Clinical and neurophysiological effects of central thalamic deep brain stimulation in the minimally conscious state after severe brain injury.

Deep brain stimulation (DBS) of the central thalamus is an experimental treatment for restoration of impaired consciousness in patients with severe acquired brain injury. Previous results of experimental DBS are heterogeneous, but significant improvements in consciousness have been reported. However, the mechanism of action of DBS remains unknown. We used magnetoencephalography to study the direct effects of DBS of the central thalamus on oscillatory activity and functional connectivity throughout the brain in a patient with a prolonged minimally conscious state. Different DBS settings were used to improve consciousness, including two different stimulation frequencies (50 Hz and 130 Hz) with different effective volumes of tissue activation within the central thalamus. While both types of DBS resulted in a direct increase in arousal, we found that DBS with a lower frequency (50 Hz) and larger volume of tissue activation was associated with a stronger increase in functional connectivity and neural variability throughout the brain. Moreover, this form of DBS was associated with improvements in visual pursuit, a reduction in spasticity, and improvement of swallowing, eight years after loss of consciousness. However, after DBS, all neurophysiological markers remained significantly lower than in healthy controls and objective increases in consciousness remained limited. Our findings provide new insights on the mechanistic understanding of neuromodulatory effects of DBS of the central thalamus in humans and suggest that DBS can re-activate dormant functional brain networks, but that the severely injured stimulated brain still lacks the ability to serve cognitive demands.

Tumor Drug Concentration and Phosphoproteomic Profiles After Two Weeks of Treatment With Sunitinib in Patients with Newly Diagnosed Glioblastoma.

PURPOSE: Tyrosine kinase inhibitors (TKI) have poor efficacy in patients with glioblastoma (GBM). Here, we studied whether this is predominantly due to restricted blood-brain barrier penetration or more to biological characteristics of GBM. PATIENTS AND METHODS: Tumor drug concentrations of the TKI sunitinib after 2 weeks of preoperative treatment was determined in 5 patients with GBM and compared with its in vitro inhibitory concentration (IC50) in GBM cell lines. In addition, phosphotyrosine (pTyr)-directed mass spectrometry (MS)-based proteomics was performed to evaluate sunitinib-treated versus control GBM tumors. RESULTS: The median tumor sunitinib concentration of 1.9 µmol/L (range 1.0-3.4) was 10-fold higher than in concurrent plasma, but three times lower than sunitinib IC50s in GBM cell lines (median 5.4 µmol/L, 3.0-8.5; P = 0.01). pTyr-phosphoproteomic profiles of tumor samples from 4 sunitinib-treated versus 7 control patients revealed 108 significantly up- and 23 downregulated (P < 0.05) phosphopeptides for sunitinib treatment, resulting in an EGFR-centered signaling network. Outlier analysis of kinase activities as a potential strategy to identify drug targets in individual tumors identified nine kinases, including MAPK10 and INSR/IGF1R. CONCLUSIONS: Achieved tumor sunitinib concentrations in patients with GBM are higher than in plasma, but lower than reported for other tumor types and insufficient to significantly inhibit tumor cell growth in vitro. Therefore, alternative TKI dosing to increase intratumoral sunitinib concentrations might improve clinical benefit for patients with GBM. In parallel, a complex profile of kinase activity in GBM was found, supporting the potential of (phospho)proteomic analysis for the identification of targets for (combination) treatment.

Microdiscectomy for sciatica: reality check study of long-term surgical treatment effects of a Lumbosacral radicular syndrome (LSRS).

