Efficacy of subperiosteal drains in chronic subdural hematoma: a prospective randomized single-center study.

Background Chronic subdural hematomas (cSDH) are most frequently treated by evacuation via a burr-hole craniostomy procedure. Subperiosteal drains have been introduced as alternatives to subdural ones but only a few prospective studies have explored their efficacy. Thus, a prospective randomized trial was designed to assess their use. Methods The study enrolled patients with newly diagnosed surgically amenable cSDH. These patients were randomized into two groups. The first group underwent cSDH evacuation via a single burr-hole craniostomy procedure followed by placement of a subperiosteal drain; the second group underwent the identical procedure without drain placement. Patient demographics, drain volumes, duration of drainage, cSDH recurrence, and postoperative outcomes were recorded. Results Eighty-eight patients presenting with cSDH (12 with bilateral findings) from a total of 100 surgical cases were enrolled. Nine patients (1 bilateral) were lost to follow-up. Of all remaining 90 procedures, 37 were carried out with drain placement and the remaining 53 without. There were 5 recurrent cases (13,5%) in the drain group and 17 (32,1%) in the control group without drain placement. This resulted in a statistical significance (OR 0.33; p<0.05) favoring the use of a drain. Conclusion Subperiosteal drain placement can be used safely and effectively to treat cSDH in conjunction with a burr-hole craniostomy procedure, significantly reducing the rate of recurrence without any additional disadvantages.

Machine Learning-Based Prediction of Glioma IDH Gene Mutation Status Using Physio-Metabolic MRI of Oxygen Metabolism and Neovascularization (A Bicenter Study).

The mutational status of the isocitrate dehydrogenase (IDH) gene plays a key role in the treatment of glioma patients because it is known to affect energy metabolism pathways relevant to glioma. Physio-metabolic magnetic resonance imaging (MRI) enables the non-invasive analysis of oxygen metabolism and tissue hypoxia as well as associated neovascularization and microvascular architecture. However, evaluating such complex neuroimaging data requires computational support. Traditional machine learning algorithms and simple deep learning models were trained with radiomic features from clinical MRI (cMRI) or physio-metabolic MRI data. A total of 215 patients (first center: 166 participants + 16 participants for independent internal testing of the algorithms versus second site: 33 participants for independent external testing) were enrolled using two different physio-metabolic MRI protocols. The algorithms trained with physio-metabolic data demonstrated the best classification performance in independent internal testing: precision, 91.7%; accuracy, 87.5%; area under the receiver operating curve (AUROC), 0.979. In external testing, traditional machine learning models trained with cMRI data exhibited the best IDH classification results: precision, 84.9%; accuracy, 81.8%; and AUROC, 0.879. The poor performance for the physio-metabolic MRI approach appears to be explainable by site-dependent differences in data acquisition methodologies. The physio-metabolic MRI approach potentially supports reliable classification of IDH gene status in the presurgical stage of glioma patients. However, non-standardized protocols limit the level of evidence and underlie the need for a reproducible framework of data acquisition techniques.

Does Temporary Externalization of Electrodes After Deep Brain Stimulation Surgery Result in a Higher Risk of Infection?

OBJECTIVES: Deep brain stimulation (DBS) is a well-established surgical therapy for movement disorders that comprises implantation of stimulation electrodes and a pacemaker. These procedures can be performed separately, leaving the possibility of externalizing the electrodes for local field potential recording or testing multiple targets for therapeutic efficacy. It is still debated whether the temporary externalization of DBS electrodes leads to an increased risk of infection. We therefore aimed to assess the risk of infection during and after lead externalization in DBS surgery. MATERIALS AND METHODS: In this retrospective study, we analyzed a consecutive series of 624 DBS surgeries, including 266 instances with temporary externalization of DBS electrodes for a mean of 6.1 days. Patients were available for follow-up of at least one year, except in 15 instances. In 14 patients with negative test stimulation, electrodes were removed. All kinds of infections related to implantation of the neurostimulation system were accounted for. RESULTS: Overall, infections occurred in 22 of 624 surgeries (3.5%). Without externalization of electrodes, infections were noted after 7 of 358 surgeries (2.0%), whereas with externalization, 15 of 252 infections were found (6.0%). This difference was significant (p = 0.01), but it did not reach statistical significance when comparing groups within different diagnoses. The rate of infection with externalized electrodes was highest in psychiatric disorders (9.1%), followed by Parkinson's disease (7.3%), pain (5.7%), and dystonia (5.5%). The duration of the externalization of the DBS electrodes was comparable in patients who developed an infection (6.1 ± 3.1 days) with duration in those who did not (6.0 ± 3.5 days). CONCLUSIONS: Although infection rates were relatively low in our study, there was a slightly higher infection rate when DBS electrodes were externalized. On the basis of our results, the indication for electrode externalization should be carefully considered, and patients should be informed about the possibility of a higher infection risk when externalization of DBS electrodes is planned.

