bleeding during surgery. Even though bleeding scales are used for a variety of surgical specialties, they cannot be transferred to cranial neurosurgery without adaption, and no consensus on the nature of such a classification exists to date. Moreover, there is plethora of topical hemostasis products with diverse mechanisms of action and application available. Clinical studies investigating those products used in neurosurgery did not define standardized procedures. This article demonstrates the systematic establishment of both a bleeding scale and a hemostasis algorithm to close this gap in the assessment of intracranial bleeding. The expert panel consisting of 7 members from different neurosurgical centers developed a qualitative bleeding scale with the peculiarities of neurosurgical procedures, based on the experience of each member in daily practice. The hemostasis algorithm is a recommendation for neurosurgeons to aid in the decision-making process to control any sort of bleeding, taking into account the rational use of available hemostatics, depending on type and location of bleeding, as well as the mechanism of action of such agents. Effectiveness of hemostasis, surgery times and economic costs can be optimized by applying the algorithm in daily practice.

Diagnostics, Management, and Outcomes in Patients with Pyogenic Spinal Intra- or Epidural Abscess.

BACKGROUND: Owing to the lack of evidence on the diagnostics, clinical course, treatment, and outcomes of patients with extremely rare spinal intradural abscess (SIA) and spinal epidural abscess (SEA), we retrospectively analyzed and compared a cohort of patients to determine the phenotyping of both entities. METHODS: Over a period of 20 years, we retrospectively analyzed the electronic medical records of 78 patients with SIA and SEA. RESULTS: The patients with SIA showed worse motor scores (MS scores) on admission (SIA: 20 ± 26 vs. SEA: 75 ± 34, p < 0.001), more often with an ataxic gait (SIA: 100% vs. SEA: 31.8%, p < 0.001), and more frequent bladder or bowel dysfunction (SIA: 91.7% vs. SEA: 27.3%, p < 0.001) compared to the SEA patients. Intraoperative specimens showed a higher diagnostic sensitivity in the SEA patients than the SIA patients (SIA: 66.7% vs. SEA: 95.2%, p = 0.024), but various pathogens such as Staphylococcus aureus (SIA 33.3% vs. SEA: 69.4%) and Streptococci and Enterococci (SIA 33.3% vs. SEA: 8.1%, p = 0.038) were detected in both entities. The patients with SIA developed sepsis more often (SIA: 75.0% vs. SEA: 18.2%, p < 0.001), septic embolism (SIA: 33.3% vs. SEA: 8.3%, p = 0.043), signs of meningism (SIA: 100% vs. 18.5%, p < 0.001), ventriculitis or cerebral abscesses (SIA: 41.7% vs. SEA: 3.0%, p < 0.001), and pneumonia (SIA: 58.3% vs. SEA: 13.6%, p = 0.002). The mean MS score improved in both patient groups after surgery (SIA: 20 to 35 vs. SEA: 75 to 90); however, the SIA patients showed a poorer MS score at discharge (SIA: 35 ± 44 vs. SEA: 90 ± 20, p < 0.001). C-reactive protein (CrP) (SIA: 159 to 49 vs. SEA: 189 to 27) and leukocyte count (SIA: 15 to 9 vs. SEA: 14 to 7) were reduced at discharge. The SIA patients had higher rates of disease-related mortality (SIA: 33.3% vs. SEA: 1.5%, p = 0.002), had more pleural empyema (SIA: 58.3% vs. SEA: 13.6%, p = 0.002), required more than one surgery (SIA: 33.3% vs. SEA 13.6%, p = 0.009), were treated longer with intravenous antibiotics (7 ± 4 w vs. 3 ± 2 w, p < 0.001) and antibiotics overall (12 ± 10 w vs. 7 ± 3 w, p = 0.022), and spent more time in the hospital (SIA: 58 ± 36 vs. SEA: 26 ± 20, p < 0.001) and in the intensive care unit (SIA: 14 ± 18 vs. SEA: 4 ± 8, p = 0.002). CONCLUSIONS: Our study highlighted distinct clinical phenotypes and outcomes between both entities, with SIA patients displaying a markedly less favorable disease course in terms of complications and outcomes.