PURPOSE: It remains unclear whether the long-term results of RCTs regarding the outcome of microdiscectomy for lumbosacral radicular syndrome (LSRS) are generalizable. The purpose of this study was to determine the external validity of the outcome preseneted in RCTs after microdicectomy for LSRS in a patient cohort from a high-volume spine center. METHODS: Between 2007 and 2010, 539 patients had a single level microdiscectomy for MRI disk-related LSRS of whom 246 agreed to participate. Questionnaires included visual analogue scores (VAS) for leg pain, RDQ, OLBD, RAND-36 and Likert scores for recovery, leg and back pain. Lumbar re-operation(s) were registered. RESULTS: Mean age was 51.3, and median time of follow-up was 8.0 years. Re-operation occurred in 64 (26%) patients. Unfavorable perceived recovery was noted in 85 (35%) patients, and they had worse leg and back pain than the 161 (65%) patients with a favorable recovery: median VAS for leg pain 28/100 mm versus 2/100 mm and median VAS for back pain 9/100 mm versus 3/100 mm, respectively. In addition, the median RDQ and OLBD scores differed significantly: 9 vs 3 for RDQ and 26 vs 4 for OLBD, respectively (p < 0.001). CONCLUSION: In this cohort study, the long-term results after microdiscectomy for LSRS were less favorable than those obtained in RCTs, possibly caused by less strict patient selection than in RCTs. Our findings emphasize that patients, who do not meet the same inclusion criteria for surgery as in RCTs, should be informed about the chances of a less favorable result.

Prehemorrhage antiplatelet use in aneurysmal subarachnoid hemorrhage and impact on clinical outcome.

BACKGROUND: Literature is inconclusive regarding the association between antiplatelet agents use and outcome after aneurysmal subarachnoid hemorrhage. AIMS: To investigate the association between clinical outcome and prehemorrhage use in aneurysmal subarachnoid hemorrhage patients as well as the impact of thrombocyte transfusion on rebleed and clinical outcome. METHODS: Data were collected from prospective databases of two European tertiary reference centers for aneurysmal subarachnoid hemorrhage patients. Patients were divided into "antiplatelet-user" and "non-user" according to the use of acetylsalicylic acid prior to the hemorrhage. Primary outcome was poor clinical outcome at six months (Glasgow Outcome Scale score 1-3). Secondary outcomes were in-hospital mortality and impact of thrombocyte transfusion. RESULTS: Of the 1033 patients, 161 (15.6%) were antiplatelet users. The antiplatelet users were older with higher incidence of cardiovascular risk factors. Antiplatelet use was associated with poor outcome and in-hospital mortality. After correction for age, sex, World Federation of Neurosurgical Societies score, infarction and heart disorder, pre-hemorrhage acetylsalicylic acid use was only associated with poor clinical outcome at six months (adjusted OR 1.80, 95% CI 1.08-3.02). Thrombocyte transfusion was not associated with a reduction in rebleed or poor clinical outcome. CONCLUSION: In this multicenter study, the prehemorrhage acetylsalicylic acid use in aneurysmal subarachnoid hemorrhage patients was independently associated with poor clinical outcome at six months. Thrombocyte transfusion was not associated with the rebleed rate or poor clinical outcome at six months.

Influence of severity and level of injury on the occurrence of complications during the subacute and chronic stage of traumatic spinal cord injury: a systematic review.

OBJECTIVE: Secondary health conditions (SHCs) are long-term complications that frequently occur due to traumatic spinal cord injury (tSCI) and can negatively affect quality of life in this patient population. This study provides an overview of the associations between the severity and level of injury and the occurrence of SHCs in tSCI. METHODS: A systematic search was conducted in PubMed and Embase that retrieved 44 studies on the influence of severity and/or level of injury on the occurrence of SHCs in the subacute and chronic phase of tSCI (from 3 months after trauma). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. RESULTS: In the majority of studies, patients with motor-complete tSCI (American Spinal Injury Association [ASIA] Impairment Scale [AIS] grade A or B) had a significantly increased occurrence of SHCs in comparison to patients with motor-incomplete tSCI (AIS grade C or D), such as respiratory and urogenital complications, musculoskeletal disorders, pressure ulcers, and autonomic dysreflexia. In contrast, an increased prevalence of pain was seen in patients with motor-incomplete injuries. In addition, higher rates of pulmonary infections, spasticity, and autonomic dysreflexia were observed in patients with tetraplegia. Patients with paraplegia more commonly suffered from hypertension, venous thromboembolism, and pain. CONCLUSIONS: This review suggests that patients with a motor-complete tSCI have an increased risk of developing SHCs during the subacute and chronic stage of tSCI in comparison with patients with motor-incomplete tSCI. Future studies should examine whether systematic monitoring during rehabilitation and the subacute and chronic phase in patients with motor-complete tSCI could lead to early detection and potential prevention of SHCs in this population.

