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Introduction: Literature regarding the safety and efficacy of antithrombotic (antiplatelet or anticoagulant) therapy and statins in patients with cavernous malformations (CMs) of the central nervous system is sparse, resulting in uncertainty about its use in clinical practice. The aim of this study was to analyze the impact of antithrombotic therapy and statins on the risk of hemorrhage and focal neurological deficit in patients with CMs. Methods: The authors’ institutional database was screened for all patients with CMs of the central nervous system treated at their institution between 2006 and 2018. Patients with radiological and/or histological diagnosis of CMs, clinical baseline characteristics, available patient’s medication history, and follow-up data were included in this study. Time-to-event probability (hemorrhage or focal neurological deficit) as well as the number of events (hemorrhage or focal neurological deficit) during follow-up were assessed in patients who were categorized according to their medical treatment (antithrombotic therapy, statins, combined therapy, or no treatment). Results: Four hundred twenty-eight patients with CMs were eligible and included in the final analysis. Sixty-nine (16.1%) patients were on long-term antithrombotic therapy and 46 (10.6%) on long-term statins, of whom 31 patients were on a combination of both. The probability of experiencing first hemorrhage or focal neurological deficit was less likely in patients on antiplatelet therapy (HR 0.09, 95% CI 0.021–0.39, p = 0.001), anticoagulant therapy (HR 0.12, 95% CI 0.016–0.85, p = 0.034), or the combination thereof (HR 0.12, 95% CI 0.016–0.93, p = 0.043) compared to patients with no antithrombotic treatment. The number of hemorrhages and focal neurological deficits were significantly lower in patients on antithrombotic therapy compared to patients on no treatment during follow-up. In patients on statins alone, the time-to-event probability was comparable to that of patients on no treatment (HR 0.91, 95% CI 0.438–1.91, p = 0.812), and the number of events was similar to patients on no treatment. Conclusion: The results of our study provide further evidence that antithrombotic therapy alone or in combination with statins in patients with CMs of the central nervous system does not increase the risk of hemorrhage or focal neurological deficit but, on the contrary, may have some benefit.

Many neurological conditions conceal specific anatomical patterns. Their study contributes to the understanding of disease biology and to tailored diagnostics and therapy. Neuroepithelial tumours exhibit distinct anatomical phenotypes and spatiotemporal dynamics that differ from those of other brain tumours. Brain metastases display a preference for the cortico-subcortical boundaries of watershed areas and have a predominantly spherical growth. Primary CNS lymphomas localize to the white matter and generally invade along fibre tracts. In neuroepithelial tumours, topographic probability mapping and unsupervised topological clustering have identified an inherent radial anatomy and adherence to ventriculopial configurations of specific hierarchical orders. Spatiotemporal probability and multivariate survival analyses have identified a temporal and prognostic sequence underlying the anatomical phenotypes of neuroepithelial tumours. Gradual neuroepithelial de-differentiation and declining prognosis follow (i) an expansion into higher order radial units; (ii) a subventricular spread; and (iii) the presence of mesenchymal patterns (expansion along white matter tracts, leptomeningeal or perivascular invasion, CSF spread). While different pathophysiological hypotheses have been proposed, the cellular and molecular mechanisms dictating this anatomical behaviour remain largely unknown. Here we adopt an ontogenetic approach towards the understanding of neuroepithelial tumour anatomy. Contemporary perception of histo- and morphogenetic processes during neurodevelopment permit us to conceptualize the architecture of the brain into hierarchically organized radial units. The anatomical phenotypes in neuroepithelial tumours and their temporal and prognostic sequences share remarkable similarities with the ontogenetic organization of the brain and the anatomical specifications that occur during neurodevelopment. This macroscopic coherence is reinforced by cellular and molecular observations that the initiation of various neuroepithelial tumours, their intratumoural hierarchy and tumour progression are associated with the aberrant reactivation of surprisingly normal ontogenetic programs. Generalizable topological phenotypes could provide the basis for an anatomical refinement of the current classification of neuroepithelial tumours. In addition, we have proposed a staging system for adult-type diffuse gliomas that is based on the prognostically critical steps along the sequence of anatomical tumour progression. Considering the parallels in anatomical behaviour between different neuroepithelial tumours, analogous staging systems may be implemented for other neuroepithelial tumour types and subtypes. Both the anatomical stage of a neuroepithelial tumour and the spatial configuration of its hosting radial unit harbour the potential to stratify treatment decisions at diagnosis and during follow-up. More data on specific neuroepithelial tumour types and subtypes are needed to increase the anatomical granularity in their classification and to determine the clinical impact of stage-adapted and anatomically tailored therapy and surveillance.

