Pain Relief-Related Structural Brain Alterations in Trigeminal Neuralgia Induced by Noninvasive Stereotactic Radiosurgery: A Pilot Study.

PURPOSE: Trigeminal neuralgia (TN) is a chronic pain disorder defined by unilateral shock-like pain in at least one division of the trigeminal nerve. Although several studies have investigated structural brain plasticity in patients with TN, treatment-induced alterations remain largely uninvestigated. METHODS AND MATERIALS: Combining T1-weighted magnetic resonance imaging with voxel-based morphometry and multiple-regression analyses, we assessed gray matter maps of patients with TN to investigate changes in gray matter volume (GMV) before and 6 months after stereotactic radiosurgery (SRS). RESULTS: Comparison of pre- and post-SRS GMV of 25 patients with TN (16 women; mean age 67 years) did not yield any significant clusters, suggesting that the effect of SRS intervention itself on gray matter structure may be negligible. Regarding SRS-induced pain relief, we found a significant GMV increase in the left superior frontal gyrus associated with greater degree of pain relief (P = .024) and a trend toward an increase in GMV in the left dorsolateral prefrontal cortex (P = .097). CONCLUSIONS: In this pilot study, we observed significant increases in GMV in the left superior frontal gyrus with SRS-induced improvements in pain and a trend toward an increase in GMV in the dorsolateral prefrontal cortex. Future studies are indicated to validate these findings and determine whether SRS-induced decrease in distracting pain events and subsequent increases in GMV result in improved functionality, decreased dependence on "top-down" control, and improved cognitive/executive balance with amelioration of pain events.

Stroke-derived neutrophils demonstrate higher formation potential and impaired resolution of CD66b + driven neutrophil extracellular traps.

BACKGROUND: Recent evidence suggests a merging role of immunothrombosis in the formation of arterial thrombosis. Our study aims to investigate its relevance in stroke patients. METHODS: We compared the peripheral immunological profile of stroke patients vs. healthy controls. Serum samples were functionally analyzed for their formation and clearance of Neutrophil-Extracellular-Traps. The composition of retrieved thrombi has been immunologically analyzed. RESULTS: Peripheral blood of stroke patients showed significantly elevated levels of DNAse-I (p < 0.001), LDG (p = 0.003), CD4 (p = 0.005) as well as the pro-inflammatory cytokines IL-17 (p < 0.001), INF-γ (p < 0.001) and IL-22 (p < 0.001) compared to controls, reflecting a TH1/TH17 response. Increased counts of DNAse-I in sera (p = 0.045) and Neutrophil-Extracellular-Traps in thrombi (p = 0.032) have been observed in patients with onset time of symptoms longer than 4,5 h. Lower values of CD66b in thrombi were independently associated with greater improvement of NIHSS after mechanical thrombectomy (p = 0.045). Stroke-derived neutrophils show higher potential for Neutrophil-Extracellular-Traps formation after stimulation and worse resolution under DNAse-I treatment compared to neutrophils derived from healthy individuals. CONCLUSIONS: Our data provide new insight in the role of activated neutrophils and Neutrophil-Extracellular-Traps in ischemic stroke. Future larger studies are warranted to further investigate the role of immunothrombosis in the cascades of stroke. TRIAL REGISTRATION: DRKS, DRKS00013278, Registered 15 November 2017, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00013278.

Deciphering the Network Effects of Deep Brain Stimulation in Parkinson's Disease.

INTRODUCTION: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an established therapy for Parkinson's disease (PD). However, a more detailed characterization of the targeted network and its grey matter (GM) terminals that drive the clinical outcome is needed. In this direction, the use of MRI after DBS surgery is now possible due to recent advances in hardware, opening a window for the clarification of the association between the affected tissue, including white matter fiber pathways and modulated GM regions, and the DBS-related clinical outcome. Therefore, we present a computational framework for reconstruction of targeted networks on postoperative MRI. METHODS: We used a combination of preoperative whole-brain T1-weighted (T1w) and diffusion-weighted MRI data for morphometric integrity assessment and postoperative T1w MRI for electrode reconstruction and network reconstruction in 15 idiopathic PD patients. Within this framework, we made use of DBS lead artifact intensity profiles on postoperative MRI to determine DBS locations used as seeds for probabilistic tractography to cortical and subcortical targets within the motor circuitry. Lastly, we evaluated the relationship between brain microstructural characteristics of DBS-targeted brain network terminals and postoperative clinical outcomes. RESULTS: The proposed framework showed robust performance for identifying the DBS electrode positions. Connectivity profiles between the primary motor cortex (M1), supplementary motor area (SMA), and DBS locations were strongly associated with the stimulation intensity needed for the optimal clinical outcome. Local diffusion properties of the modulated pathways were related to DBS outcomes. STN-DBS motor symptom improvement was highly associated with cortical thickness in the middle frontal and superior frontal cortices, but not with subcortical volumetry. CONCLUSION: These data suggest that STN-DBS outcomes largely rely on the modulatory interference from cortical areas, particularly M1 and SMA, to DBS locations.

