Sex-based survival differences in IDH-wildtype glioblastoma: Results from a retrospective cohort study.

A female survival benefit has been described for glioblastoma patients. Recent studies report that the effect of 06-methylguanine-DNA-methyltransferase gene promoter (MGMTp) methylation is only present in female patients. We retrospectively studied sex-based survival, including MGMTp-methylation, in a cohort of 159 uniformly treated isocitrate dehydrogenase wildtype (IDHwt) patients. All patients were treated with temozolomide-based chemoradiotherapy after surgery. Kaplan-Meier survival curves and Cox regression models were used to evaluate overall survival. The study included 59 female (37.1%) and 100 male patients (62.9%). There were no statistically significant differences between sexes concerning demographic, surgical or radiological characteristics. Female patients harbored MGMTp-methylated tumors in 45.8% of cases and males in 33% (P = 0.129). Median overall survival was 13.4 months for men and women alike. After adjustment of survival for age, Karnofsky Performance Score, extent of resection and MGMTp-methylation, sex did not have a significant survival impact. However, MGMTp-methylation proved to be an independent beneficial prognosticator for both sexes, contradicting earlier reports. Several sex-based molecular subtypes of glioblastoma with different response to current treatment may exist explaining conflicting survival results in different patient cohorts. Further research on sex-based differences in IDHwt glioblastoma patients is needed.

Subventricular zone contacting glioblastoma: tumor size, molecular biological factors and patient survival.

BACKGROUND: Several studies show that subventricular zone (SVZ) contact of glioblastoma at diagnosis is a negative prognosticator of survival. In this report, we study glioblastoma patient survival, molecular biological and MRI-based volumetric findings according to SVZ contact. PATIENTS AND METHODS: We conducted a retrospective study of adult patients diagnosed with supratentorial glioblastoma and uniformly treated with temozolomide-based chemoradiotherapy after surgery. The patient cohort was dichotomized according to tumor contact with the SVZ at diagnosis as determined on preoperative MR imaging. Tumor volume was measured using semi-automated segmentation technique. MGMT-gene promoter methylation and IDH mutation status were determined on stored tumor tissue. Kaplan-Meier survival curves were constructed. Cox regression analysis was used to adjust for known confounding factors of glioblastoma patient survival. RESULTS: A total of 214 patients were included in the study of whom 68% belonged to the SVZpos group. Median tumor volume was significantly larger in the SVZpos group (33,8 mL vs 15,6 mL; p < .001). MGMT-unmethylated glioblastoma was more frequent in the SVZpos group (61.4% vs 44.9%; p = .028). The overall survival and progression-free survival were 12.2 months and 5.9 months for the SVZpos patient group but 16.9 months and 10.3 months for the SVZneg group (log-rank p = .016 and .007 respectively). In multivariate Cox survival analysis, SVZ contact proved a negative prognostic parameter, independent from age, KPS, extent of resection, MGMT-methylation and IDH mutation status. CONCLUSIONS: This study confirms SVZ contact at diagnosis as an independent negative prognostic factor for glioblastoma patient survival. SVZpos glioblastoma had larger tumor size and a larger proportion of unmethylated tumors than SVZneg glioblastoma. Further research is needed to establish whether the observed differences are solely explained by a different molecular profile of SVZpos glioblastoma or by interaction of glioblastoma with the unique SVZ microenvironment.

Subthalamic nucleus activity in the processing of body and mental action verbs in people with Parkinson's disease.

Local field potentials evoked by body action and mental action verbs were recorded in the subthalamic nucleus (STN) of 18 patients with Parkinson's disease through the electrodes implanted for deep brain stimulation. Compared with the medication on-condition, the medication off-condition showed a difference in activity in the early time segments, mainly in the right STN, with larger amplitudes for body action verbs. In the on-condition a similar pattern was detected in the left STN. These patterns of early differences in activity evoked by different types of verbs might indicate the potential of the STN to rapidly detect relevant behavioural clues in verbal content and to integrate these in subsequent cortico-subcortical interactions. In addition, these lateralizations allow speculations about shifts in processing activity correlating with dopaminergic denervation. Whether this detection relies on phonological, semantic or grammatical clues remains an open question.

Weak MGMT gene promoter methylation confers a clinically significant survival benefit in patients with newly diagnosed glioblastoma: a retrospective cohort study.

