Clinical course of patients with conservatively managed cerebral cavernous malformations.

INTRODUCTION: There is uncertainty whether patients with a cerebral cavernous malformation (CCM) should undergo conservative or surgical treatment, resulting in practice variation among hospitals. Our objective was to report clinical outcomes of patients with primarily conservatively managed CCMs. PATIENTS AND METHODS: This single-center cohort study included consecutive adult CCM patients, diagnosed in 2000-2023, who underwent conservative management as primary treatment strategy. Data were extracted from medical records, and we systematically conducted telephone and questionnaire follow-up. Functional status was assessed on the modified Rankin Scale (mRS). RESULTS: Of 345 patients, we included 265 patients with a CCM (median age 46 years; 45% male). At baseline, 131 (49%) patients presented with symptomatic hemorrhage (SH), and 134 (51%) with other symptoms or asymptomatically. During 58 months (IQR 35-94) median follow-up, 51 (19%) patients experienced a SH, 33 (12%) a seizure, and 13 (5%) focal neurological deficits. Fourteen (5%) patients underwent intervention (surgery n = 11, radiosurgery n = 4). Presentation with SH was associated with higher annual bleeding rates (6.0% vs 1.5%, p < 0.001), and higher cumulative 5-/10-year bleeding risks (31%/41% vs 7%, p < 0.001). Brainstem CCM was associated with higher cumulative 5-/10-year bleeding risks (27%/38% vs 17%/21%, p = 0.038). Nineteen (7%) patients died; two (0.8%) directly attributable to CCM. Of 246 surviving patients, 205 (83%) completed the questionnaire. At follow-up, 172/224 (77%) patients were functionally independent (mRS score ⩽2). DISCUSSION AND CONCLUSION: The majority of conservatively managed CCM patients remained free of a SH during follow-up. Few patients required intervention, and death attributable to the CCM was rare. These data may help patient counseling and treatment decisions.

The immunological landscape of peripheral blood in glioblastoma patients and immunological consequences of age and dexamethasone treatment.

Background: Glioblastomas manipulate the immune system both locally and systemically, yet, glioblastoma-associated changes in peripheral blood immune composition are poorly studied. Age and dexamethasone administration in glioblastoma patients have been hypothesized to limit the effectiveness of immunotherapy, but their effects remain unclear. We compared peripheral blood immune composition in patients with different types of brain tumor to determine the influence of age, dexamethasone treatment, and tumor volume. Methods: High-dimensional mass cytometry was used to characterise peripheral blood mononuclear cells of 169 patients with glioblastoma, lower grade astrocytoma, metastases and meningioma. We used blood from medically-refractory epilepsy patients and healthy controls as control groups. Immune phenotyping was performed using FlowSOM and t-SNE analysis in R followed by supervised annotation of the resulting clusters. We conducted multiple linear regression analysis between intracranial pathology and cell type abundance, corrected for clinical variables. We tested correlations between cell type abundance and survival with Cox-regression analyses. Results: Glioblastoma patients had significantly fewer naive CD4+ T cells, but higher percentages of mature NK cells than controls. Decreases of naive CD8+ T cells and alternative monocytes and an increase of memory B cells in glioblastoma patients were influenced by age and dexamethasone treatment, and only memory B cells by tumor volume. Progression free survival was associated with percentages of CD4+ regulatory T cells and double negative T cells. Conclusion: High-dimensional mass cytometry of peripheral blood in patients with different types of intracranial tumor provides insight into the relation between intracranial pathology and peripheral immune status. Wide immunosuppression associated with age and pre-operative dexamethasone treatment provide further evidence for their deleterious effects on treatment with immunotherapy.

Recurrent Chronic Subdural Hematoma After Burr-Hole Surgery and Postoperative Drainage: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVE: Reported recurrence rates of chronic subdural hematoma treated by burr-hole surgery with postoperative drainage vary considerably in the literature. We performed a systematic review and meta-analysis to define the recurrence rate of burr-hole surgery with postoperative drainage. METHODS: PubMed and EMBASE were searched, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. We used the Newcastle-Ottawa scale and Cochrane risk-of-bias tool for quality assessment of included studies and the random-effects model to calculate pooled incidence rates in R with the metaprop function if appropriate. RESULTS: The search yielded 2969 references; 709 were screened full text, and 189 met the inclusion criteria. In 174 studies (34 393 patients), the number of recurrences was reported as per patient and 15 studies (3078 hematomas) reported the number of recurrences per hematoma, for a pooled incidence of 11.2% (95% CI: 10.3-12.1; I 2 = 87.7%) and 11.0% (95% CI: 8.6-13.4; I 2 = 78.0%), respectively. The pooled incidence of 48 studies (15 298 patients) with the highest quality was 12.8% (95% CI 11.4-14.2; I 2 = 86.1%). Treatment-related mortality (56 patients) has a pooled incidence of 0.7% (95% CI 0.0-1.4; I 2 = 0.0%). CONCLUSION: The recurrence rate of chronic subdural hematoma treated by burr-hole surgery and postoperative drainage is 12.8%.

