Genetic variants for head size share genes and pathways with cancer.

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer.

Baseline perihematomal edema, C-reactive protein, and 30-day mortality are not associated in intracerebral hemorrhage.

Background: The relationship between baseline perihematomal edema (PHE) and inflammation, and their impact on survival after intracerebral hemorrhage (ICH) are not well understood. Objective: Assess the association between baseline PHE, baseline C-reactive protein (CRP), and early death after ICH. Methods: Analysis of pooled data from multicenter ICH registries. We included patients presenting within 24 h of symptom onset, using multifactorial linear regression model to assess the association between CRP and edema extension distance (EED), and a multifactorial Cox regression model to assess the association between CRP, PHE volume and 30-day mortality. Results: We included 1,034 patients. Median age was 69 (interquartile range [IQR] 59-79), median baseline ICH volume 11.5 (IQR 4.3-28.9) mL, and median baseline CRP 2.5 (IQR 1.5-7.0) mg/L. In the multifactorial analysis [adjusting for cohort, age, sex, log-ICH volume, ICH location, intraventricular hemorrhage (IVH), statin use, glucose, and systolic blood pressure], baseline log-CRP was not associated with baseline EED: for a 50% increase in CRP the difference in expected mean EED was 0.004 cm (95%CI 0.000-0.008, p = 0.055). In a further multifactorial analysis, after adjusting for key predictors of mortality, neither a 50% increase in PHE volume nor CRP were associated with higher 30-day mortality (HR 0.97; 95%CI 0.90-1.05, p = 0.51 and HR 0.98; 95%CI 0.93-1.03, p = 0.41, respectively). Conclusion: Higher baseline CRP is not associated with higher baseline edema, which is also not associated with mortality. Edema at baseline might be driven by different pathophysiological processes with different effects on outcome.

Associations of renal function with cerebral small vessel disease and functional outcome in acute intracerebral haemorrhage: A hospital-based prospective cohort study.

BACKGROUND: Intracerebral haemorrhage (ICH) is a severe clinical consequence of cerebral small vessel disease (SVD), but associations between renal impairment and SVD in patients with ICH have not been fully characterised. METHODS: Using data from the CROMIS-2 ICH observational study, we compared SVD neuroimaging markers and total burden (score 0-3) identified using CT brain imaging in patients with and without renal impairment (estimated glomerular filtration rate, eGFR<60). We assessed functional outcome at 6-month follow-up using the modified Rankin scale. RESULTS: 1027 participants were included (mean age 72.8, 57.1% male); 274 with and 753 without renal impairment. 18.7% of the eGFR<60 group had moderate-to-severe SVD burden (score 2-3), compared with 14.0% of those with eGFR>60 (p = 0.039). SVD burden was associated with renal impairment after adjusting for hypertension (OR 1.36, 95% CI 1.04-1.77, p = 0.023), but not after adjusting for age. Cerebral atrophy was more prevalent in patients with eGFR<60 (81.2% vs. 72.0%, p = 0.002), as were WMH (45.6% vs. 36.6%, p = 0.026). Neither was associated with renal function after adjusting for age and vascular risk factors. Renal impairment was associated with functional outcome (OR 0.65, 95% CI 0.47-0.89, p = 0.007), but not after adjusting for age, pre-morbid function and comorbidities (OR 0.95, 95% CI 0.65-1.38, p = 0.774). CONCLUSION: In acute ICH, renal impairment is associated with a higher cerebral SVD burden independent of hypertension, but not age. Reduced eGFR is associated with worse functional outcome, but not independent of age and comorbidities. Since CT has limited sensitivity to detect SVD severity and distribution, further studies including MRI are needed.

Clinical and surgical results related to anterior-only multilevel cervical decompression and instrumented fusion for degenerative disease.