Tracking cell turnover in human brain using 15N-thymidine imaging mass spectrometry.

Microcephaly is often caused by an impairment of the generation of neurons in the brain, a process referred to as neurogenesis. While most neurogenesis in mammals occurs during brain development, it thought to continue to take place through adulthood in selected regions of the mammalian brain, notably the hippocampus. However, the generality of neurogenesis in the adult brain has been controversial. While studies in mice and rats have provided compelling evidence for neurogenesis occurring in the adult rodent hippocampus, the lack of applicability in humans of key methods to demonstrate neurogenesis has led to an intense debate about the existence and, in particular, the magnitude of neurogenesis in the adult human brain. Here, we demonstrate the applicability of a powerful method to address this debate, that is, the in vivo labeling of adult human patients with 15N-thymidine, a non-hazardous form of thymidine, an approach without any clinical harm or ethical concerns. 15N-thymidine incorporation into newly synthesized DNA of specific cells was quantified at the single-cell level with subcellular resolution by Multiple-isotype imaging mass spectrometry (MIMS) of brain tissue resected for medical reasons. Two adult human patients, a glioblastoma patient and a patient with drug-refractory right temporal lobe epilepsy, were infused for 24 h with 15N-thymidine. Detection of 15N-positive leukocyte nuclei in blood samples from these patients confirmed previous findings by others and demonstrated the appropriateness of this approach to search for the generation of new cells in the adult human brain. 15N-positive neural cells were easily identified in the glioblastoma tissue sample, and the range of the 15N signal suggested that cells that underwent S-phase fully or partially during the 24 h in vivo labeling period, as well as cells generated therefrom, were detected. In contrast, within the hippocampus tissue resected from the epilepsy patient, none of the 2,000 dentate gyrus neurons analyzed was positive for 15N-thymidine uptake, consistent with the notion that the rate of neurogenesis in the adult human hippocampus is rather low. Of note, the likelihood of detecting neurogenesis was reduced because of (i) the low number of cells analyzed, (ii) the fact that hippocampal tissue was explored that may have had reduced neurogenesis due to epilepsy, and (iii) the labeling period of 24 h which may have been too short to capture quiescent neural stem cells. Yet, overall, our approach to enrich NeuN-labeled neuronal nuclei by FACS prior to MIMS analysis provides a promising strategy to quantify even low rates of neurogenesis in the adult human hippocampus after in vivo15N-thymidine infusion. From a general point of view and regarding future perspectives, the in vivo labeling of humans with 15N-thymidine followed by MIMS analysis of brain tissue constitutes a novel approach to study mitotically active cells and their progeny in the brain, and thus allows a broad spectrum of studies of brain physiology and pathology, including microcephaly.

The Efficacy of Daily Local Antibiotic Lavage via an Epidural Suction-Irrigation Drainage Technique in Spondylodiscitis and Isolated Spinal Epidural Empyema: A 20-Year Experience of a Single Spine Center.

BACKGROUND: Various treatment modalities are available for local antibiotic therapy in spondylodiscitis (SD) and isolated spinal epidural empyema (ISEE), but there is no evidence-based recommendation. Postoperative epidural suction-irrigation drainage (ESID) is thought to reduce bacterial load, which may prevent the development of relapse, wound healing, hematogenous spread, and systemic complications. We evaluated the efficacy of postoperative ESID over 20 years on disease progression and outcome in SD and ISEE. METHODS: Detailed demographic, clinical, imaging, laboratory, and microbiological characteristics were examined in our cohorts of 208 SD and ISEE patients treated with and without ESID at a university spine center in Germany between 2002 and 2022. Between-group comparisons were performed to identify meaningful differences for the procedure. RESULTS: We included data from 208 patients (142 SD, 68.3% vs. 66 ISEE, 31.7%) of whom 146 were ESID patients (87 SD, 59.6% vs. 59 ISEE, 40.4%) and 62 were NON-ESID patients (55 SD, 88.7% vs. 7 ISEE, 11.3%). ESID patients with SD showed more frequent SSI (ESID: 22, 25.3% vs. NON-ESID: 3, 5.5%, p = 0.003), reoperations due to empyema persistence or instability (ESID: 37, 42.5% vs. NON-ESID: 12, 21.8%, p = 0.012), and a higher relapse rate (ESID: 21, 37.5% vs. NON-ESID: 6, 16.7%, p = 0.037) than NON-ESID patients with SD. The success rate in NON-ESID patients with SD was higher than in ESID patients with SD (ESID: 26, 29.9% vs. NON-ESID: 36, 65.6%, p < 0.001). Multivariate binary logistic regression analysis showed that ESID therapy (p < 0.001; OR: 0.201; 95% CI: 0.089-0.451) was a significant independent risk factor for treatment failure in patients with SD. CONCLUSIONS: Our retrospective cohort study with more than 20 years of experience in ESID technique shows a negative effect in patients with SD in terms of surgical site infections and relapse rate.