Distinct Behavior of Traumatic versus Nontraumatic Intracerebral Hematomas: Different Biology or Impact of Age?

BACKGROUND AND STUDY AIMS: Patients with large intracerebral hematomas (ICH) may demonstrate different demographics and underlying brain and systemic diseases, as well as different radiologic courses and distinct outcomes. It remains unclear whether their different behavior attributes to a different biology of the ICH or to the asymmetric characteristics of the two populations. To analyze and adjust for potential sources of selection and treatment bias, our study compared age-matched patients with traumatic and nontraumatic ICH in a single cohort diagnosed and treated in the same surgical department. MATERIAL AND METHODS: We analyzed 135 consecutive patients with traumatic (n = 90) or spontaneous ICH (n = 45) undergoing treatment at a surgical intensive care unit of an urban university hospital. We documented their differences before and after adjustment for age in terms of demographics, the therapies applied, their radiologic (i.e., volume and rate of ICH expansion [HE]) and clinical (patients' outcome at 30 days) course, the length of hospital and ICU stay, as well as the hospital costs. RESULTS: Patients with traumatic ICH demonstrated more favorable clinical and radiologic characteristics at admission, that is, higher Glasgow Coma Scale score (p < 0.001), less frequently dilated pupil (p = 0.028), lower Charlson Comorbidity Index (p < 0.001), smaller ICH volume (p < 0.001), noneloquent (p < 0.001) or nonintraventricular (p = 0.003) ICH locations, as well as underwent fewer neurosurgical interventions (p < 0.001) and showed a better outcome (p = 0.041), defined as Glasgow Outcome Scale 4 and 5. After adjustment for age, no different outcomes were observed. Of note, elderly patients on novel oral anticoagulants (NOACs) were more likely to develop an HE compared with those on vitamin K antagonists (VKAs, p = 0.05) after traumatic brain injury (TBI) but not after spontaneous ICH. CONCLUSION: Our data reveal a significant heterogeneity within the traumatic series. Whereas younger patients show an excellent outcome, the elderly population of the traumatic cases demonstrates a poor outcome similar to that of the nontraumatic cohort. HE under NOACs rather than under VKAs is more likely in the elderly after TBI. Larger prospective trials are warranted to elucidate the potential individual underlying molecular mechanisms for the development of an ICH and HE in these diseases.

DCE-MRI in Glioma, Infiltration Zone and Healthy Brain to Assess Angiogenesis: A Biopsy Study.

PURPOSE: To explore the focal predictability of vascular growth factor expression and neovascularization using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in glioma. METHODS: 120 brain biopsies were taken in vital tumor, infiltration zone and normal brain tissue of 30 glioma patients: 17 IDH(isocitrate dehydrogenase)-wildtype glioblastoma (GBM), 1 IDH-wildtype astrocytoma °III (together prognostic group 1), 3 IDH-mutated GBM (group 2), 3 anaplastic astrocytomas IDH-mutated (group 3), 4 anaplastic oligodendrogliomas and 2 low-grade oligodendrogliomas (together prognostic group 4). A mixed linear model evaluated the predictabilities of microvessel density (MVD), vascular area ratio (VAR), mean vessel size (MVS), vascular endothelial growth factor and receptors (VEGF-A, VEGFR­2) and vascular endothelial-protein tyrosine phosphatase (VE-PTP) expression from Tofts model kinetic and model-free curve parameters. RESULTS: All kinetic parameters were associated with VEGF­A (all p < 0.001) expression. Ktrans, kep and ve were associated with VAR (p = 0.006, 0.004 and 0.01, respectively) and MVS (p = 0.0001, 0.02 and 0.003, respectively) but not MVD (p = 0.84, 0.74 and 0.73, respectively). Prognostic groups differed in Ktrans (p = 0.007) and ve (p = 0.004) values measured in the infiltration zone. Despite significant differences of VAR, MVS, VEGF­A, VEGFR­2, and VE-PTP in vital tumor tissue and the infiltration zone (p = 0.0001 for all), there was no significant difference between kinetic parameters measured in these zones. CONCLUSION: The DCE-MRI kinetic parameters show correlations with microvascular parameters in vital tissue and also reveal blood-brain barrier abnormalities in the infiltration zones adequate to differentiate glioma prognostic groups.