Introduction: Anterior-only multilevel cervical decompression and fusion surgery (AMCS) on 3-5-levels is challenging due to potential complications. Also, outcome predictors after AMCS are poorly understood. Research Question: We hypothesize that in patients with at most mild/moderate cervical kyphosis (CK) of the cervical spine, restoration of cervical lordosis (CL) positively influences clinical outcomes. Methods: Analysis of consecutive patients presenting with symptomatic degenerative cervical disease or non-union undergoing AMCS. We measured CL from C2 to C7, Cobb angle of fused levels (fusion angle, FA), C7-Slope, and sagittal vertical axis C2-7 (cSVA, stratified into ≤4cm∖>4cm). Patients with excellent outcome were grouped in BEST-outcomes and with moderate/poor outcomes in WORST-outcomes. Results: We included 244 patients. Fifty-four percent had 3-, 39% 4-level and 7% had 5-level fusion. At mean follow-up of 26 months, 41% of patients achieved BEST-outcome and 23% WORST-outcome. Complications and reoperation rates did not significantly differ. Non-union significantly influenced outcomes. The number of patients with non-union was significantly higher in patients with a preoperative cSVA>4cm (OR 13.1 (95%CI:1.8-96.8). Our model, based on the multivariable analysis with WORST-outcome as outcome variable showed a high accuracy (NPV=73%, PPV=77%, specificity=79%, sensitivity=71%). Discussion and Conclusion: In 3-5-level AMCS, improvement of FA and cSVA were independent predictors of clinical outcome. Improvement of CL positively influenced clinical outcomes and rates of non-union.

Successful weaning versus permanent cerebrospinal fluid diversion after aneurysmal subarachnoid hemorrhage: post hoc analysis of a Swiss multicenter study.

OBJECTIVE: Acute hydrocephalus is a frequent complication after aneurysmal subarachnoid hemorrhage (aSAH). Among patients needing CSF diversion, some cannot be weaned. Little is known about the comparative neurological, neuropsychological, and health-related quality-of-life (HRQOL) outcomes in patients with successful and unsuccessful CSF weaning. The authors aimed to assess outcomes of patients by comparing those with successful and unsuccessful CSF weaning; the latter was defined as occurring in patients with permanent CSF diversion at 3 months post-aSAH. METHODS: The authors included prospectively recruited alert (i.e., Glasgow Coma Scale score 13-15) patients with aSAH in this retrospective study from six Swiss neurovascular centers. Patients underwent serial neurological (National Institutes of Health Stroke Scale), neuropsychological (Montreal Cognitive Assessment), disability (modified Rankin Scale), and HRQOL (EuroQol-5D) examinations at < 72 hours, 14-28 days, and 3 months post-aSAH. RESULTS: Of 126 included patients, 54 (42.9%) developed acute hydrocephalus needing CSF diversion, of whom 37 (68.5%) could be successfully weaned and 17 (31.5%) required permanent CSF diversion. Patients with unsuccessful weaning were older (64.5 vs 50.8 years, p = 0.003) and had a higher rate of intraventricular hemorrhage (52.9% vs 24.3%, p = 0.04). Patients who succeed in restoration of physiological CSF dynamics improve on average by 2 points on the Montreal Cognitive Assessment between 48-72 hours and 14-28 days, whereas those in whom weaning fails worsen by 4 points (adjusted coefficient 6.80, 95% CI 1.57-12.04, p = 0.01). They show better neuropsychological recovery between 48-72 hours and 3 months, compared to patients in whom weaning fails (adjusted coefficient 7.60, 95% CI 3.09-12.11, p = 0.02). Patients who receive permanent CSF diversion (ventriculoperitoneal shunt) show significant neuropsychological improvement thereafter, catching up the delay in neuropsychological improvement between 14-28 days and 3 months post-aSAH. Neurological, disability, and HRQOL outcomes at 3 months were similar. CONCLUSIONS: These results show a temporary but clinically meaningful cognitive benefit in the first weeks after aSAH in successfully weaned patients. The resolution of this difference over time may be due to the positive effects of permanent CSF diversion and underlines its importance. Patients who do not show progressive neuropsychological improvement after weaning should be considered for repeat CT imaging to rule out chronic (untreated) hydrocephalus.

The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions.

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention.

Duration between aneurysm rupture and treatment and its association with outcome in aneurysmal subarachnoid haemorrhage.