Diagnostic Sensitivity of Blood Culture, Intraoperative Specimen, and Computed Tomography-Guided Biopsy in Patients with Spondylodiscitis and Isolated Spinal Epidural Empyema Requiring Surgical Treatment.

BACKGROUND: the successful treatment of spondylodiscitis (SD) and isolated spinal epidural empyema (ISEE) depends on early detection of causative pathogens, which is commonly performed either via blood cultures, intraoperative specimens, and/or image-guided biopsies. We evaluated the diagnostic sensitivity of these three procedures and assessed how it is influenced by antibiotics. METHODS: we retrospectively analyzed data from patients with SD and ISEE treated surgically at a neurosurgery university center in Germany between 2002 and 2021. RESULTS: we included 208 patients (68 [23-90] years, 34.6% females, 68% SD). Pathogens were identified in 192 cases (92.3%), including 187 (97.4%) pyogenic and five (2.6%) non-pyogenic infections, with Gram-positive bacteria accounting for 86.6% (162 cases) and Gram-negative for 13.4% (25 cases) of the pyogenic infections. The diagnostic sensitivity was highest for intraoperative specimens at 77.9% (162/208, p = 0.012) and lowest for blood cultures at 57.2% (119/208) and computed tomography (CT)-guided biopsies at 55.7% (39/70). Blood cultures displayed the highest sensitivity in SD patients (SD: 91/142, 64.1% vs. ISEE: 28/66, 42.4%, p = 0.004), while intraoperative specimens were the most sensitive procedure in ISEE (SD: 102/142, 71.8% vs. ISEE: 59/66, 89.4%, p = 0.007). The diagnostic sensitivity was lower in SD patients with ongoing empiric antibiotic therapy (EAT) than in patients treated postoperatively with targeted antibiotic therapy (TAT) (EAT: 77/89, 86.5% vs. TAT: 53/53, 100%, p = 0.004), whereas no effect was observed in patients with ISEE (EAT: 47/51, 92.2% vs. TAT: 15/15, 100%, p = 0.567). CONCLUSIONS: in our cohort, intraoperative specimens displayed the highest diagnostic sensitivity especially for ISEE, whereas blood cultures appear to be the most sensitive for SD. The sensitivity of these tests seems modifiable by preoperative EAT in patients with SD, but not in those with ISEE, underscoring the distinct differences between both pathologies.

The impact of concomitant infective endocarditis in patients with spondylodiscitis and isolated spinal epidural empyema and the diagnostic accuracy of the modified duke criteria.

