Insights from a Multicenter Study on Adult H3 K27M-Mutated Glioma: Surgical Resection's Limited Influence on Overall Survival, ATRX as Molecular Prognosticator.

BACKGROUND: H3 K27M-mutated gliomas were first described as a new grade 4 entity in the 2016 WHO classification. Current studies have focused on its typical appearance in children and young adults, increasing the need to better understand the prognostic factors and impact of surgery on adults. Here, we report a multicentric study of this entity in adults. METHODS: We included molecularly confirmed H3 K27M-mutated glioma cases in patients >18 years diagnosed between 2016 and 2022. Clinical, radiological, and surgical features were analyzed. Univariate and multivariate analyses were performed to identify prognostic factors. RESULTS: Among 70 patients with a mean age of 36.1 years, the median overall survival (OS) was 13.6 + 14 months. Gross-total resection was achieved in 14.3% of patients, whereas 30% had a subtotal resection and 54.3% a biopsy.Tumors located in telencephalon/diencephalon/myelencephalon were associated with a poorer OS, while a location in the mesencephalon/metencephalon showed a significantly longer OS (8.7 vs. 25.0 months, p=0.007). Preoperative Karnofsky Performance Score (KPS) < 80 showed a reduced OS (4.2 vs. 18 months, p=0.02). Furthermore, ATRX loss, found in 25.7%, was independently associated with an increased OS (31 vs. 8.3 months, p=0.0029). Notably, patients undergoing resection showed no survival benefit over biopsy (12 vs. 11 months, p=0.4006). CONCLUSION: The present study describes surgical features of H3 K27M-mutated glioma in adulthood in a large multicentric study. Our data reveal that ATRX status, location and KPS significantly impact OS in H3 K27M-mutated glioma. Importantly, our dataset indicates that resection does not offer a survival advantage over biopsy.

The effect of self-management techniques on relevant outcomes in chronic low back pain: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Among many treatment approaches for chronic low back pain (CLBP), self-management techniques are becoming increasingly important. The aim of this paper was to (a) provide an overview of existing digital self-help interventions for CLBP and (b) examine the effect of these interventions in reducing pain intensity, pain catastrophizing and pain disability. DATABASES AND DATA TREATMENT: Following the PRISMA guideline, a systematic literature search was conducted in the MEDLINE, EMBASE, PsychInfo, CINAHL and Cochrane databases. We included randomized controlled trials from the last 10 years that examined the impact of digital self-management interventions on at least one of the three outcomes in adult patients with CLBP (duration ≥3 months). The meta-analysis was based on random-effects models. Standardized tools were used to assess the risk of bias (RoB) for each study and the quality of evidence for each outcome. RESULTS: We included 12 studies (n = 1545). A small but robust and statistically significant pooled effect was found on pain intensity (g = 0.24; 95% CI [0.09, 0.40], k = 12) and pain disability (g = 0.43; 95% CI [0.27, 0.59], k = 11). The effect on pain catastrophizing was not significant (g = 0.38; 95% CI [-0.31, 1.06], k = 4). The overall effect size including all three outcomes was g = 0.33 (95% CI [0.21, 0.44], k = 27). The RoB of the included studies was mixed. The quality of evidence was moderate or high. CONCLUSION: In summary, we were able to substantiate recent evidence that digital self-management interventions are effective in the treatment of CLBP. Given the heterogeneity of interventions, further research should aim to investigate which patients benefit most from which approach. SIGNIFICANCE: This meta-analysis examines the effect of digital self-management techniques in patients with CLBP. The results add to the evidence that digital interventions can help patients reduce their pain intensity and disability. A minority of studies point towards the possibility that digital interventions can reduce pain catastrophizing. Future research should further explore which patients benefit most from these kinds of interventions.

Craniectomy size and decompression of the temporal base using the altered posterior question-mark incision for decompressive hemicraniectomy.