Timely treatment of aneurysmal subarachnoid haemorrhage (aSAH) is key to prevent further rupture and poor outcome. We evaluated complications and outcome adjusting for time from haemorrhage to treatment. Retrospective analysis of aSAH patients admitted between 2006 and 2020. Data was collected using standardized case report forms. We compared risk factors using multivariable logistic regression. We included 853 patients, 698 (81.8%) were treated within 24 h. Patients with higher Hunt and Hess grades were admitted and treated significantly faster than those with lower grades (overall p-value < 0.001). Fifteen patients (1.8%) rebled before intervention. In the multivariable logistic analysis adjusting for timing, Barrow Neurological Institute score and intracerebral haemorrhage were significantly associated with rebleeding (overall p-value 0.006; OR 3.12, 95%CI 1.09-8.92, p = 0.03, respectively) but timing was not. Treatment > 24 h was associated with higher mortality and cerebral infarction in only the subgroup of lower grades aSAH (OR 3.13, 1.02-9.58 95%CI, p-value = 0.05; OR 7.69, 2.44-25.00, p-value < 0.001, respectively). Therefore treatment > 24 h after rupture is associated with higher mortality and cerebral infarction rates in lower grades aSAH. Delay in treatment primarily affects lower grade aSAH patients. Patients with lower grade aSAH ought to be treated with the same urgency as higher-grade aSAH.

A Genome-Wide Association Study of Outcome After Aneurysmal Subarachnoid Haemorrhage: Discovery Analysis.

Candidate gene studies have identified genetic variants associated with clinical outcomes following aneurysmal subarachnoid haemorrhage (aSAH), but no genome-wide association studies have been performed to date. Here we report the results of the discovery phase of a two-stage genome-wide meta-analysis of outcome after aSAH. We identified 157 independent loci harbouring 756 genetic variants associated with outcome after aSAH (p < 1 × 10-4), which require validation. A single variant (rs12949158), in SPNS2, achieved genome-wide significance (p = 4.29 × 10-8) implicating sphingosine-1-phosphate signalling in outcome after aSAH. A large multicentre international effort to recruit samples for validation is required and ongoing. Validation of these findings will provide significant insight into the pathophysiology of outcomes after aSAH with potential implications for treatment.

MRI and CT imaging biomarkers of cerebral amyloid angiopathy in lobar intracerebral hemorrhage.

BACKGROUND: Cerebral amyloid angiopathy (CAA), a common cause of intracerebral hemorrhage (ICH), is diagnosed using the Boston criteria including magnetic resonance imaging (MRI) biomarkers (cerebral microbleeds (CMBs) and cortical superficial siderosis (cSS). The simplified Edinburgh criteria include computed tomography (CT) biomarkers (subarachnoid extension (SAE) and finger-like projections (FLPs)). The underlying mechanisms and diagnostic accuracy of CT compared to MRI biomarkers of CAA are unknown. METHODS: We included 140 survivors of spontaneous lobar supratentorial ICH with both acute CT and MRI. We assessed associations between MRI and CT biomarkers and the diagnostic accuracy of CT- compared to MRI-based criteria. RESULTS: FLPs were more common in patients with strictly lobar CMB (44.7% vs 23.5%; p = 0.014) and SAE was more common in patients with cSS (61.3% vs 31.2%; p = 0.002). The high probability of the CAA category of the simplified Edinburgh criteria showed 87.2% (95% confidence interval (CI): 78.3-93.4) specificity, 29.6% (95% CI: 18.0-43.6) sensitivity, 59.3% (95% CI: 38.8-77.6) positive predictive value, and 66.4% (95%: CI 56.9-75.0) negative predictive value, 2.3 (95% CI: 1.2-4.6) positive likelihood ratio and 0.8 (95% CI 0.7-1.0) negative likelihood ratio for probable CAA (vs non-probable CAA), defined by the modified Boston criteria; the area under the receiver operating characteristic curve (AUROC) was 0.62 (95% CI: 0.54-0.71). CONCLUSION: In lobar ICH survivors, we found associations between putative biomarkers of parenchymal CAA (FLP and strictly lobar CMBs) and putative biomarkers of leptomeningeal CAA (SAE and cSS). In a hospital population, CT biomarkers might help rule-in probable CAA (diagnosed using the Boston criteria), but their absence is probably not as useful to rule it out, suggesting an important continued role for MRI in ICH survivors with suspected CAA.