Prognostic Factors for Functional Outcome of Patients with Optic Nerve Sheath Meningiomas Treated with Stereotactic Radiotherapy-Evaluation of Own and Meta-Analysis of Published Data.

OBJECTIVE: To evaluate prognostic factors for a favorable outcome (improvement of the visual acuity or visual fields) after fractionated stereotactic radiotherapy (fSRT) of optic nerve sheath meningioma (ONSM). METHODS: We performed a database search for ONSM treatments during the period from April 2008 to September 2019 in the prospective database for stereotactic radiosurgery/radiotherapy (SRS/SRT) of the Robert Janker Clinic Bonn (Department of Radiotherapy) and performed a literature review and meta-analysis of published data on ONSM between 2010 and 2019. Ophthalmic status before and after treatment was evaluated and the collective was dichotomized into two groups: functional improvement (FI; improvement of either visual acuity or visual fields) and non functional improvement (NFI; with stable or deteriorating visual acuity or visual fields). The two groups were compared regarding different variables: pretreatment visual acuity, age, gender, gross tumor volume (GTV), follow up (FU) time, tumor localization, and maximal retina dose. RESULTS: Overall, 13 stereotactic radiotherapies were performed for ONSM (12 × fSRT, 1 × SRS). Mean follow up was 3 years (range: 1-5 years). The total dose was 50.4 Gy (5 × 1.8 Gy/week) in 12 patients treated with fSRT and 1 × 14 Gy in one SRS case. Mean GTV was 1.13 ccm (range: 0.44-2.20 ccm). During follow up, all tumors were stable or showed shrinkage of tumor volume (100% tumor control), no adverse events were observed, 53% of the patients achieved either better visual acuity or visual fields. Pretreatment visual acuity was significantly different between the FI and the NFI group (0.17 vs. 0.63, p = 0.03) in our series and in the meta analysis (p < 0.01). Moreover, shorter FU time and lower retinal dose were significantly linked (p < 0.05 and p < 0.01, respectively) with a better outcome in the meta-analysis but not in our patient cohort. Intracranial tumor localization, gender, and age were not significantly different between the two outcome groups. CONCLUSION: FSRT for ONSM achieves in over 50% of cases an improvement of the ophthalmic status with low morbidity and excellent tumor control in our series and the meta analysis. Patients with a favorable outcome had in all analysis a significantly higher visual acuity before treatment start. Therefore, we advocate using fSRT as early as possible before vision deterioration occurs.

MGMT-Positive vs MGMT-Negative Patients With Glioblastoma: Identification of Prognostic Factors and Resection Threshold.

BACKGROUND: The importance of the O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status as a predictive factor for the response to chemotherapy with temozolomide is well established. Its significance though at stratifying glioblastoma (GBM) patients in regard to their prognostic factors and the impact of surgical approach on them has not been identified. OBJECTIVE: To reveal possible differences in the prognostic factors and the impact of surgery between GBM patients stratified according to their MGMT status. METHODS: The authors retrospectively analyzed 186 patients with a newly diagnosed primary supratentorial GBM treated with surgical resection followed by standard radiation and chemotherapy. A prospective quantitative volumetric analysis of tumor characteristics identified on magnetic resonance imaging was performed. RESULTS: For the 109 patients with unmethylated MGMT promoter, extent of resection (EOR) represented independent predictor of survival, whereas residual tumor volume (RTV), Karnofsky Performance Score, and age were found to be independent prognostic factors of survival for the 77 patients with methylated MGMT promoter. For the group of patients with unmethylated and the group with methylated MGMT promoter, an EOR threshold of 70% and 98% and an RTV threshold of 1.5 and 1 cm3 were identified, respectively. CONCLUSION: The selection of patients according to the MGMT promoter methylation status resulted in different prognostic factors and different resection thresholds for each patient population. A survival benefit seen from 70% EOR threshold in patients with MGMT unmethylated GBM supports the doctrine of maximum safe resection rather than the "all-or-nothing" approach.