A multidisciplinary neuro-oncological triage panel reduces the time to referral and treatment for patients with a brain tumor.

BACKGROUND: Regional collaboration and appropriate referral management are crucial in neuro-oncological care. Lack of electronic access to medical records across health care organizations impedes interhospital consultation and may lead to incomplete and delayed referrals. To improve referral management, we have established a multidisciplinary neuro-oncological triage panel (NOTP) with digital image exchange and determined the effects on lead times, costs, and time investment. METHODS: A prospective cohort study was conducted from February 2019 to March 2020. All newly diagnosed patients referred to Brain Tumor Center Amsterdam were analyzed according to referral pathway: (1) standard referral (SR), (2) NOTP. The primary outcome was lead time, defined as time-to-referral, time-to-treatment, and total time (median days [interquartile range]). Secondary outcomes were costs and time investment. RESULTS: In total, 225 patients were included, of whom 153 had SR and 72 NOTP referral. Patients discussed in the NOTP were referred more frequently for first neurosurgical consultation (44.7% vs 28.8%) or combined neurological and neurosurgical consultation (12.8% vs 2.5%, P = .002). Time-to-referral was reduced for NOTP referral compared to SR (1 [0.25-4] vs 6 [1.5-10] days, P < .001). Total time decreased from 27 [14-48] days for the standard group to 15 [12-38.25] days for the NOTP group (P = .040). Costs and time investment were comparable for both groups. CONCLUSION: Implementation of digital referral to a multidisciplinary NOTP is feasible and leads to more swift patient-tailored referrals at comparable costs and time investment as SR. This quality improvement initiative has the potential to improve collaboration and coordination of multidisciplinary care in the field of neuro-oncology.

The added value of cerebrospinal fluid analysis in patients with subarachnoid hemorrhage after negative noncontrast CT.

OBJECTIVE: In patients presenting within 6 hours after signs and symptoms of suspected subarachnoid hemorrhage (SAH), CSF examination is judged to be no longer necessary if a noncontrast CT (NCCT) scan rules out SAH. In this study, the authors evaluated the performance of NCCT to rule out SAH in patients with positive CSF findings. METHODS: Between January 2006 and April 2018, 1657 patients were admitted with a nontraumatic SAH. Of these patients, 1546 had positive SAH findings on the initial NCCT and 111 patients had an NCCT scan that was reported as negative in the acute setting, but with positive CSF examination for subarachnoid blood. Demographic data, World Federation of Neurosurgical Societies grade, and SAH time points (ictus, time of NCCT, and time of lumbar puncture) were collected. All 111 NCCT scans were reevaluated by an experienced neuroradiologist. RESULTS: Of the 111 patients with positive CSF findings, SAH was initially missed on NCCT in 25 patients (23%). Reevaluation of 21 patients presenting within 6 hours of symptom onset confirmed NCCT negative findings in 12 (5 aneurysms), an aneurysmal SAH (aSAH) pattern in 8 (7 aneurysms), and a perimesencephalic pattern in 1 patient. Reevaluation of 90 patients presenting after 6 hours confirmed negative NCCT findings in 74 patients (37 aneurysms), aSAH pattern in 10 (4 aneurysms), and a perimesencephalic pattern in 6 (2 aneurysms). CONCLUSIONS: CSF examination is still mandatory to rule out SAH as NCCT can fail to show blood, even within 6 hours after symptom onset. In addition, the diagnosis SAH was frequently missed during initial reporting.

The Dilemma of Hydrocephalus in Prolonged Disorders of Consciousness.