The altered posterior question-mark incision for decompressive hemicraniectomy (DHC) was proposed to reduce the risk of intraoperative injury of the superficial temporal artery (STA) and demonstrated a reduced rate of wound-healing disorders after cranioplasty. However, decompression size during DHC is essential and it remains unclear if the new incision type allows for an equally effective decompression. Therefore, this study evaluated the efficacy of the altered posterior question-mark incision for craniectomy size and decompression of the temporal base and assessed intraoperative complications compared to a modified standard reversed question-mark incision. The authors retrospectively identified 69 patients who underwent DHC from 2019 to 2022. Decompression and preservation of the STA was assessed on postoperative CT scans and CT or MR angiography. Forty-two patients underwent DHC with the standard reversed and 27 patients with the altered posterior question-mark incision. The distance of the margin of the craniectomy to the temporal base was 6.9 mm in the modified standard reversed and 7.2 mm in the altered posterior question-mark group (p = 0.77). There was no difference between the craniectomy sizes of 158.8 mm and 158.2 mm, respectively (p = 0.45), and there was no difference in the rate of accidental opening of the mastoid air cells. In both groups, no transverse/sigmoid sinus was injured. Twenty-four out of 42 patients in the modified standard and 22/27 patients in the altered posterior question-mark group had a postoperative angiography, and the STA was preserved in all cases in both groups. Twelve (29%) and 5 (19%) patients underwent revision due to wound-healing disorders after DHC, respectively (p = 0.34). There was no difference in duration of surgery. Thus, the altered posterior question-mark incision demonstrated technically equivalent and allows for an equally effective craniectomy size and decompression of the temporal base without increasing risks of intraoperative complications. Previously described reduction in wound-healing complications and cranioplasty failures needs to be confirmed in prospective studies to demonstrate the superiority of the altered posterior question-mark incision.

Patterns, predictors and prognostic relevance of high-grade hematotoxicity after temozolomide or temozolomide-lomustine in the CeTeG/NOA-09 trial.

PURPOSE: In the randomized phase III trial CeTeG/NOA-09, temozolomide (TMZ)/lomustine (CCNU) combination therapy was superior to TMZ in newly diagnosed MGMT methylated glioblastoma, albeit reporting more frequent hematotoxicity. Here, we analyze high grade hematotoxicity and its prognostic relevance in the trial population. METHODS: Descriptive and comparative analysis of hematotoxicity adverse events ≥ grade 3 (HAE) according to the Common Terminology of Clinical Adverse Events, version 4.0 was performed. The association of HAE with survival was assessed in a landmark analysis. Logistic regression analysis was performed to predict HAE during the concomitant phase of chemotherapy. RESULTS: HAE occurred in 36.4% and 28.6% of patients under CCNU/TMZ and TMZ treatment, respectively. The median onset of the first HAE was during concomitant chemotherapy (i.e. first CCNU/TMZ course or daily TMZ therapy), and 42.9% of patients with HAE receiving further courses experienced repeat HAE. Median HAE duration was similar between treatment arms (CCNU/TMZ 11.5; TMZ 13 days). Chemotherapy was more often discontinued due to HAE in CCNU/TMZ than in TMZ (19.7 vs. 6.3%, p = 0.036). The occurrence of HAE was not associated with survival differences (p = 0.76). Regression analysis confirmed older age (OR 1.08) and female sex (OR 2.47), but not treatment arm, as predictors of HAE. CONCLUSION: Older age and female sex are associated with higher incidence of HAE. Although occurrence of HAE was not associated with shorter survival, reliable prediction of patients at risk might be beneficial to allow optimal management of therapy and allocation of supportive measures. TRIAL REGISTRATION: NCT01149109.

Validation of the Berlin Grading System for moyamoya angiopathy with the use of [15O]H2O PET.