The functional neurological outcome of patients with intracerebral hemorrhage (ICH) strongly relates to the degree of secondary brain injury (ICH-SBI) evolving within days after the initial bleeding. Different mechanisms including the incitement of inflammatory pathways, dysfunction of the blood–brain barrier (BBB), activation of resident microglia, and an influx of blood-borne immune cells, have been hypothesized to contribute to ICH-SBI. Yet, the spatiotemporal interplay of specific inflammatory processes within different brain compartments has not been sufficiently characterized, limiting potential therapeutic interventions to prevent and treat ICH-SBI. Using a whole-blood injection model in mice, we systematically characterized the spatial and temporal dynamics of inflammatory processes after ICH using 7-Tesla magnetic resonance imaging (MRI), spatial RNA sequencing (spRNAseq), functional BBB assessment, and immunofluorescence average-intensity-mapping. We identified a pronounced early response of the choroid plexus (CP) peaking at 12 to 24h, that was characterized by inflammatory cytokine expression, epithelial and endothelial expression of leukocyte adhesion molecules, and the accumulation of leukocytes. In contrast, we observed a delayed secondary reaction pattern at the injection site (striatum) peaking at 96h, defined by gene expression corresponding to perilesional leukocyte infiltration and correlating to the delayed signal alteration seen on MRI. Pathway analysis revealed a dependence of the early inflammatory reaction in the CP on toll-like receptor 4 (TLR4) signaling via myeloid differentiation factor 88 (MyD88). TLR4 and MyD88 knockout mice corroborated this observation, lacking the early upregulation of adhesion molecules and leukocyte infiltration within the CP 24h after whole-blood injection. In conclusion, we report a biphasic brain reaction pattern after ICH with a MyD88-TLR4-dependent early inflammatory response of the CP, preceding inflammation, edema and leukocyte infiltration at the lesion site. Pharmacological targeting of the early CP-activation might harbor the potential to modulate the development of ICH-SBI.Graphical abstractAkeret, Buzzi et al. characterized the spatiotemporal dynamics after striatal whole blood injection in mice using magnetic resonance imaging (MRI), spatial RNA sequencing (spRNAseq), functional blood-brain barrier (BBB) assessment, and immunofluorescence average intensity mapping (IF). They report a biphasic brain reaction pattern with an early MyD88-TLR4-dependent inflammatory response of the CP, which preceded secondary inflammation and leukocyte infiltration at the perilesional site.

Background Neurosurgical resection is the mainstay of meningioma treatment. Adverse event (AE) rates of meningioma resections are significant, but preoperative risk factors for major AEs in patients undergoing first-time meningioma surgery are largely unknown. The aim of this study was to explore major AEs and identify preoperative risk factors in patients undergoing first-time meningioma surgery. Methods Data on all meningioma resections performed at the University Hospital Zurich from 1 January 2013 to 31 December 2018 were collected in a prospective registry. All AEs that occurred within 3 months of surgery were documented in detail and classified as “minor” or “major.” Statistical analysis included initial individual bivariate analyses of all preoperative factors and the occurrence of major AEs. Statistically significant variables were then included in a logistic regression model to identify predictors. Results Three hundred forty-five patients were included in the study. Mean age was 58.1 years, and 77.1% of patients were female. The overall major AE rate was 20.6%; the most common of which was a new focal neurological deficit (12.8% of patients). Six preoperative factors showed a significant association with the occurrence of major AEs in bivariate analysis. All variables included in the logistic regression model showed increased odds of occurrence of major AE, but only tumor complexity as measured by the Milan Complexity Scale was a statistically significant predictor, with a score of 4 or more having twice the odds of major AEs (OR: 2.00, 95% CI: 1.15–3.48). Conclusion High tumor complexity is an independent predictor of the occurrence of major AEs following meningioma resection. Preoperative assessment of tumor complexity using the Milan Complexity Scale is warranted and can aid communication with patients about AE rates and surgical decision-making.

Secondary brain injury after aneurysmal subarachnoid hemorrhage (SAH-SBI) is a significant contributor to poor outcomes in patients after rupture of an intracranial aneurysm. The lack of diagnostic biomarkers and novel drug targets represent an unmet need. Prior experimental evidence has suggested cell-free hemoglobin in the cerebrospinal fluid (CSF-Hb) as a pathophysiological driver of SAH-SBI. The aim of this study was to investigate the clinical and pathophysiological association between CSF-Hb and SAH-SBI. We prospectively enrolled 47 consecutive patients and collected daily CSF samples within 14 days after aneurysm rupture. There was very strong evidence for a positive association between CSF-Hb and SAH-SBI. The diagnostic accuracy of CSF-Hb for SAH-SBI markedly exceeded that of established methods (area under the curve: 0.89 [0.85-0.92]). Temporal LC-MS/MS CSF proteomics demonstrated that erythrolysis accompanied by an adaptive macrophage response are the two dominant biological processes occurring in the CSF space after aneurysm rupture. To further investigate the pathophysiology between CSF-Hb and SAH-SBI, we explored the vasoconstrictive and lipid peroxidation activities of Hb ex-vivo. These experiments revealed critical inflection points overlapping CSF-Hb concentration thresholds in patients with SAH-SBI. Selective Hb depletion and in-solution neutralization by the Hb-scavenger haptoglobin or the heme-scavenger hemopexin efficiently attenuated the vasoconstrictive and lipid peroxidation activities of CSF-Hb in patient CSF. Collectively, the clinical association between high CSF-Hb levels and SAH-SBI, the underlying pathophysiological rationale, and the favorable effects of haptoglobin and hemopexin in ex-vivo experiments position CSF-Hb as a highly attractive biomarker and potential drug target.

PurposeCell-free hemoglobin in the cerebrospinal fluid (CSF-Hb) may be one of the main drivers of secondary brain injury after aneurysmal subarachnoid hemorrhage. Haptoglobin scavenging of CSF-Hb has been shown to mitigate cerebrovascular disruption. Using digital subtraction angiography (DSA) and blood oxygenation-level dependent cerebrovascular reactivity imaging (BOLD-CVR) the aim was to assess the acute toxic effect of CSF-Hb on cerebral blood flow and autoregulation, as well as to test the protective effects of haptoglobin.MethodsDSA imaging was performed in eight anesthetized and ventilated sheep (mean weight: 80.4 kg) at baseline, 15, 30, 45 and 60 minutes after infusion of hemoglobin (Hb) or co-infusion with haptoglobin (Hb:Haptoglobin) into the left lateral ventricle. Additionally, 10 ventilated sheep (mean weight: 79.8 kg) underwent BOLD-CVR imaging to assess the cerebrovascular reserve capacity.ResultsDSA imaging did not show a difference in mean transit time or cerebral blood flow. Wholebrain BOLD-CVR compared to baseline decreased more in the Hb group after 15 minutes (Hb vs Hb:Haptoglobin: −0.03 ±0.01 vs −0.01 ±0.02) and remained diminished compared to Hb:Haptoglobin group after 30 minutes (Hb vs Hb:Haptoglobin: −0.03 ±0.01 vs 0.0 ±0.01), 45 minutes (Hb vs Hb:Haptoglobin: −0.03 ±0.01 vs 0.01 ±0.02) and 60 minutes (Hb vs Hb:Haptoglobin: −0.03 ±0.02 vs 0.01 ±0.01).ConclusionIt is demonstrated that CSF-Hb toxicity leads to rapid cerebrovascular reactivity impairment, which is blunted by haptoglobin co-infusion. BOLD-CVR may therefore be further evaluated as a monitoring strategy for CSF-Hb toxicity after aSAH.