INTRODUCTION: Quantitative methylation specific PCR (qMSP) is a frequently used technique to assess MGMT gene promoter methylation in glioblastoma patients. The optimal technical cut-off value to distinguish methylated from unmethylated samples is nevertheless still undetermined. In literature, a "grey zone" of diagnostic uncertainty has been described. METHODS: We performed a retrospective analysis of newly diagnosed glioblastoma patients treated according to the Stupp protocol. Epidemiological data were gathered from the individual patient files. MGMT gene promoter methylation status was determined on stored tumour samples using qMSP. A strong, weak or absent promoter methylation was determined based on Cq values (quantification value) of the MGMT and ACTB primers as well as a positive control sample. RESULTS: In total, 181 patient files were reviewed and included for statistical analysis. MGMT promoter hypermethylation was detected in 38.7% of glioblastoma patients. The median overall survival of unmethylated and strongly methylated patients was 10.1 months and 19.7 months respectively. Furthermore, 11% of the total patient cohort had a weak MGMT gene promoter methylation. The median OS in this subgroup was 15.4 months, significantly better compared to the unmethylated cohort (P < 0.001). Multivariate Cox regression analysis showed weak MGMT promoter methylation as an independent prognostic parameter for overall survival. CONCLUSION: Glioblastoma patients with weak promoter methylation show a statistically significant longer overall survival when compared to clearly unmethylated patients. Patients with grey zone qMSP test results should receive additional molecular analysis in future to further direct individual therapy strategies.

Electrophysiological registration of phonological perception in the subthalamic nucleus of patients with Parkinson's Disease.

Phonological processing is usually associated with the activation of cortical areas, especially in the left cerebral hemisphere. This study examined if phonologically elicited evoked potentials can be recorded directly from the subthalamic nucleus in patients with Parkinson's Disease (PD). Seven PD patients who had undergone implantation of deep brain electrodes for the stimulation of the subthalamic nucleus were included. Local field potentials were recorded in a pre-attentive auditory phonological task, an attentive auditory phonological discrimination task, and a word recognition task. Auditory evoked potentials related to phonological, but not lexical processing, could be demonstrated in the subthalamic nucleus for all three tasks. Only minor changes were found after levodopa administration. This study demonstrates that the subthalamic nucleus is involved in early phonological perception, which puts the subthalamic nucleus in a position to modify phonological perception in a larger cortico-subcortical network.

Training charter in epilepsy surgery added competence.

The present Training Charter in Epilepsy Surgery Added Competence constitutes the third stage of a program initiated by the European Society for Stereotactic and Functional Neurosurgery (ESSFN) and substantiated in close collaboration with the Union Européennedes Médecins Spécialists (UEMS) and the European Association of Neurosurgical Societies (EANS). This program aims to raise the standards of clinical practice by guiding education and quality control concepts. The particular sections of this Charter include: definitions and standards of added competence training, relations of the Epilepsy Unit with the Neurosurgical Department, duration of epilepsy surgery fellowship, institution and training program director requirements, operative totals for epilepsy surgery, educational program, individual requirements, and evaluation and qualification of the trainees. The specification of all these requirements is expected to improve harmonisation and quality of epilepsy surgery practice across Europe, and enhance the clinical activity and the scientific productivity of existing neurosurgical centres.

Chordoid meningioma in an adult patient presenting with chronic fatigue and systemic inflammation.

We report a 27-year-old woman presenting with chronic fatigue and depressive symptoms. Aspecific neurologic symptoms and biochemical indices of inflammation and anaemia triggered an MRI, revealing a tumor with compression of the medulla oblongata. After neurosurgical resection, anatomopathologic examination showed a chordoid meningioma. All complaints disappeared and inflammatory parameters normalized, suggesting an association with Castleman syndrome. This case demonstrates the importance of a systematic diagnostic approach in patients presenting with unexplained chronic fatigue.

Surgical successes and failures of invasive video-EEG monitoring in the presurgical evaluation of epilepsy.

Invasive monitoring with intracranial electrodes continues to play a critical role in the presurgical evaluation of patients with medically intractable epilepsy. Intracranial monitoring helps in localizing the epileptogenic zone and can be used to delineate eloquent cortical areas adjacent to this zone. In this review we analyzed surgical successes and failures of invasive video-electroencephalography (EEG) monitoring. Thorough understanding of all potential complications is of paramount importance not only for detection and successful management of intractable epilepsy but also for medicolegal purposes, as patients and their relatives need to be fully informed about the possible risks associated with invasive monitoring. A mortality rate between 0.5% and 2.8% has been reported. Cerebrospinal fluid (CSF) leaks and infections are the most frequent complications, with an incidence ranging from 0-31.3% and from 0-17.4%, respectively. The incidence of intracranial hemorrhage is reported to be up to 14% with subdural hematomas being the most prevalent. Epidural hematomas are less frequent and encountered in up to 2.6% of cases. Intraparenchymal hematomas are even less frequent and are typically associated with the placement of depth electrodes. In 47-98% of cases, invasive video-EEG monitoring results into resective surgery. Invasive video-EEG monitoring is a reasonably safe and effective method to help delineate the epileptogenic zone and its relation to eloquent cortex.

