Menno R. Germans

Ultra-early tranexamic acid after subarachnoid hemorrhage (ULTRA): study protocol for a randomized controlled trial.

BackgroundA frequent complication in patients with subarachnoid hemorrhage (SAH) is recurrent bleeding from the aneurysm. The risk is highest within the first 6 hours after the initial hemorrhage. Securing the aneurysm within this timeframe is difficult owing to logistical delays. The rate of recurrent bleeding can also be reduced by ultra-early administration of antifibrinolytics, which probably improves functional outcome. The aim of this study is to investigate whether ultra-early and short-term administration of the antifibrinolytic agent tranexamic acid (TXA), as add-on to standard SAH management, leads to better functional outcome.Methods/DesignThis is a multicenter, prospective, randomized, open-label trial with blinded endpoint (PROBE) assessment. Adult patients with the diagnosis of non-traumatic SAH, as proven by computed tomography (CT) within 24 hours after the onset of headache, will be randomly assigned to the treatment group or the control group. Patients in the treatment group will receive standard treatment with the addition of a bolus of TXA (1 g intravenously) immediately after randomization, followed by continuous infusion of 1 g per 8 hours until the start of aneurysm treatment, or a maximum of 24 hours after the start of medication. Patients in the control group will receive standard treatment without TXA. The primary outcome measure is favorable functional outcome, defined as a score of 0 to 3 on the modified Rankin Scale (mRS), at 6 months after SAH. Primary outcome will be determined by a trial nurse blinded for treatment allocation. We aim to include 950 patients in 3 years.DiscussionThe strengths of this study are: 1. the ultra-early and short-term administration of TXA, resulting in a lower dose as compared to previous studies, which should reduce the risk for delayed cerebral ischemia (DCI), an important risk factor in the long-term treatment with antifibrinolytics; 2. the power calculation is based on functional outcome and calculated with use of recent study results of our own population, supported by data from prominent studies; and 3. the participation of several specialized SAH centers, and their referring hospitals, in the Netherlands with comparative treatment protocols.Trial registrationNederlands Trial Register (Dutch Trial Registry) number NTR3272

The VASOGRADE: A Simple Grading Scale for Prediction of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage

Background and Purpose— Patients are classically at risk of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage. We validated a grading scale—the VASOGRADE—for prediction of DCI. Methods— We used data of 3 phase II randomized clinical trials and a single hospital series to assess the relationship between the VASOGRADE and DCI. The VASOGRADE derived from previously published risk charts and consists of 3 categories: VASOGRADE-Green (modified Fisher scale 1 or 2 and World Federation of Neurosurgical Societies scale [WFNS] 1 or 2); VASOGRADE-Yellow (modified Fisher 3 or 4 and WFNS 1–3); and VASOGRADE-Red (WFNS 4 or 5, irrespective of modified Fisher grade). The relation between the VASOGRADE and DCI was assessed by logistic regression models. The predictive accuracy of the VASOGRADE was assessed by receiver operating characteristics curve and calibration plots. Results— In a cohort of 746 patients, the VASOGRADE significantly predicted DCI (P<0.001). The VASOGRADE-Yellow had a tendency for increased risk for DCI (odds ratio [OR], 1.31; 95% CI, 0.77–2.23) when compared with VASOGRADE-Green; those with VASOGRADE-Red had a 3-fold higher risk of DCI (OR, 3.19; 95% CI, 2.07–4.50). Studies were not a significant confounding factor between the VASOGRADE and DCI. The VASOGRADE had an adequate discrimination for prediction of DCI (area under the receiver operating characteristics curve=0.63) and good calibration. Conclusions— The VASOGRADE results validated previously published risk charts in a large and diverse sample of subarachnoid hemorrhage patients, which allows DCI risk stratification on presentation after subarachnoid hemorrhage. It could help to select patients at high risk of DCI, as well as standardize treatment protocols and research studies.

