An exploratory study on the association between blood-based biomarkers and subacute neurometabolic changes following mild traumatic brain injury.

BACKGROUND AND OBJECTIVES: Blood-based biomarkers and advanced neuroimaging modalities such as magnetic resonance spectroscopy (MRS) or diffusion tensor imaging (DTI) have enhanced our understanding of the pathophysiology of mild traumatic brain injury (mTBI). However, there is limited published data on how blood biomarkers relate to neuroimaging biomarkers post-mTBI. METHODS: To investigate this, 30 patients with mTBI and 21 healthy controls were enrolled. Data was collected at two timepoints postinjury: acute, < 24 h, (blood) and subacute, four-to-six weeks, (blood and imaging). Interleukin (IL) 6 and 10 (inflammation), free thiols (systemic oxidative stress) and neurofilament light (NF-L) (axonal injury) were quantified in plasma. The neurometabolites total N-acetyl aspartate (tNAA) (neuronal energetics), Myo-Inositol (Ins) and total Choline (tCh) (inflammation) and, Glutathione (GSH, oxidative stress) were quantified using MRS. RESULTS: Concentrations of IL-6 and IL-10 were significantly elevated in the acute phase post-mTBI, while NF-L was elevated only in the subacute phase. Total NAA was lowered in patients with mTBI, although this difference was only nominally significant (uncorrected P < 0.05). Within the patient group, acute IL-6 and subacute tNAA levels were negatively associated (r = - 0.46, uncorrected-P = 0.01), albeit not at a threshold corrected for multiple testing (corrected-P = 0.17). When age was added as a covariate a significant increase in correlation magnitude was observed (ρ = - 0.54, corrected-P = 0.03). CONCLUSION: This study demonstrates potential associations between the intensity of the inflammatory response in the acute phase post-mTBI and neurometabolic perturbations in the subacute phase. Future studies should assess the longitudinal dynamics of blood-based and imaging biomarkers after injury.

Dexamethasone versus Surgery for Chronic Subdural Hematoma.

BACKGROUND: The role of glucocorticoids without surgical evacuation in the treatment of chronic subdural hematoma is unclear. METHODS: In this multicenter, open-label, controlled, noninferiority trial, we randomly assigned symptomatic patients with chronic subdural hematoma in a 1:1 ratio to a 19-day tapering course of dexamethasone or to burr-hole drainage. The primary end point was the functional outcome at 3 months after randomization, as assessed by the score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]). Noninferiority was defined by a lower limit of the 95% confidence interval of the odds ratio for a better functional outcome with dexamethasone than with surgery of 0.9 or more. Secondary end points included scores on the Markwalder Grading Scale of symptom severity and on the Extended Glasgow Outcome Scale. RESULTS: From September 2016 through February 2021, we enrolled 252 patients of a planned sample size of 420; 127 were assigned to the dexamethasone group and 125 to the surgery group. The mean age of the patients was 74 years, and 77% were men. The trial was terminated early by the data and safety monitoring board owing to safety and outcome concerns in the dexamethasone group. The adjusted common odds ratio for a lower (better) score on the modified Rankin scale at 3 months with dexamethasone than with surgery was 0.55 (95% confidence interval, 0.34 to 0.90), which failed to show noninferiority of dexamethasone. The scores on the Markwalder Grading Scale and Extended Glasgow Outcome Scale were generally supportive of the results of the primary analysis. Complications occurred in 59% of the patients in the dexamethasone group and 32% of those in the surgery group, and additional surgery was performed in 55% and 6%, respectively. CONCLUSIONS: In a trial that involved patients with chronic subdural hematoma and that was stopped early, dexamethasone treatment was not found to be noninferior to burr-hole drainage with respect to functional outcomes and was associated with more complications and a greater likelihood of later surgery. (Funded by the Netherlands Organization for Health Research and Development and others; DECSA EudraCT number, 2015-001563-39.).

Change in Hematoma Size after Dexamethasone Therapy in Chronic Subdural Hematoma Subtypes: A Prospective Study in Symptomatic Patients.

