Enhancing predictability of IDH mutation status in glioma patients at initial diagnosis: a comparative analysis of radiomics from MRI, [18F]FET PET, and TSPO PET.

PURPOSE: According to the World Health Organization classification for tumors of the central nervous system, mutation status of the isocitrate dehydrogenase (IDH) genes has become a major diagnostic discriminator for gliomas. Therefore, imaging-based prediction of IDH mutation status is of high interest for individual patient management. We compared and evaluated the diagnostic value of radiomics derived from dual positron emission tomography (PET) and magnetic resonance imaging (MRI) data to predict the IDH mutation status non-invasively. METHODS: Eighty-seven glioma patients at initial diagnosis who underwent PET targeting the translocator protein (TSPO) using [18F]GE-180, dynamic amino acid PET using [18F]FET, and T1-/T2-weighted MRI scans were examined. In addition to calculating tumor-to-background ratio (TBR) images for all modalities, parametric images quantifying dynamic [18F]FET PET information were generated. Radiomic features were extracted from TBR and parametric images. The area under the receiver operating characteristic curve (AUC) was employed to assess the performance of logistic regression (LR) classifiers. To report robust estimates, nested cross-validation with five folds and 50 repeats was applied. RESULTS: TBRGE-180 features extracted from TSPO-positive volumes had the highest predictive power among TBR images (AUC 0.88, with age as co-factor 0.94). Dynamic [18F]FET PET reached a similarly high performance (0.94, with age 0.96). The highest LR coefficients in multimodal analyses included TBRGE-180 features, parameters from kinetic and early static [18F]FET PET images, age, and the features from TBRT2 images such as the kurtosis (0.97). CONCLUSION: The findings suggest that incorporating TBRGE-180 features along with kinetic information from dynamic [18F]FET PET, kurtosis from TBRT2, and age can yield very high predictability of IDH mutation status, thus potentially improving early patient management.

Neurosurgical resection of multiple brain metastases: outcomes, complications, and survival rates in a retrospective analysis.

PURPOSE: This study investigates the outcomes of microsurgical resection of multiple brain metastasis (BMs). METHODS: This retrospective, monocentric analysis included clinical data from all consecutive BM patients, who underwent simultaneous resection of ≥ 2 BMs between January 2018 and May 2023. Postoperative neurological and functional outcomes, along with perioperative complications, as well as survival data were evaluated. RESULTS: A total of 47 patients, with a median age of 61 years (IQR 48-69), underwent 73 craniotomies (median 2; range 1-3) for resection of 104 BMs. Among patients, 80.8% presented with symptomatic BMs, causing focal neurological deficits in 53% of cases. Gross total resection was achieved in 87.2% of BMs. Karnofsky Performance Scale (KPS) scores improved in 42.6% of patients, remained unchanged in 46.8%, and worsened in 10.6% after surgery. Perioperative complications were observed in 29.8% of cases, with transient complications occurring in 19.2% and permanent deficits in 10.6%. The 30-days mortality rate was 2.1%. Logistic regression identified eloquent localization (p = 0.036) and infratentorial craniotomy (p = 0.018) as significant predictors of postoperative complications. Concerning overall prognosis, patients with permanent neurological deficits post-surgery (HR 11.34, p = 0.007) or progressive extracranial disease (HR: 4.649; p = 0.006) exhibited inferior survival. CONCLUSION: Microsurgical resection of multiple BMs leads to clinical stabilization or functional improvement in most patients. Although transient complications do not affect overall survival, the presence of persistent neurological deficits (> 3 months post-surgery) and progressive extracranial disease negatively impact overall survival. This highlights the importance of careful patient selection for resection of multiple BMs.

Bevacizumab as a treatment option for radiation necrosis after cranial radiation therapy: a retrospective monocentric analysis.