Yield of spinal imaging in nonaneurysmal, nonperimesencephalic subarachnoid hemorrhage

Objective: We studied the yield of MRI of the spinal neuraxis in patients with nonperimesencephalic subarachnoid hemorrhage (NPSAH). Methods: In a prospective, multicenter study, we performed T1-weighted and T2-weighted MRI of the spinal axis in a consecutive series of patients with a spontaneous NPSAH without intracranial vascular pathology on intracranial vascular imaging. Results: A spinal origin of the hemorrhage was found in 3 of 75 patients (4%; 95% confidence interval 0–8.4). The lesions were 1 lumbar ependymoma and 2 cervical cavernous malformations. All 3 patients presented without focal neurologic deficits and 2 had a CT-negative subarachnoid hemorrhage but positive lumbar puncture. Patients with a spinal origin were younger than patients without a spinal origin (38 vs 56 years; p < 0.05), which was the only significant difference between groups. Conclusions: The yield and clinical relevance of MRI of the spinal axis in patients who present with NPSAH is low. We do not recommend routine MRI of the spinal axis in this patient population, but it might be justified in a subgroup of patients.

Predictors of In-Hospital Death After Aneurysmal Subarachnoid Hemorrhage: Analysis of a Nationwide Database (Swiss SOS [Swiss Study on Aneurysmal Subarachnoid Hemorrhage])

Background and Purpose— To identify predictors of in-hospital mortality in patients with aneurysmal subarachnoid hemorrhage and to estimate their impact. Methods— Retrospective analysis of prospective data from a nationwide multicenter registry on all aneurysmal subarachnoid hemorrhage cases admitted to a tertiary neurosurgical department in Switzerland (Swiss SOS [Swiss Study on Aneurysmal Subarachnoid Hemorrhage]; 2009–2015). Both clinical and radiological independent predictors of in-hospital mortality were identified, and their effect size was determined by calculating adjusted odds ratios (aORs) using multivariate logistic regression. Survival was displayed using Kaplan–Meier curves. Results— Data of n=1866 aneurysmal subarachnoid hemorrhage patients in the Swiss SOS database were available. In-hospital mortality was 20% (n=373). In n=197 patients (10.6%), active treatment was discontinued after hospital admission (no aneurysm occlusion attempted), and this cohort was excluded from analysis of the main statistical model. In the remaining n=1669 patients, the rate of in-hospital mortality was 13.9% (n=232). Strong independent predictors of in-hospital mortality were rebleeding (aOR, 7.69; 95% confidence interval, 3.00–19.71; P<0.001), cerebral infarction attributable to delayed cerebral ischemia (aOR, 3.66; 95% confidence interval, 1.94–6.89; P<0.001), intraventricular hemorrhage (aOR, 2.65; 95% confidence interval, 1.38–5.09; P=0.003), and new infarction post-treatment (aOR, 2.57; 95% confidence interval, 1.43–4.62; P=0.002). Conclusions— Several—and among them modifiable—factors seem to be associated with in-hospital mortality after aneurysmal subarachnoid hemorrhage. Our data suggest that strategies aiming to reduce the risk of rebleeding are most promising in patients where active treatment is initially pursued. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT03245866.

Decision tree analysis in subarachnoid hemorrhage: prediction of outcome parameters during the course of aneurysmal subarachnoid hemorrhage using decision tree analysis

OBJECTIVEThe aim of this study was to create prediction models for outcome parameters by decision tree analysis based on clinical and laboratory data in patients with aneurysmal subarachnoid hemorrhage (aSAH).METHODSThe database consisted of clinical and laboratory parameters of 548 patients with aSAH who were admitted to the Neurocritical Care Unit, University Hospital Zurich. To examine the model performance, the cohort was randomly divided into a derivation cohort (60% [n = 329]; training data set) and a validation cohort (40% [n = 219]; test data set). The classification and regression tree prediction algorithm was applied to predict death, functional outcome, and ventriculoperitoneal (VP) shunt dependency. Chi-square automatic interaction detection was applied to predict delayed cerebral infarction on days 1, 3, and 7.RESULTSThe overall mortality was 18.4%. The accuracy of the decision tree models was good for survival on day 1 and favorable functional outcome at all time points, with a difference between the training and test data sets of < 5%. Prediction accuracy for survival on day 1 was 75.2%. The most important differentiating factor was the interleukin-6 (IL-6) level on day 1. Favorable functional outcome, defined as Glasgow Outcome Scale scores of 4 and 5, was observed in 68.6% of patients. Favorable functional outcome at all time points had a prediction accuracy of 71.1% in the training data set, with procalcitonin on day 1 being the most important differentiating factor at all time points. A total of 148 patients (27%) developed VP shunt dependency. The most important differentiating factor was hyperglycemia on admission.CONCLUSIONSThe multiple variable analysis capability of decision trees enables exploration of dependent variables in the context of multiple changing influences over the course of an illness. The decision tree currently generated increases awareness of the early systemic stress response, which is seemingly pertinent for prognostication.