BackgroundThe current WHO classification integrates histological and molecular features of brain tumors. The aim of this study was to identify generalizable topological patterns with the potential to add an anatomical dimension to the classification of brain tumors.MethodsWe applied non-negative matrix factorization as an unsupervised pattern discovery strategy to the fine-grained topographic tumor profiles of 936 patients with primary and secondary brain tumors. From the anatomical features alone, this machine learning algorithm enabled the extraction of latent topological tumor patterns, termed meta-topologies. The optimal parts-based representation was automatically determined in 10,000 split-half iterations. We further characterized each meta-topology’s unique histopathologic profile and survival probability, thus linking important biological and clinical information to the underlying anatomical patternsResultsIn primary brain tumors, six meta-topologies were extracted, each detailing a transpallial pattern with distinct parenchymal and ventricular compositions. We identified one infratentorial, one allopallial, three neopallial (parieto-occipital, frontal, temporal) and one unisegmental meta-topology. Each meta-topology mapped to distinct histopathologic and molecular profiles. The unisegmental meta-topology showed the strongest anatomical-clinical link demonstrating a survival advantage in histologically identical tumors. Brain metastases separated to an infra- and supratentorial meta-topology with anatomical patterns highlighting their affinity to the cortico-subcortical boundary of arterial watershed areas.ConclusionsUsing a novel data-driven approach, we identified generalizable topological patterns in both primary and secondary brain tumors Differences in the histopathologic profiles and prognosis of these anatomical tumor classes provide insights into the heterogeneity of tumor biology and might add to personalized clinical decision making.

Capturing adverse events reliably is paramount for clinical practice and research alike. In the era of "big data", prospective registries form the basis of clinical research and quality improvement.To present results of long-term implementation of a prospective patient registry, and evaluate the validity of the Clavien-Dindo grade (CDG) to classify complications in neurosurgery.A prospective registry for cranial and spinal neurosurgical procedures was implemented in 2013. The CDG - a complication grading focused on need for unplanned therapeutic intervention - was used to grade complications. We assess construct validity of the CDG.Data acquisition integrated into our hospital workflow permitted to include all eligible patients into the registry. We have registered 8226 patients that were treated in 11994 surgeries and 32494 consultations up until December 2020. Similarly, we have captured 1245 complications on 6308 patient discharge forms (20%) since full operational status of the registry. The majority of complications (819/6308 ​= ​13%) were treated without invasive treatment (CDG 1 or CDG 2). At discharge, there was a clear correlation of CDG and the Karnofsky Performance Status (KPS, rho ​= ​-0.29, slope -7 KPS percentage points per increment of CDG) and the length of stay (rho ​= ​0.43, slope 3.2 days per increment of CDG).Patient registries with high completeness and objective capturing of complications are central to the process of quality improvement. The CDG demonstrates construct validity as a measure of complication classification in a neurosurgical patient population.

Introduction Reliable preoperative identification of patients at high risk for early postoperative complications occurring within 24 h (EPC) of intracranial tumor surgery can improve patient safety and postoperative management. Statistical analysis using machine learning algorithms may generate models that predict EPC better than conventional statistical methods. Objective To train such a model and to assess its predictive ability. Methods This cohort study included patients from an ongoing prospective patient registry at a single tertiary care center with an intracranial tumor that underwent elective neurosurgery between June 2015 and May 2017. EPC were categorized based on the Clavien-Dindo classification score. Conventional statistical methods and different machine learning algorithms were used to predict EPC using preoperatively available patient, clinical, and surgery-related variables. The performance of each model was derived from examining classification performance metrics on an out-of-sample test dataset. Results EPC occurred in 174 (26%) of 668 patients included in the analysis. Gradient boosting machine learning algorithms provided the model best predicting the probability of an EPC. The model scored an accuracy of 0.70 (confidence interval [CI] 0.59-0.79) with an area under the curve (AUC) of 0.73 and a sensitivity and specificity of 0.80 (CI 0.58-0.91) and 0.67 (CI 0.53-0.77) on the test set. The conventional statistical model showed inferior predictive power (test set: accuracy: 0.59 (CI 0.47-0.71); AUC: 0.64; sensitivity: 0.76 (CI 0.64-0.85); specificity: 0.53 (CI 0.41-0.64)). Conclusion Using gradient boosting machine learning algorithms, it was possible to create a prediction model superior to conventional statistical methods. While conventional statistical methods favor patients' characteristics, we found the pathology and surgery-related (histology, anatomical localization, surgical access) variables to be better predictors of EPC.