Prolonged disorders of consciousness (DOC) are considered to be among the most severe outcomes after acquired brain injury. Medical care for these patients is mainly focused on minimizing complications, given that treatment options for patients with unresponsive wakefulness or minimal consciousness remain scarce. The complication rate in patients with DOC is high, both in the acute hospital setting, as in the rehabilitation or long-term care phase. Hydrocephalus is one of these well-known complications and usually develops quickly after acute changes in cerebrospinal fluid (CSF) circulation after different types of brain damage. However, hydrocephalus may also develop with a significant delay, weeks, or even months after the initial injury, reducing the potential for natural recovery of consciousness. In this phase, hydrocephalus is likely to be missed in DOC patients, given that their limited behavioral responsiveness camouflages the classic signs of increased intracranial pressure or secondary normal-pressure hydrocephalus. Moreover, the development of late-onset hydrocephalus may exceed the period of regular outpatient follow-up. Several controversies remain about the diagnosis of clinical hydrocephalus in patients with ventricular enlargement after severe brain injury. In this article, we discuss both the difficulties in diagnosis and dilemmas in the treatment of CSF disorders in patients with prolonged DOC and review evidence from the literature to advance an active surveillance protocol for the detection of this late, but treatable, complication. Moreover, we advocate a low threshold for CSF diversion when hydrocephalus is suspected, even months or years after brain injury.

Improved detection of diffuse glioma infiltration with imaging combinations: a diagnostic accuracy study.

BACKGROUND: Surgical resection and irradiation of diffuse glioma are guided by standard MRI: T2/fluid attenuated inversion recovery (FLAIR)-weighted MRI for non-enhancing and T1-weighted gadolinium-enhanced (T1G) MRI for enhancing gliomas. Amino acid PET has been suggested as the new standard. Imaging combinations may improve standard MRI and amino acid PET. The aim of the study was to determine the accuracy of imaging combinations to detect glioma infiltration. METHODS: We included 20 consecutive adults with newly diagnosed non-enhancing glioma (7 diffuse astrocytomas, isocitrate dehydrogenase [IDH] mutant; 1 oligodendroglioma, IDH mutant and 1p/19q codeleted; 1 glioblastoma IDH wildtype) or enhancing glioma (glioblastoma, 9 IDH wildtype and 2 IDH mutant). Standardized preoperative imaging (T1-, T2-, FLAIR-weighted, and T1G MRI, perfusion and diffusion MRI, MR spectroscopy and O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]FET) PET) was co-localized with multiregion stereotactic biopsies preceding resection. Tumor presence in the biopsies was assessed by 2 neuropathologists. Diagnostic accuracy was determined using receiver operating characteristic analysis. RESULTS: A total of 174 biopsies were obtained (63 from 9 non-enhancing and 111 from 11 enhancing gliomas), of which 129 contained tumor (50 from non-enhancing and 79 from enhancing gliomas). In enhancing gliomas, the combination of apparent diffusion coefficient (ADC) with [18F]FET PET (area under the curve [AUC], 95% CI: 0.89, 0.79‒0.99) detected tumor better than T1G MRI (0.56, 0.39‒0.72; P < 0.001) and [18F]FET PET (0.76, 0.66‒0.86; P = 0.001). In non-enhancing gliomas, no imaging combination detected tumor significantly better than standard MRI. FLAIR-weighted MRI had an AUC of 0.81 (0.65-0.98) compared with 0.69 (0.56-0.81; P = 0.019) for [18F]FET PET. CONCLUSION: Combining ADC and [18F]FET PET detects glioma infiltration better than standard MRI and [18F]FET PET in enhancing gliomas, potentially enabling better guidance of local therapy.

Predicting Delayed Cerebral Ischemia with Quantified Aneurysmal Subarachnoid Blood Volume.