Background: The co-occurrence of infective endocarditis (IE) and primary spinal infections (PSI) like spondylodiscitis (SD) and isolated spinal epidural empyema (ISEE) has been reported in up to 30% of cases and represents a life-threatening infection that requires multidisciplinary management to be successful. Therefore, we aimed to characterize the clinical phenotypes of PSI patients with concomitant IE and furthermore to assess the accuracy of the modified Duke criteria in this specific population. Methods: We conducted a retrospective cohort study in consecutive SD and ISEE patients treated surgically at our University Spine Center between 2002 and 2022 who have undergone detailed phenotyping comprising demographic, clinical, imaging, laboratory, and microbiologic assessment. Comparisons were performed between PSI patients with IE (PSICIE) and without IE (PSIWIE) to identify essential differences. Results: Methicillin-susceptible Staphylococcus aureus (MSSA) was the most common causative pathogen in PSICIE group (13 patients, 54.2%) and aortic valve IE was the most common type of IE (12 patients, 50%), followed by mitral valve IE (5 patients, 20.8%). Hepatic cirrhosis (p < 0.011; OR: 4.383; 95% CI: 1.405-13.671), septic embolism (p < 0.005; OR: 4.387; 95% CI: 1.555-12.380), and infection with Streptococcus spp. and Enterococcus spp. (p < 0.003; OR: 13.830; 95% CI: 2.454-77.929) were identified as significant independent risk factors for the co-occurrence of IE and PSI in our cohort. The modified Duke criteria demonstrated a sensitivity of 100% and a specificity of 66.7% for the detection of IE in PSI patients. Pathogens were detected more frequently via blood cultures in the PSICIE group than in the PSIWIE group (PSICIE: 23, 95.8% vs. PSIWIE: 88, 62.4%, p < 0.001). Hepatic cirrhosis (PSICIE: 10, 41.7% vs. PSIWIE: 33, 21.6%, p = 0.042), pleural abscess (PSICIE: 9, 37.5% vs. PSIWIE: 25, 16.3%, p = 0.024), sepsis (PSICIE: 20, 83.3% vs. PSIWIE: 67, 43.8%, p < 0.001), septic embolism (PSICIE: 16/23, 69.6% vs. PSIWIE: 37/134, 27. 6%, p < 0.001) and meningism (PSICIE: 8/23, 34.8% vs. PSIWIE: 21/152, 13.8%, p = 0.030) occurred more frequently in PSICIE than in PSIWIE patients. PSICIE patients received longer intravenous antibiotic therapy (PSICIE: 6 [4-7] w vs. PSIWIE: 4 [2.5-6] w, p < 0.001) and prolonged total antibiotic therapy overall (PSICIE: 11 [7.75-12] w vs. PSIWIE: 8 [6-12] w, p = 0.014). PSICIE patients spent more time in the hospital than PSIWIE (PSICIE: 43.5 [33.5-53.5] days vs. PSIWIE: 31 [22-44] days, p = 0.003). Conclusions: We report distinct clinical, radiological, and microbiological phenotypes in PSICIE and PSIWIE patients and further demonstrate the diagnostic accuracy of the modified Duke criteria in patients with PSI and concomitant IE. In the high-risk population of PSI patients, the modified Duke criteria might benefit from amending pleural abscess, meningism, and sepsis as minor criteria and hepatic cirrhosis as major criterion.

Beyond Functional Impairment: Redefining Favorable Outcome in Patients with Subarachnoid Hemorrhage.

BACKGROUND: For outcome assessment in patients surviving subarachnoid hemorrhage (SAH), the modified Rankin scale (mRS) represents the mostly established outcome tool, whereas other dimensions of outcome such as mood disorders and impairments in social life remain unattended so far. OBJECTIVE: The aim of our study was to correlate 12-month functional and subjective health outcomes in SAH survivors. METHODS: All SAH patients treated over a 5-year period received outcome assessment at 12 months, including functional scores (mRS and Barthel Index [BI]), subjective health measurement (EQ-5D), and whether they returned to work. Analyses - including utility-weighted mRS - were conducted to detect associations and correlations among different outcome measures, especially in patients achieving good functional outcome (i.e., mRS 0-2) at 12 months. RESULTS: Of 351 SAH survivors, 287 (81.2%) achieved favorable functional outcome at 12 months. Contrary to the BI, the EQ-5D visual analog scale (VAS) showed a strong association with different mRS grades, accentuated in patients with favorable functional outcome. Despite favorable functional outcome, patients reported a high rate of impairments in activities (24.0%), pain (33.4%), and anxiety/depression (42.5%). Further, multivariable analysis revealed (i) impairments in activities (odds ratio [OR] [95% confidence interval {CI}]: 0.872 [0.817-0.930]), (ii) presence of depression or anxiety (OR [95% CI]: 0.836 [0.760-0.920]), and (iii) return to work (OR [95% CI]: 1.102 [0.1.013-1.198]) to be independently associated with self-reported subjective health. CONCLUSION: Established stroke scores mainly focusing on functional outcomes do poorly reflect the high rate of subjective impairments reported in SAH survivors, specifically in those achieving good functional outcome. Further studies are needed to investigate whether psychoeducational approaches aiming at improving coping mechanisms and perceived self-efficacy may result in higher subjective health in these patients.