Background Cerebral arteriovenous malformations (CAVMs) are characterized by altered hemodynamics and associated with angioanatomic changes, such as aneurysms. We encountered a patient with a CAVM-associated dissection of the medial trunk of the posterior inferior cerebellar artery (PICA) instead of an aneurysm. Case Description We report the case of a 56-year-old male patient with spontaneous subarachnoid hemorrhage within the cisterna magna and fourth ventricle. Digital subtraction angiography revealed a cerebellar arteriovenous malformation located within the inferior semilunar lobule that did not anatomically match the bleeding pattern. The left PICA, serving as a primary feeding artery, showed a dissection of the proximal portion of the medial trunk with a precise anatomic association with the blood in the telovelotonsillar space. CAVM-induced hyperdynamic flow through the feeding vessel is the most plausible pathophysiologic explanation for the dissection. Complete microsurgical resection of the CAVM was performed, and 3-month follow-up digital subtraction angiography showed complete regression of the dissection, disappearance of irregularities, and significant caliber reduction of the medial PICA trunk. Conclusions This is the first report of a hyperdynamic flow-related dissection of a CAVM-associated feeding vessel. Microsurgical resection of the CAVM allowed for spontaneous resolution of the dissected area by restoration of normal rheodynamics.

In contrast to most other tumors, the anatomical extent of brain tumors is not objectified and quantified through staging. Staging systems are built on the understanding of the anatomical sequence of tumor progression and its relation to histopathological dedifferentiation and survival. While major advances in the understanding of primary brain tumors at a histological, cellular and molecular level have been achieved in recent decades, our understanding at a macroscopic anatomical level is limited. The aim of this study was to describe the anatomical phenotype of the most frequent brain tumor entities based on topographic probability and growth behavior analysis. The association of anatomical tumor features with survival probability was assessed and a prototypical staging system for WHO grade II-IV glioma was proposed based on the hypothesized anatomical sequence of tumor progression. The analysis is based on data from a consecutive cohort of 1000 patients with first diagnosis of a primary or secondary brain tumor. On preoperative MRI, the relative tumor density (RTD) of different topographic, phylogenetic and ontogenetic parcellation units was derived through normalization of the relative tumor prevalence to the relative volume of the respective structure. While primary central nervous system lymphoma (PCNSL) showed a high RTD along white matter tracts, the RTD in metastases was highest along terminal arterial flow areas. Neuroepithelial tumors (NT) demonstrated a high and homogeneous RTD along all sectors of the ventriculo-cortical axis, avoiding adjacent units, consistent with a transpallial behavior within phylo-ontogenetic radial units. Additionally, the topographic probability in NT correlated with morphogenetic processes of convergence and divergence of radial units during phylo- and ontogenesis. The anatomical tumor growth behavior was analyzed by comparing pre- and postoperative MRI, showing that a ventriculofugal growth dominates in NT. With progressive histopathological dedifferentiation of NT, a gradual deviation from this neuroepithelial anatomical behavior was found. By comparing survival probability, we identified prognostically critical steps in the anatomical behavior of NT. Based on a hypothesized sequence of anatomical tumor progression, we developed a three-level prototypical staging system for WHO grade II-IV glioma. This staging system proved to be accurate across histological, molecular, radiomorphological and clinical strata based on Kaplan Meier curves and multivariable survival analysis. Similar to staging systems for other tumors, a staging system such as this one may have the potential to inform stage-adapted treatment decisions.

Unlike other tumours, the anatomical extent of brain tumours is not objectified and quantified through staging. Staging systems are based on understanding the anatomical sequence of tumour progression and its relationship to histopathological dedifferentiation and survival. The aim of this study was to describe the spatiotemporal phenotype of the most frequent brain tumour entities, to assess the association of anatomical tumour features with survival probability and to develop a staging system for WHO grade 2 and 3 gliomas and glioblastoma. Anatomical phenotyping was performed on a consecutive cohort of 1000 patients with first diagnosis of a primary or secondary brain tumour. Tumour probability in different topographic, phylogenetic and ontogenetic parcellation units was assessed on preoperative MRI through normalization of the relative tumour prevalence to the relative volume of the respective structure. We analysed the spatiotemporal tumour dynamics by cross-referencing preoperative against preceding and subsequent MRIs of the respective patient. The association between anatomical phenotype and outcome defined prognostically critical anatomical tumour features at diagnosis. Based on a hypothesized sequence of anatomical tumour progression, we developed a three-level staging system for WHO grade 2 and 3 gliomas and glioblastoma. This staging system was validated internally in the original cohort and externally in an independent cohort of 300 consecutive patients. While primary CNS lymphoma showed highest probability along white matter tracts, metastases enriched along terminal arterial flow areas. Neuroepithelial tumours mapped along all sectors of the ventriculocortical axis, while adjacent units were spared, consistent with a transpallial behaviour within phylo-ontogenetic radial units. Their topographic pattern correlated with morphogenetic processes of convergence and divergence of radial units during phylo- and ontogenesis. While a ventriculofugal growth dominated in neuroepithelial tumours, a gradual deviation from this neuroepithelial spatiotemporal behaviour was found with progressive histopathological dedifferentiation. The proposed three-level staging system for WHO grade 2 and 3 gliomas and glioblastoma correlated with the degree of histological dedifferentiation and proved accurate in terms of survival upon both internal and external validation. In conclusion, this study identified specific spatiotemporal phenotypes in brain tumours through topographic probability and growth pattern assessment. The association of anatomical tumour features with survival defined critical steps in the anatomical sequence of neuroepithelial tumour progression, based on which a staging system for WHO grade 2 and 3 gliomas and glioblastoma was developed and validated.

ObjectiveSpecific anatomical patterns are seen in various diseases affecting the brain. Clinical studies on the topography of pathologies are often limited by the absence of a normalization of the prevalence of pathologies to the relative volume of the affected anatomical structures. A comprehensive reference on the relative volumes of clinically relevant anatomical structures serving for such a normalization, is currently lacking.MethodsThe analyses are based on anatomical high-resolution three-dimensional T1-weighted magnetic resonance imaging data of 30 healthy Caucasian volunteers, including 14 females (mean age 37.79 years, SD 13.04) and 16 males (mean age 38.31 years, SD 16.91). Semi-automated anatomical segmentation was used, guided by a neuroanatomical parcellation algorithm differentiating 96 structures. Relative volumes were derived by normalizing parenchymal structures to the total individual encephalic volume and ventricular segments to the total individual ventricular volume.ResultsThe present investigation provides the absolute and relative volumes of 96 anatomical parcellation units of the human encephalon. A larger absolute volume in males than in females is found for almost all parcellation units. While parenchymal structures display a trend towards decreasing volumes with increasing age, a significant inverse effect is seen with the ventricular system. The variances in volumes as well as the effects of gender and age are given for each structure before and after normalization.ConclusionThe provided atlas constitutes an anatomically detailed and comprehensive analysis of the absolute and relative volumes of the human encephalic structures using a clinically oriented parcellation algorithm. It is intended to serve as a reference for volume-standardization in clinical studies on the topographic prevalence of pathologies.

