Additional treatment after primary conservative treatment in patients with chronic subdural hematoma-A retrospective study.

OBJECTIVE: Chronic subdural hematoma (CSDH) is a common neurological condition and is typically treated with burr hole craniostomy. Nevertheless, conservative treatment may lead to spontaneous hematoma resolution in some patients. This study aims to describe the characteristics of patients who were treated conservatively without the eventual need for additional treatment. METHODS: Data were retrospectively collected from patients who were primarily treated conservatively in three hospitals in the Netherlands from 2008 to 2018. The Primary outcome was the nonnecessity of additional treatment within 3 months after the initial CSDH diagnosis. We used univariable and multivariable logistic regression analyses to identify factors associated with not receiving additional treatment. RESULTS: In this study, 83 patients were included and 61 patients (73%) did not receive additional treatment within 3 months. Upon first presentation, the patients had a Markwalder Grading Scale score (MGS) of 0 (n = 5, 6%), 1 (n = 43, 52%), and 2 (n = 35, 42%). Additional treatment was less often received by patients with smaller hematoma volumes (adjusted odds ratio [aOR] 0.78 per 10 mL; 95% confidence interval [CI] 0.64-0.92). Patients using antithrombotic medication also received less additional treatment, but this association was not significant (aOR 2.02; 95% CI 0.61-6.69). CONCLUSIONS: Three quarters of the initially conservatively treated CSDH patients do not receive additional management. Typically, these patients have smaller hematoma volumes. Further, prospective research is needed to distinguish which patients require surgical intervention and in whom primary conservative treatment suffices.

Exploring the kynurenine pathway in mild traumatic brain injury: A longitudinal study.

A potential source of novel biomarkers for mTBI is the kynurenine pathway (KP), a metabolic pathway of tryptophan (Trp), that is up-regulated by neuroinflammation and stress. Considering that metabolites of the KP (kynurenines) are implicated in various neuropsychiatric diseases, exploration of this pathway could potentially bridge the gap between physiological and psychological factors in the recovery process after mTBI. This study, therefore, set out to characterize the KP after mTBI and to examine associations with long-term outcome. Patients were prospectively recruited at the emergency department (ED), and blood samples were obtained in the acute phase (<24 h; N = 256) and at 1-month follow-up (N = 146). A comparison group of healthy controls (HC; N = 32) was studied at both timepoints. Trp, kynurenines, and interleukin (IL)-6 and IL-10 were quantified in plasma. Clinical outcome was measured at six months post-injury. Trp, xanthurenic acid (XA), and picolinic acid (PA) were significantly reduced in patients with mTBI relative to HC, corrected for age and sex. For Trp (d = -0.57 vs. d = -0.29) and XA (d = -0.98 vs. d = -0.32), larger effects sizes were observed during the acute phase compared to one-month follow-up, while for PA (d = -0.49 vs. d = -0.52) effect sizes remained consistent. Findings for other kynurenines (e.g., kynurenine, kynurenic acid, and quinolinic acid) were non-significant after correction for multiple testing. Within the mTBI group, lower acute Trp levels were significantly related to incomplete functional recovery and higher depression scores at 6 months post-injury. No significant relationships were found for Trp, XA, and PA with IL-6 or IL-10 concentrations. In conclusion, our findings indicate that perturbations of the plasma KP in the hyperacute phase of mTBI and 1 month later are limited to the precursor Trp, and glutamate system modulating kynurenines XA and PA. Correlations between acute reductions of Trp and unfavorable outcomes may suggest a potential substrate for pharmacological intervention.

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.).

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.

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.

Posterior fossa progressive multifocal leukoencephalopathy: first presentation of an unknown autoimmune disease.

We present a case of a 57-year-old man who presented with progressive cerebellar dysarthria and cerebellar ataxia. Additional investigations confirmed the diagnosis of progressive multifocal leukoencephalopathy (PML) in the posterior fossa. This is a demyelinating disease of the central nervous system, caused by an opportunistic infection with John Cunningham virus. PML has previously been considered a lethal condition, but because of careful monitoring of patients with HIV and of patients using immunosuppressive drugs it is discovered in earlier stages and prognosis can be improved. Our patient had no known immune-compromising state, but further work-up revealed that the PML was most likely the first presentation of a previous untreated autoimmune disorder: sarcoidosis.

Burnout and engagement among resident doctors in the Netherlands: a national study.

OBJECTIVES: This study was performed in order to gather insight into the well-being of Dutch medical residents. METHODS: In 2005, all Dutch residents registered through the Medical Registration Committee (n = 5245) were sent a self-report questionnaire to assess socio-demographic and work-related characteristics, burnout and engagement. RESULTS: Of the 5140 eligible residents, 2115 completed the questionnaire (41%). Of those, 21% fulfilled the criteria for moderate to severe burnout and 27% were highly engaged with their work. Women reported more emotional exhaustion and less depersonalisation than men; age was weakly but significantly related to depersonalisation, and married residents and parents reported less depersonalisation than their single or childless counterparts. More men than women were found to be highly engaged and men specifically reported more vigour. Number of years in training was weakly but significantly related to absorption. With regard to occupational risk factors, significant between-group differences were found for the effects of clinical setting on emotional exhaustion, engagement, vigour and absorption. Residents in training in a mental health clinic were most emotionally exhausted and those in a rehabilitation centre were least engaged. General surgery represented the specialty with the lowest number of residents suffering from burnout, followed by obstetrics and gynaecology and any supportive specialty. General surgery residents were also found to be more highly engaged, vigorous, dedicated and absorbed than others. CONCLUSIONS: As more than a fifth of the medical residents who responded could be diagnosed as suffering from burnout, we conclude that this problem needs addressing in the Dutch health care system, especially given that a relationship was proven between burnout and suboptimal patient care. We must look for solutions and interventions which will improve the work situation of medical residents. Striving for healthy workers in health care has to become daily practice.