Parenchymatous hematoma in patients with atraumatic subarachnoid hemorrhage: Characteristics, treatment, and clinical outcomes.

BACKGROUND: Data regarding the influence of concomitant parenchymatous hematoma (PH) on long-term outcomes in patients with atraumatic subarachnoid hemorrhage (SAH) are scarce. Further, it is not established if these patients benefit from surgical intervention. AIM: The aim of this study was to determine the influence of concomitant PH in SAH patients on functional long-term outcome, and whether these patients may benefit from surgical hematoma evacuation. METHODS: Over a 5-year period, all consecutive patients with SAH treated at the Departments of Neurology, Neuroradiology, and Neurosurgery, at the University Hospital Erlangen (Germany) were recorded. In addition to the clinical and imaging characteristics of SAH, we documented the presence, location, and volume of PH as well as treatment parameters. Outcome assessment at 12 months included functional outcome (modified Rankin scale (mRS), favorable = 0-2), health-related quality of life, and long-term complications. For outcome analysis, a propensity score matching (ratio 1:1, caliper 0.1) was performed to compare SAH patients with and without PH. Sub-analyses were performed regarding PH treatment (surgical evacuation vs. conservative). RESULTS: A total of 494 patients with atraumatic SAH were available. Eighty-five (17.2%) had PH on initial imaging. SAH patients with PH had a worse clinical condition on admission and had a greater extent of subarachnoid/intraventricular hemorrhage. Median PH volume was 11.0 ml (5.4-31.8) with largest volumes observed in patients with ruptured middle cerebral artery (MCA)-aneurysm (31.7 ml (16.3-43.2)). After propensity-score matching (PSM), patients with PH had worse functional outcomes at 12 months (modified Rankin scale (mRS) 0-2: PH 31.8% vs. ØPH57.7% p < 0.001), and a lower rate of self-reported health compared to patients without PH (EQ-5D VAS: PH 50(30-70) vs. ØPH 80(65-95); p < 0.001). In PH patients, surgical evacuation was associated with a higher rate of favorable outcome at 12 months compared to those treated conservatively (surgery 14/28 (50.0%) vs. conservative 14/57 (24.6%); adjusted odds-ratio (OR; 95%CI): 1.34 (1.08-1.66); p = 0.001), irrespective of aneurysm location. Subgroup-analysis revealed positive associations of surgical hematoma evacuation with outcome in subgroups with larger PH volumes (>10 ml; OR (95%CI): 1.39 (1.09-1.79)), frontal PH location (OR 1.59 (1.14-2.23)), and early surgery (within 600 min after onset; OR 1.42 (1.03-1.94)). CONCLUSIONS: Concomitant PH occurs frequently in patients with SAH and is associated with functional impairment after 1 year. Surgical evacuation of PH may improve outcomes in these patients, irrespective of aneurysm-location.

Long-Term Complications and Influence on Outcome in Patients Surviving Spontaneous Subarachnoid Hemorrhage.