The main treatment strategy for chronic subdural hematoma is surgical intervention. When a conservative pharmacological approach is considered in symptomatic patients, mainly dexamethasone therapy is applied. Recent trials revealed dexamethasone therapy to be an ineffective treatment in symptomatic patients with chronic subdural hematoma. Whether the efficacy of dexamethasone therapy differs in radiological hematoma subtypes is unknown. The aim of this substudy was to identify which hematoma subtype might be favorable for dexamethasone therapy. As part of a randomized controlled trial, symptomatic chronic subdural hematoma patients received 19-days dexamethasone therapy. The primary outcome measure was the change in hematoma size as measured on follow-up computed tomography (CT) after 2 weeks of dexamethasone in six hematoma (architectural and density) subtypes: homogeneous total, laminar, separated and trabecular architecture types, and hematoma without hyperdense components (homogeneous hypodense, isodense) and with hyperdense components (homogeneous hyperdense, mixed density). We analyzed hematoma thickness, midline shift, and volume using multi-variable linear regression adjusting for age, sex and baseline value of the specific radiological parameter. From September 2016 until February 2021, 85 patients were included with a total of 114 chronic subdural hematoma. The mean age was 76 years and 25% were women. Larger decrease in hematoma thickness and midline shift was revealed in hematoma without hyperdense components compared with hematoma with hyperdense components (adjusted [adj.] b -2.2 mm, 95% confidence interval [CI] -4.1 to -0.3 and adj. b -1.3 mm, 95% CI -2.7 to 0.0 respectively). Additional surgery was performed in 57% of patients with the highest observed rate (81%) in separated hematoma. Largest hematoma reduction and better clinical improvement was observed in chronic subdural hematoma without hyperdense components after dexamethasone therapy. Evaluation of these parameters can be part of an individualized treatment strategy.

Surgery After Primary Dexamethasone Treatment for Patients with Chronic Subdural Hematoma-A Retrospective Study.

BACKGROUND: We aimed to quantify the need for additional surgery in patients with chronic subdural hematoma (CSDH) primarily treated with dexamethasone and to identify patient characteristics associated with additional surgery. METHODS: Data were retrospectively collected from 283 patients with CSDH, primarily treated with dexamethasone, in 3 hospitals from 2008 to 2018. Primary outcome was the need for additional surgery. The association between baseline characteristics and additional surgery was analyzed with univariable and multivariable logistic regression analysis and presented as adjusted odds ratios (aOR). RESULTS: In total, 283 patients with CSDH were included: 146 patients (51.6%) received 1 dexamethasone course (DXM group), 30 patients (10.6%) received 2 dexamethasone courses (DXM-DXM group), and 107 patients (37.8%) received additional surgery (DXM-SURG group). Patients who underwent surgery more often had a Markwalder Grading Scale of 2 (as compared with 1, aOR 2.05; 95% confidence interval [CI] 0.90-4.65), used statins (aOR 2.09; 95% CI 1.01-4.33), had a larger midline shift (aOR 1.10 per mm; 95% CI 1.01-1.21) and had larger hematoma thickness (aOR 1.16 per mm; 95% CI 1.09-1.23), had a bilateral hematoma (aOR 1.85; 95% CI 0.90-3.79), and had a separated hematoma (as compared with homogeneous, aOR 1.77; 95% CI 0.72-4.38). Antithrombotics (aOR 0.45; 95% CI 0.21-0.95) and trabecular hematoma (as compared with homogeneous, aOR 0.31; 95% CI 0.12-0.77) were associated with a lower likelihood of surgery. CONCLUSIONS: More than one-third of patients with CSDH primarily treated with dexamethasone received additional surgery. These patients were more severely affected amongst others with larger hematomas.

National survey on the current practice and attitudes toward the management of chronic subdural hematoma.

