Subarachnoid hemorrhage due to pituitary adenoma apoplexy-case report and review of the literature.

Pituitary apoplexy (PA) may be complicated by development of subarachnoid hemorrhage (SAH). We conducted a literature review to evaluate the rate of PA-associated tumor rupture and SAH. We conducted a systematic literature search (PubMed, Web of Science, Medline) for patients with PA-associated SAH and report a case SAH following PA. Suitable articles, case series, and case reports were selected based on predefined criteria following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). We reviewed included publications for clinical, radiological, surgical, and histopathological parameters.We present the case of a patient with PA developing extensive SAH whilst on the MRI who underwent delayed transsphenoidal resection. According to our literature review, we found 55 patients with a median age of 46 years; 18 (32.7%) were female. Factors associated with PA-related SAH were hypertension, diabetes mellitus, prior trauma, anticoagulant, and/or antiplatelet therapy. The most common presenting symptoms included severe headache, nausea and/or vomiting, impaired consciousness, and meningeal irritation. Acute onset was described in almost all patients. Twenty-two of the included patients underwent resection. In patients with available outcome, 45.1% had a favorable outcome, 10 (19.6%) had persisting focal neurological deficits, 7 developed cerebral vasospasms (12.7%), and 18 (35.3%) died. Mortality greatly differed between surgically (9.1%) and non-surgically (44.8%) treated patients. PA-associated SAH is a rare condition developing predominantly in males with previously unknown macroadenomas. Timely surgery often prevents aggravation or development of severe neuro-ophthalmological defects and improves clinical outcome.

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.

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.

Genome-Wide Association Study Identifies Risk Loci for Cluster Headache.

OBJECTIVE: This study was undertaken to identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways. METHODS: We carried out a genome-wide association study, where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model for each cohort. The 2 cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene-set enrichment, functional variant annotation, prediction and pathway analyses, were performed. RESULTS: Initial independent analysis identified 2 replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 × 10-17 , odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.37-1.66) and rs4519530 (p = 6.98 × 10-17 , OR = 1.47, 95% CI = 1.34-1.61) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 × 10-8 , OR = 1.36, 95% CI = 1.22-1.52), and rs11153082 (p = 1.85 × 10-8 , OR = 1.30, 95% CI = 1.19-1.42) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache. INTERPRETATION: We identified and replicated several genome-wide significant associations supporting a genetic predisposition in cluster headache in a genome-wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to, for example, treatment response and cluster headache subtypes, could provide unprecedented insights into genotype-phenotype correlations and the pathophysiological pathways underlying cluster headache. ANN NEUROL 2021;90:193-202.

Small vessel disease burden and intracerebral haemorrhage in patients taking oral anticoagulants.

OBJECTIVE: We investigated the contribution of small vessel disease (SVD) to anticoagulant-associated intracerebral haemorrhage (ICH). METHODS: Clinical Relevance of Microbleeds in Stroke-2 comprised two independent multicentre observation studies: first, a cross-sectional study of patients with ICH; and second, a prospective study of patients taking anticoagulants for atrial fibrillation (AF) after cerebral ischaemia. In patients with ICH, we compared SVD markers on CT and MRI according to prior anticoagulant therapy. In patients with AF and cerebral ischaemia treated with anticoagulants, we compared the rates of ICH and ischaemic stroke according to SVD burden score during 2 years follow-up. RESULTS: We included 1030 patients with ICH (421 on anticoagulants), and 1447 patients with AF and cerebral ischaemia. Medium-to-high severity SVD was more prevalent in patients with anticoagulant-associated ICH (CT 56.1%, MRI 78.7%) than in those without prior anticoagulant therapy (CT 43.5%, p<0.001; MRI 64.5%, p=0.072). Leukoaraiosis and atrophy were more frequent and severe in ICH associated with prior anticoagulation. In the cerebral ischaemia cohort (779 with SVD), during 3366 patient-years of follow-up the rate of ICH was 0.56%/year (IQR 0.27-1.03) in patients with SVD, and 0.06%/year (IQR 0.00-0.35) in those without (p=0.001); ICH was independently associated with severity of SVD (HR 5.0, 95% CI 1.9 to 12.2,p=0.001), and was predicted by models including SVD (c-index 0.75, 95% CI 0.63 to 0.85). CONCLUSIONS: Medium-to-high severity SVD is associated with ICH occurring on anticoagulants, and independently predicts ICH in patients with AF taking anticoagulants; its absence identifies patients at low risk of ICH. Findings from these two complementary studies suggest that SVD is a contributory factor in ICH in patients taking anticoagulants and suggest that anticoagulation alone should no longer be regarded as a sufficient 'cause' of ICH. TRIAL REGISTRATION: NCT02513316.