Controllability and Robustness of Functional and Structural Connectomic Networks in Glioma Patients.

Previous studies suggest that the topological properties of structural and functional neural networks in glioma patients are altered beyond the tumor location. These alterations are due to the dynamic interactions with large-scale neural circuits. Understanding and describing these interactions may be an important step towards deciphering glioma disease evolution. In this study, we analyze structural and functional brain networks in terms of determining the correlation between network robustness and topological features regarding the default-mode network (DMN), comparing prognostically differing patient groups to healthy controls. We determine the driver nodes of these networks, which are receptive to outside signals, and the critical nodes as the most important elements for controllability since their removal will dramatically affect network controllability. Our results suggest that network controllability and robustness of the DMN is decreased in glioma patients. We found losses of driver and critical nodes in patients, especially in the prognostically less favorable IDH wildtype (IDHwt) patients, which might reflect lesion-induced network disintegration. On the other hand, topological shifts of driver and critical nodes, and even increases in the number of critical nodes, were observed mainly in IDH mutated (IDHmut) patients, which might relate to varying degrees of network plasticity accompanying the chronic disease course in some of the patients, depending on tumor growth dynamics. We hereby implement a novel approach for further exploring disease evolution in brain cancer under the aspects of neural network controllability and robustness in glioma patients.

Deep Brain Stimulation for Chronic Facial Pain: An Individual Participant Data (IPD) Meta-Analysis.

Despite available, advanced pharmacological and behavioral therapies, refractory chronic facial pain of different origins still poses a therapeutic challenge. In circumstances where there is insufficient responsiveness to pharmacological/behavioral therapies, deep brain stimulation should be considered as a potential effective treatment option. We performed an individual participant data (IPD) meta-analysis including searches on PubMed, Embase, and the Cochrane Library (2000-2022). The primary endpoint was the change in pain intensity (visual analogue scale; VAS) at a defined time-point of ≤3 months post-DBS. In addition, correlation and regression analyses were performed to identify predictive markers (age, duration of pain, frequency, amplitude, intensity, contact configuration, and the DBS target). A total of seven trials consisting of 54 screened patients met the inclusion criteria. DBS significantly reduced the pain levels after 3 months without being related to a specific DBS target, age, contact configuration, stimulation intensity, frequency, amplitude, or chronic pain duration. Adverse events were an infection or lead fracture (19%), stimulation-induced side effects (7%), and three deaths (unrelated to DBS-from cancer progression or a second stroke). Although comparable long-term data are lacking, the current published data indicate that DBS (thalamic and PVG/PAG) effectively suppresses facial pain in the short-term. However, the low-quality evidence, reporting bias, and placebo effects must be considered in future randomized-controlled DBS trials for facial pain.

Non-invasive estimation of muscle fibre size from high-density electromyography.

Because of the biophysical relation between muscle fibre diameter and the propagation velocity of action potentials along the muscle fibres, motor unit conduction velocity could be a non-invasive index of muscle fibre size in humans. However, the relation between motor unit conduction velocity and fibre size has been only assessed indirectly in animal models and in human patients with invasive intramuscular EMG recordings, or it has been mathematically derived from computer simulations. By combining advanced non-invasive techniques to record motor unit activity in vivo, i.e. high-density surface EMG, with the gold standard technique for muscle tissue sampling, i.e. muscle biopsy, here we investigated the relation between the conduction velocity of populations of motor units identified from the biceps brachii muscle, and muscle fibre diameter. We demonstrate the possibility of predicting muscle fibre diameter (R2  = 0.66) and cross-sectional area (R2  = 0.65) from conduction velocity estimates with low systematic bias (∼2% and ∼4% respectively) and a relatively low margin of individual error (∼8% and ∼16%, respectively). The proposed neuromuscular interface opens new perspectives in the use of high-density EMG as a non-invasive tool to estimate muscle fibre size without the need of surgical biopsy sampling. The non-invasive nature of high-density surface EMG for the assessment of muscle fibre size may be useful in studies monitoring child development, ageing, space and exercise physiology, although the applicability and validity of the proposed methodology need to be more directly assessed in these specific populations by future studies. KEY POINTS: Because of the biophysical relation between muscle fibre size and the propagation velocity of action potentials along the sarcolemma, motor unit conduction velocity could represent a potential non-invasive candidate for estimating muscle fibre size in vivo. This relation has been previously assessed in animal models and humans with invasive techniques, or it has been mathematically derived from simulations. By combining high-density surface EMG with muscle biopsy, here we explored the relation between the conduction velocity of populations of motor units and muscle fibre size in healthy individuals. Our results confirmed that motor unit conduction velocity can be considered as a novel biomarker of fibre size, which can be adopted to predict muscle fibre diameter and cross-sectional area with low systematic bias and margin of individual error. The proposed neuromuscular interface opens new perspectives in the use of high-density EMG as a non-invasive tool to estimate muscle fibre size without the need of surgical biopsy sampling.