BACKGROUND: The amount of blood detected on brain computed tomography scan is frequently used in prediction models for delayed cerebral ischemia (DCI) in patients with aneurysmal subarachnoid hemorrhage (aSAH). These models, which include coarse grading scales to assess the amount of blood, have only moderate predictive value. Therefore, we aimed to develop a predictive model for DCI including automatically quantified total blood volume (TBV). METHODS: We included patients from a prospective aSAH registry. TBV was assessed with an automatic hemorrhage quantification algorithm. The outcome measure was clinical deterioration due to DCI. Clinical and radiologic variables were included in a logistic regression model. The final model was selected by bootstrapped backward selection and internally validated by assessing the optimism-corrected R2 value, c-statistic, and calibration plot. The c-statistic of the TBV model was compared with models that used the (modified) Fisher scale instead. RESULTS: We included 369 patients. After backward selection, only TBV was included in the final model. The internally validated R2 value was 6%, and the c-statistic was 0.64. The c-statistic of the TBV model was higher than both the Fisher scale model (0.56; P < 0.001) and the modified Fisher scale model (0.58; P < 0.05). CONCLUSIONS: In our registry, only TBV independently predicted DCI. TBV discriminated better than the (modified) Fisher scale, but still had only moderate value for predicting DCI. Our findings suggest that other factors need to be identified to achieve better accuracy for predicting DCI.

Direct comparison of [11C] choline and [18F] FET PET to detect glioma infiltration: a diagnostic accuracy study in eight patients.

BACKGROUND: Positron emission tomography (PET) is increasingly used to guide local treatment in glioma. The purpose of this study was a direct comparison of two potential tracers for detecting glioma infiltration, O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F] FET) and [11C] choline. METHODS: Eight consecutive patients with newly diagnosed diffuse glioma underwent dynamic [11C] choline and [18F] FET PET scans. Preceding craniotomy, multiple stereotactic biopsies were obtained from regions inside and outside PET abnormalities. Biopsies were assessed independently for tumour presence by two neuropathologists. Imaging measurements were derived at the biopsy locations from 10 to 40 min [11C] choline and 20-40, 40-60 and 60-90 min [18F] FET intervals, as standardized uptake value (SUV) and tumour-to-brain ratio (TBR). Diagnostic accuracies of both tracers were compared using receiver operating characteristic analysis and generalized linear mixed modelling with consensus histopathological assessment as reference. RESULTS: Of the 74 biopsies, 54 (73%) contained tumour. [11C] choline SUV and [18F] FET SUV and TBR at all intervals were higher in tumour than in normal samples. For [18F] FET, the diagnostic accuracy of TBR was higher than that of SUV for intervals 40-60 min (area under the curve: 0.88 versus 0.81, p = 0.026) and 60-90 min (0.90 versus 0.81, p = 0.047). The diagnostic accuracy of [18F] FET TBR 60-90 min was higher than that of [11C] choline SUV 20-40 min (0.87 versus 0.67, p = 0.005). CONCLUSIONS: [18F] FET was more accurate than [11C] choline for detecting glioma infiltration. Highest accuracy was found for [18F] FET TBR for the interval 60-90 min post-injection.

Comparing Glioblastoma Surgery Decisions Between Teams Using Brain Maps of Tumor Locations, Biopsies, and Resections.

PURPOSE: The aim of glioblastoma surgery is to maximize the extent of resection while preserving functional integrity, which depends on the location within the brain. A standard to compare these decisions is lacking. We present a volumetric voxel-wise method for direct comparison between two multidisciplinary teams of glioblastoma surgery decisions throughout the brain. METHODS: Adults undergoing first-time glioblastoma surgery from 2012 to 2013 performed by two neuro-oncologic teams were included. Patients had had a diagnostic biopsy or resection. Preoperative tumors and postoperative residues were segmented on magnetic resonance imaging in three dimensions and registered to standard brain space. Voxel-wise probability maps of tumor location, biopsy, and resection were constructed for each team to compare patient referral bias, indication variation, and treatment variation. To evaluate the quality of care, subgroups of differentially resected brain regions were analyzed for survival and functional outcome. RESULTS: One team included 101 patients, and the other included 174; 91 tumors were biopsied, and 181 were resected. Patient characteristics were largely comparable between teams. Distributions of tumor locations were dissimilar, suggesting referral bias. Distributions of biopsies were similar, suggesting absence of indication variation. Differentially resected regions were identified in the anterior limb of the right internal capsule and the right caudate nucleus, indicating treatment variation. Patients with (n = 12) and without (n = 6) surgical removal in these regions had similar overall survival and similar permanent neurologic deficits. CONCLUSION: Probability maps of tumor location, biopsy, and resection provide additional information that can inform surgical decision making across multidisciplinary teams for patients with glioblastoma.

