Fatal Subarachnoid Hemorrhage in a Deep Brain Stimulation Patient: Displacement of Stimulation Leads for Deep Brain Stimulation Indicate Subarachnoid Hemorrhage on X-ray.

We depict the rare case of a patient with aneurysmatic subarachnoid hemorrhage previously treated with deep brain stimulation for Parkinson's disease. Initial CT scans showed a Fisher grade 4 subarachnoid hemorrhage with lead displacement due to midline-shift. CT angiogram revealed a supra-ophthalmic aneurysm of the internal carotid artery. The patient subsequently underwent clipping of the aneurysm and decompressive hemicraniecomy.

sPinal coRd stimulatiOn coMpared with lumbar InStrumEntation for low back pain after previous lumbar decompression (PROMISE): a prospective multicentre RCT.

INTRODUCTION: Persistent spine pain syndrome type 2 (PSPS2) represents a significant burden to the individual and society. Treatment options include revision surgery, stabilisation surgery of the spine, neuromodulation, analgesics and cognitive behavioural therapy. Nevertheless, structured treatment algorithms are missing as high-level evidence on the various treatments is sparse. The aim of this study is to compare higher frequency neuromodulation with instrumentation surgery in patients suffering from PSPS2. METHODS AND ANALYSIS: The sPinal coRd stimulatiOn coMpared with lumbar InStrumEntation for low back pain after previous lumbar decompression (PROMISE) trial is a prospective randomised rater blinded multicentre study. Patients suffering from PSPS2 with a functional burden of Oswestry Disability Index (ODI) >20 points are randomised to treatment via spinal cord stimulation or spinal instrumentation. Primary outcome is back-related functional outcome according to the ODI 12 months after treatment. Secondary outcomes include pain perception (visual analogue scale), Short Form-36, EuroQOL5D, the amount of analgesics, the length of periprocedural hospitalisation and adverse events. Follow-up visits are planned at 3 and 12 months after treatment. Patients with previous lumbar instrumentation, symptomatic spinal stenosis, radiographical apparent spinal instability or severe psychiatric or systemic comorbidities are excluded from the study. In order to detect a significant difference of ≥10 points (ODI) with a power of 80%, n=72 patients need to be included. The recruitment period will be 24 months with a subsequent 12 months follow-up. The beginning of enrolment is planned for October 2022. ETHICS AND DISSEMINATION: The PROMISE trial is the first randomised rater blinded multicentre study comparing the functional effectiveness of spinal instrumentation versus neuromodulation in patients with PSPS2 in order to achieve high-level evidence for these commonly used treatment options in this severely disabling condition. Patient recruitment will be performed at regular outpatient clinic visits. No further (print, social media) publicity is planned. The study is approved by the local ethics committee (LMU Munich, Germany) and will be conducted according to the Declaration of Helsinki. TRIAL REGISTRATION NUMBER: NCT05466110.

Bipolar Lumbar Radiofrequency Medial Branch Neurotomy in a Patient with Deep Brain Stimulation Implant.

Chronic axial lower back pain is one of the most common conditions that patients seek medical attention for in pain practices. About 15 to 40% of axial lower back pain is due to facet-mediated pain. Diagnostic blocks of the medial branch reliably identify the facet joint as the pain generator and offer a prognostic factor for response to radiofrequency neurotomy of the identified facet joints resulting in profound pain relief. However, deep brain stimulation implants have been considered a contraindication for neurotomy. We present an illustrative case of a patient with deep brain stimulation system treated with bipolar medial branch neurotomy using a two-needle technique.

Patient Safety Comparison of Frameless and Frame-Based Stereotactic Navigation for Brain Biopsy-A Single Center Cohort Study.

Leksell stereotactic system-based aspiration biopsy is a common procedure in the neurosurgical treatment of deep-seated or multiple brain lesions. This study aimed to evaluate the benefit of frameless biopsy using VarioGuide compared to frame-based biopsy using the Leksell stereotactic system (LSS). We analyzed all brain biopsies using VarioGuide or LSS at our neurooncological Department of Neurosurgery in the University Hospital of Bonn between January 2018 and August 2020. We analyzed demographic data, duration of surgery, size of lesion, localization, and early complications. Uni-variable analyses were carried out on data from both groups. In total, 109 biopsies were compared (40 VarioGuide vs. 69 LSS). Patients with VarioGuide were significant older (74 (62−80) years vs. 67 (57−76) years; p = 0.03) and had a shorter duration of general anesthesia (163 (138−194) min vs. 193 (167−215) min, p < 0.001). We found no significant differences in surgery duration (VarioGuide median 28 min (IQR 20−38); LSS: median 30 min (IQR 25−39); p = 0.1352) or in early complication rates (5% vs. 7%; p = 0.644). A slightly higher false negative biopsy rate was registered in the LSS group (3 vs. 1; p = 0.1347). The size of the lesions also did not differ significantly between the two groups (18.31 ± 26.35 cm3 vs. 12.63 ± 14.62; p = 0.15). Our data showed that biopsies performed using VarioGuide took significantly less time than LSS biopsies and did not differ in complication rates. Both systems offered a high degree of patient safety.