Are Transventricular Approaches Associated With Increased Hemorrhage? A Comparative Study in a Series of 624 Deep Brain Stimulation Surgeries.

BACKGROUND: Deep brain stimulation (DBS) surgery has advanced tremendously, for both clinical applications and technology. Although DBS surgery is an overall safe procedure, rare side effects, in particular, hemorrhage, may result in devastating consequences. Although there are certain advantages with transventricular trajectories, it has been reasoned that avoidance of such trajectories would likely reduce hemorrhage. OBJECTIVE: To investigate the possible impact of a transventricular trajectory as compared with a transcerebral approach on the occurrence of symptomatic and asymptomatic hemorrhage after DBS electrode placement. METHODS: Retrospective evaluation of 624 DBS surgeries in 582 patients, who underwent DBS surgery for movement disorders, chronic pain, or psychiatric disorders. A stereotactic guiding cannula was routinely used for DBS electrode insertion. All patients had postoperative computed tomography scans within 24 hours after surgery. RESULTS: Transventricular transgression was identified in 404/624 DBS surgeries. The frequency of hemorrhage was slightly higher in transventricular than in transcerebral DBS surgeries (15/404, 3.7% vs 6/220, 2.7%). While 7/15 patients in the transventricular DBS surgery group had a hemorrhage located in the ventricle, 6 had an intracerebral hemorrhage along the electrode trajectory unrelated to transgression of the ventricle and 2 had a subdural hematoma. Among the 7 patients with a hemorrhage located in the ventricle, only one became symptomatic. Overall, a total of 7/404 patients in the transventricular DBS surgery group had a symptomatic hemorrhage, whereas the hemorrhage remained asymptomatic in all 6/220 patients in the transcerebral DBS surgery group. CONCLUSION: Transventricular approaches in DBS surgery can be performed safely, in general, when special precautions such as using a guiding cannula are routinely applied.

Neural decoding from surface high-density EMG signals: influence of anatomy and synchronization on the number of identified motor units.

Objective.High-density surface electromyography (HD-sEMG) allows the reliable identification of individual motor unit (MU) action potentials. Despite the accuracy in decomposition, there is a large variability in the number of identified MUs across individuals and exerted forces. Here we present a systematic investigation of the anatomical and neural factors that determine this variability.Approach. We investigated factors of influence on HD-sEMG decomposition, such as synchronization of MU discharges, distribution of MU territories, muscle-electrode distance (MED-subcutaneous adipose tissue thickness), maximum anatomical cross-sectional area (ACSAmax), and fiber cross-sectional area. For this purpose, we recorded HD-sEMG signals, ultrasound and magnetic resonance images, and took a muscle biopsy from the biceps brachii muscle from 30 male participants drawn from two groups to ensure variability within the factors-untrained-controls (UT = 14) and strength-trained individuals (ST = 16). Participants performed isometric ramp contractions with elbow flexors (at 15%, 35%, 50% and 70% maximum voluntary torque-MVT). We assessed the correlation between the number of accurately detected MUs by HD-sEMG decomposition and each measured parameter, for each target force level. Multiple regression analysis was then applied.Main results.ST subjects showed lower MED (UT = 5.1 ± 1.4 mm; ST = 3.8 ± 0.8 mm) and a greater number of identified MUs (UT: 21.3 ± 10.2 vs ST: 29.2 ± 11.8 MUs/subject across all force levels). The entire cohort showed a negative correlation between MED and the number of identified MUs at low forces (r= -0.6,p= 0.002 at 15% MVT). Moreover, the number of identified MUs was positively correlated to the distribution of MU territories (r= 0.56,p= 0.01) and ACSAmax(r= 0.48,p= 0.03) at 15% MVT. By accounting for all anatomical parameters, we were able to partly predict the number of decomposed MUs at low but not at high forces.Significance.Our results confirmed the influence of subcutaneous tissue on the quality of HD-sEMG signals and demonstrated that MU spatial distribution and ACSAmaxare also relevant parameters of influence for current decomposition algorithms.