The Berlin Grading System assesses clinical severity of moyamoya angiopathy (MMA) by combining MRI, DSA, and cerebrovascular reserve capacity (CVRC). Our aim was to validate this grading system using [15O]H2O PET for CVRC. We retrospectively identified bilateral MMA patients who underwent [15O]H2O PET examination and were treated surgically at our department. Each hemisphere was classified using the Suzuki and Berlin Grading System. Preoperative symptoms and perioperative ischemias were collected, and a logistic regression analysis was performed. A total of 100 hemispheres in 50 MMA patients (36 women, 14 men) were included. Using the Berlin Grading System, 2 (2.8%) of 71 symptomatic hemispheres were categorized as grade I, 14 (19.7%) as grade II, and 55 (77.5%) as grade III. The 29 asymptomatic hemispheres were characterized as grade I in 7 (24.1%) hemispheres, grade II in 12 (41.4%), and grade III in 10 (34.5%) hemispheres. Berlin grades were independent factors for identifying hemispheres as symptomatic and higher grades correlated with increasing proportion of symptomatic hemispheres (p < 0.01). The Suzuki grading did not correlate with preoperative symptoms (p = 0.26). Perioperative ischemic complications occurred in 8 of 88 operated hemispheres. Overall, complications did not occur in any of the grade I hemispheres, but in 9.1% (n = 2 of 22) and 9.8% (n = 6 of 61) of grade II and III hemispheres, respectively. In this study, we validated the Berlin Grading System with the use of [15O]H2O PET for CVRC as it could stratify preoperative symptomatology. Furthermore, we highlighted its relevance for predicting perioperative ischemic complications.

The Genetic Basis of Moyamoya Disease.

Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by progressive spontaneous bilateral occlusion of the intracranial internal cerebral arteries (ICA) and their major branches with compensatory capillary collaterals resembling a "puff of smoke" (Japanese: Moyamoya) on cerebral angiography. These pathological alterations of the vessels are called Moyamoya arteriopathy or vasculopathy and a further distinction is made between primary and secondary MMD. Clinical presentation depends on age and population, with hemorrhage and ischemic infarcts in particular leading to severe neurological dysfunction or even death. Although the diagnostic suspicion can be posed by MRA or CTA, cerebral angiography is mandatory for diagnostic confirmation. Since no therapy to limit the stenotic lesions or the development of a collateral network is available, the only treatment established so far is surgical revascularization. The pathophysiology still remains unknown. Due to the early age of onset, familial cases and the variable incidence rate between different ethnic groups, the focus was put on genetic aspects early on. Several genetic risk loci as well as individual risk genes have been reported; however, few of them could be replicated in independent series. Linkage studies revealed linkage to the 17q25 locus. Multiple studies on the association of SNPs and MMD have been conducted, mainly focussing on the endothelium, smooth muscle cells, cytokines and growth factors. A variant of the RNF213 gene was shown to be strongly associated with MMD with a founder effect in the East Asian population. Although it is unknown how mutations in the RNF213 gene, encoding for a ubiquitously expressed 591 kDa cytosolic protein, lead to clinical features of MMD, RNF213 has been confirmed as a susceptibility gene in several studies with a gene dosage-dependent clinical phenotype, allowing preventive screening and possibly the  development of new therapeutic approaches. This review focuses on the genetic basis of primary MMD only.

A snapshot of European neurosurgery December 2019 vs. March 2020: just before and during the Covid-19 pandemic.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or Covid-19), which began as an epidemic in China and spread globally as a pandemic, has necessitated resource management to meet emergency needs of Covid-19 patients and other emergent cases. We have conducted a survey to analyze caseload and measures to adapt indications for a perception of crisis. METHODS: We constructed a questionnaire to survey a snapshot of neurosurgical activity, resources, and indications during 1 week with usual activity in December 2019 and 1 week during SARS-CoV-2 pandemic in March 2020. The questionnaire was sent to 34 neurosurgical departments in Europe; 25 departments returned responses within 5 days. RESULTS: We found unexpectedly large differences in resources and indications already before the pandemic. Differences were also large in how much practice and resources changed during the pandemic. Neurosurgical beds and neuro-intensive care beds were significantly decreased from December 2019 to March 2020. The utilization of resources decreased via less demand for care of brain injuries and subarachnoid hemorrhage, postponing surgery and changed surgical indications as a method of rationing resources. Twenty departments (80%) reduced activity extensively, and the same proportion stated that they were no longer able to provide care according to legitimate medical needs. CONCLUSION: Neurosurgical centers responded swiftly and effectively to a sudden decrease of neurosurgical capacity due to relocation of resources to pandemic care. The pandemic led to rationing of neurosurgical care in 80% of responding centers. We saw a relation between resources before the pandemic and ability to uphold neurosurgical services. The observation of extensive differences of available beds provided an opportunity to show how resources that had been restricted already under normal conditions translated to rationing of care that may not be acceptable to the public of seemingly affluent European countries.