BACKGROUND: While the short-term clinical outcome of patients with subarachnoid hemorrhage (SAH) is well described, there are limited data on long-term complications and their impact on social reintegration. This study aimed to assess the frequency of complications post-SAH and to investigate whether these complications attribute to functional and self-reported outcomes as well as the ability to return to work in these patients. METHODS: This retrospective single-center study included patients with atraumatic SAH over a 5-year period at a tertiary care center. Patients received a clinical follow-up for 12 months. In addition to demographics, imaging data, and parameters of acute treatment, the rate and extent of long-term complications after SAH were recorded. The functional outcome was assessed using the modified Rankin Scale (mRS; favorable outcome defined as mRS = 0-2). Further outcomes comprised self-reported subjective health measured by the EQ-5D and return to work for SAH patients with appropriate age. Multivariable analyses including in-hospital parameters and long-term complications were conducted to identify parameters independently associated with outcomes in SAH survivors. RESULTS: This study cohort consisted of 505 SAH patients of whom 405 survived the follow-up period of 12 months (i.e., mortality rate of 19.8%). Outcome data were available in 359/405 (88.6%) patients surviving SAH. At 12 months, a favorable functional outcome was achieved in 287/359 (79.9%) and 145/251 (57.8%) SAH patients returned to work. The rates of post-acute complications were headache (32.3%), chronic hydrocephalus requiring permanent ventriculoperitoneal shunting (VP shunt 25.4%) and epileptic seizures (9.5%). Despite patient's and clinical characteristics, both presence of epilepsy and need for VP shunt were independently and negatively associated with a favorable functional outcome (epilepsy: adjusted odds ratio [aOR] (95% confidence interval [95% CI]): 0.125 [0.050-0.315]; VP shunt: 0.279 [0.132-0.588]; both p < 0.001) as well as with return to work (aOR [95% CI]: epilepsy 0.195 [0.065-0.584], p = 0.003; VP shunt 0.412 [0.188-0.903], p = 0.027). Multivariable analyses revealed presence of headache, VP shunt, or epilepsy to be significantly related to subjective health impairment (aOR [95% CI]: headache 0.248 [0.143-0.430]; epilepsy 0.223 [0.085-0.585]; VP shunt 0.434 [0.231-0.816]; all p < 0.01). CONCLUSIONS: Long-term complications occur frequently after SAH and are associated with an impairment of functional and social outcomes. Further studies are warranted to investigate if treatment strategies specifically targeting these complications, including preventive aspects, may improve the outcomes after SAH.

Neutrophil-to-lymphocyte ratio as an independent predictor for unfavorable functional outcome in aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Stroke-associated immunosuppression and inflammation are increasingly recognized as factors triggering infections and thus potentially influencing outcome after stroke. Several studies have demonstrated that elevated neutrophil-to-lymphocyte ratio (NLR) is a significant predictor of adverse outcomes for patients with ischemic stroke or intracerebral hemorrhage. Thus far, in patients with subarachnoid hemorrhage the association between NLR and outcome is insufficiently established. The authors sought to investigate the association between NLR on admission and functional outcome in aneurysmal subarachnoid hemorrhage (aSAH). METHODS: This observational study included all consecutive aSAH patients admitted to a German tertiary center over a 5-year period (2008-2012). Data regarding patient demographics and clinical, laboratory, and in-hospital measures, as well as neuroradiological data, were retrieved from institutional databases. Functional outcome was assessed at 3 and 12 months using the modified Rankin Scale (mRS) score and categorized into favorable (mRS score 0-2) and unfavorable (mRS score 3-6). Patients' radiological and laboratory characteristics were compared between aSAH patients with favorable and those with unfavorable outcome at 3 months. In addition, multivariate analysis was conducted to investigate parameters independently associated with favorable outcome. Receiver operating characteristic (ROC) curve analysis was undertaken to identify the best cutoff for NLR to discriminate between favorable and unfavorable outcome in these patients. To account for imbalances in baseline characteristics, propensity score matching was carried out to assess the influence of NLR on outcome measures. RESULTS: Overall, 319 patients with aSAH were included. Patients with unfavorable outcome at 3 months were older, had worse clinical status on admission (Glasgow Coma Scale score and Hunt and Hess grade), greater amount of subarachnoidal and intraventricular hemorrhage (modified Fisher Scale grade and Graeb score), and higher rates of infectious complications (pneumonia and sepsis). A significantly higher NLR on admission was observed in patients with unfavorable outcome according to mRS score (median [IQR] NLR 5.8 [3.0-10.0] for mRS score 0-2 vs NLR 8.3 [4.5-12.6] for mRS score 3-6; p < 0.001). After adjustments, NLR on admission remained a significant predictor for unfavorable outcome in SAH patients (OR [95% CI] 1.014 [1.001-1.027]; p = 0.028). In ROC analysis, an NLR of 7.05 was identified as the best cutoff value to discriminate between favorable and unfavorable outcome (area under the curve = 0.614, p < 0.001, Youden's index = 0.211; mRS score 3-6: 94/153 [61.4%] for NLR ≥ 7.05 vs 67/166 [40.4%] for NLR < 7.05; p < 0.001). Subanalysis of patients with NLR levels ≥ 7.05 vs < 7.05, performed using 2 propensity score-matched cohorts (n = 133 patients in each group), revealed an increased proportion of patients with unfavorable functional outcome at 3 months in patients with NLR ≥ 7.05 (mRS score 3-6 at 3 months: NLR ≥ 7.05 82/133 [61.7%] vs NLR < 7.05 62/133 [46.6%]; p = 0.014), yet without differences in mortality at 3 months (NLR ≥ 7.05 37/133 [27.8%] vs NLR < 7.05 27/133 [20.3%]; p = 0.131). CONCLUSIONS: Among aSAH patients, NLR represents an independent parameter associated with unfavorable functional outcome. Whether the impact of NLR on functional outcome is related to preexisting comorbidities or represents independent causal relationships in the context of stroke-associated immunosuppression should be investigated in future studies.