Frequency and risk factors for postoperative aneurysm residual after microsurgical clipping.

OBJECTIVE: Aneurysm residuals after clipping are a well-known problem, but the course of aneurysm remnants in follow-up is not well studied. No standards or follow-up guidelines exist for treatment of aneurysm remnants. The aim of this study was to evaluate the risk factors for postoperative aneurysm remnants and their changes during follow-up. METHODS: We performed a retrospective analysis of 666 aneurysms treated via clipping in our hospital from 2006 to 2016. Postoperative and follow-up angiographic data were analyzed for aneurysm remnants and regrowth. Clinical parameters and aneurysm-specific characteristics were correlated with radiological results. RESULTS: The frequency of aneurysm residuals was 12% (78/666). Aneurysms located in the middle cerebral artery (p = 0.02) showed a significantly lower risk for incomplete aneurysm occlusion. Larger aneurysms with a diameter of 11-25 mm (p = 0.005) showed a significantly higher risk for incomplete aneurysm occlusion. Five patients underwent re-clipping during the same hospital stay. Remnants were stratified based on morphological characteristics into "dog ears" (n = 60) and "broad based" (n = 13). The majority of the "dog ears" stayed stable, decreased in size, or vanished during follow-up. Broad-based remnants showed a higher risk of regrowth. CONCLUSIONS: A middle cerebral artery location seems to lower the risk for the incomplete clip occlusion of an aneurysm. Greater aneurysm size (11-25 mm) is associated with a postoperative aneurysm remnant. The majority of "dog-ear" remnants appear to remain stable during follow-up. In these cases, unnecessarily frequent angiographic checks could be avoided. By contrast, broad-based residuals show a higher risk of regrowth that requires close imaging controls if retreatment cannot be performed immediately.

Longer term stroke risk in intracerebral haemorrhage survivors.

OBJECTIVE: To evaluate the influence of intracerebral haemorrhage (ICH) location on stroke outcomes. METHODS: We included patients recruited to a UK hospital-based, multicentre observational study of adults with imaging confirmed spontaneous ICH. The outcomes of interest were occurrence of a cerebral ischaemic event (either stroke or transient ischaemic attack) or a further ICH following study entry. Haematoma location was classified as lobar or non-lobar. RESULTS: All 1094 patients recruited to the CROMIS-2 (Clinical Relevance of Microbleeds in Stroke) ICH study were included (mean age 73.3 years; 57.4% male). There were 45 recurrent ICH events (absolute event rate (AER) 1.88 per 100 patient-years); 35 in patients presenting with lobar ICH (n=447, AER 3.77 per 100 patient-years); and 9 in patients presenting with non-lobar ICH (n=580, AER 0.69 per 100 patient-years). Multivariable Cox regression found that lobar ICH was associated with ICH recurrence (HR 8.96, 95% CI 3.36 to 23.87, p<0.0001); similar results were found in multivariable completing risk analyses. There were 70 cerebral ischaemic events (AER 2.93 per 100 patient-years); 29 in patients presenting with lobar ICH (AER 3.12 per 100 patient-years); and 39 in patients with non-lobar ICH (AER 2.97 per 100 patient-years). Multivariable Cox regression found no association with ICH location (HR 1.13, 95% CI 0.66 to 1.92, p = 0.659). Similar results were seen in completing risk analyses. CONCLUSIONS: In ICH survivors, lobar ICH location was associated with a higher risk of recurrent ICH events than non-lobar ICH; ICH location did not influence risk of subsequent ischaemic events. TRIAL REGISTRATION NUMBER: NCT02513316.