Comparison of the Minimally Invasive Tubular Transmuscular Approach with the Conventional Microsurgical Approach for Microsurgical Treatment of Lumbar Disk Herniation: A Prospective Randomized Study.

BACKGROUND: The aim of this study is to compare the outcome of the minimally invasive transmuscular approach using a tubular retractor system (Metrx) with the conventional microsurgical standard approach (CM) for microsurgical treatment of lumbar disk herniation. METHODS: This is a prospective randomized controlled study with a 1:1 distribution of patients in CM and Metrx study groups. Two hundred and twenty-seven (117 CM and 110 Metrx) patients were included. The primary outcome parameters are postoperative pain intensity reduction, length of hospitalization, postoperative quality of life, and daily life performance based on the standardized questionnaires: Visual Analog Scale (VAS), 36-Item Short Form Survey (SF-36), Oswestry Disability Index (ODI), and Prolo scores. The secondary outcome parameters are intraoperative variables: surgery duration, blood loss, and fluoroscopy dose. RESULTS: There were no significant statistical differences in the primary outcome measures between the two groups with respect to postoperative pain relief (median VAS pre-op to 3 months post-op for sciatica: 9-2 [CM] vs. 8-2 [Metrx]; for lumbago: 7-2.5 [CM] vs. 6-3 [Metrx]), the length of hospitalization (median of 5 days), or the frequency of occupational reintegration after 3 months (59.1 vs. 60.7%). CONCLUSION: The microsurgical therapy of lumbar disk herniation via a Metrx approach is a safe and effective treatment option and is equivalent to the CM approach.

Intake of NOAC is associated with hematoma expansion of intracerebral hematomas after traumatic brain injury.

PURPOSE: Novel oral anticoagulants are increasingly replacing vitamin K antagonists in the prophylaxis of thromboembolism as they are associated with lower incidence of spontaneous intracerebral hematomas and they do not require drug level monitoring. However, management dilemmas are apparent in patients on novel oral anticoagulants who have developed intracerebral hematomas after traumatic brain injury, since clinical experience with their reversal strategies is limited. METHODS: We retrospectively studied 90 patients with traumatic intracerebral hematomas undergoing treatment at the surgical intensive care unit of the BG University Clinic Bergmannsheil in Bochum between 2015 and 2018. We analyzed potential prognostic factors for their radiological (expansion of intracerebral hematoma) and clinical (patients' outcome) course, in particular the role of novel oral anticoagulants. RESULTS: 71.1% of patients were male; mean age was 67.3 years. Hematoma's expansion occurred in 35.9% of our patients, whereas 62.2% of our cohort showed a favorable outcome, defined as Glasgow Outcome Scale 4 and 5. Intake of novel oral anticoagulants was associated with a higher rate of hematoma's expansion compared to patients on vitamin K antagonists (p = 0.05) or to patients with normal coagulation status (p = 0.002). A younger age (p < 0.001) was identified as the sole independent prognostic factor for a more favorable outcome, after excluding our cases, who underwent a cardiopulmonary resuscitation. CONCLUSIONS: Our data showed a higher rate of hematoma's expansion in patients with traumatic intracerebral hematomas on novel oral anticoagulants vs. vitamin K antagonists and recommend the consideration of prophylactic reversal of the novel oral anticoagulants at admission. Larger prospective trials are warranted to conclude whether the current specific reversal protocols are safe and effective.

Cross-frequency coupling between gamma oscillations and deep brain stimulation frequency in Parkinson's disease.