BACKGROUND: Chronic subdural hematoma (CSDH) is a frequent pathological entity in daily clinical practice. However, evidence-based CSDH-guidelines are lacking and level I evidence from randomized clinical trials (RCTs) is limited. In order to establish and subsequently implement a guideline, insight into current clinical practice and attitudes toward CSDH-treatment is required. The aim is to explore current practice and attitudes toward CSDH-management in the Netherlands. METHODS: A national online survey was distributed among Dutch neurologists and neurosurgeons, examining variation in current CSDH-management through questions on treatment options, (peri)operative management, willingness to adopt new treatments and by presenting four CSDH-cases. RESULTS: One hundred nineteen full responses were received (8% of neurologists, N = 66 and 35% of neurosurgeons, N = 53). A majority of the respondents had a positive experience with burr-hole craniostomy (93%) and with a conservative policy (56%). Around a third had a positive experience with the use of dexamethasone as primary (30%) and additional (33.6%) treatment. These numbers were also reflected in the treatment preferences in the presented cases. (Peri)operative management corresponded among responding neurosurgeons. Most respondents would be willing to implement dexamethasone (98%) if equally effective as surgery and tranexamic acid (93%) if effective in CSDH-management. CONCLUSION: Variation was found regarding preferential CSDH-treatment. However, this is considered not to be insurmountable when implementing evidence-based treatments. This baseline inventory on current clinical practice and current attitudes toward CSDH-treatment is a stepping-stone in the eventual development and implementation of a national guideline.

Prevalence of Cognitive Complaints and Impairment in Patients with Chronic Subdural Hematoma and Recovery after Treatment: A Systematic Review.

Chronic subdural hematoma (CSDH) is a frequently occurring neurological disease associated with older age and use of anticoagulants. Symptoms vary from headaches to coma, but cognitive deficits can also be present. However, exact prevalence and severity of cognitive deficits in CSDH are still unknown. In this systematic review, we aim to assess cognitive status of patients with CSDH, at presentation and after treatment. PubMed, Embase and PsycInfo were searched for articles concerning cognition in CSDH. We divided cognitive changes into subjective cognitive deficit (cognitive complaints [CC]) and objective cognitive deficit (cognitive impairment [CI]). Two reviewers independently selected studies for inclusion and subsequently extracted data. Quality assessment was done by means of the Newcastle-Ottawa Scale. Reported prevalence of CC and CI was pooled with random effects meta-analysis. Out of 799 identified references, 22 met inclusion criteria. Twenty-one articles reported on prevalence of CC/CI and one study reported solely on CSDH patients with cognitive deficit. Estimated pooled prevalence of both CC and CI in CSDH at presentation was 45% (95% confidence interval [CI]: 36-54%). Four studies concerned a prospective evaluation of the effect of surgical treatment on cognition. These proved to be of fair to good quality after quality assessment. The estimated pre-treatment prevalence of objectified cognitive impairment was 61% (95% CI: 51-70%) decreasing to 18% (95% CI: 8-32%) post-surgery. From this review it can be concluded that CC and CI are very common in CSDH, with a tendency to improve after treatment. Therefore, we underline the importance of increased attention to cognitive status of these patients, with proper testing methods and treatment-testing intervals.

Drugs with anti-inflammatory effects to improve outcome of traumatic brain injury: a meta-analysis.