Genetic variation in NFE2L2 is associated with outcome following aneurysmal subarachnoid haemorrhage.

BACKGROUND AND PURPOSE: Nuclear factor erythroid 2-related factor 2 (NRF2; encoded by the NFE2L2 gene) has been implicated in outcome following aneurysmal subarachnoid haemorrhage (aSAH) through its activity as a regulator of inflammation, oxidative injury and blood breakdown product clearance. The aim of this study was to identify whether genetic variation in NFE2L2 is associated with clinical outcome following aSAH. METHODS: Ten tagging single nucleotide polymorphisms (SNPs) in NFE2L2 were genotyped and tested for association with dichotomized clinical outcome, assessed by the modified Rankin scale, in both a discovery and a validation cohort. In silico functional analysis was performed using a range of bioinformatic tools. RESULTS: One SNP, rs10183914, was significantly associated with outcome following aSAH in both the discovery (n = 1007) and validation cohorts (n = 466). The risk of poor outcome was estimated to be 1.33-fold (95% confidence interval 1.12-1.58) higher in individuals with the T allele of rs10183914 (pmeta-analysis  = 0.001). In silico functional analysis identified rs10183914 as a potentially regulatory variant with effects on transcription factor binding in addition to alternative splicing with the T allele, associated with a significant reduction in the NFE2L2 intron excision ratio (psQTL  = 1.3 × 10-7 ). CONCLUSIONS: The NFE2L2 SNP, rs10183914, is significantly associated with outcome following aSAH. This is consistent with a clinically relevant pathophysiological role for oxidative and inflammatory brain injury due to blood and its breakdown products in aSAH. Furthermore, our findings support NRF2 as a potential therapeutic target following aSAH and other forms of intracranial haemorrhage.

A genome-wide association study with tissue transcriptomics identifies genetic drivers for classic bladder exstrophy.

Classic bladder exstrophy represents the most severe end of all human congenital anomalies of the kidney and urinary tract and is associated with bladder cancer susceptibility. Previous genetic studies identified one locus to be involved in classic bladder exstrophy, but were limited to a restrict number of cohort. Here we show the largest classic bladder exstrophy genome-wide association analysis to date where we identify eight genome-wide significant loci, seven of which are novel. In these regions reside ten coding and four non-coding genes. Among the coding genes is EFNA1, strongly expressed in mouse embryonic genital tubercle, urethra, and primitive bladder. Re-sequence of EFNA1 in the investigated classic bladder exstrophy cohort of our study displays an enrichment of rare protein altering variants. We show that all coding genes are expressed and/or significantly regulated in both mouse and human embryonic developmental bladder stages. Furthermore, nine of the coding genes residing in the regions of genome-wide significance are differentially expressed in bladder cancers. Our data suggest genetic drivers for classic bladder exstrophy, as well as a possible role for these drivers to relevant bladder cancer susceptibility.

Intracranial Aneurysm Classifier Using Phenotypic Factors: An International Pooled Analysis.

Intracranial aneurysms (IAs) are usually asymptomatic with a low risk of rupture, but consequences of aneurysmal subarachnoid hemorrhage (aSAH) are severe. Identifying IAs at risk of rupture has important clinical and socio-economic consequences. The goal of this study was to assess the effect of patient and IA characteristics on the likelihood of IA being diagnosed incidentally versus ruptured. Patients were recruited at 21 international centers. Seven phenotypic patient characteristics and three IA characteristics were recorded. The analyzed cohort included 7992 patients. Multivariate analysis demonstrated that: (1) IA location is the strongest factor associated with IA rupture status at diagnosis; (2) Risk factor awareness (hypertension, smoking) increases the likelihood of being diagnosed with unruptured IA; (3) Patients with ruptured IAs in high-risk locations tend to be older, and their IAs are smaller; (4) Smokers with ruptured IAs tend to be younger, and their IAs are larger; (5) Female patients with ruptured IAs tend to be older, and their IAs are smaller; (6) IA size and age at rupture correlate. The assessment of associations regarding patient and IA characteristics with IA rupture allows us to refine IA disease models and provide data to develop risk instruments for clinicians to support personalized decision-making.