Pressure monitoring during neuroendoscopy: new insights.

BACKGROUND: Significant increases in intracranial pressure (ICP) may occur during neuroendoscopic procedures. To detect and prevent serious and sustained increases, ICP should be monitored. At present, controversy exists on the optimal location of the monitoring sensor. Therefore, we conducted an in vitro study to estimate the pressure gradients between the ventricle, the 'gold standard' site, and the rinsing inlet and outlet. METHODS: A head model and a standard endoscope were used. Rinsing was enforced by using a pressurized infusion bag. Using clinically relevant flow rates, pressure was measured at the rinsing inlet and outlet, in the ventricle, and at the distal end of the rinsing channel using a tip sensor or a capillary tube. RESULTS: At a flow of 61 ml min(-1), the steady-state pressures measured at the rinsing inlet, in the ventricle, and at the rinsing outlet were 38, 26, and 12 mm Hg, respectively. At 135 ml min(-1), these increased to 136, 89, and 42 mm Hg. Transendoscopic pressure measurements were always within 1 mm Hg of the ventricular pressure. CONCLUSIONS: During endoscopy, measurements at the rinsing inlet overestimated the ventricular pressure by ∼50 mm Hg during heavy rinsing, whereas measurements at the rinsing outlet underestimated the pressure by ∼50 mm Hg. An electronic tip sensor or a pressure capillary tube placed at the distal end of the lumen of the rinsing channel of the endoscope did not interfere with rinsing flow and produced measurements that were equal to ventricular pressures.

Experimental and numerical modelling of the ventriculosinus shunt (El-Shafei shunt).

This study assesses malresorptive hydrocephalus treatment by ventriculosinus shunting with the shunt in the antegrade or retrograde position. First, an experimental model of the cerebral ventricles, the arachnoid villi, the cortical veins, and the superior sagittal sinus was built. For this purpose, the compliance of a human cortical vein was measured and then modelled by means of Penrose tubes. The dimensions of the superior sagittal sinus were determined in vivo by measurements on magnetic resonance imaging scans of 21 patients. Second, a numerical model of the cortical veins and the superior sagittal sinus was built. The numerical results were validated with the results from the experimental model. The experimental and numerical pressure difference between the intracranial pressure and the static sinus pressure was small (0-20 Pa) and corresponded to the theoretically expected values. No overdrainage was found in either the antegrade or the retrograde position of the shunt. Blood reflow was only found while mimicking lumbar puncture or changes in position with the experimental model (lowering the intracranial pressure or increasing the sinus pressure rapidly). Optimal results can be obtained with the shunt positioned in the most downstream half of the superior sagittal sinus. The experimental and numerical results confirm the potential of ventriculosinus shunting as therapy for malresorptive hydrocephalus patients. The ventriculosinus shunt thus proves to be a promising technique.

Intradural endoscopic closure of dural breaches in a case of post-traumatic tension pneumocephalus.

INTRODUCTION: Post-traumatic tension pneumocephalus can become a life-threatening condition that urges the surgeon to repair the causal breach in the dura. Dural repair via craniotomy may be jeopardised by the fragility of the dura and by its firm adhesions to the bone, especially in aged patients. Transnasal sealing requires the opening of each of the paranasal sinuses or cells that line the frontal base. METHOD: We present the case of a 92-year-old man, in whom an alternative, minimally invasive procedure was chosen. The patient was in a poor general condition and suffered from progressive obtundation till coma, because of a massive tension pneumocephalus, which was not reversed by drainage of the intracranial air via a burr hole, but even increased instead. Through the existing burr hole at the coronal suture, a rigid endoscope was introduced. Because of a massive backward compression of the brain, the endoscope could be passed in front of it to visualize the dural defects at the level of the ethmoidal roof. Pericranium, harvested from around the burr hole, was glued against the defects. The procedure was repeated at the contralateral side. RESULT: After surgery, a gradual decrease of the amount of intracranial air was documented. The patient regained consciousness and was extubated. In spite of this favourable course, he suddenly died two weeks after surgery from combined pulmonary and renal dysfunction. Autopsy documented the efficacious endoscopic sealing of the skull base, which was the least invasive procedure in the given circumstances.

Clinical experience with vagus nerve stimulation and deep brain stimulation in epilepsy.