Outcome after traumatic brain injury (TBI) varies largely and degree of immune activation is an important determinant factor. This meta-analysis evaluates the efficacy of drugs with anti-inflammatory properties in improving neurological and functional outcome. The systematic search following PRISMA guidelines resulted in 15 randomized placebo-controlled trials (3734 patients), evaluating progesterone, erythropoietin and cyclosporine. The meta-analysis (15 studies) showed that TBI patients receiving a drug with anti-inflammatory effects had a higher chance of a favorable outcome compared to those receiving placebo (RR = 1.15; 95% CI 1.01-1.32, p = 0.041). However, publication bias was indicated together with heterogeneity (I2 = 76.59%). Stratified analysis showed that positive effects were mainly observed in patients receiving this treatment within 8 h after injury. Subanalyses by drug type showed efficacy for progesterone (8 studies, RR 1.22; 95% CI 1.01-1.47, p = 0.040), again heterogeneity was high (I2 = 62.92%) and publication bias could not be ruled out. The positive effect of progesterone covaried with younger age and was mainly observed when administered intramuscularly and not intravenously. Erythropoietin (4 studies, RR 1.20; p = 0.110; I2 = 76.59%) and cyclosporine (3 studies, RR 0.75; p = 0.189, I2 = 0%) did not show favorable significant effects. While negative findings for erythropoietin may reflect insufficient power, cyclosporine did not show better outcome at all. Current results do not allow firm conclusions on the efficacy of drugs with anti-inflammatory properties in TBI patients. Included trials showed heterogeneity in methodological and sample parameters. At present, only progesterone showed positive results and early administration via intramuscular administration may be most effective, especially in young people. The anti-inflammatory component of progesterone is relatively weak and other mechanisms than mitigating overall immune response may be more important.

Neurosurgical and Perioperative Management of Chronic Subdural Hematoma.

Objective: Surgery and specifically burr hole craniostomy is the most common first choice treatment of patients with Chronic Subdural Hematoma (CSDH). However, several aspects of neurosurgical and peri-operative management are still a subject of research, such as how to treat bilateral CSDH and the anesthetic approach. We aim to investigate the effect of the surgical approach to bilateral CSDH and the effect of anesthesia modality on outcome of CSDH patients. Methods: We retrospectively included surgically treated CSDH patients between 2005 and 2019 in three hospitals in the Netherlands. The effect of the surgical approach to bilateral CSDH (unilateral vs. bilateral decompression) and anesthesia modality (general vs. local anesthesia) on outcome (complications, recurrence, and length of hospital stay over 4 days) was studied with logistic regression adjusting for potentially confounding radiological and clinical characteristics. Results: Data of 1,029 consecutive patients were analyzed, mean age was 73.5 years (±11) and 75% of patients were male. Bilateral CSDH is independently associated with an increased risk of recurrence within 3 months in logistic regression analysis (aOR 1.7, 95% CI: 1.1-2.5) but recurrence rate did not differ between primary bilateral or unilateral decompression of bilateral CSDH. (15 vs. 17%, p = 0.775). Logistic regression analysis showed that general anesthesia was independently associated with an increased risk of complications (aOR 1.8, 95% CI: 1.0-3.3) and with a length of hospital admission of over 4 days (aOR 8.4, 95% CI: 5.6-12.4). Conclusions: Bilateral CSDH is independently associated with higher recurrence rates. As recurrence rates in bilateral CSDH are similar for different surgical approaches, the optimal choice for primary bilateral decompression of bilateral CSDH could vary per patient. General anesthesia for surgical treatment of CSDH is associated with higher complication rates and longer hospital admission.

Dexamethasone therapy versus surgery for chronic subdural haematoma (DECSA trial): study protocol for a randomised controlled trial.