BACKGROUND AND PURPOSE: Radiation necrosis is a possible adverse event after cranial radiation therapy and can cause severe symptoms, such as an increased intracranial pressure or neurological deterioration. The vascular endothelial growth factor (VEGF) inhibitor bevacizumab (BEV) has been shown to be a feasible therapeutic option for symptomatic radiation necrosis, either when traditional antiedematous steroid treatment fails, or as an alternative to steroid treatment. However, to the best of our knowledge, only one randomized study with a rather small cohort exists to prove a beneficial effect in this setting. Therefore, further real-life data are needed. This retrospective monocentric case study evaluates patients who received BEV due to radiation necrosis, with a specific focus on the respective clinical course. METHODS: Using the internal database for pharmaceutical products, all patients who received BEV in our department were identified. Only patients who received BEV as symptomatic treatment for radiation necrosis were included. Patient characteristics, symptoms before, during, and after treatment, and the use of dexamethasone were evaluated using medical reports and systematic internal documentation. The symptoms were graded using CTCAE version 5.0 for general neurological symptoms. Symptoms were graded directly before each cycle and after the treatment (approximately 6 weeks). Additionally, the daily steroid dose was collected at these timepoints. Patients who either improved in symptoms, received less dexamethasone after treatment, or both were considered to have a benefit from the treatment. RESULTS: Twenty-one patients who received BEV due to radiation necrosis were identified. For 10 patients (47.6%) symptoms improved and 11 patients (52.4%) remained clinically stable during the treatment. In 14 patients (66.7%) the dexamethasone dose could be reduced during therapy, 5 patients (23.8%) received the same dose of dexamethasone before and after the treatment, and 2 patients (9.5%) received a higher dose at the end of the treatment. According to this analysis, overall, 19 patients (90.5%) benefited from the treatment with BEV. No severe adverse effects were reported. CONCLUSION: BEV might be an effective and safe therapeutic option for patients with radiation necrosis as a complication after cranial radiation therapy. Patients seem to benefit from this treatment by improving symptomatically or through reduction of dexamethasone.

Prevalence of superficial siderosis following singular, acute aneurysmal subarachnoid hemorrhage.

INTRODUCTION: Superficial siderosis is presumably a consequence of recurrent bleeding into the subarachnoid space. The objective of this study was to assess the prevalence of superficial siderosis after singular, aneurysmal subarachnoid hemorrhage (SAH) in the long term. METHODS: We retrospectively identified all patients who presented with a singular, acute, aneurysmal SAH at our institution between 2010 and 2013 and in whom a magnetic resonance imaging (MRI) including T2*-weighted imaging was available at least 4 months after the acute bleeding event. MRI scans were judged concerning the presence and distribution of superficial siderosis. Influence of clinical data, Fisher grade, localization, and cause of SAH as well as the impact of neurosurgical interventions on the occurrence of superficial siderosis was tested. RESULTS: Seventy-two patients with a total of 117 MRIs were included. Mean delay between SAH and the last available MRI was 47.4 months (range 4-129). SAH was Fisher grade 1 in 2 cases, 2 in 4 cases, 3 in 10 cases, and 4 in 56 cases. Superficial siderosis was detected in 39 patients (54.2%). In all patients with more than one MRI scan, localization and distribution of superficial siderosis did not change over time. Older age (p = 0.02) and higher degree of SAH (p = 0.03) were significantly associated with the development of superficial siderosis. CONCLUSION: Superficial siderosis develops in approximately half of patients after singular, aneurysmal SAH and might be more common in patients with an older age and a greater amount of blood. However, additional factors must play a role in whether a patient is prone to develop superficial siderosis or not.

Assessing and treating alcohol relapse risk in liver transplantation candidates.

In Europe between 30 and 50% of all liver transplantations (LTX) are done within the context of chronic end-stage alcoholic liver disease (ALD). However, post-operatively 20-25% of these patients lapse or relapse into heavy alcohol use. Thus, assessment of alcohol relapse risk before enlisting and therapeutic follow-up during and after LTX is of utmost importance. However, as yet there are enormous differences between European countries and between transplant centers, with regard to the assessment methods and criteria and the implementation of therapeutic follow-up. Only the so-called '6-month abstinence' rule is widely used. However, there are not much scientific data validating its use in predicting relapse. Thus, there is a clear need of a more homogeneous approach, which was the focus of a symposium of the European Federation of Addiction Societies during the 14th conference of the European Society for Biomedical Research on Alcoholism, 2013 (ESBRA), entitled 'Liver transplantation: A European perspective'. In a follow-up on this symposium, the authors aim to sum up the evidence of psychiatric assessment criteria and psychiatric treatment interventions relevant in the context of patient selection and patient follow-up within ALD transplantation procedures. Based upon these findings, we propose elements of a procedure that can serve as a first step toward a model of good practice regarding addiction-specialist input within the pre- and post-transplantation period.

Gross total but not incomplete resection of glioblastoma prolongs survival in the era of radiochemotherapy.