Treatment during cerebral vasospasm phase-complication association and outcome in aneurysmal subarachnoid haemorrhage.

BACKGROUND: Aneurysm treatment during cerebral vasospasm (CVS) phase is frequently considered as particularly dangerous, mainly because of the risk of cerebral infarct. OBJECTIVE: We aimed to evaluate the risk of aneurysmal subarachnoid haemorrhage (aSAH)-specific complications and functional outcome in patients treated during CVS phase. METHODS: We retrospectively analysed a large, retro- and prospectively collected database of aSAH patients admitted to our department between March 2006 and March 2020. We conducted a uni- and multivariable logistic regression analysis to evaluate influencing factors on rebleeding, cerebral infarct, Glasgow Outcome Score (GOS) at discharge and mortality and assessed the rate of angiographic vasospasm on admission. RESULTS: We included 853 patients. The majority of patients were female (66.6%), mean age was 57.3 years. Out of 853 included patients, 92 (10.8%) were treated during CVS phase, 312 (36.6%) underwent clipping and 541 (63.4%) endovascular treatment. Treatment during CVS phase was significantly associated with cerebral infarct in the multivariable logistic regression analysis, unrelated to the nature of intervention (OR 2.42, 1.29-4.54 95% CI p-value = 0.006). However, patients treated during CVS phase did not have increased risk of unfavourable outcome by GOS on discharge. In addition, they did not have a higher rate of rebleeding or mortality. CONCLUSIONS: Treatment during CVS phase was significantly associated with a higher rate of cerebral infarct as confirmed by imaging. This did not reflect on GOS on discharge, rebleeding, or mortality. Aneurysm treatment during CVS phase is relatively safe and should not be postponed due to the risk of rebleeding and subsequent devastating deterioration.

Surgical Realignment After Anterior Multilevel Decompression Using Cages and Plate for 3-level to 5-level Degenerative Fusions: Lessons Learned From the Analysis of Geometric Changes, Reciprocal Coupling, and Prediction of Sagittal Cervical Balance.

STUDY DESIGN: Retrospective, single-center case study. OBJECTIVE: Postoperative cervical imbalance with cervical sagittal vertical axis (cSVA) >4 cm can be predicted in 3-level to 5-level anterior-only cervical multilevel fusion surgery (ACMS). SUMMARY OF BACKGROUND DATA: Previous studies established correlations between cervical kyphosis (CK) correction and postoperative balance (cSVA ≤4 cm) with improved clinical outcomes. Understanding of what influences restoration of cervical lordosis (CL) in patients with degenerative disease with mild to moderate CK subjected to ACMS is important. To achieve a better understanding of geometric changes after ACMS, this study examines factors predicting perioperative alignment changes and regional interdependencies. MATERIALS AND METHODS: Analysis of patients with ACMS. Analysis included patient baseline characteristics, demographics and complications, and focused on radiographic measures including CL C2-7, fusion angle (FA), C7-Slope (C7S), T1-slope (T1S), T1-CL mismatch, and cSVA (cSVA ≤4 cm/>4 cm). We aimed to predict postoperative imbalance (cSVA >4 cm) and conducted a multivariable logistic regression analysis. RESULTS: Inclusion of 126 patients with 3-level to 5-level ACMS, mean age was 56 years and 4 fusion levels on average. Preoperative CK was present in 9%, mean FA-correction was 8 degrees, maximum 46 degrees. Postoperatively, 14 patients had cSVA >4 cm. A neural network model for prediction of cSVA >4 cm was established including preoperative cSVA, preoperative CL and correction of FA. The model achieved high performance (positive predictive value=100%, negative predictive value=94%, specificity=100%, sensitivity=20%). Also, variables such as nonunion, chronic lumbar pain or thoracolumbar multilevel fusion influenced the postoperative cSVA >4 cm rate. Alignment analysis highlighted strong correlations between C7S/T1S and cSVA/C2-tilt ( r =0.06/ r =0.7, P <0.0001). A formula was established to transfer cSVA data into C2-tilt data. CONCLUSION: This study identified independent variables predicting postoperative cSVA >4 cm including FA, which can be influenced by the surgeon. Our model supports the decision-making process targeting a postoperative cSVA ≤4 cm.