Coherent Structural and Functional Network Changes after Thalamic Lesions in Essential Tremor.

BACKGROUND: Magnetic resonance-guided focused ultrasound of the ventral intermediate nucleus is a novel incisionless ablative treatment for essential tremor (ET). OBJECTIVE: The aim was to study the structural and functional network changes induced by unilateral sonication of the ventral intermediate nucleus in ET. METHODS: Fifteen essential tremor patients (66.2 ± 15.4 years) underwent probabilistic tractography and functional magnetic resonance imaging (MRI) during unilateral postural tremor-eliciting tasks using 3-T MRI before, 1 month (N = 15), and 6 months (N = 10) post unilateral sonication. RESULTS: Tractography identified tract-specific alterations within the dentato-thalamo-cortical tract (DTCT) affected by the unilateral lesion after sonication. Relative to the treated hand, task-evoked activation was significantly reduced in contralateral primary sensorimotor cortex and ipsilateral cerebellar lobules IV/V and VI, and vermis. Dynamic causal modeling revealed a significant decrease in excitatory drive from the cerebellum to the contralateral sensorimotor cortex. CONCLUSIONS: Thalamic lesions induced by sonication induce specific functional network changes within the DTCT, notably reducing excitatory input to ipsilateral sensorimotor cortex in ET. ©[2022] International Parkinson and Movement Disorder Society. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Endoscopic Lateral Approach for Dorsal Root Ganglion Burst Stimulation: Technical Note and Illustrative Case Series.

INTRODUCTION: Dorsal root ganglion (DRG) stimulation demonstrated superiority over traditional spinal cord stimulation with better pain relief and greater improvement of quality of life. However, leads specifically designed for DRG stimulation are difficult to implant in patients who previously underwent spinal surgery and show epidural scarring at the desired site of implantation because of the reduced stiffness of the lead. Nevertheless, recurrent leg or arm pain after spinal surgery usually manifests as a single level radiculopathy, which should theoretically be amenable to DRG stimulation. MATERIALS AND METHODS: We present the percutaneous transforaminal placement of cylindrical leads through a lateral endoscopic approach for DRG stimulation in burst mode. RESULTS: We could successfully show that percutaneous transforaminal lead placement is feasible in three illustrative cases. CONCLUSION: This technical note combines two innovations, one linked to the other. The first innovation involves a novel endoscopic lateral transforaminal approach to insert a cylindrical lead to the DRG. Because this electrode is compatible with burst stimulation-enabled devices, a second innovation consists of the application of burst stimulation on the DRG.

Molecular monitoring of glioblastoma's immunogenicity using a combination of Raman spectroscopy and chemometrics.

Raman spectroscopy (RS) has been used as a powerful diagnostic and non-invasive tool in cancer diagnosis as well as in discrimination of cancer and immune cells. In this study RS in combination with chemometrics was applied to cellular Raman spectral data to distinguish the phenotype of T-cells and monocytes after incubation with media conditioned by glioblastoma stem-cells (GSCs) showing different molecular background. For this purpose, genetic modulations of epithelial-to-mesenchymal transition (EMT) process and expression of immunomodulator CD73 were introduced. Principal component analysis of the Raman spectral data showed that T-cells and monocytes incubated with tumour-conditioned media (TCMs) of GSCs with inhibited EMT activator ZEB1 or CD73 formed distinct clusters compared to controls highlighting their differences. Further discriminatory analysis performed using linear discriminant analysis (LDA) and support vector machine classification (SVM), yielded sensitivities and specificities of over 70 and 67% respectively upon validation against an independent test set. Supporting those results, flow cytometric analysis was performed to test the influence of TCMs on cytokine profile of T-cells and monocytes. We found that ZEB1 and CD73 influence T-cell and monocyte phenotype and promote monocyte differentiation into a population of mixed pro- and anti-tumorigenic macrophages (MΦs) and dendritic cells (DCs) respectively. In conclusion, Raman spectroscopy in combination with chemometrics enabled tracking T-cells and monocytes.