Radiophysiomics: Brain Tumors Classification by Machine Learning and Physiological MRI Data.

The precise initial characterization of contrast-enhancing brain tumors has significant consequences for clinical outcomes. Various novel neuroimaging methods have been developed to increase the specificity of conventional magnetic resonance imaging (cMRI) but also the increased complexity of data analysis. Artificial intelligence offers new options to manage this challenge in clinical settings. Here, we investigated whether multiclass machine learning (ML) algorithms applied to a high-dimensional panel of radiomic features from advanced MRI (advMRI) and physiological MRI (phyMRI; thus, radiophysiomics) could reliably classify contrast-enhancing brain tumors. The recently developed phyMRI technique enables the quantitative assessment of microvascular architecture, neovascularization, oxygen metabolism, and tissue hypoxia. A training cohort of 167 patients suffering from one of the five most common brain tumor entities (glioblastoma, anaplastic glioma, meningioma, primary CNS lymphoma, or brain metastasis), combined with nine common ML algorithms, was used to develop overall 135 classifiers. Multiclass classification performance was investigated using tenfold cross-validation and an independent test cohort. Adaptive boosting and random forest in combination with advMRI and phyMRI data were superior to human reading in accuracy (0.875 vs. 0.850), precision (0.862 vs. 0.798), F-score (0.774 vs. 0.740), AUROC (0.886 vs. 0.813), and classification error (5 vs. 6). The radiologists, however, showed a higher sensitivity (0.767 vs. 0.750) and specificity (0.925 vs. 0.902). We demonstrated that ML-based radiophysiomics could be helpful in the clinical routine diagnosis of contrast-enhancing brain tumors; however, a high expenditure of time and work for data preprocessing requires the inclusion of deep neural networks.

Deep Brain Stimulation, Stereotactic Radiosurgery and High-Intensity Focused Ultrasound Targeting the Limbic Pain Matrix: A Comprehensive Review.

Chronic pain (CP) represents a socio-economic burden for affected patients along with therapeutic challenges for currently available therapies. When conventional therapies fail, modulation of the affective pain matrix using reversible deep brain stimulation (DBS) or targeted irreversible thalamotomy by stereotactic radiosurgery (SRS) and magnetic resonance (MR)-guided focused ultrasound (MRgFUS) appear to be considerable treatment options. We performed a literature search for clinical trials targeting the affective pain circuits (thalamus, anterior cingulate cortex [ACC], ventral striatum [VS]/internal capsule [IC]). PubMed, Ovid, MEDLINE and Scopus were searched (1990-2021) using the terms "chronic pain", "deep brain stimulation", "stereotactic radiosurgery", "radioneuromodulation", "MR-guided focused ultrasound", "affective pain modulation", "pain attention". In patients with CP treated with DBS, SRS or MRgFUS the somatosensory thalamus and periventricular/periaquaeductal grey was the target of choice in most treated subjects, while affective pain transmission was targeted in a considerably lower number (DBS, SRS) consisting of the following nodi of the limbic pain matrix: the anterior cingulate cortex; centromedian-parafascicularis of the thalamus, pars posterior of the central lateral nucleus and internal capsule/ventral striatum. Although DBS, SRS and MRgFUS promoted a meaningful and sustained pain relief, an effective, evidence-based comparative analysis is biased by heterogeneity of the observation period varying between 3 months and 5 years with different stimulation patterns (monopolar/bipolar contact configuration; frequency 10-130 Hz; intensity 0.8-5 V; amplitude 90-330 µs), source and occurrence of lesioning (radiation versus ultrasound) and chronic pain ethology (poststroke pain, plexus injury, facial pain, phantom limb pain, back pain). The advancement of neurotherapeutics (MRgFUS) and novel DBS targets (ACC, IC/VS), along with established and effective stereotactic therapies (DBS-SRS), increases therapeutic options to impact CP by modulating affective, pain-attentional neural transmission. Differences in trial concept, outcome measures, targets and applied technique promote conflicting findings and limited evidence. Hence, we advocate to raise awareness of the potential therapeutic usefulness of each approach covering their advantages and disadvantages, including such parameters as invasiveness, risk-benefit ratio, reversibility and responsiveness.