Sepsis syndrome and death in trauma patients are associated with variation in the gene encoding tumor necrosis factor.

OBJECTIVE: Patients encountering severe trauma are at risk of developing sepsis syndrome and subsequent multiple organ failure. This is often associated with fatal outcome despite survival of the initial injury. We postulate that variation of the gene coding for tumor necrosis factor (TNF)-alpha is associated with increased occurrence of sepsis syndrome and mortality in trauma patients. DESIGN: Prospective cohort study; validation in an external replication sample. SETTING: Tertiary academic medical center. PATIENTS: We included 159 severely traumatized patients from a single center. Serial blood samples were analyzed for serum concentrations of TNF-alpha and lymphotoxin-alpha (LTA). We genotyped nine polymorphisms in the TNF gene and tested for an association with sepsis syndrome and outcome. Genetic associations were validated in an external replication sample (n = 76). We examined the peripheral blood transcriptome in 28 patients by whole genome-based profiling and validated the results. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Carriage of the TNF rs1800629 A allele was associated with higher TNF-alpha serum concentrations on the first day after trauma and during follow-up (two-sided p = 5.0 x 10(-5)), with development of sepsis syndrome (odds ratio 7.14, two-sided p = 1.2 x 10(-6); external validation sample [n = 76]: odds ratio 3.3, one-sided p = .03), and with fatal outcome (odds ratio 7.65, two-sided p = 1.9 x 10(-6)). Carriage of the TNF rs1800629 A allele was associated with differential expression of genes representing stronger proinflammatory and apoptotic responses compared with carriage of the wild-type allele. CONCLUSIONS: Common TNF gene variants are associated with sepsis syndrome and death after severe injury. These findings are strongly supported by functional data and may be important for developing preemptive anti-inflammatory interventions in carriers of the risk-associated allele.

Molecular analysis as a tool in the differential diagnosis of VHL disease-related tumors.

Von Hippel-Lindau (VHL) disease is an autosomal dominant tumor syndrome, in which hemangioblastomas (HBs), clear cell renal cell carcinomas (RCCs), and pheochromocytomas are the most frequently encountered tumors. The differential diagnosis of dedifferentiated tumors in general can be difficult, as standard histologic and immunohistochemical investigations do not always allow a definitive diagnosis. We used molecular genetic analysis to resolve the differential diagnosis of sarcomatoid RCC versus pheochromocytoma of a (peri)renal tumor in a VHL patient. Germline mutation analysis identified the C407T mutation, which has been related to a VHL phenotype in which pheochromocytomas are rare. Chromosomal imbalances detected in the tumor by CGH showed a pattern typical for RCCs and not for pheochromocytomas. CGH analysis of the multiple tumors of this VHL patient revealed a comparable karyotype in the metastatic tumors and the (peri)renal tumor. Concordantly, although the germline mutation was detected in all analyzed tumors, LOH 3p was only detected in the (peri)renal mass and most metastases. Overall, based on all genetic data, this tumor corroborated a diagnosis of metastatic sarcomatoid RCC. In line with these observations is the immunopositivity for the RCC-specific RC38 detected in the (peri)renal mass and the metastases that was not detected in pheochromocytomas. The RCC specific marker G250 was uninformative as it stains positive in all types of VHL tumors. This case report illustrates the promising role of genetic analysis in the differential diagnosis of histologically dedifferentiated tumors.

Analysis of von hippel-lindau mutations with comparative genomic hybridization in sporadic and hereditary hemangioblastomas: possible genetic heterogeneity.

OBJECT: Hemangioblastomas (HBs) occur sporadically or as a manifestation of von Hippel-Lindau (VHL) disease. In the majority of VHL-related HBs, inactivation of the VHL tumor suppressor gene (TSG), which is located on chromosome 3p25-26, is found. The VHL gene is assumed to be involved also in the development of sporadic HBs. In a previous study of chromosomal aberrations of sporadic HBs, multiple chromosomal imbalances were found in the majority of tumors. The aim of this study was to analyze further both sporadic HBs and VHL-related HBs to determine if these histopathologically identical tumors have a different genetic background. METHODS: Sixteen sporadic HBs and seven VHL-related HBs were identified by clinical criteria and analyzed. Comparative genomic hybridization was used to screen for chromosomal imbalances throughout the entire HB genome. Additionally, mutation analysis of the VHL gene was performed using direct sequencing. Loss of chromosome 3 and multiple other chromosomal imbalances were found in the sporadic HBs, although only one imbalance, a loss of chromosome 3, was detected in the seven VHL-related HBs. Somatic VHL gene mutations were found in one third of sporadic HBs, whereas a mutation of the VHL gene was detected in all VHL-related HBs. CONCLUSIONS: These results indicate that the molecular mechanisms underlying sporadic HBs and VHL-related HBs are different. Inactivation of the VHL gene is probably not the most important event in the tumorigenesis of sporadic HBs. Other mechanisms of inhibition of VHL protein function, or inactivation of other TSGs, on chromosome 3p or on other chromosomes, might be important in the development of sporadic HBs.