Properties of an In Vivo Fractured Poly(Methyl Methacrylate) Cranioplasty After 15 Years.

BACKGROUND: In 2001, a 27-year-old man was diagnosed with a meningioma with skull bone involvement. A craniectomy was performed and a CMW-3 poly(methyl methacrylate) cranioplasty was manually manufactured to reconstruct the remaining cranial defect. In 2016, he complained about progressive neurologic impairment. A computed tomography scan revealed that the cranioplasty had fractured into 4 dislocated pieces. Removal was indicated, and during the same operation a polyetheretherketone patient-specific implant was inserted. METHODS: The fractured cranioplasty was compared with freshly prepared CMW-3 specimens to determine whether the material properties had changed during 15 years in vivo. Gel permeation chromatography, microcomputed tomography, and flexural strength tests were performed. The fracture itself was analyzed using finite element analysis. RESULTS: The polydispersity index and molecular weight were not significantly different for the fractured cranioplasty and CMW-3. The fractured cranioplasty contained a total porosity of 10.7%, fresh CMW-3 cured at atmospheric pressure contained 4.1%, and 0.06% when cured at 2.2 bar. The flexural strength of the CMW-3 cured at 2.2 bar was significantly higher than both the fractured cranioplasty and CMW-3 cured at atmospheric pressure. Finite element analysis showed stress of 12.2 MPa under a load of 100 N on a weak spot. CONCLUSIONS: This ex vivo study shows that CMW-3 after 15 years in vivo was not influenced in molecular weight or flexural strength. However, the design of the implant and the handling of the poly(methyl methacrylate) seem to be important factors to improve mechanical properties of cranial reconstructions.

Do older patients with acute or subacute subdural hematoma benefit from surgery?

PURPOSE: According to the international guidelines, acute subdural hematomas (aSDH) with a thickness of >10 mm, or causing a midline shift of >5 mm, should be surgically evacuated. However, high mortality rates in older patients resulted in ongoing controversy whether elderly patients benefit from surgery. We identified predictors of outcome in a single-centre cohort of elderly patients undergoing surgical evacuation of aSDH or subacute subdural hematoma (saSDH). MATERIALS AND METHODS: This retrospective study included all patients aged ≥65 years undergoing surgical evacuation of aSDH/saSDH from 2000 to 2015. One-year outcome was dichotomized into favourable (Glasgow Outcome Scale (GOS) 4-5) and unfavourable (GOS 1-3). Predictors of outcome were identified by analysing patient characteristics. RESULTS: Eighty-four patients aged ≥65 years underwent craniotomy for aSDH/saSDH during the 16 year time period. Twenty-five percent regained functional independence, 11% survived severely disabled, and 64% died. Most patients died of respiratory failure following withdrawal of artificial respiration or following restriction of treatment. Age of the SDH or Glasgow Coma Scores ≤8/intubation did not predict unfavourable outcome. All patients with bilaterally absent pupillary light reflexes died, also those who still exhibited one normal-sized pupil. CONCLUSION: The low number of operated patients per year probably suggests that this cohort represents a selection of patients who were judged to have good chances of favouring from surgery. Functional independence at one-year follow-up was reached in 25% of patients, 64% died. Patients with bilaterally absent pupillary light reflexes did not benefit from surgery. The tendency to restrict treatment because of presumed poor prognosis may have acted as a self-fulfilling prophecy.