Patients with refractory epilepsy present a particular challenge to new therapies. Vagus nerve stimulation (VNS) for the control of intractable seizures has become available since 1989. VNS is a relatively noninvasive treatment. It reduces seizure frequency by > or =50% in 1/3 of patients; an additional 1/3 of patients experience a worthwhile reduction of seizure frequency between 30 and 50%. In the remaining 1/3 of the patients there is little or no effect. Efficacy has a tendency to improve with longer duration of treatment up to 18 months postoperatively. Deep brain stimulation (DBS) or direct electrical stimulation of brain areas is an alternative neurostimulation modality. The cerebellum, various thalamic nuclei, the pallidum, and, more recently, medial temporal lobe structures have been chosen as targets. DBS for epilepsy is beyond the stage of proof-of-concept but still needs thorough evaluation in confirmatory pilot studies before it can be offered to larger patient populations. Analysis of larger patient groups and insight in the mode of action may help to identify patients with epileptic seizures or syndromes that respond better either to VNS or to DBS. Randomized and controlled studies in larger patient series are mandatory to identify the potential treatment population and optimal stimulation paradigms. Further improvements of clinical efficacy may result from these studies.

Anatomical and physiological basis and mechanism of action of neurostimulation for epilepsy.

Neurostimulation is an emerging treatment for neurological diseases. Different types of neurostimulation exist mainly depending of the part of the nervous system that is being affected and the way this stimulation is being administered. Vagus nerve stimulation (VNS) is a neurophysiological treatment for patients with medically or surgically refractory epilepsy. Over 30,000 patients have been treated with VNS. No clear predictive factors for responders have been identified. To date, the precise mechanism of action remains to be elucidated. Better insight in the mechanism of action may identify seizure types or syndromes that respond better to VNS and may guide the search for optimal stimulation parameters and finally improve clinical efficacy. Deep brain stimulation (DBS) has been used extensively as a treatment for movement disorders. Several new indications such as obsessive compulsive behaviour and cluster headache are being investigated with promising results. The vast progress in biotechnology along with the experience in other neurological diseases in the past ten years has led to a renewed interest in intracerebral stimulation for epilepsy. Epilepsy centers around the world have recently reinitiated trials with deep brain stimulation in different intracerebral structures such as the thalamus, the hippocampus and the subthalamic nucleus.

Neurosurgical aspects of temporal deep brain stimulation for epilepsy.

Deep brain stimulation (DBS), which mimics the effect of ablative surgery in movement disorders, is considered by analogy as potentially useful in the epileptic temporal lobe as an alternative to resection. It could be applied to patients in whom resective surgery is less beneficial, e.g. cases without memory impairment or with bilateral hippocampal involvement. In patients who undergo invasive presurgical analysis, the necessary intrahippocampal leads can serve for the application of DBS, provided that they are suited for chronic use. The hippocampus, in which the focus of epilepsy is detected, is stimulated continuously using high-frequency square-wave pulses. The reduction of interictal spike activity during a period of acute stimulation is the criterion for deciding whether the leads will be connected to an internal pulse generator. We are conducting a pilot study, with 16 patients enrolled so far, ten of whom have been followed up for more than one year. Some theoretical considerations are dedicated to hippocampal DBS.

Cryptococcoma unresponsive to antifungal treatment in a 63-year-old non-HIV-infected male.

Cryptococcosis is an invasive fungal infection mainly due to Cryptococcus neoformans which has become increasingly prevalent in immunocompromised patients. The majority of patients with disseminated infection are immunocompromised due to AIDS, prolonged treatment with corticosteroids, organ transplantation, or malignancy. Invasive cryptococcal infection is rare in healthy immunocompetent individuals. We present a case of cerebral cryptococcoma in a previously healthy individual with development of meningitis and multiple intracerebral lesions in spite of persistently negative cultures and refractory to conventional antifungal therapy. The diagnosis was confirmed by two independent anatomopathological examinations.

Characterization of hemorrhagic complications after surgery for temporal lobe epilepsy.