Bypass in neurosurgery-indications and techniques.

Since the introduction of cerebral bypass surgery by Professor Yasargil in 1967, a plethora of literature has been published on direct cerebral revascularization. Against this background, it is remarkable that at present, only three randomized controlled trials (RCTs) exist in the field, both dealing with extracranial to intracranial bypass surgery for flow augmentation in patients at risk to suffer ischemic or hemorrhagic stroke due to cerebrovascular disease. Next to flow augmentation, the other main indication for bypass surgery is to provide flow replacement following proximal vessel sacrifice for treatment of complex aneurysms or skull base tumors. The aim of this review was to provide a comprehensive overview of the literature regarding the indications and the techniques of cerebral bypass surgery for prevention of cerebral ischemia.

Cranial nerve deficits in giant cavernous carotid aneurysms and their relation to aneurysm morphology and location.

BACKGROUND: Giant cavernous carotid aneurysms (GCCAs) usually exert substantial mass effect on adjacent intracavernous cranial nerves. Since predictors of cranial nerve deficits (CNDs) in patients with GCCA are unknown, we designed a study to identify associations between CND and GCCA morphology and the location of mass effect. METHODS: This study was based on data from the prospective clinical and imaging databases of the Giant Intracranial Aneurysm Registry. We used magnetic resonance imaging and digital subtraction angiography to examine GCCA volume, presence of partial thrombosis (PT), GCCA origins, and the location of mass effect. We also documented whether CND was present. RESULTS: We included 36 GCCA in 34 patients, which had been entered into the registry by eight participating centers between January 2009 and March 2016. The prevalence of CND was 69.4%, with one CND in 41.7% and more than one in 27.5%. The prevalence of PT was 33.3%. The aneurysm origin was most frequently located at the anterior genu (52.8%). The prevalence of CND did not differ between aneurysm origins (p = 0.29). Intracavernous mass effect was lateral in 58.3%, mixed medial/lateral in 27.8%, and purely medial in 13.9%. CND occurred significantly more often in GCCA with lateral (81.0%) or mixed medial/lateral (70.0%) mass effect than in GCCA with medial mass effect (20.0%; p = 0.03). After adjusting our data for the effects of the location of mass effect, we found no association between the prevalence of CND and aneurysm volume (odds ratio (OR) 1.30 (0.98-1.71); p = 0.07), the occurrence of PT (OR 0.64 (0.07-5.73); p = 0.69), or patient age (OR 1.02 (95% CI 0.95-1.09); p = 0.59). CONCLUSIONS: Distinguishing between medial versus lateral location of mass effect may be more helpful than measuring aneurysm volumes or examining aneurysm thrombosis in understanding why some patients with GCCA present with CND while others do not. CLINICAL TRIAL REGISTRATION NO: NCT02066493 ( clinicaltrials.gov ).

[Surgical treatment of adult spinal deformities]. / Operative Behandlung adulter spinaler Deformitäten.