Sex differences in delayed cerebral ischemia after subarachnoid hemorrhage

OBJECTIVE In this study the authors sought to investigate the sex differences in the risk of delayed cerebral ischemia (DCI), delayed cerebral infarction, and the role of hormonal status. METHODS Ten studies included in the SAHIT (SAH International Trialists) repository were analyzed using a fitting logistic regression model. Heterogeneity between the studies was tested using I2 statistics, and the results were pooled using a random-effects model. Multivariable analysis was adjusted for the effects of neurological status and fixed effect of study. An additional model was examined in which women and men were split into groups according to an age cut point of 55 years, as a surrogate to define hormonal status. RESULTS A pooled cohort of 6713 patients was analyzed. The risk of DCI was statistically significantly higher in women than in men (OR 1.29, 95% CI 1.12-1.48); no difference was found with respect to cerebral infarction (OR 1.17, 95% CI 0.98-1.40). No difference was found in the risk of DCI when comparing women ≤ 55 and > 55 years (OR 0.87, 95% CI 0.74-1.02; p = 0.08) or when comparing men ≤ 55 and > 55 years (p = 0.38). Independent predictors of DCI were World Federation of Neurosurgical Societies (WFNS) grade, Fisher grade, age, and sex. Independent predictors of infarction included WFNS grade, Fisher grade, and aneurysm size. CONCLUSIONS Female sex is associated with a higher risk of DCI. Sex differences may play a role in the pathogenesis of DCI but are not associated with menopausal status. The predictors of DCI and cerebral infarction were identified in a very large cohort and reflect experience from multiple institutions.

Spontaneous Spinal Subarachnoid Hemorrhage with Development of an Arachnoid Cyst—A Case Report and Review of the Literature

BACKGROUND Spontaneous spinal subarachnoid hemorrhage (SAH) is extremely rare and occurs in <1% of all cases of SAH. To the best of our knowledge, only 1 case of spontaneous spinal SAH with later development of a symptomatic spinal arachnoid cyst (SAC) has been described in the literature to date. The objective of the present study was to report the challenging clinical management of SAC based on a literature review. CASE DESCRIPTION We report the case of a 51-year-old woman with acute onset of back pain, neck pain, and headaches with an angiogram-negative supratentorial SAH. Further magnetic resonance imaging screening of the spine revealed additional subarachnoid blood at the level of the thoracic spine, without evidence of vascular malformations. Several weeks after the hemorrhage, the patient developed progressive numbness in her trunk and lower extremities and weakness in her lower extremities. A follow-up magnetic resonance imaging study revealed a large arachnoid cyst at level T4-T7 with spinal cord compression. The patient underwent left hemilaminectomy at T4-T6 and fenestration of the SAC. In a second surgery, right-sided hemilaminectomy at T7 was performed with complete marsupialization of the larger cyst and placement of an intradural shunt. At the 6-month clinical follow-up examination, she showed improvement of her clinical symptoms. CONCLUSIONS Treatment of secondary SAC is challenging, and surgery of the SAC with or without placement of a shunt is a possible treatment option.