Real-time imaging of glutamate transients in the extracellular space of acute human brain slices using a single-wavelength glutamate fluorescence nanosensor.

Glutamate is the most important excitatory neurotransmitter in the brain. The ability to assess glutamate release and re-uptake with high spatial and temporal resolution is crucial to understand the involvement of this primary excitatory neurotransmitter in both normal brain function and different neurological disorders. Real-time imaging of glutamate transients by fluorescent nanosensors has been accomplished in rat brain slices. We performed for the first time single-wavelength glutamate nanosensor imaging in human cortical brain slices obtained from patients who underwent epilepsy surgery. The glutamate fluorescence nanosensor signals of the electrically stimulated human cortical brain slices showed steep intensity increase followed by an exponential decrease. The spatial distribution and the time course of the signal were in good agreement with the position of the stimulation electrode and the dynamics of the electrical stimulation, respectively. Pharmacological manipulation of glutamate release and reuptake was associated with corresponding changes in the glutamate fluorescence nanosensor signals. We demonstrated that the recently developed fluorescent nanosensors for glutamate allow to detect neuronal activity in acute human cortical brain slices with high spatiotemporal precision. Future application to tissue samples from different pathologies may provide new insights into pathophysiology without the limitations of an animal model.

Physiological MRI of microvascular architecture, neovascularization activity, and oxygen metabolism facilitate early recurrence detection in patients with IDH-mutant WHO grade 3 glioma.

PURPOSE: This study aimed to determine the diagnostic performance of physiological MRI biomarkers including microvascular perfusion and architecture, neovascularization activity, tissue oxygen metabolism, and tension for recurrence detection of IDH-mutant WHO grade 3 glioma. METHODS: Sixty patients with IDH-mutant WHO grade 3 glioma who received overall 288 follow-up MRI examinations at 3 Tesla after standard treatment were retrospectively evaluated. A conventional MRI protocol was extended with a physiological MRI approach including vascular architecture mapping and quantitative blood-oxygen-level-dependent imaging which required 7 min extra data acquisition time. Custom-made MATLAB software was used for the calculation of MRI biomarker maps of microvascular perfusion and architecture, neovascularization activity, tissue oxygen metabolism, and tension. Statistical procedures included receiver operating characteristic analysis. RESULTS: Overall, 34 patients showed recurrence of the WHO grade 3 glioma; of these, in 15 patients, recurrence was detected one follow-up examination (averaged 160 days) earlier by physiological MRI data than by conventional MRI. During this time period, the tumor volume increased significantly (P = 0.001) on average 7.4-fold from 1.5 to 11.1 cm3. Quantitative analysis of MRI biomarkers demonstrated microvascular but no macrovascular hyperperfusion in early recurrence. Neovascularization activity (AUC = 0.833), microvascular perfusion (0.682), and oxygen metabolism (0.661) showed higher diagnostic performance for early recurrence detection of WHO grade 3 glioma compared to conventional MRI including cerebral blood volume (0.649). CONCLUSION: This study demonstrated that the targeted assessment of microvascular features and tissue oxygen tension as an early sign of neovascularization activity provided valuable information for recurrence diagnostic of WHO grade 3 glioma.

Association between tissue hypoxia, perfusion restrictions, and microvascular architecture alterations with lesion-induced impairment of neurovascular coupling.

Functional magnetic resonance imaging (fMRI) has been mainly utilized for the preoperative localization of eloquent cortical areas. However, lesion-induced impairment of neurovascular coupling (NVC) in the lesion border zone may lead to false-negative fMRI results. The purpose of this study was to determine physiological factors impacting the NVC. Twenty patients suffering from brain lesions were preoperatively examined using multimodal neuroimaging including fMRI, magnetoencephalography (MEG) during language or sensorimotor tasks (depending on lesion location), and a novel physiologic MRI approach for the combined quantification of oxygen metabolism, perfusion state, and microvascular architecture. Congruence of brain activity patterns between fMRI and MEG were found in 13 patients. In contrast, we observed missing fMRI activity in perilesional cortex that demonstrated MEG activity in seven patients, which was interpreted as lesion-induced impairment of NVC. In these brain regions with impaired NVC, physiologic MRI revealed significant brain tissue hypoxia, as well as significantly decreased macro- and microvascular perfusion and microvascular architecture. We demonstrated that perilesional hypoxia with reduced vascular perfusion and architecture is associated with lesion-induced impairment of NVC. Our physiologic MRI approach is a clinically applicable method for preoperative risk assessment for the presence of false-negative fMRI results and may prevent severe postoperative functional deficits.