Impact of Surgical Timing on Motor Level Lowering in Motor Complete Traumatic Spinal Cord Injury Patients.

Patients with complete traumatic spinal cord injury (tSCI) have a low potential to recover ambulation. Motor level recovery, adjacent to the level of injury, could influence functional independency. This study addresses whether surgical timing influences motor level recovery in patients with motor complete (American Spinal Injury Association [ASIA] Impairment Scale A [AIS A]) and motor incomplete (AIS B) tSCI. A retrospective cohort study was performed in the Netherlands in patients with AIS A/B tSCI (C2-L2), who consecutively underwent surgery between January 2010 and April 2020. Neurological examination was performed directly at presentation to the emergency room and at discharge from the rehabilitation facility. Motor level lowering, AIS grade, and upper and lower extremity motor score recovery were calculated for patients who underwent early (< 24 h) and late (24 h+) surgery. A total of 96 patients met the inclusion criteria. In the multi-variate analysis, late surgical decompression (24 h+) was negatively associated with ≥1 motor level lowering and ≥2 AIS grade improvement [odds ratio (OR) 0.11 [95% confidence interval (CI): 0.01, 0.67], p = 0.046, and OR 0.06 [95% CI: 0.00, 047], p = 0.030. respectively). The presence of sacral sparing (AIS B) at initial examination, and cervical level of the tSCI were associated with ≥1 motor level lowering. In addition, AO Spine C-type injuries were negatively associated with any type of neurological recovery, except motor level lowering. Although sensorimotor complete injuries as well as thoracolumbar injuries negatively influence neurological recovery, early surgical decompression (< 24 h) appears independently associated with enhanced neurological recovery in patients with traumatic spinal cord injury despite level and severity of injury.

Tranexamic acid for chronic subdural hematoma.

BACKGROUND: There is no consensus on optimal treatment for a chronic subdural hematoma (cSDH). In patients with only moderate symptoms treatment with tranexamic acid (TXA) has been suggested. We report off-label use of TXA in seven patients. METHODS: Between August 2016 and May 2018 we identified seven patients for primary conservative treatment with TXA until satisfactory clinical and radiological status was achieved. Primary outcome was surgery for cSDH evacuation. Radiological follow-up was performed at regular intervals for hematoma volume measurements. RESULTS: Five patients experienced complete resolution of symptoms, one patient had a burr-hole craniostomy five days after initiation of TXA treatment due to an increase of left-sided weakness and dysarthria and in one patient symptoms did not improve. Median follow-up was 15 weeks (range 6-25, without the operated patient). The median total volume before start of treatment was 83 mL (range 11-137) for all patients. At the last follow-up, the median total volume in the non-operated patients decreased by 73% to 33 mL (range 0-77). CONCLUSIONS: TXA could be considered as primary medical treatment in patients with a cSDH and mild symptoms. The results of current randomized clinical trials must be awaited.

Spatial concordance of DNA methylation classification in diffuse glioma.

BACKGROUND: Intratumoral heterogeneity is a hallmark of diffuse gliomas. DNA methylation profiling is an emerging approach in the clinical classification of brain tumors. The goal of this study is to investigate the effects of intratumoral heterogeneity on classification confidence. METHODS: We used neuronavigation to acquire 133 image-guided and spatially separated stereotactic biopsy samples from 16 adult patients with a diffuse glioma (7 IDH-wildtype and 2 IDH-mutant glioblastoma, 6 diffuse astrocytoma, IDH-mutant and 1 oligodendroglioma, IDH-mutant and 1p19q codeleted), which we characterized using DNA methylation arrays. Samples were obtained from regions with and without abnormalities on contrast-enhanced T1-weighted and fluid-attenuated inversion recovery MRI. Methylation profiles were analyzed to devise a 3-dimensional reconstruction of (epi)genetic heterogeneity. Tumor purity was assessed from clonal methylation sites. RESULTS: Molecular aberrations indicated that tumor was found outside imaging abnormalities, underlining the infiltrative nature of this tumor and the limitations of current routine imaging modalities. We demonstrate that tumor purity is highly variable between samples and explains a substantial part of apparent epigenetic spatial heterogeneity. We observed that DNA methylation subtypes are often, but not always, conserved in space taking tumor purity and prediction accuracy into account. CONCLUSION: Our results underscore the infiltrative nature of diffuse gliomas and suggest that DNA methylation subtypes are relatively concordant in this tumor type, although some heterogeneity exists.