Quality of life and return to work and sports after spinal ependymoma resection.

Adult spinal ependymoma presents a rare low-grade tumor entity. Due to its incidence peak in the fourth decade of life, it mostly affects patients during a professionally and physically active time of life. We performed a retrospective monocentric study, including all patients operated upon for spinal ependymoma between 2009 and 2020. We prospectively collected data on professional reintegration, physical activities and quality-of-life parameters using EQ-5D and SF-36. Issues encountered were assessed using existing spinal-cord-specific questionnaires and free-text questions. In total, 65 of 114 patients agreed to participate. Most patients suffered from only mild pre- and postoperative impairment on the modified McCormick scale, but 67% confirmed difficulties performing physical activities in which they previously engaged due to pain, coordination problems and fear of injuries after a median follow-up of 5.4 years. We observed a shift from full- to part-time employment and patients unable to work, independently from tumor dignity, age and neurological function. Despite its benign nature and occurrence of formal only mild neurological deficits, patients described severe difficulties returning to their preoperative physical activity and profession. Clinical scores such as the McCormick grade and muscle strength may not reflect the entire self-perceived impairment appropriately.

Genome-Wide Association Study of Clinical Outcome After Aneurysmal Subarachnoid Haemorrhage: Protocol.

Aneurysmal subarachnoid haemorrhage (aSAH) results in persistent clinical deficits which prevent survivors from returning to normal daily functioning. Only a small fraction of the variation in clinical outcome following aSAH is explained by known clinical, demographic and imaging variables; meaning additional unknown factors must play a key role in clinical outcome. There is a growing body of evidence that genetic variation is important in determining outcome following aSAH. Understanding genetic determinants of outcome will help to improve prognostic modelling, stratify patients in clinical trials and target novel strategies to treat this devastating disease. This protocol details a two-stage genome-wide association study to identify susceptibility loci for clinical outcome after aSAH using individual patient-level data from multiple international cohorts. Clinical outcome will be assessed using the modified Rankin Scale or Glasgow Outcome Scale at 1-24 months. The stage 1 discovery will involve meta-analysis of individual-level genotypes from different cohorts, controlling for key covariates. Based on statistical significance, supplemented by biological relevance, top single nucleotide polymorphisms will be selected for replication at stage 2. The study has national and local ethical approval. The results of this study will be rapidly communicated to clinicians, researchers and patients through open-access publication(s), presentation(s) at international conferences and via our patient and public network.

Center of rotation analysis for thoracic and lumbar 3-column osteotomies in patients with sagittal plane spinal deformity: insights in geometrical changes can improve understanding of correction mechanics.