Objective: Brainstem cavernous malformations (BSCM)-associated mortality has been reported up to 20% in patients managed conservatively, whereas postoperative mortality rates range from 0 to 1.9%. Our aim was to analyze the actual risk and causes of BSCM-associated mortality in patients managed conservatively and surgically based on our own patient cohort and a systematic literature review. Methods: Observational, retrospective single-center study encompassing all patients with BSCM that presented to our institution between 2006 and 2018. In addition, a systematic review was performed on all studies encompassing patients with BSCM managed conservatively and surgically. Results: Of 118 patients, 54 were treated conservatively (961.0 person years follow-up in total). No BSCM-associated mortality was observed in our conservatively as well as surgically managed patient cohort. Our systematic literature review and analysis revealed an overall BSCM-associated mortality rate of 2.3% (95% CI: 1.6–3.3) in 22 studies comprising 1,251 patients managed conservatively and of 1.3% (95% CI: 0.9–1.7) in 99 studies comprising 3,275 patients with BSCM treated surgically. Conclusion: The BSCM-associated mortality rate in patients managed conservatively is almost as low as in patients treated surgically and much lower than in frequently cited reports, most probably due to the good selection nowadays in regard to surgery.

BACKGROUND The most widely used classifications of adverse events (AEs) in neurosurgery define their severity according to the therapy used to treat them. This concept has substantial shortcomings because it does not reflect the severity of AEs that are not treated, such as new neurological deficits. OBJECTIVE To present a novel multidimensional and patient-centered classification of the severity of AE in neurosurgery and evaluate its applicability. METHODS The Therapy-Disability-Neurology (TDN) grading system classifies AEs depending on the associated therapy, disability, and neurological deficits. We conducted a 2-center retrospective observational study on 6071 interventions covering the whole neurosurgical spectrum with data prospectively recorded between 2013 and 2019 at 2 institutions from 2 countries. RESULTS Using the first patient cohort (4680 interventions), a positive correlation was found between severity of AE and LOS as well as treatment cost. Each grade was associated with a greater deterioration of the Karnofsky Performance Status Scale (KPS) at discharge and at follow-up. When using the same methods on the external validation cohort (1391 interventions), correlations between the grades of AE, LOS, and KPS at discharge were even more pronounced. CONCLUSION Our results suggest that the TDN grade is consistent with clinical and economic repercussions of AE and thus reflects AE severity. It is easily interpreted and enables comparison between different medical centers. The standardized report of the severity of AE in the scientific literature could constitute an important step forward toward a more critical, patient-centered, and evidence-based decision-making in neurosurgery.

Clinical observations suggest dynamic alterations in behavior after brain surgery. While some alterations reportedly occur within days others gradually develop over several months. These alterations can be attributed to the pre-surgical impact of the diseased tissue, neuronal damage caused by the surgery, and subsequent plasticity. A key step towards a systems-level understanding of the brain-behavior relationships is to capture the dynamics of the cognitive alterations. Here, we first established in 38 healthy individuals that the day-to-day smartphone interactions can be used to inform on cognitive processing speed. Next, we analyzed the smartphone interactions in 12 patients undergoing intracranial tumor surgery, with postsurgical follow-up of up to a year. In healthy individuals, the speed of the touchscreen interactions was highly correlated to choice reaction times (R2 = 0.71) but less so to simple reaction times (R2 = 0.15) on Deary-Liewald tests. Touchscreen interactions slowed immediately after surgery but the post-surgical changes varied between patients. Data-driven models revealed the time-constant of the short-term postsurgical changes and the time taken to stabilize after the surgery. Furthermore, by using conceptually distinct types of touchscreen interaction speeds – i.e. unlocking time and app locating speed – we established that the post-surgical changes are domain-specific. Interestingly, in this small sample, the pre-surgical smartphone speeds were highly related to the speeds post-stabilization (R2 = 0.75 to 0.95). The proxy measures of cognition seamlessly captured on the smartphone can reveal postsurgical dynamics inaccessible to conventional testing. We propose that the transient cognitive alterations indicate the time-constrained influence of distinct neuronal mechanisms triggered by the surgery.

BackgroundThe most widely used classifications of adverse events (AE) in surgical neurology assign a grade to AE that depends on the therapy used to treat them or on new neurologic deficits. Both concepts have substantial shortcomings in grading AE severity. We present a novel multidimensional approach to this challenge and aim at validating the new grading system.MethodsThe new Therapy-Disability-Neurology (TDN) grading system classifies AE into five grades, depending on the associated therapy, disability, and neurologic deficits. We conducted a two-center study on 6071 interventions covering the whole neurosurgical spectrum with data prospectively recorded between January 2013 and September 2019 at the University Hospital Zurich (USZ) and at the Fondazione IRCCS Istituto Neurologico Carlo Besta (FINCB).FindingsUsing data from USZ, a positive correlation was found between the severity of AE and the length of hospital stay (LOS) as well as treatment cost. Each grade was associated with a greater deterioration of the Karnofsky Performance Status Scale (KPS) at discharge and at follow-up. Additionally, there was a correlation between the severity of AE and absolute KPS values. When using the same methods on an external validation cohort from FINCB, correlations between the grade of AE, LOS, and KPS at discharge were even more pronounced.InterpretationOur results suggest that the TDN grade is consistent with clinical and economic repercussions of AE and thus reflects AE severity. It is objective, practical, easily interpreted, and enables comparison between different medical centers. The TDN grade will constitute an important step forward towards a more precise and standardized documentation of AE and ultimately lead to a more critical and patient-centered appraisal of process and outcome measures in surgical neurology.FundingNone.

