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.

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.

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.

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.

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.

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.

Real-time tracking of memory formation in the human rhinal cortex and hippocampus.

A fundamental question about human memory is which brain structures are involved, and when, in transforming experiences into memories. This experiment sought to identify neural correlates of memory formation with the use of intracerebral electrodes implanted in the brains of patients with temporal lobe epilepsy. Event-related potentials (ERPs) were recorded directly from the medial temporal lobe (MTL) as the patients studied single words. ERPs elicited by words subsequently recalled in a memory test were contrasted with ERPs elicited by unrecalled words. Memory formation was associated with distinct but interrelated ERP differences within the rhinal cortex and the hippocampus, which arose after about 300 and 500 milliseconds, respectively. These findings suggest that declarative memory formation is dissociable into subprocesses and sequentially organized within the MTL.

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.

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.

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.

Presence and removal of arteriovenous malformation: Impact of regional cerebral blood flow, as assessed with xenon/CT.

In 26 patients with supratentorial AVMs and 1 patient with a dural arteriovenous fistula, the regional cerebral blood flow (rCBF) was assessed by means of xenon-enhanced computed tomography (Xe/CT) before and after complete resective surgery. Each assessment comprised an acetazolamide challenge in order to check the cerebrovascular reserve capacity. While scanning through the AVM was purposely avoided, a single brain slice at the level of the basal ganglia was examined. Five regions of interest (ROIs) in gray matter of the AVM-bearing hemisphere were compared to the contralateral ROIs and categorized into 7 CBF groups. Interhemispherical differences exceeding 20% of the contralateral value in either direction were considered to the significant. AVM-related (AVM-R) and AVM-non-related (AVM-NR) ROIs were looked at separately. Before surgery, all possible rCBF patterns were found, including a normal rCBF as well as a reduced or an increased rCBF, either in AVM-R, AVM-NR, or both. After AVM removal, a rCBF increase in AVM-R is relatively rare, whereas a rCBF decrease is twice as frequent. A rCBF drop to a level of impaired reserve capacity correlates with the occurrence of post-operative neurological deficit.

Amobarbital effects on the posterior hippocampus during the intracarotid amobarbital test.

OBJECTIVE: To relate functional effects on the hippocampus during the intracarotid amobarbital test (IAT) to its direct perfusion with amobarbital. METHODS: In 17 patients with intractable temporal lobe epilepsy, 28 hemispheres were perfused with 2.3 mL of 10% solution of 200 mg amobarbital and 37 MBq 99mTc-hexamethylpropylene amine oxime (HMPAO). For evaluation of amobarbital effects, data were combined from stereo-EEG (S-EEG) recordings from intrahippocampal depth electrodes and high-resolution SPECT after intracarotid injection of HMPAO. RESULTS: Perfusion of the entire hippocampus was observed only in hemispheres with a fetal origin of the posterior cerebral artery (PCA). In 10 hemispheres, S-EEG recordings could not unequivocally be assigned to either the anterior or the posterior part of the hippocampus. In the remaining 18 hemispheres, only the two with a fetal type of PCA showed perfusion of the entire hippocampus. In both, hippocampal electrical activity changed under the influence of amobarbital but did not differ in anterior and posterior contacts. In 15 of 16 hemispheres in which SPECT demonstrated perfusion of the anterior hippocampus only, amobarbital injection resulted in significant S-EEG activity change in both the anterior and the posterior parts of the hippocampus. CONCLUSION: S-EEG effects on the posterior hippocampus during the IAT can occur without direct perfusion of those brain areas.

Human temporal lobe potentials in verbal learning and memory processes.

Animal experiments and lesion studies have shown the importance of temporal lobe structures for language and memory. We recorded intracranial cognitive potentials from the human lateral and medial temporal lobe in 26 patients with temporal lobe epilepsy undergoing presurgical evaluation, using a word- and a picture-recognition paradigm. Neuropsychological testing included word fluency, verbal reasoning, sustained attention and a verbal learning memory test (VLMT), which was an adapted version of the Rey auditory verbal learning test. Word-specific N400-potentials elicited in the middle temporal gyrus of the dominant left hemisphere (LTL-N400) predicted immediate recall performance after learning, whereas N400s, elicited by words but not pictures in the left anterior medial temporal lobe (AMTL-N400), predicted delayed recall. The number of words that were learned but forgotten after a 30-min delay correlated only with N400s elicited by words in the left anterior medial temporal lobe. Thus, intracranial recordings indicated that different electrophysiological responses in different temporal lobe structures were linked to memory scores from specific neuropsychological tests.