Haptoglobin genotype and outcome after aneurysmal subarachnoid haemorrhage.

OBJECTIVE: After aneurysmal subarachnoid haemorrhage (aSAH), extracellular haemoglobin (Hb) in the subarachnoid space is bound by haptoglobin, neutralising Hb toxicity and helping its clearance. Two exons in the HP gene (encoding haptoglobin) exhibit copy number variation (CNV), giving rise to HP1 and HP2 alleles, which influence haptoglobin expression level and possibly haptoglobin function. We hypothesised that the HP CNV associates with long-term outcome beyond the first year after aSAH. METHODS: The HP CNV was typed using quantitative PCR in 1299 aSAH survivors in the Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study, a retrospective multicentre cohort study with a median follow-up of 18 months. To investigate mediation of the HP CNV effect by haptoglobin expression level, as opposed to functional differences, we used rs2000999, a single nucleotide polymorphism associated with haptoglobin expression independent of the HP CNV. Outcome was assessed using modified Rankin and Glasgow Outcome Scores. SAH volume was dichotomised on the Fisher grade. Haemoglobin-haptoglobin complexes were measured in cerebrospinal fluid (CSF) of 44 patients with aSAH and related to the HP CNV. RESULTS: The HP2 allele associated with a favourable long-term outcome after high-volume but not low-volume aSAH (multivariable logistic regression). However rs2000999 did not predict outcome. The HP2 allele associated with lower CSF haemoglobin-haptoglobin complex levels. The CSF Hb concentration after high-volume and low-volume aSAH was, respectively, higher and lower than the Hb-binding capacity of CSF haptoglobin. CONCLUSION: The HP2 allele carries a favourable long-term prognosis after high-volume aSAH. Haptoglobin and the Hb clearance pathway are therapeutic targets after aSAH.

Haptoglobin genotype and outcome after spontaneous intracerebral haemorrhage.

OBJECTIVE: Haptoglobin is a haemoglobin-scavenging protein that binds and neutralises free haemoglobin and modulates inflammation and endothelial progenitor cell function. A HP gene copy number variation (CNV) generates HP1 and HP2 alleles, while the single-nucleotide polymorphism rs2000999 influences their levels. The HP1 allele is hypothesised to improve outcome after spontaneous (non-traumatic) intracerebral haemorrhage (ICH). We investigated the associations of the HP CNV genotype and rs2000999 with haematoma volume, perihaematomal oedema (PHO) volume, functional outcome and mortality after ICH. METHODS: We included patients with neuroimaging-proven ICH, available DNA and 6-month follow-up in an observational cohort study (CROMIS-2). We classified patients into three groups according to the HP CNV: 1-1, 2-1 or 2-2 and also dichotomised HP into HP1-containing genotypes (HP1-1 and HP2-1) and HP2-2 to evaluate the HP1 allele. We measured ICH and PHO volume on CT; PHO was measured by oedema extension distance. Functional outcome was assessed by modified Rankin score (unfavourable outcome defined as mRS 3-6). RESULTS: We included 731 patients (mean age 73.4, 43.5% female). Distribution of HP CNV genotype was: HP1-1 n=132 (18.1%); HP2-1 n=342 (46.8%); and HP2-2 n=257 (35.2%). In the multivariable model mortality comparisons between HP groups, HP2-2 as reference, were as follows: OR HP1-1 0.73, 95% CI 0.34 to 1.56 (p value=0.41) and OR HP2-1 0.5, 95% CI 0.28 to 0.89 (p value=0.02) (overall p value=0.06). We found no evidence of association of HP CNV or rs200999 with functional outcome, ICH volume or PHO volume. CONCLUSION: The HP2-1 genotype might be associated with lower 6-month mortality after ICH; this finding merits further study.

Detection of intracranial hematomas in the emergency department using near infrared spectroscopy.