Purpose Understanding the topographic-anatomical patterns of brain tumors has the potential to improve our pathophysiological understanding and may allow for anatomical tailoring of surgery and radiotherapy. This study analyzed topographic-anatomical patterns underlying neuroepithelial tumors, primary CNS lymphoma and metastases. Methods Any histologically confirmed supra- or infratentorial parenchymal neoplasia of one institution over a 4-year period was included. Using high-resolution magnetic resonance imaging data, a detailed analysis of the topographic-anatomical tumor features was performed. Differences between neuroepithelial tumors, primary central nervous system lymphoma (PCNSL) and metastases were assessed using pairwise comparisons adjusted for multiple testing, upon significance of the omnibus test. Results Based on image analysis of 648 patients—419 (65%) neuroepithelial tumors, 28 (5%) PCNSL and 201 (31%) metastases—entity-specific topographic-anatomical patterns were identified. Neuroepithelial tumors showed a radial ventriculo-cortical orientation, inconsistent with the current belief of a growth along white matter tracts, whereas the pattern in PCNSL corresponded to a growth along such. Metastases preferentially affected the cortex and subcortical white matter of large arteries’ terminal supply areas. This study provides a comprehensive anatomical description of the topography of NT, PCNSL and metastases intended to serve as a topographic reference for clinicians and neuroscientists. Conclusions The identified distinct anatomical patterns provide evidence for a specific interaction between tumor and anatomical structures, following a pathoclitic concept. Understanding differences in their anatomical behavior has the potential to improve our pathophysiological understanding and to tailor therapy of brain tumors.

OBJECTIVEThe goal of this study was to assess the reproducibility and safety of the recently introduced paramedian supracerebellar–transtentorial (PST) approach for selective amygdalohippocampectomy (SA).METHODSThe authors performed a retrospective analysis of prospectively collected data originating from their surgical register of patients undergoing SA via a PST approach for lesional medial temporal lobe epilepsy. All patients received thorough pre- and postoperative clinical (neurological, neuropsychological, psychiatric) and instrumental (ictal and long-term EEG, invasive EEG if needed, MRI) workup. Surgery-induced complications were assessed at discharge and at every follow-up thereafter and were classified according to Clavien-Dindo grade (CDG). Epilepsy outcome was defined according to Engel classification. Data were reported according to common descriptive statistical methods.RESULTSBetween May 2015 and May 2018, 17 patients underwent SA via a PST approach at the authors’ institution (hippocampal sclerosis in 13 cases, WHO grade II glioma in 2 cases, and reactive gliosis in 2 cases). The median postoperative follow-up was 7 months (mean 9 months, range 3–19 months). There was no surgery-related mortality and no complication (CDG ≥ 2) in the whole series. Transitory CDG 1 surgical complications occurred in 4 patients and had resolved in all of them by the first postoperative follow-up. One patient showed a deterioration of neuropsychological performance with new slight mnestic deficits. No patient experienced a clinically relevant postoperative visual field defect. No morbidity due to semisitting position was recorded. At last follow-up 13/17 (76.4%) patients were in Engel class I (9/17 [52.9%] were in class IA).CONCLUSIONSThe PST approach is a reproducible and safe surgical route for SA. The achievable complication rate is in line with the best results in the literature. Visual function outcome particularly benefits from this highly selective, neocortex-sparing approach. A larger patient sample and longer follow-up will show in the future if the seizure control rate and neuropsychological outcome also compare better than those achieved with current common surgical techniques.

Background The aesthetic outcome after burr hole trepanation for the evacuation of chronic subdural hematomas (cSDH) is often unsatisfactory, as the bony skull defects may cause visible skin depressions. The purpose of this study was to evaluate the efficacy of burr hole cover placement to improve the aesthetic outcome. Methods We reviewed consecutive patients treated by burr hole trepanation for cSDH with or without placement of burr hole covers by a single surgeon between October 2016 and May 2018. The clinical data, including complications, were derived from the institution’s prospective patient registry. The primary endpoint was the aesthetic outcome, as perceived by patients on the aesthetic numeric analog (ANA) scale, assessed by means of a standardized telephone interview. Secondary endpoints were skin depression rates and wound pain, as well as complications. Results From n = 33, outcome evaluation was possible in n = 28 patients (n = 24 male; mean age of 70.4 ± 16.1 years) with uni- (n = 20) or bilateral cSDH (n = 8). A total of 14 burr hole covers were placed in 11 patients and compared to 50 burr holes that were not covered. Patient satisfaction with the aesthetic outcome was significantly better for covered burr holes (mean ANA 9.3 ± 0.74 vs. 7.9 ± 1.0; p