BACKGROUND: Chronic subdural haematoma (CSDH) is a common neurological disease with a rapidly rising incidence due to increasing age and widespread use of anticoagulants. Surgical intervention by burr-hole craniotomy (BHC) is the current standard practice for symptomatic patients, but associated with complications, a recurrence rate of up to 30% and increased mortality. Dexamethasone (DXM) therapy is, therefore, used as a non-surgical alternative but considered to achieve a lower success rate. Furthermore, the benefit of DXM therapy appears much more deliberate than the immediate relief from BHC. Lack of evidence and clinical equipoise among caregivers prompts the need for a head-to-head randomised controlled trial. The objective of this study is to compare the effect of primary DXM therapy versus primary BHC on functional outcome and cost-effectiveness in symptomatic patients with CSDH. METHODS/DESIGN: This study is a prospective, multicentre, randomised controlled trial (RCT). Consecutive patients with a CSDH with a Markwalder Grading Scale (MGS) grade 1 to 3 will be randomised to treatment with DXM or BHC. The DXM treatment scheme will be 16 mg DXM per day (8 mg twice daily, days 1 to 4) which is then halved every 3 days until a dosage of 0.5 mg a day on day 19 and stopped on day 20. If the treatment response is insufficient (i.e. persistent or progressive symptomatology due to insufficient haematoma resolution), additional surgery can be performed. The primary outcomes are the functional outcome by means of the modified Rankin Scale (mRS) score at 3 months and cost-effectiveness at 12 months. Secondary outcomes are quality of life at 3 and 12 months using the Short Form Health Survey (SF-36) and Quality of Life after Brain Injury Overall Scale (QOLIBRI), haematoma thickness after 2 weeks on follow-up computed tomography (CT), haematoma recurrence during the first 12 months, complications and drug-related adverse events, failure of therapy within 12 months after randomisation and requiring intervention, mortality during the first 3 and 12 months, duration of hospital stay and overall healthcare and productivity costs. To test non-inferiority of DXM therapy compared to BHC, 210 patients in each treatment arm are required (assumed adjusted common odds ratio DXM compared to BHC 1.15, limit for inferiority < 0.9). The aim is to include a total of 420 patients in 3 years with an enrolment rate of 60%. DISCUSSION: The present study should demonstrate whether treatment with DXM is as effective as BHC on functional outcome, at lower costs. TRIAL REGISTRATION: EUCTR 2015-001563-39 . Date of registration: 29 March 2015.

Prognosis in moderate and severe traumatic brain injury: external validation of the IMPACT models and the role of extracranial injuries.

BACKGROUND: Several prognostic models to predict outcome in traumatic brain injury (TBI) have been developed, but few are externally validated. We aimed to validate the International Mission on Prognosis and Analysis of Clinical Trials in TBI (IMPACT) prognostic models in a recent unselected patient cohort and to assess the additional prognostic value of extracranial injury. METHODS: The Prospective Observational COhort Neurotrauma (POCON) registry contains 508 patients with moderate or severe TBI, who were admitted in 2008 and 2009 to five trauma centers in the Netherlands. We predicted the probability of mortality and unfavorable outcome at 6 months after injury with the IMPACT prognostic models. We studied discrimination (area under the curve [AUC]) and calibration. We added the extracranial component of the Injury Severity Score (ISS) to the models and calculated the increase in AUC. RESULTS: The IMPACT models had an adequate discrimination in the POCON registry, with AUCs in the external validation between 0.85 and 0.90 for mortality and between 0.82 and 0.87 for unfavorable outcome. Observed outcomes agreed well with predicted outcomes. Adding extracranial injury slightly improved predictions in the overall population (unfavorable outcome: AUC increase of 0.002, p = 0.02; mortality: AUC increase of 0.000, p = 0.37) but more clearly in patients with moderate TBI (unfavorable outcome: AUC increase of 0.008, p < 0.01, mortality: AUC increase of 0.012, p = 0.02) and patients with minor computed tomographic result abnormalities (unfavorable outcome: AUC increase of 0.013, p < 0.01; mortality: AUC increase of 0.001, p = 0.08). CONCLUSION: The IMPACT models performed well in a recent series of TBI patients. We found some additional impact of extracranial injury on outcome, specifically in patients with less severe TBI or minor computed tomographic result abnormalities. LEVEL OF EVIDENCE: Epidemiologic/prognostic study.

Gas chromatography-mass spectrometric assay for propofol in cerebrospinal fluid of traumatic brain patients.

A sensitive gas chromatography-mass spectrometry method for measuring propofol in cerebrospinal fluid is described, validated and applied to four patients after traumatic brain injury. The limit of quantitation was 2 microg/L using a volume of 0.5 mL. The inter- and intra-assay coefficients of variation were 5.9 and 5.1%, respectively. The assay covers the linear concentration range of 2-50 microg/L, which is relevant in clinical pharmacokinetic studies when propofol is used in the Intensive Care Unit as a sedative agent or to lower the intracranial pressure.