BACKGROUND: Adult spinal deformity (ASD) is mostly a progressive disease which usually leads to chronic pain. Due to increased prevalence in older people many patients suffer from comorbidities, which make conservative and surgical treatment even more complex. OBJECTIVE: This article provides an overview on the current conservative and surgical treatment options. MATERIAL AND METHODS: An extensive literature search was carried out via Medline plus an additional evaluation of the authors' personal experiences was performed. RESULTS: The current conservative and surgical treatments are outlined and potential risk factors and predictors which may lead to inferior clinical outcome are discussed. CONCLUSION: Patients for whom even conservative treatment leads to success should be identified earlier and better. The surgical treatment ranges from minimally invasive decompression to multilevel fusions. Complications in large corrective interventions can be substantial but if the indications are correctly assessed, such complex surgical treatment has excellent clinical results in terms of pain and quality of life.

[Operative treatment of degenerative diseases of the lumbar spine]. / Operative Versorgung degenerativer Erkrankungen der Lendenwirbelsäule.

BACKGROUND: Degenerative diseases of the lumbar spine and associated lower back pain represent a major epidemiological and health-related economic challenge. A distinction is made between specific and unspecific lower back pain. In specific lower back pain lumbar disc herniation and spinal canal stenosis with or without associated segment instability are among the most frequent pathologies. Diverse conservative and operative strategies for treatment of these diseases are available. OBJECTIVES: The aim of this article is to present an overview of current data and an evidence-based assessment of the possible forms of treatment. MATERIAL AND METHODS: An extensive literature search was carried out via Medline plus an additional evaluation of the authors' personal experiences. RESULTS: Conservative and surgical treatment represent efficient treatment options for degenerative diseases of the lumbar spine. Surgical treatment of lumbar disc herniation shows slight advantages compared to conservative treatment consisting of faster recovery of neurological deficits and a faster restitution of pain control. Surgical decompression is superior to conservative measures for the treatment of spinal canal stenosis and degenerative spondylolisthesis. In this scenario conservative treatment represents an important supporting measure for surgical treatment in order to improve the mobility of patients and the outcome of surgical treatment. CONCLUSION: The treatment of specific lower back pain due to degenerative lumbar pathologies represents an interdisciplinary challenge, requiring both conservative and surgical treatment strategies in a synergistic treatment concept in order to achieve the best results for patients.

Inflammatory Events Following Subarachnoid Hemorrhage (SAH).

Acute SAH from a ruptured intracranial aneurysm contributes for 30% of all hemorrhagic strokes. The bleeding itself occurs in the subarachnoid space. Nevertheless, injury to the brain parenchyma occurs as a consequence of the bleeding, directly, via several well-defined mechanisms and pathways, but also indirectly, or secondarily. This secondary brain injury following SAH has a variety of causes and possible mechanisms. Amongst others, inflammatory events have been shown to occur in parallel to, contribute to, or even to initiate programmed cell death (PCD) within the central nervous system (CNS) in human and animal studies alike. Mechanisms of secondary brain injury are of utmost interest not only to scientists, but also to clinicians, as they often provide possibilities for translational approaches as well as distinct time windows for tailored treatment options. In this article, we review secondary brain injury due to inflammatory changes, that occur on cellular, as well as on molecular level in the various different compartments of the CNS: the brain vessels, the subarachnoid space, and the brain parenchyma itself and hypothesize about possible signaling mechanisms between these compartments.

[Operative treatment of the degenerative cervical spine]. / Operative Versorgung der degenerativen Halswirbelsäule.

BACKGROUND: Degenerative alterations of the cervical spine often entail disc herniations and stenoses of the spinal canal and/or neural foramen. Mediolateral or lateral compression of nerve roots causes cervical radiculopathy, which is an indication for surgery in cases of significant motor deficits or refractory pain. Median canal encroachment may result in compression of the spinal cord and cervical myelopathy. Its natural history is typically characterized by episodic deterioration, so that surgical decompression is indicated in cases of clear myelopathic signs. OBJECTIVE: The aim of the present article is to outline the operative options for patients with cervical radiculopathy and myelopathy. Furthermore, we describe the operative complications and the outcome in these patients. MATERIAL AND METHODS: For this manuscript a systematic PubMed search was carried out, the papers were systematically analyzed for the best evidence and this was combined with the authors' experience. RESULTS AND CONCLUSION: Depending on the cervical pathology, the most prevalent surgical options for radiculopathy include anterior cervical discectomy and fusion (ACDF), cervical arthroplasty or posterior cervical foraminotomy. Cervical myelopathy may be decompressed by ACDF, corpectomy or posterior approaches like laminectomy plus instrumented fusion or laminoplasty. The outcome depends on the cervical pathology and the type of operation. Overall, in long-term follow-up studies the results of all surgical techniques on the cervical spine are generally considered to be very good, although specific patient characteristics are more suited for a particular approach.