OBJECTIVESkin depressions may appear as undesired effects after burr-hole trepanation for the evacuation of chronic subdural hematomas (cSDH). Placement of burr-hole covers to reconstruct skull defects can prevent skin depressions, with the potential to improve the aesthetic result and patient satisfaction. The perception of the relevance of this practice, however, appears to vary substantially among neurosurgeons. The authors aimed to identify current practice variations with regard to the application of burr-hole covers after trepanation for cSDH.METHODSAn electronic survey containing 12 questions was sent to resident and faculty neurosurgeons practicing in different parts of the world, as identified by an Internet search. All responses completed between September 2018 and December 2018 were considered. Descriptive statistics and logistic regression were used to analyze the data.RESULTSA total of 604 responses were obtained, of which 576 (95.4%) provided complete data. The respondents’ mean age was 42.4 years (SD 10.5), and 86.5% were male. The sample consisted of residents, fellows, junior/senior consultants, and department chairs from 79 countries (77.4% Europe, 11.8% Asia, 5.4% America, 3.5% Africa, and 1.9% Australasia). Skin depressions were considered a relevant issue by 31.6%, and 76.0% indicated that patients complain about skin depressions more or less frequently. Burr-hole covers are placed by 28.1% in the context of cSDH evacuation more or less frequently. The most frequent reasons for not placing a burr-hole cover were the lack of proven benefit (34.8%), followed by additional costs (21.9%), technical difficulty (19.9%), and fear of increased complications (4.9%). Most respondents (77.5%) stated that they would consider placing burr-hole covers in the future if there was evidence for superiority of the practice. The use of burr-hole covers varied substantially across countries, but a country’s gross domestic product per capita was not associated with their placement.CONCLUSIONSOnly a minority of neurosurgeons place burr-hole covers after trepanation for cSDH on a regular basis, even though the majority of participants reported complaints from patients regarding postoperative skin depressions. There are significant differences in the patterns of care among countries. Class I evidence with regard to patient satisfaction and safety of burr-hole cover placement is likely to have an impact on future cSDH management.

Background Studies detailing the anatomy of the basal forebrain (BF) from a neurosurgical perspective are missing. Objective To describe the anatomy of the BF and of the anterior perforated substance (APS), the BF emphasizing surgical useful anatomical relationship between surface landmarks and deep structures. Methods White matter fiber microdissection was performed on 5 brain specimens to analyze the topographic anatomy of the APS and expose layer-by-layer fiber tracts and nuclei of the BF. Results The APS, as identified anatomically, surgically, and neuroradiologically, has clear borders measured 23.3 ± 3.4 mm (19-27) in the mediolateral and 12.5 ± 1.2 mm (11-14) in the anteroposterior directions. A detailed stratigraphy of the BF was performed from the APS up to basal ganglia and thalamus allowing identification and dissection of the main components of the BF (septum, nucleus accumbens, amygdala, innominate substance) and its white matter tracts (band of Broca, extracapsular thalamic peduncle, ventral amygdalohypothalamic fibers). The olfactory trigone together with diagonal gyrus and the APS proper is a relevant superficial landmark for the basal ganglia (inferior to the nucleus accumbens, lateral to the caudate head, and medial to the lentiform nucleus). Conclusion The findings in our study supplement available anatomic knowledge of APS and BF, providing reliable landmarks for precise topographic diagnosis of BF lesions and for intraoperative orientation. Surgically relevant relationships between surface and deep anatomic structures are highlighted offering thus a contribution to neurosurgeons willing to perform surgery in this delicate area.

OBJECTIVEAlthough rates of postoperative morbidity and mortality have become relatively low in patients undergoing transnasal transsphenoidal surgery (TSS) for pituitary adenoma, cerebrospinal fluid (CSF) fistulas remain a major driver of postoperative morbidity. Persistent CSF fistulas harbor the potential for headache and meningitis. The aim of this study was to investigate whether neural network–based models can reliably identify patients at high risk for intraoperative CSF leakage.METHODSFrom a prospective registry, patients who underwent endoscopic TSS for pituitary adenoma were identified. Risk factors for intraoperative CSF leaks were identified using conventional statistical methods. Subsequently, the authors built a prediction model for intraoperative CSF leaks based on deep learning.RESULTSIntraoperative CSF leaks occurred in 45 (29%) of 154 patients. No risk factors for CSF leaks were identified using conventional statistical methods. The deep neural network–based prediction model classified 88% of patients in the test set correctly, with an area under the curve of 0.84. Sensitivity (83%) and specificity (89%) were high. The positive predictive value was 71%, negative predictive value was 94%, and F1 score was 0.77. High suprasellar Hardy grade, prior surgery, and older age contributed most to the predictions.CONCLUSIONSThe authors trained and internally validated a robust deep neural network–based prediction model that identifies patients at high risk for intraoperative CSF. Machine learning algorithms may predict outcomes and adverse events that were previously nearly unpredictable, thus enabling safer and improved patient care and better patient counseling.

Delayed ischemic neurological deficit (DIND) is a major driver of adverse outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH), defining an unmet need for therapeutic development. Cell-free hemoglobin that is released from erythrocytes into the cerebrospinal fluid (CSF) is suggested to cause vasoconstriction and neuronal toxicity, and correlates with the occurrence of DIND. Cell-free hemoglobin in the CSF of patients with aSAH disrupted dilatory NO signaling ex vivo in cerebral arteries, which shifted vascular tone balance from dilation to constriction. We found that selective removal of hemoglobin from patient CSF with a haptoglobin-affinity column or its sequestration in a soluble hemoglobin-haptoglobin complex was sufficient to restore physiological vascular responses. In a sheep model, administration of haptoglobin into the CSF inhibited hemoglobin-induced cerebral vasospasm and preserved vascular NO signaling. We identified 2 pathways of hemoglobin delocalization from CSF into the brain parenchyma and into the NO-sensitive compartment of small cerebral arteries. Both pathways were critical for hemoglobin toxicity and were interrupted by the large hemoglobin-haptoglobin complex that inhibited spatial requirements for hemoglobin reactions with NO in tissues. Collectively, our data show that compartmentalization of hemoglobin by haptoglobin provides a novel framework for innovation aimed at reducing hemoglobin-driven neurological damage after subarachnoid bleeding.