Metabolic Tumor Microenvironment Characterization of Contrast Enhancing Brain Tumors Using Physiologic MRI.

The tumor microenvironment is a critical regulator of cancer development and progression as well as treatment response and resistance in brain neoplasms. The available techniques for investigation, however, are not well suited for noninvasive in vivo characterization in humans. A total of 120 patients (59 females; 61 males) with newly diagnosed contrast-enhancing brain tumors (64 glioblastoma, 20 brain metastases, 15 primary central nervous system (CNS) lymphomas (PCNSLs), and 21 meningiomas) were examined with a previously established physiological MRI protocol including quantitative blood-oxygen-level-dependent imaging and vascular architecture mapping. Six MRI biomarker maps for oxygen metabolism and neovascularization were fused for classification of five different tumor microenvironments: glycolysis, oxidative phosphorylation (OxPhos), hypoxia with/without neovascularization, and necrosis. Glioblastoma showed the highest metabolic heterogeneity followed by brain metastasis with a glycolysis-to-OxPhos ratio of approximately 2:1 in both tumor entities. In addition, glioblastoma revealed a significant higher percentage of hypoxia (24%) compared to all three other brain tumor entities: brain metastasis (7%; p < 0.001), PCNSL (8%; p = 0.001), and meningioma (8%; p = 0.003). A more aggressive biological brain tumor behavior was associated with a higher percentage of hypoxia and necrosis and a lower percentage of remaining vital tumor tissue and aerobic glycolysis. The proportion of oxidative phosphorylation, however, was rather similar (17-26%) for all four brain tumor entities. Tumor microenvironment (TME) mapping provides insights into neurobiological differences of contrast-enhancing brain tumors and deserves further clinical cancer research attention. Although there is a long roadmap ahead, TME mapping may become useful in order to develop new diagnostic and therapeutic approaches.

Deep brain stimulation in patients on chronic antiplatelet or anticoagulation treatment.

BACKGROUND: In the aging society, many patients with movement disorders, pain syndromes, or psychiatric disorders who are candidates for deep brain stimulation (DBS) surgery suffer also from cardiovascular co-morbidities that require chronic antiplatelet or anticoagulation treatment. Because of a presumed increased risk of intracranial hemorrhage during or after surgery and limited knowledge about perioperative management, chronic antiplatelet or anticoagulation treatment often has been considered a relative contraindication for DBS. Here, we evaluate whether or not there is an increased risk for intracranial hemorrhage or thromboembolic complications in patients on chronic treatment (paused for surgery or bridged with subcutaneous heparin) as compared to those without. METHODS: Out of a series of 465 patients undergoing functional stereotactic neurosurgery, 34 patients were identified who were on chronic treatment before and after receiving DBS. In patients with antiplatelet treatment, medication was stopped in the perioperative period. In patients with vitamin K antagonists or novel oral anticoagulants (NOACs), heparin was used for bridging. All patients had postoperative stereotactic CT scans, and were followed up for 1 year after surgery. RESULTS: In patients on chronic antiplatelet or anticoagulation treatment, intracranial hemorrhage occurred in 2/34 (5.9%) DBS surgeries, whereas the rate of intracranial hemorrhage was 15/431 (3.5%) in those without, which was statistically not significant. Implantable pulse generator pocket hematomas were seen in 2/34 (5.9%) surgeries in patients on chronic treatment and in 4/426 (0.9%) without. There were only 2 instances of thromboembolic complications which both occurred in patients without chronic treatment. There were no hemorrhagic complications during follow-up for 1 year. CONCLUSIONS: DBS surgery in patients on chronic antiplatelet or anticoagulation treatment is feasible. Also, there was no increased risk of hemorrhage in the first year of follow-up after DBS surgery. Appropriate patient selection and standardized perioperative management are necessary to reduce the risk of intracranial hemorrhage and thromboembolic complications.