Intraosseous basivertebral nerve ablation for the treatment of chronic low back pain: a prospective randomized double-blind sham-controlled multi-center study.

PURPOSE: To evaluate the safety and efficacy of radiofrequency (RF) ablation of the basivertebral nerve (BVN) for the treatment of chronic low back pain (CLBP) in a Food and Drug Administration approved Investigational Device Exemption trial. The BVN has been shown to innervate endplate nociceptors which are thought to be a source of CLBP. METHODS: A total of 225 patients diagnosed with CLBP were randomized to either a sham (78 patients) or treatment (147 patients) intervention. The mean age within the study was 47 years (range 25-69) and the mean baseline ODI was 42. All patients had Type I or Type II Modic changes of the treated vertebral bodies. Patients were evaluated preoperatively, and at 2 weeks, 6 weeks and 3, 6 and 12 months postoperatively. The primary endpoint was the comparative change in ODI from baseline to 3 months. RESULTS: At 3 months, the average ODI in the treatment arm decreased 20.5 points, as compared to a 15.2 point decrease in the sham arm (p = 0.019, per-protocol population). A responder analysis based on ODI decrease ≥ 10 points showed that 75.6% of patients in the treatment arm as compared to 55.3% in the sham control arm exhibited a clinically meaningful improvement at 3 months. CONCLUSION: Patients treated with RF ablation of the BVN for CLBP exhibited significantly greater improvement in ODI at 3 months and a higher responder rate than sham treated controls. BVN ablation represents a potential minimally invasive treatment for the relief of chronic low back pain. These slides can be retrieved under Electronic Supplementary Material.

Prediction of cerebral infarction and patient outcome in aneurysmal subarachnoid hemorrhage: comparison of new and established radiographic, clinical and combined scores.

BACKGROUND AND PURPOSE: There are numerous grading scales to describe the severity of aneurysmal subarachnoid hemorrhage (aSAH) and to predict outcome. Historically, outcome measures are heterogeneous and the comparability of grading scales is therefore limited. We designed this study to compare radiographic, clinical and combined grading systems in aSAH. METHODS: Data from 423 consecutive patients with aSAH were analyzed. Modified Fisher (mFish), Barrow Neurological Institute (BNI), Hunt and Hess (HH), World Federation of Neurosurgical Societies (WFNS), VASOGRADE (VG) and HAIR scores were calculated from clinical and radiographic data or the combination of both. Outcome measures included the development of new cerebral infarction (CI) and functional patient outcome assessed by the modified Rankin scale. RESULTS: Cerebral infarction and unfavorable outcome were predicted by radiographic, clinical and combined measures (each with P ≤ 0.001). Clinical (HH, WFNS) and combined (VG, HAIR) scores had superior predictive power for CI compared with mFish grading but not BNI [area under the curve (AUC)mFish 0.612, AUCBNI 0.616, AUCWFNS 0.672, AUCHH 0.673, AUCVG 0.674, AUCHAIR 0.638]. Predictive performances of clinical gradings (HH, WFNS) for patient outcome were superior to radiographic measures and of similar quality or better than combined systems (AUCBNI 0.628, AUCmFish 0.654, AUCWFNS 0.736, AUCHH 0.749, AUCVG 0.711, AUCHAIR 0.739). CONCLUSIONS: Knowledge of the merits and limitations of clinical, radiographic and combined scores is necessary in routine clinical practice. The new combined grading systems (HAIR, VG) showed no superiority compared with the established clinical measures (WFNS, HH) in predicting CI and unfavorable patient outcome.