The disruption of pathologically enhanced beta oscillations is considered one of the key mechanisms mediating the clinical effects of deep brain stimulation on motor symptoms in Parkinson's disease. However, a specific modulation of other distinct physiological or pathological oscillatory activities could also play an important role in symptom control and motor function recovery during deep brain stimulation. Finely tuned gamma oscillations have been suggested to be prokinetic in nature, facilitating the preferential processing of physiological neural activity. In this study, we postulate that clinically effective high-frequency stimulation of the subthalamic nucleus imposes cross-frequency interactions with gamma oscillations in a cortico-subcortical network of interconnected regions and normalizes the balance between beta and gamma oscillations. To this end we acquired resting state high-density (256 channels) EEG from 31 patients with Parkinson's disease who underwent deep brain stimulation to compare spectral power and power-to-power cross-frequency coupling using a beamformer algorithm for coherent sources. To show that modulations exclusively relate to stimulation frequencies that alleviate motor symptoms, two clinically ineffective frequencies were tested as control conditions. We observed a robust reduction of beta and increase of gamma power, attested in the regions of a cortical (motor cortex, supplementary motor area, premotor cortex) and subcortical network (subthalamic nucleus and cerebellum). Additionally, we found a clear cross-frequency coupling of narrowband gamma frequencies to the stimulation frequency in all of these nodes, which negatively correlated with motor impairment. No such dynamics were revealed within the control posterior parietal cortex region. Furthermore, deep brain stimulation at clinically ineffective frequencies did not alter the source power spectra or cross-frequency coupling in any region. These findings demonstrate that clinically effective deep brain stimulation of the subthalamic nucleus differentially modifies different oscillatory activities in a widespread network of cortical and subcortical regions. Particularly the cross-frequency interactions between finely tuned gamma oscillations and the stimulation frequency may suggest an entrainment mechanism that could promote dynamic neural processing underlying motor symptom alleviation.

Headache Perception in an Epilepsy Patient with Neuromodulation by Anterior Thalamic Nuclei Deep Brain Stimulation: A Case Report.

OBJECTIVE: Headache disorders are frequently associated with epilepsy. Some neuromodulation techniques for refractory epilepsy have been reported to positively influence the associated chronic headache. However, the exact mechanism of action of vagus nerve stimulation (VNS) and anterior thalamic nuclei-deep brain stimulation (ANT-DBS) on pain perception is unclear. METHOD: We report a structured assessment of pain perception in a patient who experienced headache relief after ANT-DBS for refractory focal epilepsy and compare it with pain perception of epilepsy patients with chronic headache who were treated with and without VNS. RESULTS: The pain-associated symptoms in the ANT-DBS case were on the Pain Anxiety Symptoms Scale (PASS-40) subscore "physiological anxiety" closer to the control collective, whereas in patients with VNS, this was more likely for the PASS-40 subscores "cognitive anxiety" or "escape and avoidance." CONCLUSION: ANT-DBS and VNS may influence epilepsy-associated chronic headache in different ways.

Alterations in White Matter Network and Microstructural Integrity Differentiate Parkinson's Disease Patients and Healthy Subjects.

Parkinson's disease (PD) is a neurodegenerative disease, neuropathologically characterized by progressive loss of neurons in distinct brain areas. We hypothesize that quantifiable network alterations are caused by neurodegeneration. The primary motivation of this study was to assess the specific network alterations in PD patients that are distinct but appear in conjunction with physiological aging. 178 subjects (130 females) stratified into PD patients, young, middle-aged and elderly healthy controls (age- and sex-matched with PD patients), were analyzed using 3D-T1 magnetization-prepared rapid gradient-echo (MPRAGE) and diffusion weighted images acquired in 3T MRI scanner. Diffusion modeling and probabilistic tractography analysis were applied for generating voxel-based connectivity index maps from each seed voxel. The obtained connectivity matrices were analyzed using graph theoretical tools for characterization of involved network. By network-based statistic (NBS) the interregional connectivity differences between the groups were assessed. Measures evaluating local diffusion properties for anisotropy and diffusivity were computed for characterization of white matter microstructural integrity. The graph theoretical analysis showed a significant decrease in distance measures - eccentricity and characteristic path length - in PD patients in comparison to healthy subjects. Both measures as well were lower in PD patients when compared to young and middle-aged healthy controls. NBS analysis demonstrated lowered structural connectivity in PD patients in comparison to young and middle-aged healthy subject groups, mainly in frontal, cingulate, olfactory, insula, thalamus, and parietal regions. These specific network differences were distinct for PD and were not observed between the healthy subject groups. Microstructural analysis revealed diffusivity alterations within the white matter tracts in PD patients, predominantly in the body, splenium and tapetum of corpus callosum, corticospinal tract, and corona radiata, which were absent in normal aging. The identified alterations of network connectivity presumably caused by neurodegeneration indicate the disruption in global network integration in PD patients. The microstructural changes identified within the white matter could endorse network reconfiguration. This study provides a clear distinction between the network changes occurring during aging and PD. This will facilitate a better understanding of PD pathophysiology and the direct link between white matter changes and their role in the restructured network topology.