Autologous Bone Is Inferior to Alloplastic Cranioplasties: Safety of Autograft and Allograft Materials for Cranioplasties, a Systematic Review.

BACKGROUND: Currently, various materials are routinely used for cranioplasty after decompressive craniectomy, each with their own features, potential benefits, and harms. OBJECTIVES: To systematically review available literature about safety (infection, resorption, and removal) of different materials used for cranioplasty for any indication. METHODS: A comprehensive search in MEDLINE, EMBASE, and the Cochrane library was performed for relevant studies published up to January 2017. Study quality was assessed according to the Cochrane Collaboration risk of bias assessment tool, and a set of 27 predetermined parameters was extracted by 2 investigators independently for further analysis. RESULTS: The search yielded 2 randomized, 14 prospective, and 212 retrospective studies, totaling 10,346 cranioplasties in which 1952 (18.9%) complications were reported in patients between 0 and 90 years old. Overall, study quality was low and heterogeneity was large. Graft infections and resorption were most prevalent: overall infection rate was 5.6%. Autologous cranioplasties showed an infection rate of 6.9% versus 5.0% in combined alloplastic materials, including poly(methyl methacrylate) with 7.8%. Resorption occurred almost exclusively in autologous cranioplasties (11.3%). The greatest removal rate was reported for autologous cranioplasties (overall: 10.4%), which was significantly greater than that of combined alloplastic materials (overall: 5.1%; risk difference = 0.052 [95% confidence interval: 0.039-0.066]; NNT = 19 [95% confidence interval: 15-25]). CONCLUSIONS: Available evidence on the safety of cranioplasty materials is limited due to a large diversity in study conduct, patients included, and outcomes reported. Autografts appear to carry a greater failure risk than allografts. Future publications concerning cranioplasties will benefit by a standardized reporting of surgical procedures, outcomes, and graft materials used.

Deceptive morphologic and epigenetic heterogeneity in diffuse intrinsic pontine glioma.

Historically, the diagnosis of diffuse intrinsic pontine glioma (DIPG) was based on typical imaging findings and clinical characteristics instead of pathology. However, the discovery of mutations in histone H3 variants, and the availability of tumor material for molecular analysis, has led to a paradigm shift in DIPG research and clinical practice. Using data from whole-brain autopsies in a series of nine DIPG patients with known histone mutational status, we here aim to review histopathological characteristics with special focus on intratumoral heterogeneity (ITH) and histone 3 K27 trimethylation (H3 K27me3). All DIPGs showed marked histologic ITH, with 56% even showing focal areas resembling a WHO grade I phenotype. As expected, H3 K27me3 immunoreactivity was lost in the tumors that were H3 K27M-mutated (seven patients; 67% H3.3, 11% H3.1). Strikingly, the H3K27 wildtype tumors (two patients; 22%) also contained H3 K27me3-immunonegative areas. Our study underscores the importance of the choice of the biopsy site, as ITH in DIPGs could theoretically lead to erroneous histological diagnoses with small biopsies. New in this respect is our finding that a substantial number of otherwise typical DIPGs has areas resembling WHO grade I tumors (esp. pilocytic astrocytoma, subependymoma). Furthermore, our study shows that negative H3 K27me3 immunohistochemistry in a DIPG does not imply a H3 K27-mutant tumor.

External validation of the diffuse intrinsic pontine glioma survival prediction model: a collaborative report from the International DIPG Registry and the SIOPE DIPG Registry.