Limbic ERPs predict verbal memory after left-sided hippocampectomy.

Surgical removal of the dominant medial temporal lobe regions runs a considerable risk of verbal memory deficits which may be compensated for postoperatively by corresponding regions in the non-dominant medial temporal lobe. We examined this possibility by recording event-related potentials (ERPs) to words from the medial temporal lobes of patients with left-sided temporal lobe epilepsy (TLE) undergoing presurgical evaluation. N400 amplitudes in the right anterior medial temporal lobe predicted the postoperative verbal recall performance of individual patients with surprising accuracy, indicating that intracranial recordings can be used to quantify the functional capacities of the right hemisphere that can compensate for the verbal memory deficits after loss of medial temporal lobe structures in the left hemisphere.

What factors are related to impairment of cerebrovascular reserve before and after arteriovenous malformation resection? A cerebral blood flow study using xenon-enhanced computed tomography.

OBJECTIVE: To examine the incidence and possible determinants of impaired vascular reserve in arteriovenous malformation (AVM)-affected brain, before and after surgery. METHODS: In a prospective study of 30 patients, the regional cerebrovascular reserve capacity (rCRC) and the vasodilated regional cerebral blood flow (rCBF) were assessed during an acetazolamide challenge, using xenon-enhanced computed tomography, before and after complete AVM resection. Single brain slices at the level of the basal ganglia were examined, and scanning through the AVMs was avoided. Five regions of interest in the AVM-bearing hemisphere were compared with their counterparts in the unaffected hemisphere. Vasodilated rCBF reductions of at least 20% in one or more regions of interest and rCRC values of less than 10 ml/100 g/min were considered to be significant. RESULTS: Ipsilateral vasodilated rCBF was significantly reduced in 17 patients before surgery and 15 patients after surgery. Ipsilateral rCRC was impaired in 14 patients before surgery and 12 patients after surgery. Large AVM size, venous congestion, and AVM-related vascular territories were correlated with impaired vascular reserve in AVM-nonadjacent brain tissue before surgery. Similar correlations were observed after surgery, except that not AVM size but a large number of AVM-supplying vascular territories was correlated. Moreover, the smallest AVMs and those supplied by a single vascular territory, as well as hemorrhage and nonhemorrhagic neurological deficits as presenting symptoms, were correlated with reduced ipsilateral vasodilated rCBF before surgery. Among patients with AVMs and nonhemorrhagic epilepsy, a trend of impaired cerebrovascular reserve was observed. In the only case of postresectional "breakthrough," the preoperative rCRC was not impaired but abnormally high. CONCLUSION: Among the determinants of impaired cerebrovascular reserve, AVM size is already a constituent of current grading scales and decision-making paradigms, whereas factors such as venous congestion have been less closely considered or less obvious but may deserve increased attention in the future. Nonhemorrhagic epilepsy in patients with AVMs may constitute the clinical equivalent of chronic cerebral ischemia in a murine model. Postresectional breakthrough may be partly attributable to individual predisposition to excessive vasoreactivity in the whole brain.

Depth electrode implantation in the length axis of the hippocampus for the presurgical evaluation of medial temporal lobe epilepsy: a computed tomography-based stereotactic insertion technique and its accuracy.