Effect of Steroids as an Adjunct to Surgical Treatment in Patients with Chronic Subdural Hematoma.

The role of steroids as an adjunct to surgery for chronic subdural hematoma (cSDH) remains unclear. We evaluated the effect of steroids as an adjunct to surgery on recurrence rates, complications, and mortality. We retrospectively collected data of 525 patients operated on for cSDH between January 2010 and April 2015 at the Amsterdam University Medical Centers and Erasmus Medical Center Rotterdam. Data from patients with and without steroid use as an adjunct to surgery were obtained from medical records and compared using the chi-square test, independent-samples t-test, and Mann-Whitney U test, where applicable. Associations between adjuvant steroid use and complications were analyzed with univariable (penalized likelihood) logistic regression analysis. Multi-variate logistic regression was performed to analyze the influence of adjuvant steroid use on recurrence. Propensity-score matching was used to assemble a cohort of patients with similar baseline characteristics. Two hundred seventy-eight of the 525 patients (53%) were treated with adjuvant steroids. Surgery for recurrences occurred less in patients of the steroid group (9% vs. 14%; odds ratio [OR] 0.57; 95% confidence interval [CI], 0.33-0.99), but the effect was not significant after correction for confounders (adjusted aOR, 0.59; 95% CI, 0.33-1.05). In the steroid group, delirium (10% vs. 3%; OR, 3.99; 95% CI, 1.72-9.29) and dysregulated glucose levels occurred more frequently (2% vs. 0%; OR, 11.81; 95% CI, 1.38-1542.79), but multi-variate analysis was not possible. After propensity-score matching, McNemar's chi-square test showed that adjuvant steroid use was not significantly associated with recurrence rate (p = 0.10). Steroids as an adjunct to surgery in patients with cSDH did not have a favorable effect on the recurrence rate in our data after controlling for confounders.

Complete Traumatic Spinal Cord Injury: Current Insights Regarding Timing of Surgery and Level of Injury.

STUDY DESIGN: A narrative literature review. OBJECTIVES: To review the neurological recovery patterns in traumatic spinal cord injury (tSCI) patients with a complete lack of motor and sensory function below the level of injury (ie, ASIA A [American Spinal Injury Association scale]), as well as the impact of level of injury and timing of surgical intervention. RESULTS: Spontaneous neurological recovery in patients with complete tSCI differs per level of injury: patients with cervical and thoracolumbar tSCI recover ≥1 ASIA grade in 17.3% to 34.0% 1 year after injury, compared with 10.7% to 18.6% in thoracic tSCI. Surgical decompression within 24 hours has a beneficial effect on neurological recovery in patients with complete cervical tSCI, whereas this effect is less clear for thoracic and thoracolumbar tSCI. A 1- or 2-grade improvement in the ASIA scale does not necessarily result in functional recovery. CONCLUSION: In complete tSCI, the level of injury as well as surgical timing affect neurological recovery. There appears to be a beneficial effect of early surgical decompression in patients with complete cervical tSCI, more so than for thoracic and thoracolumbar tSCI. Frequently, the effect of surgical intervention is evaluated by an improvement in ASIA grade, but it is unclear whether this scale is sensitive enough to evaluate meaningful effectiveness of the intervention and desired outcome for patients with tSCI.

Neurological recovery after traumatic spinal cord injury: what is meaningful? A patients' and physicians' perspective.

STUDY DESIGN: Cross-sectional survey. OBJECTIVES: Most studies on neurological recovery after traumatic spinal cord injury (tSCI) assess treatment effects using the American Spinal Injury Association Impairment Scale (AIS grade) or motor points recovery. To what extent neurological recovery is considered clinically meaningful is unknown. This study investigated the perceived clinical benefit of various degrees of neurological recovery one year after C5 AIS-A tSCI. SETTING: The Netherlands. METHODS: By means of a web-based survey SCI patients and physicians evaluated the benefit of various scenarios of neurological recovery on a scale from 0 to 100% (0% no benefit to 100% major benefit). Recovery to AIS-C and D, was split into C/C+ and D/D+, which was defined by the lower and upper limit of recovery for each grade. RESULTS: A total of 79 patients and 77 physicians participated in the survey. Each AIS grade improvement from AIS-A was considered significant benefit (all p < 0.05), ranging from 47.8% (SD 26.1) for AIS-B to 86.8% (SD 24.3) for AIS-D+. Motor level lowering was also considered significant benefit (p < 0.05), ranging from 66.1% (SD 22.3) for C6 to 81.7% (SD 26.0) for C8. CONCLUSIONS: Meaningful recovery can be achieved without improving in AIS grade, since the recovery of functional motor levels appears to be as important as improving in AIS grade by both patients and physicians. Moreover, minor neurological improvements within AIS-C and D are also considered clinically meaningful. Future studies should incorporate more detailed neurological outcomes to prevent potential underestimation of neurological recovery by only using the AIS grade.