BACKGROUND: This prospective multicenter study assessed the prognostic influence of the extent of resection when compared with biopsy only in a contemporary patient population with newly diagnosed glioblastoma. PATIENTS AND METHODS: Histology, O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, and clinical data were centrally analyzed. Survival analyses were carried out with the Kaplan-Meier method. Prognostic factors were assessed with proportional hazard models. RESULTS: Of 345 patients, 273 underwent open tumor resection and 72 biopsies; 125 patients had gross total resections (GTRs) and 148, incomplete resections. Surgery-related morbidity was lower after biopsy (1.4% versus 12.1%, P = 0.007). 64.3% of patients received radiotherapy and chemotherapy (RT plus CT), 20.0% RT alone, 4.3% CT alone, and 11.3% best supportive care as an initial treatment. Patients ≤60 years with a Karnofsky performance score (KPS) of ≥90 were more likely to receive RT plus CT (P < 0.01). Median overall survival (OS) (progression free survival; PFS) ranged from 33.2 months (15 months) for patients with MGMT-methylated tumors after GTR and RT plus CT to 3.0 months (2.4 months) for biopsied patients receiving supportive care only. Favorable prognostic factors in multivariate analyses for OS were age ≤60 years [hazard ratio (HR) = 0.52; P < 0.001], preoperative KPS of ≥80 (HR = 0.55; P < 0.001), GTR (HR = 0.60; P = 0.003), MGMT promoter methylation (HR = 0.44; P < 0.001), and RT plus CT (HR = 0.18, P < 0.001); patients undergoing incomplete resection did not better than those receiving biopsy only (HR = 0.85; P = 0.31). CONCLUSIONS: The value of incomplete resection remains questionable. If GTR cannot be safely achieved, biopsy only might be used as an alternative surgical strategy.

[Direct metabolites of ethanol as biological markers of alcohol use: basic aspects and applications]. / Direkte ethanolmetaboliten als biomarker für alkoholkonsum: grundlagen und anwendungen.

In addition to self reports and questionnaires, biomarkers are of relevance in the diagnosis of and therapy for alcohol use disorders. Traditional biomarkers such as gamma-glutamyl transpeptidase or mean corpuscular volume are indirect biomarkers and are subject to the influence of age, gender and non-alcohol related diseases, among others. Direct metabolites of ethanol such as ethyl glucuronide (EtG), ethyl sulphate (EtS) and phosphatidylethanol (PEth) are direct metabolites of ethanol, that are positive after intake of ethyl alcohol. They represent useful diagnostic tools for identifying alcohol use even more accurately than traditional biomarkers. Each of these drinking indicators remains positive in serum and urine for a characteristic time spectrum after the cessation of ethanol intake - EtG and EtS in urine up to 7 days, EtG in hair for months after ethanol has left the body. Applications include clinical routine use, emergency room settings, proof of abstinence in alcohol rehabilitation programmes, driving under influence offenders, workplace testing, assessment of alcohol intake in the context of liver transplantation and foetal alcohol syndrome. Due to their properties, they open up new perspectives for prevention, interdisciplinary cooperation, diagnosis of and therapy for alcohol-related problems.

Perifocal Edema in Patients with Meningioma is Associated with Impaired Whole-Brain Connectivity as Detected by Resting-State fMRI.

BACKGROUND AND PURPOSE: Meningiomas are intracranial tumors that usually carry a benign prognosis. Some meningiomas cause perifocal edema. Resting-state fMRI can be used to assess whole-brain functional connectivity, which can serve as a marker for disease severity. Here, we investigated whether the presence of perifocal edema in preoperative patients with meningiomas leads to impaired functional connectivity and if these changes are associated with cognitive function. MATERIALS AND METHODS: Patients with suspected meningiomas were prospectively included, and resting-state fMRI scans were obtained. Impairment of functional connectivity was quantified on a whole-brain level using our recently published resting-state fMRI-based marker, called the dysconnectivity index. Using uni- and multivariate regression models, we investigated the association of the dysconnectivity index with edema and tumor volume as well as cognitive test scores. RESULTS: Twenty-nine patients were included. In a multivariate regression analysis, there was a highly significant association of dysconnectivity index values and edema volume in the total sample and in a subsample of 14 patients with edema, when accounting for potential confounders like age and temporal SNR. There was no statistically significant association with tumor volume. Better neurocognitive performance was strongly associated with lower dysconnectivity index values. CONCLUSIONS: Resting-state fMRI showed a significant association between impaired functional connectivity and perifocal edema, but not tumor volume, in patients with meningiomas. We demonstrated that better neurocognitive function was associated with less impairment of functional connectivity. This result shows that our resting-state fMRI marker indicates a detrimental influence of peritumoral brain edema on global functional connectivity in patients with meningiomas.