A Rare Case of Diffuse Midline Glioma, H3 K27M Mutant, of the Spinal Cord Mimicking Meningitis

Spinal cord tumors account for 2–4% of central nervous system neoplasms in adults, the majority comprising low-grade gliomas of ependymal or astrocytic origin [7]. Only 10% are astrocytomas, which are almost exclusively located in the intramedullary compartment. Malignant astrocytomas of the spinal cord, found mostly in young adults in the second and third decade, are rare and the prognosis is dismal [8, 14]. On magnetic resonance imaging (MRI), such tumors appear in the cervical or thoracic cord as expansive, intramedullary masses with heterogeneous contrast enhancement [8, 14, 17]. Exceedingly rare is leptomeningeal gliomatosis, characterized by extensive dissemination of neoplastic glial cells in the leptomeninges. Most high-grade cases arise in the setting of intracranial glioblastoma, which has been reported to seed along the spine in 23% of cases [2]. There are only isolated case reports of primary leptomeningeal gliomatosis [7, 13]. Only few publications have investigated the genetic landscape of high-grade spinal astrocytomas [1, 3, 11, 16]. The most common finding is the H3 K27M mutation, which corresponds to the Bdiffuse midline glioma, H3 K27M mutant,^ a recently introduced entity in the revised fourth edition of the WHO classification of Tumors of the Central Nervous System [6, 7]. Even when anaplastic features such as mitotic activity, vascular proliferation, and necrosis are lacking, tumors that harbor the H3 K27M mutation are associated with a 2-year survival rate of < 10% and therefore correspond to WHO grade IV [7]. This entity arises in midline locations, including the thalamus, pons, and spinal cord and typically affects children and young adults [7]. Here, we report the case of a 25-year-old female, who presented with rapidly progressive meningeal symptoms and a rapidly fatal course due to leptomeningeal g l iomatos is , H3 K27M mutant . Al though rare , leptomeningeal gliomatosis should be considered in the differential diagnosis of patients with rapidly progressive meningea l symptoms and imaging evidence of leptomeningeal enhancement. Early operative exploration and pathological evaluation are essential to provide the correct diagnosis.

Whole-exome sequencing of a meningeal melanocytic tumour reveals activating CYSLTR2 and EIF1AX hotspot mutations and similarities to uveal melanoma

Melanocytic tumours originating in the leptomeninges range from low-grade melanocytomas to malignant melanomas. These tumours, referred to as meningeal melanocytic tumours (MMT), occur at a median age of 45 years and have a predilection for the cervical/thoracic spine and the posterior cranial fossa [4]. MMTs are sometimes associated with melanocytic nevi of the skin; however, the association with vascular lesions is not well documented [4]. MMTs share certain mutations with uveal melanoma (UM), including hotspot mutations in GNAQ/GNA11 and lack BRAF mutations frequently present in cutaneous melanoma (CM) [4]. Herein, we report the first whole-exome sequencing analysis of a cervical intradural MMT, associated with a port-wine stain. This previously healthy 85-year-old male presented with progressive cervical pain and mild dysesthesia in both hands. Physical examination was unremarkable. Other than a large congenital nuchal port-wine stain, no other cutaneous lesions were identified (Fig. 1a). Magnetic resonance (MR) imaging showed a homogenous enhancing intradural extramedullary tumour extending from C2 to C4 compressing the spinal cord (Fig. 1b, c). Cervical laminectomy and opening of the dura revealed a dark-colored extramedullary lesion (Fig. 1d) firmly adherent to the pia. As a result, subtotal resection was performed and histology revealed a melanocytic tumour of intermediate-grade malignancy (Fig. 1e). DNA methylation profiling confirmed its primary origin in the central nervous system (ESM_1). The patient received no additional therapy. Follow-up at 2 years showed no neurological deficits or growth of the residual tumour. Formalin-fixed and paraffin-embedded material from the MMT was available for whole-exome sequencing. A biopsy of the port-wine stain underwent cancer-related and selected vascular-associated gene panel sequencing (ESM_1). Whole-exome sequencing of the MMT (alongside matched germline DNA) revealed only 27 somatic mutations in protein-coding regions of the genome, of which 19 were protein-altering and 8 were silent (Fig. 2a, b, ESM_2). This low number of mutations is in stark contrast to CM and may reflect the lack of UV-exposure [48% of all nucleotide changes were cytidine to thymidine (C>T) transitions] (Fig. 2c). Comparing both the mutational rate and spectrum of this MMT to those of 80 primary UM [1] revealed a median correlation coefficient of 0.973, which is significantly higher than the corresponding median correlation across 64 primary CM (p <0.00001, T-test). This Heidi V. N. Küsters-Vandevelde and Menno R. Germans contributed equally to this work.