OBJECTIVE: An individualized computed tomography-based stereotactic technique for the longitudinal insertion of intrahippocampal electrodes is presented and its accuracy described. METHODS: The technique makes use of one well reproducible target in the hippocampal head and of the approximate inclination of the anteroposterior length axis of the hippocampus, for which the orbital floor is taken as an auxiliary landmark. It was used in 141 patients with medically intractable complex partial seizures. In 106 patients, magnetic resonance imaging (MRI) was available for assessment of implantation accuracy. Each of the 212 electrodes was plotted on topographic drawings and its goodness of fit rated. RESULTS: Whereas hippocampal head and body were hit by 97 and 96% of the electrodes, respectively, the amygdala was hit by only 75% of the electrodes and mainly at its basal margin. For 93% of the electrodes, the inclination in a sagittal plane corresponded exactly to that of the hippocampus. The implantation morbidity amounted to 5.7%, whereas permanent neurological deficit occurred in one (0.7%) of the 141 patients. CONCLUSION: This computed tomography-based protocol proved to be reliable and hence can be considered as an adequate alternative to MRI-based stereotactic implantation if MRI is not available or if a single MRI-based stereotactic set-up is unreliable because of intolerable distortions.

Recombinant human thyrotropin in thyroid cancer and hypopituitarism due to sella metastasis.

We present a patient with thyroid cancer and hypopituitarism who required recombinant human thyrotropin (rhTSH) for 131I scanning with respect to subsequent therapy. The thyroid cancer had been unknown until central neurological symptoms developed, leading to the diagnosis of a huge metastasis to the sella that was the only manifestation of metastatic spread. The failure to generate endogenous thyrotropin (TSH) was overcome by the use of rhTSH for performing a 131I test. Unfortunately, the 131I uptake was not sufficient for therapy. This subject is the first reported case who required the application of rhTSH due to a single thyroid cancer metastasis in the sella region with secondary failure to generate endogenous TSH.

Intravascular papillary endothelial hyperplasia of the sellar region. Report of three cases and review of the literature.

Intravascular papillary endothelial hyperplasia (IPEH) is considered a reactive proliferation of endothelium associated with thrombosis. The occurrence of IPEH in the cranial cavity is exceedingly rare. In this article, the authors report three cases of IPEH that originated from the cavernous sinus and extended into the sellar contents. The lesions were resected incompletely in two cases and completely in one case. The IPEH in one of the patients was incompletely resected and exhibited further growth on magnetic resonance imaging 3 months postoperatively; local radiation therapy was instituted. This led to shrinkage of the lesion over an additional follow-up period of 3.5 years. In a review of the literature, the authors located seven other cases of intracranial IPEH. The authors conclude that clinically symptomatic intracranial IPEH should be completely resected whenever possible, because it can cause considerable morbidity and mortality and because it is prone to progression or recurrence.

Corrosion on an internal spinal fixator system.

STUDY DESIGN: Thirteen spinal fixators with 26 stabilization bridges and 52 pedicle screws and a mean length of implantation of 10 months were prospectively examined for corrosion. OBJECTIVES: To determine the type of corrosion and the correlation between the construction of the spinal fixator and the type of corrosion. SUMMARY OF BACKGROUND DATA: Evidence of fretting and crevice corrosion is seen in many stainless steel implants in retrieval studies. Such reactions have not been described in the literature on spinal fixator systems. METHODS: Macroscopic and microscopic alterations in the adjacent tissue were examined, and the corrosive alterations were documented photographically using stereoscopic optical light microscopy. The chemical composition of the implants was determined spectrographically. Microradiography and x-ray fluorescence analysis of the soft tissue were performed. RESULTS: At surgery, tissue discoloration was found in four cases. Histologic examination showed extensive fibrosis, foreign body reaction and inflammation associated with a small number of metal particles, indicating metallosis in five cases. Corresponding particles were detected by microradiography. Corrosion was found on 13 telescopic rods and on two pedicle screws. The alterations on the telescopic rods could be interpreted as crevice corrosion and the alterations in the pedicle screws as fretting corrosion. The two monobloc fixator bridges did not show signs of corrosion. In these implants, the neighboring tissue was macroscopically inconspicuous, and histologic examination showed minimal fibrosis or presence of metal particles. Spectrographic examination of the spinal fixators showed no structural imperfection. CONCLUSIONS: The construction constraints of a spinal fixator make it prone to corrosion. New spinal implants should be examined not only in vitro but also in vivo to ascertain whether corrosion and adjacent tissue reaction occur. Corrosion is one reason to explant the internal fixation system after fusion of the spinal fracture.