OBJECTIVES: To assess the significance of symptomatic hemorrhagic complications occurring after different temporal resections for temporal lobe epilepsy (TLE) and to compare this data to findings with postoperative hematomas after temporal surgery for mostly glial or metastatic tumors. PATIENTS AND METHODS: Patient charts were retrospectively reviewed for 442 patients who underwent surgery for refractory TLE between 1995 and 2000. Procedures were 247 transsylvian amygdalohippocampectomies (AH), 40 transcortical AH, 57 anterior temporal lobectomies (ATL), 23 lesionectomies plus AH, and 75 lesionectomies without AH. All patients with delayed awakening or new neurological deficits due to hemorrhages were included in the study. An identical procedure was performed to detect symptomatic hemorrhages after 208 procedures for temporal tumor resection during the same time period. RESULTS: Symptomatic postoperative hemorrhages were found in 17 patients (3.8 %) undergoing epilepsy surgery, while the incidence was 3.0 % in a group with space-occupying temporal tumors (six patients). Hemorrhages showed a characteristic distribution after epilepsy surgery: in eight patients they were located remote from the site of surgery in the upper cerebellar vermis and foliae. Five typical hemorrhages associated with dysphasia were found in the left frontal operculum, only three patients had hematomas in the resection cavity, and one was located epidurally. Two patients had more than one location of hemorrhage. Transsylvian AH and ATL had a similar risk for postoperative hemorrhage, whereas none was found after lateral lesionectomies or transcortical AH. Intraoperative manipulations were associated with opercular hemorrhages; the only predisposing factor for resection site hematomas was older age, whereas cerebellar hemorrhages were associated with cerebrospinal fluid (CSF) loss during AH and ATL. There was no mortality in the TLE group, and 0.75 % permanent mild deficits. Seizure outcome did not differ from the rest of the group (82.5 % satisfactory seizure control). In contrast, all intraaxial hematomas after tumor surgery (N = 4, incidence 1.9 %) were located in or adjacent to the resection cavity. Prognosis was much worse with parenchymal hemorrhages after tumor surgery: three of four patients died, one survived with a severe hemiparesis, only two patients with extraaxial hematomas (incidence 1 %) had a complete recovery. The 3 % incidence of symptomatic hemorrhages was only insignificantly lower compared to the TLE group, patients with tumor surgery were older than TLE patients (49 versus 33 years), and in five of six patients only incomplete tumor resection was achieved. CONCLUSION: Although associated with a low permanent morbidity, features of postoperative hemorrhages after TLE surgery are characteristically different to complications after surgery for other indications, which has to be kept in mind for patient counseling and obtaining informed consent.

Clonal evolution as pathogenetic mechanism in relapse of primary CNS lymphoma.

Comparative investigation of immunoglobulin (Ig) heavy chain gene rearrangements and DNA sequence analyses of a primary lymphoma of the CNS (PCNSL) and its recurrence revealed that both tumors used the same Ig gene segment. In addition to shared somatic mutations, the primary and the recurrent PCNSLs harbored somatic mutations unique to each tumor. Clonal evolution rather than subclone selection appears to underlie the development of tumor recurrence in this case.

Collateral brain damage, a potential source of cognitive impairment after selective surgery for control of mesial temporal lobe epilepsy.

BACKGROUND: Highly selective epilepsy surgery in temporal lobe epilepsy is intended to achieve seizure freedom at a lower cognitive risk than standard en bloc resections, but bears the risk of collateral cortical damage resulting from the surgical approach. OBJECTIVE: To investigate cortical damage associated with selective amygdalo-hippocampectomy (SAH). METHODS: 34 epileptic patients were evaluated. They were randomly assigned to SAH using either a sylvian (9 left/10 right) or a transcortical surgical approach (5 left/10 right). Postoperative MRI signal intensity changes adjacent to the approach were correlated with performance changes in serial word and design list learning. RESULTS: Losses in verbal learning and recognition memory were positively related to signal intensity changes, independent of the side of the resection, the surgical approach, or the extent of the mesial resection. Losses in consolidation/retrieval (memory) were greater after left sided surgery. Losses in design learning were related to right sided surgery and signal intensity changes. Seizure outcome (85% seizure-free) did not differ depending on the side or type of surgery. CONCLUSIONS: Collateral damage to cortical tissues adjacent to the surgical approach contributes to postoperative verbal and figural memory outcome after SAH. Controlling for collateral damage may clarify the controversial memory outcomes after SAH reported by different surgical centres.

The pathophysiology of motor symptoms in Parkinson's disease.

This review focuses on some of the known and hypothetical pathophysiological mechanisms underlying the motor symptoms in Parkinson's disease (PD). Current views on these mechanisms have largely been influenced by models of basal ganglia functioning and dysfunctioning. These models have allowed to explain some clinical findings and to predict a number of results of basal ganglia surgery in movement disorders. However, neurophysiological studies as well as neurochemical data have broadened our vision on basal ganglia functioning and dysfunctioning in PD. Moreover, these more fundamental insights in basal ganglia functioning allow new concepts on the development of treatment strategies, and on the prevention of motor fluctuations in PD.