Enzymatic Activity of CD73 Modulates Invasion of Gliomas via Epithelial-Mesenchymal Transition-Like Reprogramming.

Glioblastoma (GBM) is the most aggressive malignant primary brain tumour in adulthood. Despite strong research efforts current treatment options have a limited impact on glioma stem-like cells (GSCs) which contribute to GBM formation, progression and chemoresistance. Invasive growth of GSCs is in part associated with epithelial-mesenchymal-like transition (EMT), a mechanism associated with CD73 in several cancers. Here, we show that CD73 regulates the EMT activator SNAIL1 and further investigate the role of enzymatic and non-enzymatic CD73 activity in GBM progression. Reduction of CD73 protein resulted in significant suppression of GSC viability, proliferation and clonogenicity, whereas CD73 enzymatic activity exhibited negative effects only on GSC invasion involving impaired downstream adenosine (ADO) signalling. Furthermore, application of phosphodiesterase inhibitor pentoxifylline, a potent immunomodulator, effectively inhibited ZEB1 and CD73 expression and significantly decreased viability, clonogenicity, and invasion of GSC in vitro cultures. Given the involvement of adenosine and A3 adenosine receptor in GSC invasion, we investigated the effect of the pharmacological inhibition of A3AR on GSC maintenance. Direct A3AR inhibition promoted apoptotic cell death and impaired the clonogenicity of GSC cultures. Taken together, our data indicate that CD73 is an exciting novel target in GBM therapy. Moreover, pharmacological interference, resulting in disturbed ADO signalling, provides new opportunities to innovate GBM therapy.

Can neuromodulation support the fight against the COVID19 pandemic? Transcutaneous non-invasive vagal nerve stimulation as a potential targeted treatment of fulminant acute respiratory distress syndrome.

The COVID-19 pandemic has rapidly spread all over the world and caused a major health care crisis. About 20% of patients develop severe disease and require hospitalisation, which is associated with a high mortality rate of up to 97% in those being ventilated and respiratory failure being the leading cause of death. Despite many therapeutic agents being under current investigation there is yet no panacea available. With increasing rates of infection throughout the world, there is an urgent need for new therapeutic approaches to counteract the infection. As the nervous system has shown to be a strong modulator of respiratory function and the immune response, we want to highlight pathways involved in regulation of respiratory function, the neuro-immune axis as well as the rationale for a potential targeted treatment of fulminant acute respiratory distress syndrome via transcutaneous non-invasive vagal nerve stimulation in critically-ill COVID-19 patients.

A comparative pharmaco-metabolomic study of glutaminase inhibitors in glioma stem-like cells confirms biological effectiveness but reveals differences in target-specificity.

Cancer cells upregulate anabolic processes to maintain high rates of cellular turnover. Limiting the supply of macromolecular precursors by targeting enzymes involved in biosynthesis is a promising strategy in cancer therapy. Several tumors excessively metabolize glutamine to generate precursors for nonessential amino acids, nucleotides, and lipids, in a process called glutaminolysis. Here we show that pharmacological inhibition of glutaminase (GLS) eradicates glioblastoma stem-like cells (GSCs), a small cell subpopulation in glioblastoma (GBM) responsible for therapy resistance and tumor recurrence. Treatment with small molecule inhibitors compound 968 and CB839 effectively diminished cell growth and in vitro clonogenicity of GSC neurosphere cultures. However, our pharmaco-metabolic studies revealed that only CB839 inhibited GLS enzymatic activity thereby limiting the influx of glutamine derivates into the TCA cycle. Nevertheless, the effects of both inhibitors were highly GLS specific, since treatment sensitivity markedly correlated with GLS protein expression. Strikingly, we found GLS overexpressed in in vitro GSC models as compared with neural stem cells (NSC). Moreover, our study demonstrates the usefulness of in vitro pharmaco-metabolomics to score target specificity of compounds thereby refining drug development and risk assessment.

Inhibition of Wnt/beta-catenin signaling downregulates expression of aldehyde dehydrogenase isoform 3A1 (ALDH3A1) to reduce resistance against temozolomide in glioblastoma in vitro.