We aimed to perform external validation of the recently developed survival prediction model for diffuse intrinsic pontine glioma (DIPG), and discuss its utility. The DIPG survival prediction model was developed in a cohort of patients from the Netherlands, United Kingdom and Germany, registered in the SIOPE DIPG Registry, and includes age <3 years, longer symptom duration and receipt of chemotherapy as favorable predictors, and presence of ring-enhancement on MRI as unfavorable predictor. Model performance was evaluated by analyzing the discrimination and calibration abilities. External validation was performed using an unselected cohort from the International DIPG Registry, including patients from United States, Canada, Australia and New Zealand. Basic comparison with the results of the original study was performed using descriptive statistics, and univariate- and multivariable regression analyses in the validation cohort. External validation was assessed following a variety of analyses described previously. Baseline patient characteristics and results from the regression analyses were largely comparable. Kaplan-Meier curves of the validation cohort reproduced separated groups of standard (n = 39), intermediate (n = 125), and high-risk (n = 78) patients. This discriminative ability was confirmed by similar values for the hazard ratios across these risk groups. The calibration curve in the validation cohort showed a symmetric underestimation of the predicted survival probabilities. In this external validation study, we demonstrate that the DIPG survival prediction model has acceptable cross-cohort calibration and is able to discriminate patients with short, average, and increased survival. We discuss how this clinico-radiological model may serve a useful role in current clinical practice.

Angiogenesis in steno-occlusive vasculopathies as a common pathway for intracranial haemorrhage. A report of six cases.

Vasculopathies, including vasculitis of the central nervous system, can lead to stenosed, cicatrized vessels and the development of arterio-arteriolar collateral vessels. Bleeding due to these vascular changes, although rare, does occur. We describe six patients (all female, age range, 21-52 years; mean age, 42 years) with steno-occlusive lesions of intracranial vessels who presented with an acute intracranial haemorrhage. All had arterial steno-occlusive changes in conjunction with extensive leptomeningeal and arterio-arteriolar collaterals. Within the collaterals, focal dilatations could be identified, which were in close spatial relationship with the intracranial haemorrhage. Cause of bleeding was depicted on CT angiography in four out of six patients. One patient presented in childhood with acute stroke, one patient was diagnosed with Buerger's disease and one with sickle cell disease; the other three patients had no relevant history and the exact cause remained unclear. Outcome was favourable in all patients. Despite focal vascular weaknesses, no recurrent haemorrhage was seen during follow-up, supporting, at least in this small patient group, a conservative wait-and-see policy.

Surgery versus prolonged conservative treatment for sciatica: 5-year results of a randomised controlled trial.

OBJECTIVE: This study describes the 5 years' results of the Sciatica trial focused on pain, disability, (un)satisfactory recovery and predictors for unsatisfactory recovery. DESIGN: A randomised controlled trial. SETTING: Nine Dutch hospitals. PARTICIPANTS: Five years' follow-up data from 231 of 283 patients (82%) were collected. INTERVENTION: Early surgery or an intended 6 months of conservative treatment. MAIN OUTCOME MEASURES: Scores from Roland disability questionnaire, visual analogue scale (VAS) for leg and back pain and a Likert self-rating scale of global perceived recovery were analysed. RESULTS: There were no significant differences between groups on the 5 years' primary outcome scores. Despite at least 6 months of conservative treatment 46% of the conservatively allocated patients were treated surgically because of severe leg pain and disability. Forty-nine (21%) patients had an unsatisfactory recovery at 5 years and the recovery pattern showed that there was a variable group of 66 patients (31%) with at least one unsatisfactory outcome at 1, 2 or 5 years of follow-up. Multivariate logistic regression showed that age (>40; OR 2.42 (95% CI 1.16 to 5.02)), severity of leg pain (VAS >70; OR 3.32 (95% CI 1.69 to 6.54)) and the Mc Gill affective score (score >3; OR 6.23 (95% CI 2.23 to 17.38)) were the only significant predictors for an unsatisfactory outcome at 5 years. CONCLUSIONS: In the long term, 8% of the patients with sciatica never showed any recovery and in at least 23%, sciatica appears to result in ongoing complaints, which fluctuate over time, irrespective of treatment. Prolonged conservative care might give patients a fair chance for pain and disability to resolve without surgery, but with the risk to receive delayed surgery after prolonged suffering of sciatica. Age above 40 years, severe leg pain at baseline and a higher affective Mc Gill pain score were predictors for unsatisfactory recovery. Trial Registry ISRCT No 26872154.