Revision surgery for cervical artificial disc: Surgical technique and clinical results.

OBJECTIVE: Cervical artificial disc replacement (C-ADR) was developed with the goal of preserving mobility of the cervical segment in patients with degenerative disc disease. So far, little is known about experiences with revision surgery and explantation of C-ADRs. Here, we report our experience with revision the third generation, Galileo-type disc prosthesis from a retrospective study of two institutions. PATIENTS AND METHODS: Between November 2008 and July 2016, 16 patients with prior implantation of C-ADR underwent removal of the Galileo-type disc prosthesis (Signus, Medizintechnik, Germany) due to a call back by industry. In 10 patients C-ADR was replaced with an alternative prosthesis, 6 patients received an ACDF. Duration of surgery, time to revision, surgical procedure, complication rate, neurological status, histological findings and outcome were examined in two institutions. RESULTS: The C-ADR was successfully revised in all patients. Surgery was performed through the same anterior approach as the initial access. Duration of the procedure varied between 43 and 80min. Access-related complications included irritation of the recurrent nerve in one patient and mal-positioning of the C-ADR in another patient. Follow up revealed two patients with permanent mild/moderate neurologic deficits, NDI (neck disability index) ranged between 10 and 42%. CONCLUSIONS: Anterior exposure of the cervical spine for explantation and revision of C-ADR performed through the initial approach has an overall complication rate of 18.75%. Replacements of the Galileo-type disc prosthesis with an alternative prosthesis or conversion to ACDF are both suitable surgical options without significant difference in outcome.

COXIBRAIN: results of the prospective, randomised, phase II/III study for the selective COX-2 inhibition in chronic subdural haematoma patients.

BACKGROUND: Chronic subdural haematomas (cSDHs) have shown an increasing incidence in an ageing population over the last 20 years, while unacceptable recurrence rates of up to 30 % persist. The recurrence rate of cSDH seems to be related to the excessive neoangiogenesis in the parietal membrane, which is mediated via vascular endothelial growth factor (VEGF). This is found to be elevated in the haematoma fluid and is dependent on eicosanoid/prostaglandin and thromboxane synthesis via cyclo-oxygenase-2 (COX-2). With this investigator-initiated trial (IIT) it was thought to diminish the recurrence rate of operated-on cSDHs by administering a selective COX-2 inhibitor (Celecoxib) over 4 weeks' time postoperatively in comparison to a control group. METHOD: The thesis of risk reduction of cSDH recurrence in COX-2-inhibited patients was to be determined in a prospective, randomised, two-armed, open phase-II/III study with inclusion of 180 patients over a 2-year time period in four German university hospitals. The treated- and untreated-patient data were to be analysed by Fisher's exact test (significance level of alpha, 0.05 [two-sided]). RESULTS: After screening of 246 patients from January 2009 to April 2010, the study had to be terminated prematurely as only 23 patients (9.3 %) could be enrolled because of on-going non-steroid anti-rheumatic (NSAR) drug treatment or contraindication to Celecoxib medication. In the study population, 13 patients were treated in the control group (six women, seven men; average age 66.8 years; one adverse event (AE)/serious adverse event (SAE) needing one re-operation because of progressive cSDH (7.7 %); ten patients were treated in the treatment group (one woman, nine men; average age 64.7 years; five AEs/SAEs needing two re-operations because of one progressive cSDH and one wound infection [20 %]). Significance levels are obsolete because of insufficient patient numbers. CONCLUSIONS: The theoretical advantage of COX-2 inhibition in the recurrent cSDH could not be transferred into the treatment of German cSDH patients as 66.6 % of the patients showed strict contraindications for Celecoxib. Furthermore, 55 % of the patients were already treated with some kind of COX-2 inhibition and, nevertheless, developed cSDH. Thus, although conceptually appealing, an anti-angiogenic therapy with COX-2 inhibitors for cSDH could not be realised in this patient population due to the high prevalence of comorbidities excluding the administration of COX2 inhibitors.