Glioblastoma is the most aggressive type of glioma. The Wingless (Wnt) signaling pathway has been shown to promote stem cell properties and resistance to radio- and chemotherapy in glioblastoma. Here, we demonstrate that pharmacological Wnt pathway inhibition using the porcupine inhibitor LGK974 acts synergistically with temozolomide (TMZ), the chemotherapeutic drug currently used as standard treatment for glioblastoma, to suppress in vitro growth of glioma cells. Synergistic growth inhibition was independent of the O6-alkylguanine DNA alkyltransferase (MGMT) promoter methylation status. Transcriptomic analysis revealed that expression of aldehyde dehydrogenase 3A1 (ALDH3A1) was significantly down-regulated when cells were treated with LGK974 and TMZ. Suppressing ALDH3A1 expression increased the efficacy of TMZ and reduced clonogenic potential accompanied by decreased expression of stem cell markers CD133, Nestin and Sox2. Taken together, our study suggests that previous observations concerning Wnt signaling blockade to reduce chemoresistance in glioblastoma is at least in part mediated by inhibition of ALDH3A1.

Reciprocal regulation of the cholinic phenotype and epithelial-mesenchymal transition in glioblastoma cells.

Glioblastoma (GBM) is the most malignant brain tumor with very limited therapeutic options. Standard multimodal treatments, including surgical resection and combined radio-chemotherapy do not target the most aggressive subtype of glioma cells, brain tumor stem cells (BTSCs). BTSCs are thought to be responsible for tumor initiation, progression, and relapse. Furthermore, they have been associated with the expression of mesenchymal features as a result of epithelial-mesenchymal transition (EMT) thereby inducing tumor dissemination and chemo resistance. Using high resolution proton nuclear magnetic resonance spectroscopy (1H NMR) on GBM cell cultures we provide evidence that the expression of well-known EMT activators of the ZEB, TWIST and SNAI families and EMT target genes N-cadherin and VIMENTIN is associated with aberrant choline metabolism. The cholinic phenotype is characterized by high intracellular levels of phosphocholine and total choline derivatives and was associated with malignancy in various cancers. Both genetic and pharmacological inhibition of the cardinal choline metabolism regulator choline kinase alpha (CHKα) significantly reduces the cell viability, invasiveness, clonogenicity, and expression of EMT associated genes in GBM cells. Moreover, in some cell lines synergetic cytotoxic effects were observed when combining the standard of care chemotherapeutic temozolomide with the CHKα inhibitor V-11-0711. Taken together, specific inhibition of the enzymatic activity of CHKα is a powerful strategy to suppress EMT which opens the possibility to target chemo-resistant BTSCs through impairing their mesenchymal transdifferentiation. Moreover, the newly identified EMT-oncometabolic network may be helpful to monitor the invasive properties of glioblastomas and the success of anti-EMT therapy.

Clipping the Wings of Glioblastoma: Modulation of WNT as a Novel Therapeutic Strategy.

Glioblastoma (GBM) is the most malignant brain tumor and has a dismal prognosis. Aberrant WNT signaling is known to promote glioma cell growth and dissemination and resistance to conventional radio- and chemotherapy. Moreover, a population of cancer stem-like cells that promote glioma growth and recurrence are strongly dependent on WNT signaling. Here, we discuss the role and mechanisms of aberrant canonical and noncanonical WNT signaling in GBM. We present current clinical approaches aimed at modulating WNT activity and evaluate their clinical perspective as a novel treatment option for GBM.

Bevacizumab Plus Irinotecan Versus Temozolomide in Newly Diagnosed O6-Methylguanine-DNA Methyltransferase Nonmethylated Glioblastoma: The Randomized GLARIUS Trial.