Impact of Early (<24 h) Surgical Decompression on Neurological Recovery in Thoracic Spinal Cord Injury: A Meta-Analysis.

The impact of surgical timing in neurological recovery in thoracic and thoracolumbar traumatic spinal cord injury (tSCI) is still a subject of discussion. While in cervical tSCI one may expect a beneficial effect of early intervention within 24 h, especially in complete cases, this has not yet been demonstrated clearly for thoracic tSCI. This study addresses neurological improvement after early and late surgery for thoracic and thoracolumbar tSCI. A systematic search retrieved 14 publications of observational studies reporting outcome measurements after surgery in 1075 patients with thoracic and thoracolumbar tSCI from PubMed and Embase databases. Surgery was considered early within 24 h and late thereafter. An improvement of at least one and two grades on the American Spinal Injury Association Impairment Scale (ASIA) was evaluated. The Meta-Analyses and Systematic Reviews of Observational Studies guidelines were followed. Improvement rates were summarized using individual patient data in a Bayesian random effects model and compared for those with early and late surgery. In the qualitative analysis, six of seven studies, which investigated the effect of surgical timing, observed a significant effect of early surgery on at least one ASIA grade improvement. Quantitative analysis in 948 patients with thoracic and thoracolumbar tSCI data, however, did not reveal a significant increase in odds of ≥1 ASIA grade recovery in early surgery (66.8% [95% confidence interval (CI): 45.0-87.8%] compared with late surgery (48.9% [95% CI: 25.1-70.7%; odds ratio (OR) 2.2 (95% CI: 0.6-14.0]). This study did not observe a significant beneficial effect of surgical decompression within 24 h in patients with thoracic and thoracolumbar tSCI.

Early Surgical Decompression Improves Neurological Outcome after Complete Traumatic Cervical Spinal Cord Injury: A Meta-Analysis.

In patients with traumatic spinal cord injury (tSCI) a distinction in surgical urgency is made on the basis of the severity of the initial neurological injury. The optimal timing of surgical decompression, as well as its impact on neurological recovery, is as of yet undetermined. This study addresses neurological improvement after early and late surgery for complete and incomplete cervical tSCI. A systematic search retrieved 15 publications of observational studies reporting outcome measurements after surgery in 1126 patients with cervical tSCI from PubMed and Embase databases. Surgery was considered early within 24 h, and late thereafter. An improvement of at least two grades on the American Spinal Injury Association (ASIA) scale was considered clinically meaningful. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed. Improvement rates were summarized using individual patient data in a Bayesian random effects model and compared for those with complete and incomplete tSCI after early and late surgery. In patients with complete cervical tSCI (n = 422), improvement was more frequent after early surgery than after late surgery (respectively, 22.6%, 95% credibility interval [CI]: 16.6-28.7% and 10.4%, 95% CI: 5.6-15.8%; odds ratio [OR] 2.6 [95% CI: 1.4-5.1]). Whereas in patients with incomplete cervical tSCI (n = 636), improvement was similar between early and late surgery (respectively 30.4%, 95% CI: 19.8-41.6% and 32.5%, 95% CI: 21.4-45.8%; OR 0.9 [95% CI: 0.4-1.9]). These data suggest a paradigm shift in the treatment of patients with complete cervical tSCI, as surgical decompression within 24 h is more frequently associated with clinically meaningful improvement. In incomplete cervical tSCI, neurological outcome is similar between early and late surgery.

Deep learning-based preoperative predictive analytics for patient-reported outcomes following lumbar discectomy: feasibility of center-specific modeling.