Personalized surgical therapy.

Gliomas are more or less diffuse tumours with the ability to infiltrate surrounding functional brain tissue. Thus, curative surgical treatment generally cannot be achieved. Despite these limitations, open tumour resection represents one of the mainstays in glioma treatment settings. Beyond tissue sampling for accurate histological and molecular genetic evaluation, decompressive effects in the case of space occupying tumours and oncologically relevant cytoreductive effects of microsurgery have been reported in selected patients with glioma of different grades. This paper provides practical considerations in order to integrate the concept of a personalized surgical therapy into the prognostic network of low- and high-grade gliomas, covering both microsurgery and stereotactic biopsy techniques.

MRI-based contrast clearance analysis shows high differentiation accuracy between radiation-induced reactions and progressive disease after cranial radiotherapy.

BACKGROUND: Pseudoprogression (PsP) or radiation necrosis (RN) may frequently occur after cranial radiotherapy and show a similar imaging pattern compared with progressive disease (PD). We aimed to evaluate the diagnostic accuracy of magnetic resonance imaging-based contrast clearance analysis (CCA) in this clinical setting. PATIENTS AND METHODS: Patients with equivocal imaging findings after cranial radiotherapy were consecutively included into this monocentric prospective study. CCA was carried out by software-based automated subtraction of imaging features in late versus early T1-weighted sequences after contrast agent application. Two experienced neuroradiologists evaluated CCA with respect to PsP/RN and PD being blinded for histological findings. The radiological assessment was compared with the histopathological results, and its accuracy was calculated statistically. RESULTS: A total of 33 patients were included; 16 (48.5%) were treated because of a primary brain tumor (BT), and 17 (51.1%) because of a secondary BT. In one patient, CCA was technically infeasible. The accuracy of CCA in predicting the histological result was 0.84 [95% confidence interval (CI) 0.67-0.95; one-sided P = 0.051; n = 32]. Sensitivity and specificity of CCA were 0.93 (95% CI 0.66-1.00) and 0.78 (95% CI 0.52-0.94), respectively. The accuracy in patients with secondary BTs was 0.94 (95% CI 0.71-1.00) and nonsignificantly higher compared with patients with primary BT with an accuracy of 0.73 (95% CI 0.45-0.92), P = 0.16. CONCLUSIONS: In this study, CCA was a highly accurate, easy, and helpful method for distinguishing PsP or RN from PD after cranial radiotherapy, especially in patients with secondary tumors after radiosurgical treatment.

Persistently modified h-channels after complex febrile seizures convert the seizure-induced enhancement of inhibition to hyperexcitability.

Febrile seizures are the most common type of developmental seizures, affecting up to 5% of children. Experimental complex febrile seizures involving the immature rat hippocampus led to a persistent lowering of seizure threshold despite an upregulation of inhibition. Here we provide a mechanistic resolution to this paradox by showing that, in the hippocampus of rats that had febrile seizures, the long-lasting enhancement of the widely expressed intrinsic membrane conductance Ih converts the potentiated synaptic inhibition to hyperexcitability in a frequency-dependent manner. The altered gain of this molecular inhibition-excitation converter reveals a new mechanism for controlling the balance of excitation-inhibition in the limbic system. In addition, here we show for the first time that h-channels are modified in a human neurological disease paradigm.

The place of interstitial brachytherapy and radiosurgery for low-grade gliomas.

Even though stereotactic brachytherapy has been used for treatment of complex located low-grade glioma for many years, its place within modern treatment concepts is still debated and only a few centers have gained experience with this complex treatment modality. The current article reviews selection criteria, treatment protocols, radiobiology, treatment effects, risk models and side effects of stereotactic brachytherapy. Potentially alternative techniques such as radiosurgery were also reviewed under consideration of radiobiological similarities and differences.

State of Practice: Endovascular Treatment of Acute Aneurysmal SAH in Germany.