Large-scale network architecture and associated structural cortico-subcortical abnormalities in patients with sleep/awake-related seizures.

STUDY OBJECTIVES: In this study, we aimed to estimate the alterations of brain networks and structural integrity linked to seizure occurrence during sleep and awake states. METHODS: Using a graph theory approach to magnetic resonance imaging-derived volumes of cortical and subcortical regions, we investigated the topological organization of structural networks in patients with sleep seizures (n = 13), patients with awake seizures (n = 12), and age- and sex-matched healthy controls (n = 10). Abnormalities in regional structural substrates (cortical volume/surface area, subcortical volumes) associated with sleep seizures and awake seizures were further analyzed. RESULTS: Brain networks in patients with sleep seizures compared to patients with awake seizures displayed a more integrated structural organization coupled with greater networks' stability. When compared to healthy controls, networks in both patients with sleep and awake seizures were analogously compromised, exhibiting a less integrated and preserved organization. Patients with sleep seizures in contrast to awake seizures had larger volumes of bilateral insula, superior temporal, and orbitofrontal cortices but lower volumes of left postcentral and right middle temporal cortices in comparison to healthy controls. Patients with awake seizures compared to healthy controls displayed reduced volumes mainly in frontal, temporal, and parietal regions of right hemisphere. Volumes of hippocampus, amygdala, caudate, pallidum, and putamen were larger in patients with sleep seizures than in patients with awake seizures. CONCLUSIONS: Despite epileptogenesis, patients with sleep and awake seizures had distinct network and structural correlates across different epilepsy types. Identified regional cortical/subcortical abnormalities can endorse the pathophysiological alterations that induce seizures during the sleep or awake states.

Effect of transcutaneous vagus nerve stimulation on muscle activity in the gastrointestinal tract (transVaGa): a prospective clinical trial.

PURPOSE: Postoperative ileus (POI) is a common complication after abdominal surgery. Invasive stimulation of the cervical vagus nerve is known to reduce inflammatory response and ameliorated POI after surgery in a mouse model. However, the transcutaneous vagus nerve stimulation (tVNS) is a possible non-invasive approach. In this clinical study, we aimed to investigate the effect of tVNS on the activation of the stomach muscle in humans. METHODS: Patients requiring open laparotomy were screened for this prospective proof of concept clinical study. After open laparotomy, muscle activity of the stomach was measured by a free running electromyography (EMG) before and during tVNS on the ear. Frequency and amplitude of compound gastric action potentials were the electrophysiological parameters we assessed to reveal the changes in electro motor gastric activity. Gastrin levels as a surrogate marker for vagus nerve activation was analyzed before, 1 and 3 h after tVNS. RESULTS: Fourteen patients were included, no severe adverse events and no medical device related adverse events occurred. tVNS led to significant reduction of action potential frequency and significant elevation of action potential amplitude in the stomach compared to control. Gastrin levels were significantly elevated 3 h after tVNS compared to levels before tVNS. CONCLUSION: Application of tVNS is a safe and feasible procedure during surgical intervention. Our results provide evidence that tVNS activates efferent visceral vagal fibers. Therefore, this low risk and easy to perform method could be useful to prevent postoperative ileus. CLINICAL TRIAL REGISTER NUMBER: DRKS00013340.

Silencing of the nucleocytoplasmic shuttling protein karyopherin a2 promotes cell-cycle arrest and apoptosis in glioblastoma multiforme.