Initiating anticoagulant therapy after ICH is associated with patient characteristics and treatment recommendations.

BACKGROUND: The proportion of patients with intracerebral hemorrhage (ICH) and concomitant indication for oral anticoagulant (OAC) therapy is increasing. Although recent studies documented a favorable risk-benefit profile of OAC initiation, deciding whether, when, and which OAC should be started remains controversial. We investigated (1) OAC recommendations, its implementation, and adherence and (2) factors associated with OAC initiation after ICH. METHODS: This prospective observational study analyzed consecutive ICH patients (n = 246) treated at the neurological and neurosurgical department of the University-Hospital Erlangen, Germany over a 21-month inclusion period (05/2013-01/2015). We analyzed the influence of patient characteristics, in-hospital measures, and functional status on treatment recommendations and on OAC initiation during 12-month follow-up. RESULTS: In-hospital mortality of 24.8% (n = 61/246) left 185 patients discharged alive of which 34.1% (n = 63/185) had OAC indication. In these patients, OAC initiation was clearly recommended in only 49.2% (n = 31/63) and associated with favorable [modified Rankin Scale (mRS) = 0-3] functional discharge status [OR 7.18, CI (1.05-49.13), p = 0.04], less frequent heart failure [OR 0.19, CI (0.05-0.71), p = 0.01], and younger age [OR 0.95, CI (0.90-1.00), p = 0.05]. OAC was more often started if clearly recommended [n = 19/31 (61.3%) versus (no recommendation) n = 4/26 (15.4%), p < 0.001; (clearly not recommended, n = 6)] and associated with younger age [67 (58-74) versus 79 (73-83), p < 0.001], favorable functional outcome [n = 10/23 (43.5%) versus n = 5/40 (12.5%), p = 0.01], decreased mortality [n = 6/23 (26.1%) versus n = 19/40 (47.5%), p = 0.06], and functional improvement [n = 13/17 (76.5%) versus n = 7/21 (33.3%), p = 0.01]. We observed no differences in rates of intracranial complications [thromboembolism, n = 3/23 (13.0%) versus n = 4/40 (10.0%), p = 1.00; hemorrhage, n = 1/23 (4.3%) versus n = 3/40 (7.5%), p = 1.00]. CONCLUSIONS: Clear treatment recommendations by attending stroke physicians significantly influence OAC initiation after ICH. OAC were more frequently recommended and started in younger patients with better functional recovery independent from intracranial complications. This might represent an important determinant of observed beneficial associations, hinting towards an indication bias which might affect observational analyses.

Meningioma growth dynamics assessed by radiocarbon retrospective birth dating.

It is not known how long it takes from the initial neoplastic transformation of a cell to the detection of a tumor, which would be valuable for understanding tumor growth dynamics. Meningiomas show a broad histological, genetic and clinical spectrum, are usually benign and considered slowly growing. There is an intense debate regarding their age and growth pattern and when meningiomas should be resected. We have assessed the age and growth dynamics of 14 patients with meningiomas (WHO grade I: n=6 with meningothelial and n=6 with fibrous subtype, as well as n=2 atypical WHO grade II meningiomas) by combining retrospective birth-dating of cells by analyzing incorporation of nuclear-bomb-test-derived 14C, analysis of cell proliferation, cell density, MRI imaging and mathematical modeling. We provide an integrated model of the growth dynamics of benign meningiomas. The mean age of WHO grade I meningiomas was 22.1±6.5years, whereas atypical WHO grade II meningiomas originated 1.5±0.1years prior to surgery (p<0.01). We conclude that WHO grade I meningiomas are very slowly growing brain tumors, which are resected in average two decades after time of origination.