BACKGROUND AND PURPOSE: Acute aneurysmal SAH is a severe disease that requires prompt treatment. Endovascular coiling and neurosurgical clipping are established treatment options. Our intention was to determine the state of current practice in acute aneurysmal SAH treatment in Germany, with emphasis on logistic and temporal aspects. MATERIALS AND METHODS: We interviewed 74 German university and nonuniversity hospitals with an anonymous questionnaire comprising 15 questions concerning the practice of treatment and diagnostics of acute aneurysmal SAH at their respective institutions. The response rate was 74% among all institutions (55/74); among university hospitals, 77%; and among nonuniversity hospitals, 72%. RESULTS: The majority of all aneurysms were treated endovascularly (66% of acute aneurysmal SAH, 66% of unruptured aneurysms). Treatment on weekends was provided by 100% of endovascular and 96% of neurosurgical facilities. Average patients with acute aneurysmal SAH were not treated during the night (98%). Seventy percent of endovascular and 78% of neurosurgical treatments were not started later than 8:00 pm. Fifty-three percent of hospitals would not start a same-day diagnostic angiography in acute aneurysmal SAH if treatment was scheduled for the following day. Eighty-two percent of all centers performed DSA after clipping to evaluate the treatment results. CONCLUSIONS: Our survey gives a detailed summary of the current practice of endovascular treatment and related topics in acute aneurysmal SAH in Germany and also reveals considerable changes in practice in comparison with older data.

Entorhinal cortex lesion in adult rats induces the expression of the neuronal chondroitin sulfate proteoglycan neurocan in reactive astrocytes.

The chondroitin sulfate proteoglycan neurocan is a major component of brain extracellular matrix during development. Neurocan is primarily synthesized by neurons and has the ability to interact with cell adhesion molecules involved in the regulation of cell migration and axonal growth. Within the first weeks postnatally, neurocan expression is strongly downregulated. To test whether neurocan is reexpressed in areas of axonal growth (sprouting) after brain injury, the time course of neurocan expression was analyzed in the denervated fascia dentata of the rat after entorhinal cortex lesion (12 hr; 1, 2, 4, and 10 d; 2 and 4 weeks; and 6 months after lesion). In the denervated zone, immunohistochemistry revealed neurocan-positive astrocytes by 2 d after lesion and a diffuse labeling of the extracellular matrix at all later time points. Electron microscopy confirmed the deposition of neurocan in the extracellular matrix compartment. In situ hybridization demonstrated a strong upregulation of neurocan mRNA within the denervated outer molecular layer 1 and 4 d after lesion. The combination of in situ hybridization with immunohistochemistry for glial fibrillary acidic protein demonstrated that the neurocan mRNA-expressing cells are astrocytes. These data demonstrate that neurocan is reexpressed in the injured brain. In contrast to the situation during development, astrocytes, but not neurons, express neurocan and enrich the extracellular matrix with this molecule. Similar to the situation during development, neurocan is expressed in an area of active axon growth, and it is suggested that neurocan acts to maintain the boundaries of the denervated fascia dentata after entorhinal cortex lesion.

Prevalence of suicide attempts in pathological gamblers in a nationwide Austrian treatment sample.

BACKGROUND: For pathological gambling (PG), a 12-month prevalence rate of up to 0.66% has been reported. Multiple financial, occupational and relationship problems and losses, humiliation of the person and the environment are possible side effects and may lead to hopelessness, suicidal ideation and suicidal behavior. Suicide attempt rates among pathological gamblers of between 4% and 40% and suicidal ideation of between 12% and 92% have been reported. AIM: This study aims at assessing the prevalence of suicide attempts in PG and at elucidating differences between the patients with and without suicide attempt history (SAH) in a large nationwide Austrian sample. METHODS: Between 2002 and 2011, the Austrian Society for the Research of Non-Substance Related Addiction collected 862 questionnaires of pathological gamblers undergoing outpatient and inpatient treatment for PG in Austria. RESULTS: (a) Of all pathological gamblers, 9.7% had an SAH. (b) The SAH group suffered significantly more from a comorbid disorder and was more often in previous inpatient treatments. (c) The SAH patients had a longer time of an abstinence period in their PG career. DISCUSSION: One in 10 pathological gamblers has an SAH, demonstrating the relevance of suicidality in this population. Significant differences for several parameters were found for PG with and without SAH. However, a regression analysis only explained 15% of the variance. This suggests that suicidality must be considered in pathological gamblers in general.

Hot spots in dynamic (18)FET-PET delineate malignant tumor parts within suspected WHO grade II gliomas.