We have previously shown that the nucleocytoplasmic carrier karyopherin a2 (KPNA2) is overexpressed in glioblastoma multiforme (GBM) whereas its expression is inversely associated with patient prognosis. However, the promoting role of KPNA2 in gliomagenesis is still poorly understood. This study aims to further elucidate this role of KPNA2 in in vitro GBM models. From four different tested GBM cell lines, the U87MG showed the highest proliferation, low adherence and outgrowth in 3D clusters as well as the highest expression of KPNA2, all features conferring greater malignant behaviour. Silencing of KPNA2 via siRNA interference in those cells significantly decreased their proliferative capacity (p = 0.001). We further observed both a significant cell cycle phase arrest (p = 0.040) and the promoting of cellular apoptosis (p = 0.016) as well as a strong trend (p = 0.062) for an inhibition of nuclear import of c-Myc. This study confirms that a higher expression of KPNA2 in GBM is associated with a more malignant phenotype also in in vitro models. While increased expression of KPNA2 promotes proliferation and survival of GBM tumour cells, silencing of KPNA2 conferred a less malignant behaviour. Our results strongly suggest that silencing of KPNA2 may play an important role in modulation of malignant features of GBM cells.

Deep Brain Stimulation and L-DOPA Therapy: Concepts of Action and Clinical Applications in Parkinson's Disease.

L-DOPA is still the most effective pharmacological therapy for the treatment of motor symptoms in Parkinson's disease (PD) almost four decades after it was first used. Deep brain stimulation (DBS) is a safe and highly effective treatment option in patients with PD. Even though a clear understanding of the mechanisms of both treatment methods is yet to be obtained, the combination of both treatments is the most effective standard evidenced-based therapy to date. Recent studies have demonstrated that DBS is a therapy option even in the early course of the disease, when first complications arise despite a rigorous adjustment of the pharmacological treatment. The unique feature of this therapeutic approach is the ability to preferentially modulate specific brain networks through the choice of stimulation site. The clinical effects have been unequivocally confirmed in recent studies; however, the impact of DBS and the supplementary effect of L-DOPA on the neuronal network are not yet fully understood. In this review, we present emerging data on the presumable mechanisms of DBS in patients with PD and discuss the pathophysiological similarities and differences in the effects of DBS in comparison to dopaminergic medication. Targeted, selective modulation of brain networks by DBS and pharmacodynamic effects of L-DOPA therapy on the central nervous system are presented. Moreover, we outline the perioperative algorithms for PD patients before and directly after the implantation of DBS electrodes and strategies for the reduction of side effects and optimization of motor and non-motor symptoms.

LINAC stereotactic radiosurgery for trigeminal neuralgia -retrospective two-institutional examination of treatment outcomes.

BACKGROUND: In this pooled 2-center series LINAC radiosurgery (SRS) has been applied as a treatment option for a subset of refractory trigeminal neuralgia (TN) patients. This study approached to retrospectively assess the efficacy and safety of LINAC SRS and to provide a brief overview addressed to the technical development from frame-based towards frameless robotic SRS. METHODS: From 2001 to 2017 n = 55 patients (pts) were treated, n = 28 were female (51%), mean age: 66 years (range 36-93 years); TN etiology: 37 classic TN, 15 multiple sclerosis (MS)-related TN, 2 symptomatic TN, and 1 atypical TN. Previous treatment was present in n = 35 (63.6%) pts. (some multiple or combined) with n = 23 microsurgical vascular decompression and n = 17 percutaneous retrogasserian rhizotomy. A 6 MV LINAC (4-5 mm collimators) was applied in all pts. (n = 26 framebased - n = 29 frameless robotic). The dorsal root entry zone (DREZ) was targeted in n = 35 cases and the retrogasserian target in n = 20 pts. with a homogeneous dose for the entire study cohort (90 Gy). SRS outcome was measured using the Barrow Neurological Institute (BNI) score for pain and hypaesthesia and statistically evaluated by univariate and multivariate analyzes. RESULTS: Mean follow-up (FU) was 30 months (2 lost FU); the total rate of post SRS BNI pain I-IIIa (=painfree w or w/o medication) was 69% (88% for the classic TN pts), 29% (38.8% classic TN) were classified as BNI pain I-II (=painfree w/o medication). A BNI hypaesthesia II-III was present in 9.4% (n = 5) and BNI hypaesthesia IV in n = 2. Between groups analysis demonstrated no correlation of SRS responsiveness with age, gender, MS- or not MS-associated TN, previous surgery, framebased/frameless robotic SRS. DREZ targeting significantly better suppressed TN compared to RG targeting (p = 0.01). Additionally, a statistical trend for a better BNI pain outcome (p = 0.07) along with a significant increase in BNI hypaesthesia (p = 0.01) was found when using a larger partial trigeminal 70 Gy volume. CONCLUSION: Our retrospective analysis support LINAC SRS as an effective and safe treatment option in TN. Frameless robotic SRS of TN is safe when using a dedicated LINAC system. A target definition closer to the brainstem and tendencially a larger target volume were associated with a better outcome for pain.