OBJECTIVEGross-total resection (GTR) is often the primary surgical goal in transsphenoidal surgery for pituitary adenoma. Existing classifications are effective at predicting GTR but are often hampered by limited discriminatory ability in moderate cases and by poor interrater agreement. Deep learning, a subset of machine learning, has recently established itself as highly effective in forecasting medical outcomes. In this pilot study, the authors aimed to evaluate the utility of using deep learning to predict GTR after transsphenoidal surgery for pituitary adenoma.METHODSData from a prospective registry were used. The authors trained a deep neural network to predict GTR from 16 preoperatively available radiological and procedural variables. Class imbalance adjustment, cross-validation, and random dropout were applied to prevent overfitting and ensure robustness of the predictive model. The authors subsequently compared the deep learning model to a conventional logistic regression model and to the Knosp classification as a gold standard.RESULTSOverall, 140 patients who underwent endoscopic transsphenoidal surgery were included. GTR was achieved in 95 patients (68%), with a mean extent of resection of 96.8% ± 10.6%. Intraoperative high-field MRI was used in 116 (83%) procedures. The deep learning model achieved excellent area under the curve (AUC; 0.96), accuracy (91%), sensitivity (94%), and specificity (89%). This represents an improvement in comparison with the Knosp classification (AUC: 0.87, accuracy: 81%, sensitivity: 92%, specificity: 70%) and a statistically significant improvement in comparison with logistic regression (AUC: 0.86, accuracy: 82%, sensitivity: 81%, specificity: 83%) (all p < 0.001).CONCLUSIONSIn this pilot study, the authors demonstrated the utility of applying deep learning to preoperatively predict the likelihood of GTR with excellent performance. Further training and validation in a prospective multicentric cohort will enable the development of an easy-to-use interface for use in clinical practice.

The extent of resection (EOR) is a crucial outcome parameter in transsphenoidal pituitary surgery (TSS), and is linked to endocrinological outcome, postoperative morbidity, and mortality. We aimed to build a robust, quantitative, and easily reproducible imaging score able to predict EOR in TSS.The ratio (R) between the maximum horizontal adenoma diameter and intercarotid distance at the horizontal C4 segment was used to stratify our patient series in four classes: class I R ≤ 0.75, class II 0.75 R ≤ 1.25, and class III R ≥ 1.25. Class IV included adenomas which completely encased the internal carotid artery. The resulting score was internally validated for robustness.One hundred sixteen patients were included in the study, of which 96 (83%) for derivation and 20 (17%) for validation. EOR showed significant differences between grades (grade I, 100%; II, 97.9%; III, 94.2%; IV, 87.2%; all P 0.05). The same applied to residual volume (RV) (grade I, 0 cmThe proposed score is a simple and reproducible tool which reliably predicts surgical outcome including EOR, RV, and GTR of pituitary adenoma patients undergoing TSS.

OBJECTIVESurgery has proven to be the best therapeutic option for drug-refractory cases of focal cortical dysplasia (FCD)–associated epilepsy. Seizure outcome primarily depends on the completeness of resection, rendering the intraoperative FCD identification and delineation particularly important. This study aims to assess the diagnostic yield of intraoperative ultrasound (IOUS) in surgery for FCD-associated drug-refractory epilepsy.METHODSThe authors prospectively enrolled 15 consecutive patients with drug-refractory epilepsy who underwent an IOUS-assisted microsurgical resection of a radiologically suspected FCD between January 2013 and July 2016. The findings of IOUS were compared with those of presurgical MRI postprocessing and the sonographic characteristics were analyzed in relation to the histopathological findings. The authors investigated the added value of IOUS in achieving completeness of resection and improving postsurgical seizure outcome.RESULTSThe neurosurgeon was able to identify the dysplastic tissue by IOUS in all cases. The visualization of FCD type I was more challenging compared to FCD II and the demarcation of its borders was less clear. Postsurgical MRI showed residual dysplasia in 2 of the 3 patients with FCD type I. In all FCD type II cases, IOUS allowed for a clear intraoperative visualization and demarcation, strongly correlating with presurgical MRI postprocessing. Postsurgical MRI confirmed complete resection in all FCD type II cases. Sonographic features correlated with the histopathological classification of dysplasia (sonographic abnormalities increase continuously in the following order: FCD IA/IB, FCD IC, FCD IIA, FCD IIB). In 1 patient with IOUS features atypical for FCD, histopathological investigation showed nonspecific gliosis.CONCLUSIONSMorphological features of FCD, as identified by IOUS, correlate well with advanced presurgical imaging. The resolution of IOUS was superior to MRI in all FCD types. The appreciation of distinct sonographic features on IOUS allows the intraoperative differentiation between FCD and non-FCD lesions as well as the discrimination of different histological subtypes of FCD. Sonographic demarcation depends on the underlying degree of dysplasia. IOUS allows for more tailored resections by facilitating the delineation of the dysplastic tissue.

Background Aneurysmal subarachnoid hemorrhage (aSAH) is often complicated by the occurrence of delayed ischemic neurologic deficits (DIND), which impairs the clinical outcome of patients. The release of oxyhemoglobin (oxyHb) from lysing erythrocytes into cerebrospinal fluid (CSF) may critically contribute to the development of DIND. Methods Ventricular CSF of 18 high-grade (Fisher 3 and 4) aSAH patients was sampled daily from external ventricular drains between days 0 and 14 after bleeding. CSF was spectrophotometrically analyzed with precise quantification of cell-free oxyHb levels. Results OxyHb levels in CSF showed a delayed peak reaching the highest levels in the high-risk period for developing of DIND between days 3 and 14 after aneurysm rupture. Patients with DIND had a significantly higher cumulative oxyHb exposure within the first week after bleeding. Conclusions OxyHb levels in CSF may be useful as a biomarker to predict DIND in aSAH patients. The contribution of oxyHb in CSF to the pathogenesis of DIND should be further investigated as a potential therapeutic target.