PURPOSE: In patients with newly diagnosed glioblastoma that harbors a nonmethylated O(6)-methylguanine-DNA methyltransferase promotor, standard temozolomide (TMZ) has, at best, limited efficacy. The GLARIUS trial thus explored bevacizumab plus irinotecan (BEV+IRI) as an alternative to TMZ. PATIENTS AND METHODS: In this phase II, unblinded trial 182 patients in 22 centers were randomly assigned 2:1 to BEV (10 mg/kg every 2 weeks) during radiotherapy (RT) followed by maintenance BEV (10 mg/kg every 2 weeks) plus IRI(125 mg/m(2) every 2 weeks) or to daily TMZ (75 mg/m(2)) during RT followed by six courses of TMZ (150-200 mg/m(2)/d for 5 days every 4 weeks). The primary end point was the progression-free survival rate after 6 months (PFS-6). RESULTS: In the modified intention-to-treat (ITT) population, PFS-6 was increased from 42.6% with TMZ (95% CI, 29.4% to 55.8%) to 79.3% with BEV+IRI (95% CI, 71.9% to 86.7%; P <.001). PFS was prolonged from a median of 5.99 months (95% CI, 2.7 to 7.3 months) to 9.7 months (95% CI, 8.7 to 10.8 months; P < .001). At progression, crossover BEV therapy was given to 81.8% of all patients who received any sort of second-line therapy in the TMZ arm. Overall survival (OS) was not different in the two arms: the median OS was 16.6 months (95% CI, 15.4 to 18.4 months) with BEV+IRI and was 17.5 months (95% CI, 15.1 to 20.5 months) with TMZ. The time course of quality of life (QOL) in six selected domains of the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire (QLQ) -C30 and QLQ-BN20 (which included cognitive functioning), of the Karnofsky performance score, and of the Mini Mental State Examination score was not different between the treatment arms. CONCLUSION: BEV+IRI resulted in a superior PFS-6 rate and median PFS compared with TMZ. However, BEV+IRI did not improve OS, potentially because of the high crossover rate. BEV+IRI did not alter QOL compared with TMZ.

ZEB1 Promotes Invasion in Human Fetal Neural Stem Cells and Hypoxic Glioma Neurospheres.

Diffuse spread through brain parenchyma and the presence of hypoxic foci rimmed by neoplastic cells are two cardinal features of glioblastoma, and low oxygen is thought to drive movement of malignant gliomas in the core of the lesions. Transcription factors associated with epithelial-to-mesenchymal transition (EMT) have been linked to this invasion, and we found that hypoxia increased in vitro invasion up to fourfold in glioblastoma neurosphere lines and induced the expression of ZEB1. Immunohistochemical assessment of 295 surgical specimens consisting of various types of pediatric and adult brain cancers showed that ZEB1 expression was significantly higher in infiltrative lesions than less invasive tumors such as pilocytic astrocytoma and ependymoma. ZEB1 protein was also present in human fetal periventricular stem and progenitor cells and ZEB1 inhibition impaired migration of in vitro propagated human neural stem cells. The induction of ZEB1 protein in hypoxic glioblastoma neurospheres could be partially blocked by the HIF1alpha inhibitor digoxin. Targeting ZEB1 blocked hypoxia-augmented invasion of glioblastoma cells in addition to slowing them in normoxia. These data support the role for ZEB1 in invasive and high-grade brain tumors and suggest its key role in promoting invasion in the hypoxic tumor core as well as in the periphery.

A microsurgical procedure for middle cerebral artery occlusion by intraluminal monofilament insertion technique in the rat: a special emphasis on the methodology.

INTRODUCTION: Although there are many experimental studies describing the methodology of the middle cerebral artery occlusion (MCAO) in the literature, only limited data on these distinct anatomical structures and the details of the surgical procedure in a step by step manner. The aim of the present study simply is to examine the surgical anatomy of MCAO model and its modifications in the rat. MATERIALS AND METHODS: Forty Sprague-Dawley rats were used; 20 during the training phase and 20 for the main study. The monofilament sutures were prepared as described in the literature. All surgical steps of the study were performed under the operating microscope, including insertion of monofilament into middle cerebral artery through the internal carotid artery. RESULTS: After an extensive training period, we lost two rats in four weeks. The effects of MCAO were confirmed by the evidence of severe motor deficit during the recovery period, and histopathological findings of infarction were proved in all 18 surviving rats. CONCLUSION: In this study, a microsurgical guideline of the MCAO model in the rat is provided with the detailed description of all steps of the intraluminal monofilament insertion method with related figures.

Characterization of a setup to test the impact of high-amplitude pressure waves on living cells.

The impact of pressure waves on cells may provide several possible applications in biology and medicine including the direct killing of tumors, drug delivery or gene transfection. In this study we characterize the physical properties of mechanical pressure waves generated by a nanosecond laser pulse in a setup with well-defined cell culture conditions. To systematically characterize the system on the relevant length and time scales (micrometers and nanoseconds) we use photon Doppler velocimetry (PDV) and obtain velocity profiles of the cell culture vessel at the passage of the pressure wave. These profiles serve as input for numerical pressure wave simulations that help to further quantify the pressure conditions on the cellular length scale. On the biological level we demonstrate killing of glioblastoma cells and quantify experimentally the pressure threshold for cell destruction.