Hypothesis: Traumatic brain injury (TBI) is one of the most important causes of morbidity and mortality in our society. The development of near infrared technology for the detection of intracranial hematomas may assist earlier diagnosis of TBI. This in turn may enable earlier targeted treatments minimizing the harm and subsequent social and economic effects of TBI. Methods: A handheld, noninvasive Near Infrared Spectroscopy device, Infrascanner 2000, (Infrascan Inc., Philadelphia, PA, USA) was used in a major trauma center to screen for traumatic intracranial hematomas. The Infrascanner was used successfully in 205 patients on their arrival in the emergency department prior to CT head. Results: In the whole cohort, sensitivity was 75%, specificity was 50.43%, with negative predictive value 72.84%, and positive predictive value 53.23%. In 45 patients, where the volume of blood was >3.5mL, the sensitivity was 89.36%, specificity 48.73% with negative predictive value 93.9% and positive predictive value 34.15%. Conclusions: The Infrascanner has a relatively high specificity and negative predictive value; therefore, it could in association with the Neurological examination, help in the triage of the trauma patient with potential brain injury. Further investigation is necessary to determine the use of Infrascanner 2000 as a diagnostic method in TBI.

Characterization of HSP90 isoforms in transformed bovine leukocytes infected with Theileria annulata.

HSP90 chaperones are essential regulators of cellular function, as they ensure the appropriate conformation of multiple key client proteins. Four HSP90 isoforms were identified in the protozoan parasite Theileria annulata. Partial characterization was undertaken for three and localization confirmed for cytoplasmic (TA12105), endoplasmic reticulum (TA06470), and apicoplast (TA10720) forms. ATPase activity and binding to the HSP90 inhibitor geldanamycin were demonstrated for recombinant TA12105, and all three native forms could be isolated to varying extents by binding to geldanamycin beads. Because it is essential, HSP90 is considered a potential therapeutic drug target. Resistance to the only specific Theileriacidal drug is increasing, and one challenge for design of drugs that target the parasite is to limit the effect on the host. An in vitro cell culture system that allows comparison between uninfected bovine cells and the T. annulata-infected counterpart was utilized to test the effects of geldanamycin and the derivative 17-AAG. T. annulata-infected cells had greater tolerance to geldanamycin than uninfected cells yet exhibited significantly more sensitivity to 17-AAG. These findings suggest that parasite HSP90 isoform(s) can alter the drug sensitivity of infected host cells and that members of the Theileria HSP90 family are potential targets worthy of further investigation.

Case report on the spontaneous resolution of a traumatic intracranial acute subdural haematoma: evaluation of the guidelines.

Rapid spontaneous resolution of traumatic acute subdural haematomas (ASDH) can occur but is rare. We present an 88-year-old female who presents with a large left acute subdural haematoma (ASDH) measuring 18 mm in thickness with midline shift of 10.7 mm. We managed her conservatively based upon good consciousness level and absent neurological deficits. Repeat computed tomography (CT) the following day demonstrated near complete resolution of the ASDH and midline shift regression; a further CT confirmed resolution. Most patients with large ASDH require surgical evacuation; however, in rare cases, they can resolve spontaneously with extreme rapidity. Conservative management can be a valid option in carefully selected cases.

In Vitro Screening of the Open-Source Medicines for Malaria Venture Malaria Box Reveals Novel Compounds with Profound Activities against Theileria annulata Schizonts.

Intracellular schizonts of the apicomplexans Theileria annulata and Theileria parva immortalize bovine leukocytes and thereby cause fatal diseases. The hydroxynaphthoquinone buparvaquone is currently the only option for the treatment of theileriosis, and resistance development has been reported. It is therefore tempting to investigate the repurposing of compounds effective against related apicomplexan parasites, such as Plasmodium Here, we present the results of a screen of 400 compounds included in the open-access Medicines for Malaria Venture (MMV) malaria box on TaC12 cells, a macrophage-derived cell line immortalized by T. annulata schizonts. Using a combination of the classical alamarBlue vitality assay and a recently developed quantitative reverse transcriptase real-time PCR method based on the Theileria TaSP gene, we have identified 5 compounds, characterized their effects on the ultrastructure of TaC12 cells, and investigated whether they easily induce resistance formation. Two compounds, the quinolinols MMV666022 and MMV666054, have 50% inhibitory concentrations (IC50s) of 0.5 and 0.2 µM on TaC12 cells and 5.3 and 5.2 µM on BoMac cells, respectively. Thus, with therapeutic indexes of 11 and 18, they represent promising leads for further development of antitheilerial chemotherapeutics.