OBJECTIVE: Three-column osteotomy (3CO) is used for severe spinal deformities. Associated complications include sagittal translation (ST), which can lead to neurological symptoms. Mismatch between the surgical center of rotation (COR) and the concept of the ideal COR is a potential cause of ST. Matching surgical with conceptual COR is difficult with pedicle subtraction osteotomy (PSO) and vertebral column resection (VCR). This mismatch influences correction geometry, which can prevent maximum possible correction. The authors' objective was to examine the sagittal correction geometry and surgical COR of thoracic and lumbar 3CO. METHODS: In a retrospective study of patients with PSO or VCR for severe sagittal plane deformity, analysis of surgical COR was performed using pre- and postoperative CT scans in the PSO group and digital radiographs in the VCR group. Radiographic analysis included standard deformity measurements and regional kyphosis angle (RKA). All patients had 2-year follow-up, including neurological outcome. Preoperative CT scans were studied for rigid osteotomy sites versus mobile osteotomy sites. Additional radiographic analysis of surgical COR was based on established techniques superimposing pre- and postoperative images. Position of the COR was defined in a rectangular net layered onto the osteotomy vertebrae (OVs). RESULTS: The study included 34 patients undergoing PSO and 35 undergoing VCR, with mean ages of 57 and 29 years and mean RKA corrections of 31° and 49°, respectively. In the PSO group, COR was mainly in the anterior column, and surgical and conceptual COR matched in 22 patients (65%). Smaller RKA correction (27° vs 32°, p = 0.09) was seen in patients with anterior eccentric COR. Patients with rigid osteotomy sites were more likely to have an anterior eccentric COR (41% vs 11%, p = 0.05). In the VCR group, 20 patients (57%) had single-level VCR and 15 (43%) had multilevel VCR. COR was mainly located in the anterior or middle column. Mismatch between surgical and conceptual COR occurred in 24 (69%) patients. Larger RKA correction (63° vs 45°, p = 0.03) was seen in patients with anterior column COR. Patients with any posterior COR had a smaller RKA correction compared to the rest of the patients (42° vs 61°, p = 0.007). CONCLUSIONS: Matching the surgical with the conceptual COR is difficult and in this study failed in one- to two-thirds of all patients. In order to avoid ST during correction of severe deformities, temporary rods, tracking rods, or special instruments should be used for correction maneuvers.

Prehemorrhage antiplatelet use in aneurysmal subarachnoid hemorrhage and impact on clinical outcome.

BACKGROUND: Literature is inconclusive regarding the association between antiplatelet agents use and outcome after aneurysmal subarachnoid hemorrhage. AIMS: To investigate the association between clinical outcome and prehemorrhage use in aneurysmal subarachnoid hemorrhage patients as well as the impact of thrombocyte transfusion on rebleed and clinical outcome. METHODS: Data were collected from prospective databases of two European tertiary reference centers for aneurysmal subarachnoid hemorrhage patients. Patients were divided into "antiplatelet-user" and "non-user" according to the use of acetylsalicylic acid prior to the hemorrhage. Primary outcome was poor clinical outcome at six months (Glasgow Outcome Scale score 1-3). Secondary outcomes were in-hospital mortality and impact of thrombocyte transfusion. RESULTS: Of the 1033 patients, 161 (15.6%) were antiplatelet users. The antiplatelet users were older with higher incidence of cardiovascular risk factors. Antiplatelet use was associated with poor outcome and in-hospital mortality. After correction for age, sex, World Federation of Neurosurgical Societies score, infarction and heart disorder, pre-hemorrhage acetylsalicylic acid use was only associated with poor clinical outcome at six months (adjusted OR 1.80, 95% CI 1.08-3.02). Thrombocyte transfusion was not associated with a reduction in rebleed or poor clinical outcome. CONCLUSION: In this multicenter study, the prehemorrhage acetylsalicylic acid use in aneurysmal subarachnoid hemorrhage patients was independently associated with poor clinical outcome at six months. Thrombocyte transfusion was not associated with the rebleed rate or poor clinical outcome at six months.

Impacting the Treatment of Highly Eloquent Supratentorial Cerebral Cavernous Malformations by Noninvasive Functional Mapping-An Observational Cohort Study.