Centromedian-Parafascicular and Somatosensory Thalamic Deep Brain Stimulation for Treatment of Chronic Neuropathic Pain: A Contemporary Series of 40 Patients.

Introduction: The treatment of neuropathic and central pain still remains a major challenge. Thalamic deep brain stimulation (DBS) involving various target structures is a therapeutic option which has received increased re-interest. Beneficial results have been reported in several more recent smaller studies, however, there is a lack of prospective studies on larger series providing long term outcomes. Methods: Forty patients with refractory neuropathic and central pain syndromes underwent stereotactic bifocal implantation of DBS electrodes in the centromedian-parafascicular (CM-Pf) and the ventroposterolateral (VPL) or ventroposteromedial (VPM) nucleus contralateral to the side of pain. Electrodes were externalized for test stimulation for several days. Outcome was assessed with five specific VAS pain scores (maximum, minimum, average pain, pain at presentation, allodynia). Results: The mean age at surgery was 53.5 years, and the mean duration of pain was 8.2 years. During test stimulation significant reductions of all five pain scores was achieved with either CM-Pf or VPL/VPM stimulation. Pacemakers were implanted in 33/40 patients for chronic stimulation for whom a mean follow-up of 62.8 months (range 3-180 months) was available. Of these, 18 patients had a follow-up beyond four years. Hardware related complications requiring secondary surgeries occurred in 11/33 patients. The VAS maximum pain score was improved by ≥50% in 8/18, and by ≥30% in 11/18 on long term follow-up beyond four years, and the VAS average pain score by ≥50% in 10/18, and by ≥30% in 16/18. On a group level, changes in pain scores remained statistically significant over time, however, there was no difference when comparing the efficacy of CM-Pf versus VPL/VPM stimulation. The best results were achieved in patients with facial pain, poststroke/central pain (except thalamic pain), or brachial plexus injury, while patients with thalamic lesions had the least benefit. Conclusion: Thalamic DBS is a useful treatment option in selected patients with severe and medically refractory pain.

Hypoxia and Microvascular Alterations Are Early Predictors of IDH-Mutated Anaplastic Glioma Recurrence.

Anaplastic gliomas (AG) represents aggressive brain tumors that often affect young adults. Although isocitrate-dehydrogenase (IDH) gene mutation has been identified as a more favorable prognostic factor, most IDH-mutated AG patients are confronted with tumor recurrence. Hence, increased knowledge about pathophysiological precursors of AG recurrence is urgently needed in order to develop precise diagnostic monitoring and tailored therapeutic approaches. In this study, 142 physiological magnetic resonance imaging (phyMRI) follow-up examinations in 60 AG patients after standard therapy were evaluated and magnetic resonance imaging (MRI) biomarker maps for microvascular architecture and perfusion, neovascularization activity, oxygen metabolism, and hypoxia calculated. From these 60 patients, 34 patients developed recurrence of the AG, and 26 patients showed no signs for AG recurrence during the study period. The time courses of MRI biomarker changes were analyzed regarding early pathophysiological alterations over a one-year period before radiological AG recurrence or a one-year period of stable disease for patients without recurrence, respectively. We detected intensifying local tissue hypoxia 250 days prior to radiological recurrence which initiated upregulation of neovascularization activity 50 to 70 days later. These changes were associated with a switch from an avascular infiltrative to a vascularized proliferative phenotype of the tumor cells another 30 days later. The dynamic changes of blood perfusion, microvessel density, neovascularization activity, and oxygen metabolism showed a close physiological interplay in the one-year period prior to radiological recurrence of IDH-mutated AG. These findings may path the wave for implementing both new MR-based imaging modalities for routine follow-up monitoring of AG patients after standard therapy and furthermore may support the development of novel, tailored therapy options in recurrent AG.

Pallidal Deep Brain Stimulation in Patients with Prior Bilateral Pallidotomy and Selective Peripheral Denervation for Treatment of Dystonia.