Molecular imaging studies have recently found inter- and intratumoral heterogeneity in World Health Organization (WHO) grade II gliomas. A correlative analysis with tumor histology, however, is still lacking. For elucidation we conducted the current prospective study. Fifty-five adult patients with an MRI-based suspicion of a WHO grade II glioma were included. [F-18]Fluoroethyltyrosine ((18)FET) uptake kinetic studies were combined with frame-based stereotactic localization techniques and used as a guide for stepwise (1-mm steps) histopathological evaluation throughout the tumor space. In tumors with heterogeneous PET findings, the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status and expression of mutated protein isocitrate dehydrogenase variant R132H (IDH1) were determined inside and outside of hot spot volumes. Metabolic imaging revealed 3 subgroups: the homogeneous WHO grade II glioma group (30 patients), the homogeneous malignant glioma group (10 patients), and the heterogeneous group exhibiting both low- and high-grade characteristics at different sites (15 patients). Stepwise evaluation of 373 biopsy samples indicated a strong correlation with analyses of uptake kinetics (p < 0.0001). A homogeneous pattern of uptake kinetics was linked to homogeneous histopathological findings, whereas a heterogeneous pattern was associated with histopathological heterogeneity; hot spots exhibiting malignant glioma characteristics covered 4-44% of the entire tumor volumes. Both MGMT and IDH1 status were identical at different tumor sites and not influenced by heterogeneity. Maps of (18)FET uptake kinetics strongly correlated with histopathology in suspected grade II gliomas. Anaplastic foci can be accurately identified, and this finding has implications for prognostic evaluation and treatment planning.

Expression of VEGFR3 in glioma endothelium correlates with tumor grade.

Angiogenic processes are regulated by vascular endothelial growth factors (VEGFs) and their receptors VEGFR1 (Flt-1), 2 (Flk-1) and 3 (Flt-4). While VEGFR2 is thought to play a central role in tumor angiogenesis, anti-angiogenic therapies targeting VEGFR2 in glioma models can show escape phenomena with secondary onset of angiogenesis. The purpose of this study was to find explanations for these processes by searching for alternative pathways regulating glioma angiogenesis and reveal a correlation with tumor grade. Thus, VEGFR3, which is not expressed in normal brain, and its ligands VEGF-C and -D, were assessed in high grade (WHO degrees IV, glioblastomas, GBM) and low grade gliomas [WHO degrees II astrocytomas (AII)]. In all GBM, a strong protein expression of VEGFR3 was found on tumor endothelium, VEGF-C and -D expression was found on numerous cells in areas of high vascularization. On RNA level, a significant up-regulation of VEGFR3 was detected in GBM compared to AII and non-neoplastic brain. In AII, only very moderate VEGFR3, VEGF-C and -D expression was found on protein and RNA level indicating a correlation of VEGFR3 expression with tumor grade. VEGFR3 signal in both grades was found predominantly on endothelial cells, confirmed by VEGFR3 expression on isolated CD31 positive cells and the expression of various endothelial markers on VEGFR3-positive cells isolated from GBM. The demonstration of a complete angiogenic signaling system that is dependent on tumor grade may influence the traditional paradigm of glioma angiogenesis and may provide a basis for more effective anti-angiogenic treatment strategies.

The chondroitin sulphate proteoglycan brevican is upregulated by astrocytes after entorhinal cortex lesions in adult rats.

The chondroitin sulphate proteoglycan brevican is one of the most abundant extracellular matrix molecules in the adult rat brain. It is primarily synthesized by astrocytes and is believed to influence astroglial motility during development and under certain pathological conditions. In order to study a potential role of brevican in the glial reaction after brain injury, its expression was analysed following entorhinal cortex lesion in rats (12 h, 1, 2, 4, 10, 14 and 28 days and 6 months post lesion). In situ hybridization and immunohistochemistry were employed to study brevican mRNA and protein, respectively, in the denervated outer molecular layer of the fascia dentata and at the lesion site. In both regions brevican mRNA was upregulated between 1 and 4 days post lesion. The combination of in situ hybridization with immunohistochemistry for glial fibrillary acidic protein demonstrated that many brevican mRNA-expressing cells are astrocytes. In the denervated zone of the fascia dentata, immunostaining for brevican was increased by 4 days, reached a maximum by 4 weeks and remained detectable up to 6 months post lesion. Electron microscopic immunocytochemistry showed that brevican is a component of the extracellular matrix compartment. At the lesion site a similar time course of brevican upregulation was observed. These data demonstrate that brevican is upregulated in areas of brain damage as well as in areas denervated by a lesion. They suggest a role of brevican in reactive gliosis and are compatible with the hypothesis that brevican is involved in the synaptic reorganization of denervated brain areas.