BACKGROUND: Cerebral cavernous malformations (CCM) may cause cavernoma-related epilepsy (CRE) and intracranial hemorrhage (ICH). Functional mapping has shown its usefulness during the resection of eloquent lesions including the treatment of brain arteriovenous malformations. OBJECTIVE: To evaluate the impact of noninvasive functional mapping on decision-making and resection of eloquently located CCM. METHODS: Of 126 patients with intracranial cavernomas, we prospectively included 40 consecutive patients (31.7%) with highly eloquent CCM between 2012 and 2020. We performed functional mapping via navigated transcranial magnetic stimulation (nTMS) motor mapping in 30 cases and nTMS language mapping in 20 cases. Twenty patients suffered from CRE. CCM caused ICH in 18 cases. RESULTS: We used functional mapping data including function-based tractography in all cases. Indication toward (31 cases) or against (9 cases) CCM resection was influenced by noninvasive functional mapping in 36 cases (90%). We resected CCMs in 24 cases, and 7 patients refused the recommendation for surgery. In 19 and 4 cases, we used additional intraoperative neuromonitoring and awake craniotomy, respectively. Patients suffered from transient postoperative motor or language deficits in 2 and 2 cases, respectively. No patient suffered from permanent deficits. After 1 yr of follow-up, anti-epileptic drugs could be discontinued in all patients who underwent surgery but 1 patient. CONCLUSION: Surgery-related deficit rates are low even for highly eloquent CCM and seizure outcome is excellent. The present results show that noninvasive functional mapping and function-based tractography is a useful tool for the decision-making process and during microsurgical resection of eloquently located CCM.

Surgical outcomes with anatomic reduction of high-grade spondylolisthesis revisited: an analysis of 101 patients.

OBJECTIVE: The ideal strategy for high-grade L5-S1 isthmic spondylolisthesis (HGS) remains controversial. Critical questions include the impact of reduction on clinical outcomes, rate of pseudarthrosis, and postoperative foot drop. The scope of this study was to delineate predictors of radiographic and clinical outcome factors after surgery for HGS and to identify risk factors of foot drop. METHODS: This was a single-center analysis of patients who were admitted for HGS, defined as grade III or greater L5 translation according to the Meyerding (MD) classification. Complete postoperative reduction was defined as MD grade I or less and L5 slip < 20%. Forty-six patients completed health-related quality-of-life questionnaires (Oswestry Disability Index, Physical Component Summary of SF-36, and visual analog scale) and ≥ 2 years' follow-up (average 105 months). A 540° approach was used in 61 patients, a 360° approach was used in 40, and L5 corpectomy was used in 17. Radiographic analysis included measures of global spinopelvic balance (e.g., pelvic incidence [PI], lumbar lordosis) and measurement of lumbosacral kyphosis angle (LSA), L4 slope (L4S), L5 slip (%), and postoperative increase of L5-S1 height. RESULTS: The authors included 101 patients with > 1 year of clinical and radiographic follow-up. The mean age was 26 years. Average preoperative MD grade was 3.8 and average L5 slip was 81%; complete reduction was achieved in 55 and 42 patients, respectively, according to these criteria. At follow-up, LSA correlated with all clinical outcomes (r ≥ 0.4, p < 0.05). Forty patients experienced a major complication. Risk was increased in patients with greater preoperative deformity (i.e., LSA) (p = 0.04) and those who underwent L5 corpectomy (p < 0.01) and correlated with greater deformity correction. Thirty-one patients needed revision surgery, including 17 for pseudarthrosis. Patients who needed revision surgery had greater preoperative deformity (i.e., MD grade and L5 slip) (p < 0.01), greater PI (p = 0.02), and greater postoperative L4S (p < 0.01) and were older (p = 0.02), and these patients more often underwent L5 corpectomy (p < 0.01). Complete reduction was associated with lower likelihood of pseudarthrosis (p = 0.08) and resulted in better lumbar lordosis correction (p = 0.03). Thirty patients had foot drop, and these patients had greater MD grade and L5 slip (p < 0.01) and greater preoperative LSA (p < 0.01). These patients with foot drop more often required L5 corpectomy (p < 0.01). Change in preoperative L4S (p = 0.02), LSA (p < 0.01), and L5-S1 height (p = 0.02) were significantly different between patients with foot drop and those without foot drop. A significant risk model was established that included L4S change and PI as independent variables and foot drop as a dependent variable (82% negative predictive value and 71% positive predictive value, p < 0.01). CONCLUSIONS: Multivariable analysis identified factors associated with foot drop, major complications, and need for revision surgery, including degree of deformity (MD grade and L5 slip) and correction of LSA. Functional outcome correlated with LSA correction.