The impact of MRI steady-state sequences as an additional assessment modality in vestibular schwannoma patients after LINAC stereotactic radiotherapy or radiosurgery.

PURPOSE: Data concerning the clinical usefulness of steady-state sequences (SSS) for vestibular schwannomas (VS) after linear accelerator (LINAC) stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT) are scarce. The aim of the study was to investigate whether SSS provide an additional useful follow-up (FU) tool to the established thin-layered T1 sequences with contrast enhancement. METHODS: Pre- and post-treatment SSS were identified in 45 consecutive VS patients (2012-2016) with a standardized FU protocol including SSS at 2-3 months and 6 months/yearly in our prospective database and were retrospectively re-evaluated. The SSS were used throughout for the segmentation of the cochlea and partly of the trigeminal nerve in the treatment planning. Data analysis included signal conversion in SSS and possible correlation with neuro-otological outcome and volumetric assessment after a certain time interval. RESULTS: The series included 42 SRS and 3 SRT patients (31 female/14 male; mean age 59.3 years, range: 25-81 years). An SSS signal conversion was observed in 20 tumors (44.4%) within a mean time of 11 months (range: 7-15 months). Mean FU time was 26 months (median of 4 FU visits) and demonstrated tumor volume shrinkage in 29 cases (64.4%) correlating with FU time (p = 0.07). The incidence rate of combined shrinkage and signal conversion (48.3%) compared to those without signal conversion (51.7%) did not differ significantly (p = 0.49). In case of an early signal conversion at the first FU, a weak statistical significance (p = 0.05) for a higher shrinkage rate of VS with signal conversion was found. Side effects in cases with signal conversion (9/20, 45%) were more frequently than without signal conversion (6/25, 24%) without reaching statistical significance (p = 0.13). CONCLUSION: Our data confirmed the usefulness of SSS for anatomical segmentation of VS in LINAC-SRS/SRT treatment planning and add data supporting their potential as an adjunctive FU option in VS patients.

Meningioma assessment: Kinetic parameters in dynamic contrast-enhanced MRI appear independent from microvascular anatomy and VEGF expression.

BACKGROUND AND PURPOSE: Kinetic parameters of T1-weighted dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) are considered to be influenced by microvessel environment. This study was performed to explore the extent of this association for meningiomas. MATERIALS AND METHODS: DCE-MRI kinetic parameters (contrast agent transfer constants Ktrans and kep, volume fractions vp and ve) were determined in pre-operative 3T MRI of meningioma patients for later biopsy sites (19 patients; 15 WHO Io, no previous radiation, and 4 WHO IIIo pre-radiated recurrent tumors). Sixty-three navigated biopsies were consecutively retrieved. Biopsies were immunohistochemically investigated with endothelial marker CD34 and VEGF antibodies, stratified in a total of 4383 analysis units and computationally assessed for VEGF expression and vascular parameters (vessel density, vessel quantity, vascular fraction within tissue [vascular area ratio], vessel wall thickness). Derivability of kinetic parameters from VEGF expression or microvascularization was determined by mixed linear regression analysis. Tissue kinetic and microvascular parameters were tested for their capacity to identify the radiation status in a subanalysis. RESULTS: Kinetic parameters were neither significantly related to the corresponding microvascular parameters nor to tissue VEGF expression. There was no significant association between microvessel density and its presumed correlate vp (P=0.07). The subgroup analysis of high-grade radiated meningiomas showed a significantly reduced microvascular density (AUC 0.91; P<0.0001) and smaller total vascular fraction (AUC 0.73; P=0.01). CONCLUSIONS: In meningioma, DCE-MRI kinetic parameters neither allow for a reliable prediction of tumor microvascularization, nor for a prediction of VEGF expression. Kinetic parameters seem to be determined from different independent factors.