INTRODUCTION: Deep brain stimulation (DBS) of the globus pallidus internus has become an accepted treatment for severe isolated idiopathic and inherited dystonia. Patients who had other forms of surgery earlier, such as radiofrequency lesioning or selective peripheral denervation, however, usually are not considered candidates for DBS. OBJECTIVE: The aim of this study was to evaluate the long-term outcome of pallidal DBS in a rare subgroup of patients who had undergone both pallidotomy and selective peripheral denervation previously with a waning effect over the years. METHODS: Pallidal DBS was performed according to a prospective study protocol in 2 patients with isolated idiopathic dystonia, and patients were followed for a period of at least 6 years. RESULTS: Both patients benefitted from long-lasting amelioration of dystonia after pallidal DBS, which was comparable to that of patients who did not have previous surgeries. In a 62-year-old female with cervical dystonia both the Burke-Fahn-Marsden (BFM) and the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) motor scores were improved at follow-up 8 years after surgery (50 and 39%). In a 32-year-old male with generalized dystonia, the BFM motor and disability scores showed marked improvement at 6.5 years of follow-up (82 and 66%). CONCLUSIONS: Pallidal DBS can yield marked and long-lasting improvement in patients who underwent both pallidotomy and selective peripheral denervation earlier. Therefore, such patients, in general, should not be excluded from DBS.

Tissue Hypoxia and Alterations in Microvascular Architecture Predict Glioblastoma Recurrence in Humans.

PURPOSE: Insufficient control of infiltrative glioblastoma (GBM) cells is a major cause of treatment failure and tumor recurrence. Hence, detailed insights into pathophysiologic changes that precede GBM recurrence are needed to develop more precise neuroimaging modalities for tailored diagnostic monitoring and therapeutic approaches. EXPERIMENTAL DESIGN: Overall, 168 physiologic MRI follow-up examinations of 56 patients with GBM who developed recurrence after standard therapy were retrospectively evaluated, that is, two post-standard-therapeutic follow-ups before and one at radiological recurrence. MRI biomarkers for microvascular architecture and perfusion, neovascularization activity, oxygen metabolism, and hypoxia were determined for brain areas that developed in the further course into recurrence and for the recurrent GBM itself. The temporal pattern of biomarker changes was fitted with locally estimated scatterplot smoothing functions and analyzed for pathophysiologic changes preceding radiological GBM recurrence. RESULTS: Our MRI approach demonstrated early pathophysiologic changes prior to radiological GBM recurrence in all patients. Analysis of the time courses revealed a model for the pathophysiology of GBM recurrence: 190 days prior to radiological recurrence, vascular cooption by GBM cells induced vessel regression, detected as decreasing vessel density/perfusion and increasing hypoxia. Seventy days later, neovascularization activity was upregulated, which reincreased vessel density and perfusion. Hypoxia, however, continued to intensify for 30 days and peaked 90 days before radiological recurrence. CONCLUSIONS: Hypoxia may represent an early sign for GBM recurrence. This might become useful in the development of new combined diagnostic-therapeutic approaches for tailored clinical management of recurrent GBM. Further preclinical and in-human studies are required for validation and evaluation.

The Diagnostic and Therapeutic Role of Leptin and Its Receptor ObR in Glioblastoma Multiforme.

Leptin has been recognized as a potential tumor growth promoter in various cancers including cranial tumor pathologies such as pituitary adenomas, meningiomas and gliomas. Despite recent advances in adjunctive therapy and the established surgical resection, chemo- and radiotherapy regimen, glioblastoma multiforme remains a particular diagnostic and therapeutic challenge among the intracranial tumor pathologies, with a poor long-term prognosis. Systemic inflammation and immune-metabolic signaling through diverse pathways are thought to impact the genesis and recurrence of brain tumors, and glioblastoma multiforme in particular. Among the various circulating mediators, leptin has gained especial diagnostic and therapeutic interest, although the precise relationship between leptin and glioblastoma biology remains largely unknown. In this narrative review (MEDLINE/OVID, SCOPUS, PubMed and manual searches of the bibliographies of known primary and review articles), we discuss the current literature using the following search terms: leptin, glioblastoma multiforme, carcinogenesis, immunometabolism, biomarkers, metformin, antidiabetic medication and metabolic disorders. An increasing body of experimental evidence implicates a relationship between the development and maintenance of gliomas (and brain tumors in general) with a dysregulated central and peripheral immune-metabolic network mediated by circulating adipokines, chemokines and cellular components, and in particular the leptin adipokine. In this review, we summarize the current evidence of the role of leptin in glioblastoma pathophysiology. In addition, we describe the status of alternative diagnostic tools and adjunctive therapeutics targeting leptin, leptin-receptors, antidiabetic drugs and associated pathways. Further experimental and clinical trials are needed to elucidate the mechanism of action and the value of immune-metabolism molecular phenotyping (central and peripheral) in order to develop novel adjunctive diagnostics and therapeutics for newly diagnosed and recurrent glioblastoma patients.