BACKGROUND CONTEXT: There is considerable variability in patient-reported outcome measures following surgery for lumbar disc herniation. Individualized prediction tools that are derived from center- or even surgeon-specific data could provide valuable insights for shared decision-making. PURPOSE: To evaluate the feasibility of deriving robust deep learning-based predictive analytics from single-center, single-surgeon data. STUDY DESIGN: Derivation of predictive models from a prospective registry. PATIENT SAMPLE: Patients who underwent single-level tubular microdiscectomy for lumbar disc herniation. OUTCOME MEASURES: Numeric rating scales for leg and back pain severity and Oswestry Disability Index scores at 12 months postoperatively. METHODS: Data were derived from a prospective registry. We trained deep neural network-based and logistic regression-based prediction models for patient-reported outcome measures. The primary endpoint was achievement of the minimum clinically important difference (MCID) in numeric rating scales and Oswestry Disability Index, defined as a 30% or greater improvement from baseline. Univariate predictors of MCID were also identified using conventional statistics. RESULTS: A total of 422 patients were included (mean [SD] age: 48.5 [11.5] years; 207 [49%] female). After 1 year, 337 (80%), 219 (52%), and 337 (80%) patients reported a clinically relevant improvement in leg pain, back pain, and functional disability, respectively. The deep learning models predicted MCID with high area-under-the-curve of 0.87, 0.90, and 0.84, as well as accuracy of 85%, 87%, and 75%. The regression models provided inferior performance measures for each of the outcomes. CONCLUSIONS: Our study demonstrates that generating personalized and robust deep learning-based analytics for outcome prediction is feasible even with limited amounts of center-specific data. With prospective validation, the ability to preoperatively and reliably inform patients about the likelihood of symptom improvement could prove useful in patient counselling and shared decision-making.

Neurologic Outcome After Decompressive Craniectomy: Predictors of Outcome in Different Pathologic Conditions.

OBJECTIVE: Decompressive craniectomy (DC) has been proposed as a lifesaving treatment in patients with elevated intracranial pressure, but its effectiveness on reaching a favorable neurologic outcome remains unclear. We identified predictors of outcome in a large, single-center cohort of patients undergoing DC for different pathologic conditions. METHODS: This retrospective study included all patients undergoing DC from 2006 to 2014. The 1-year outcome, assessed using the Glasgow Outcome Scale (GOS), was dichotomized into favorable (GOS 4-5) and unfavorable (GOS 1-3) outcome. Predictors of outcome were identified by analyzing patient characteristics. RESULTS: DC was performed in 204 patients for ischemic stroke (n = 57), traumatic brain injury (n = 50), aneurysmal subarachnoid hemorrhage (aSAH) (n = 44), intracerebral hemorrhage (ICH) (n = 29), cerebral venous thrombosis (CVT) (n = 14), or other indications (n = 10). Overall, 69 (34%) patients survived favorably, 39 (19%) survived unfavorably, and 96 (47%) died. Higher age, poor Glasgow Coma Scale score, intubated status before DC, bilateral absence of pupillary light reflexes, DC for aSAH, and additional surgeries after DC (excluding cranioplasty) were significant predictors of unfavorable outcome. When patients were sorted for pathologic conditions and predictors of outcome, favorable outcome rates differed remarkably, ranging from 91% for CVT patients undergoing uncomplicated DC to 0% for aSAH patients undergoing DC for secondary infarction or ICH patients with unilateral or bilateral abnormal pupillary light reflexes upon admission. CONCLUSIONS: Long-term neurologic outcome after DC differed remarkably among subpopulations of patients, with favorable outcome rates ranging from 0% to >90%.

In vitro drug response and efflux transporters associated with drug resistance in pediatric high grade glioma and diffuse intrinsic pontine glioma.

Pediatric high-grade gliomas (pHGG), including diffuse intrinsic pontine gliomas (DIPG), are the leading cause of cancer-related death in children. While it is clear that surgery (if possible), and radiotherapy are beneficial for treatment, the role of chemotherapy for these tumors is still unclear. Therefore, we performed an in vitro drug screen on primary glioma cells, including three DIPG cultures, to determine drug sensitivity of these tumours, without the possible confounding effect of insufficient drug delivery. This screen revealed a high in vitro cytotoxicity for melphalan, doxorubicine, mitoxantrone, and BCNU, and for the novel, targeted agents vandetanib and bortezomib in pHGG and DIPG cells. We subsequently determined the expression of the drug efflux transporters P-gp, BCRP1, and MRP1 in glioma cultures and their corresponding tumor tissues. Results indicate the presence of P-gp, MRP1 and BCRP1 in the tumor vasculature, and expression of MRP1 in the glioma cells themselves. Our results show that pediatric glioma and DIPG tumors per se are not resistant to chemotherapy. Treatment failure observed in clinical trials, may rather be contributed to the presence of drug efflux transporters that constitute a first line of drug resistance located at the blood-brain barrier or other resistance mechanism. As such, we suggest that alternative ways of drug delivery may offer new possibilities for the treatment of pediatric high-grade glioma patients, and DIPG in particular.