The influence of intraoperative resection control modalities on survival following gross total resection of glioblastoma.

The purpose of the present study is to analyze the impact of intraoperative resection control modalities on overall survival (OS) and progression-free survival (PFS) following gross total resection (GTR) of glioblastoma. We analyzed data of 76 glioblastoma patients (30f, mean age 57.4 ± 11.6 years) operated at our institution between 2009 and 2012. Patients were only included if GTR was achieved as judged by early postoperative high-field MRI. Intraoperative technical resection control modalities comprised intraoperative ultrasound (ioUS, n = 48), intraoperative low-field MRI (ioMRI, n = 22), and a control group without either modality (n = 11). The primary endpoint of our study was OS, and the secondary endpoint was PFS-both analyzed in Kaplan-Meier plots and Cox proportional hazards models. Median OS in all 76 glioblastoma patients after GTR was 20.4 months (95 % confidence interval (CI) 18.5-29.0)-median OS in patients where GTR was achieved using ioUS was prolonged (21.9 months) compared to those without ioUS usage (18.8 months). A multiple Cox model adjusting for age, preop Karnofsky performance status, tumor volume, and the use of 5-aminolevulinic acid showed a beneficial effect of ioUS use, and the estimated hazard ratio was 0.63 (95 % CI 0.31-1.2, p = 0.18) in favor of ioUS, however not reaching statistical significance. A similar effect was found for PFS (hazard ratio 0.59, p = 0.072). GTR of glioblastoma performed with ioUS guidance was associated with prolonged OS and PFS. IoUS should be compared to other resection control devices in larger patient cohorts.

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.

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.

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.

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.

VPS dependency after aneurysmal subarachnoid haemorrhage and influence of admission hyperglycaemia.

Introduction: Hydrocephalus after aneurysmal subarachnoid haemorrhage (aSAH) is a common complication which may lead to insertion of a ventriculoperitoneal shunt (VPS). Our aim is to evaluate a possible influence of specific clinical and biochemical factors on VPS dependency with special emphasis on hyperglycaemia on admission. Patients and methods: Retrospective analysis of a monocentric database of aSAH patients. Using univariable and multivariable logistic regression analysis we evaluated factors influencing VPS dependency, with a special focus on hyperglycaemia on blood sample within 24 h of admission, dichotomised at 126 mg/dl. Factors evaluated in the univariable analysis were age, sex, known diabetes, Hunt and Hess grade, Barrow Neurological Institute scale, treatment modality, extra-ventricular drain (EVD) insertion, complications (rebleeding, vasospasm, infarction, decompressive craniectomy, ventriculitis), outcome variables and laboratory parameters (glucose, C-reactive protein, procalcitonin). Results: We included 510 consecutive patients treated with acute aSAH requiring a VPS (mean age 58.2 years, 66% were female). An EVD was inserted in 387 (75.9%) patients. In the univariable analysis, VPS dependency was associated with hyperglycaemia on admission (OR 2.56, 95%CI 1.58-4.14, p < 0.001). In the multivariable regression analysis after stepwise backward regression, factors associated with VPS dependency were hyperglycaemia >126 mg/dl on admission (OR 1.93, 95%CI 1.13-3.30, p = 0.02), ventriculitis (OR 2.33, 95%CI 1.33-4.04, p = 0.003), Hunt and Hess grade (overall p-value 0.02) and decompressive craniectomy (OR 2.68, 95%CI 1.55-4.64, p < 0.001). Conclusion: Hyperglycaemia on admission was associated with an increased probability of VPS placement. If confirmed, this finding might facilitate treatment of these patients by accelerating insertion of a permanent draining system.

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.