The oxido-metabolic driver ATF4 enhances temozolamide chemo-resistance in human gliomas.

Malignant gliomas are devastating neoplasia with limited curative treatment options. Temozolomide (TMZ, Temcat®, Temodal® or Temodar®) is a first-line treatment for malignant gliomas but the development of drug resistance remains a major concern. Activating transcription factor 4 (ATF4) is a critical oxido-metabolic regulator in gliomas, and its role in the pathogenesis of TMZ-resistance remains elusive. We investigated the effect of TMZ on human glioma cells under conditions of enhanced ATF4 expression (ATF4OE) and ATF4 knock down (ATF4KD). We monitored cell survival, ATF4 mRNA expression of ATF4 and xCT (SLC7a11) regulation within human gliomas. TMZ treatment induces a transcriptional response with elevated expression of ATF4, xCT and Nrf2, as a sign of ER stress and toxic cell damage response. ATF4 overexpression (ATF4OE) fosters TMZ resistance in human gliomas and inhibits TMZ-induced autophagy. Conversely, ATF4 suppression by small interfering RNAs (ATF4KD) leads to increased TMZ susceptibility and autophagy in comparison to wild type gliomas. ATF4OE gliomas show reduced cell cycle shift and apoptotic cell death, whereas ATF4KD gliomas reveal higher susceptibility towards cell cycle rearrangements. Hence, the migration capacity of ATF4OE glioma cells is almost not affected by TMZ treatment. In contrast, ATF4KD gliomas show a migratory stop following TMZ application. Mechanistically, xCT elevation is a consequence of ATF4 activation and increased levels of xCT amplifies ATF4-induced TMZ resistance. Our data show that ATF4 operates as a chemo-resistance gene in gliomas, and the tumor promoting function of ATF4 is mainly determined by its transcriptional target xCT. Therefore, therapeutic inactivation of ATF4 can be a promising strategy to overcome chemo-resistance and promote drug efficacy in human gliomas.

Intraoperative Vascular Neuromonitoring in Patients with Subarachnoid Hemorrhage: A Pilot Study Using Combined Laser-Doppler Spectrophotometry.

BACKGROUND: Intraoperative monitoring of cerebral microcirculation in patients with subarachnoid hemorrhage (SAH) may predict the postoperative neurologic outcome. In this pilot study, we examined the value of a novel noninvasive real-time measurement technique for detecting changes in local microcirculation. METHODS: We used the O2C (Oxygen to see) laser-Doppler spectrophotometry system in 14 patients with Hunt & Hess grade 2-5 SAH who underwent microsurgical cerebral aneurysm clipping. A subdural probe recorded capillary venous oxygenation (SO2), relative hemoglobin concentration, blood cell velocity, and blood flow at a tissue depth of 7 mm. Data were recorded immediately before dural closure. We also recorded somatosensory evoked potentials (SEPs) with median and tibial nerve stimulation. Results were compared with neurologic performance, as measured on the modified Rankin Scale, at the day of discharge from the hospital and 12 months thereafter. RESULTS: Patient functional outcomes after discharge and 12 months were correlated with pathological decreased flow and increased SO2 values. In 6 of 8 patients, microcirculatory monitoring parameters indicated ischemia during surgery, as shown by electrophysiological SEP changes and infarction detected on the postoperative computed tomography (CT) scan. Pathological SEP results correlated closely with infarct demarcation as seen on CT. CONCLUSIONS: Our results indicate the potential benefit of intraoperative combined laser-Doppler flowmetry and spectrophotometry for predicting postoperative clinical outcomes in this small patient sample. Larger-cohort testing is needed to verify our findings and show the possible merits of this novel method.