Repeat surgery of recurrent glioma for molecularly informed treatment in the age of precision oncology: A risk-benefit analysis.

PURPOSE: Surgery for recurrent glioma provides cytoreduction and tissue for molecularly informed treatment. With mostly heavily pretreated patients involved, it is unclear whether the benefits of repeat surgery outweigh its potential risks. METHODS: Patients receiving surgery for recurrent glioma WHO grade 2-4 with the goal of tissue sampling for targeted therapies were analyzed retrospectively. Complication rates (surgical, neurological) were compared to our institutional glioma surgery cohort. Tissue molecular diagnostic yield, targeted therapies and post-surgical survival rates were analyzed. RESULTS: Between 2017 and 2022, tumor board recommendation for targeted therapy through molecular diagnostics was made for 180 patients. Of these, 70 patients (38%) underwent repeat surgery. IDH-wildtype glioblastoma was diagnosed in 48 patients (69%), followed by IDH-mutant astrocytoma (n = 13; 19%) and oligodendroglioma (n = 9; 13%). Gross total resection (GTR) was achieved in 50 patients (71%). Tissue was processed for next-generation sequencing in 64 cases (91%), and for DNA methylation analysis in 58 cases (83%), while immunohistochemistry for mTOR phosphorylation was performed in 24 cases (34%). Targeted therapy was recommended in 35 (50%) and commenced in 21 (30%) cases. Postoperatively, 7 patients (11%) required revision surgery, compared to 7% (p = 0.519) and 6% (p = 0.359) of our reference cohorts of patients undergoing first and second craniotomy, respectively. Non-resolving neurological deterioration was documented in 6 cases (10% vs. 8%, p = 0.612, after first and 4%, p = 0.519, after second craniotomy). Median survival after repeat surgery was 399 days in all patients and 348 days in GBM patients after repeat GTR. CONCLUSION: Surgery for recurrent glioma provides relevant molecular diagnostic information with a direct consequence for targeted therapy under a reasonable risk of postoperative complications. With satisfactory postoperative survival it can therefore complement a multi-modal glioma therapy approach.

Stereotactic frame-based biopsy of infratentorial lesions via the suboccipital-transcerebellar approach with the Zamorano-Duchovny stereotactic system-a retrospective analysis of 79 consecutive cases.

OBJECTIVE: Lesions of the posterior fossa (brainstem and cerebellum) are challenging in diagnosis and treatment due to the fact that they are often located eloquently and total resection is rarely possible. Therefore, frame-based stereotactic biopsies are commonly used to asservate tissue for neuropathological diagnosis and further treatment determination. The aim of our study was to assess the safety and diagnostic success rate of frame-based stereotactic biopsies for lesions in the posterior fossa via the suboccipital-transcerebellar approach. METHODS: We performed a retrospective database analysis of all frame-based stereotactic biopsy cases at our institution since 2007. The aim was to identify all surgical cases for infratentorial lesion biopsies via the suboccipital-transcerebellar approach. We collected clinical data regarding outcomes, complications, diagnostic success, radiological appearances, and stereotactic trajectories. RESULTS: A total of n = 79 cases of stereotactic biopsies for posterior fossa lesions via the suboccipital-transcerebellar approach (41 female and 38 male) utilizing the Zamorano-Duchovny stereotactic system were identified. The mean age at the time of surgery was 42.5 years (± 23.3; range, 1-87 years). All patients were operated with intraoperative stereotactic imaging (n = 62 MRI, n = 17 CT). The absolute diagnostic success rate was 87.3%. The most common diagnoses were glioma, lymphoma, and inflammatory disease. The overall complication rate was 8.7% (seven cases). All patients with complications showed new neurological deficits; of those, three were permanent. Hemorrhage was detected in five of the cases having complications. The 30-day mortality rate was 7.6%, and 1-year survival rate was 70%. CONCLUSIONS: Our data suggests that frame-based stereotactic biopsies with the Zamorano-Duchovny stereotactic system via the suboccipital-transcerebellar approach are safe and reliable for infratentorial lesions bearing a high diagnostic yield and an acceptable complication rate. Further research should focus on the planning of safe trajectories and a careful case selection with the goal of minimizing complications and maximizing diagnostic success.

Choice of Implantable Pulse Generators for Deep Brain Stimulation: An Overview of Clinical Practice.

INTRODUCTION: The success of deep brain stimulation (DBS) treatment depends on several factors, including proper patient selection, accurate electrode placement, and adequate stimulation settings. Another factor that may impact long-term satisfaction and therapy outcomes is the type of implantable pulse generator (IPG) used: rechargeable or non-rechargeable. However, there are currently no guidelines on the choice of IPG type. The present study investigates the current practices, opinions, and factors DBS clinicians consider when choosing an IPG for their patients. METHODS: Between December 2021 and June 2022, we sent a structured questionnaire with 42 questions to DBS experts of two international, functional neurosurgery societies. The questionnaire included a rating scale where participants could rate the factors influencing their choice of IPG type and their satisfaction with certain IPG aspects. Additionally, we presented four clinical case scenarios to assess preference of choice of IPG-type in each case. RESULTS: Eighty-seven participants from 30 different countries completed the questionnaire. The three most relevant factors for IPG choice were "existing social support," "cognitive status," and "patient age." Most participants believed that patients valued avoiding repetitive replacement surgeries more than the burden of regularly recharging the IPG. Participants reported that they implanted the same amount of rechargeable as non-rechargeable IPGs for primary DBS insertions and 20% converted non-rechargeable to rechargeable IPGs during IPG replacements. Most participants estimated that rechargeable was the more cost-effective option. CONCLUSION: This present study shows that the decision-making of the choice of IPG is very individualized. We identified the key factors influencing the physician's choice of IPG. Compared to patient-centric studies, clinicians may value different aspects. Therefore, clinicians should rely not only on their opinion but also counsel patients on different types of IPGs and consider the patient's preferences. Uniform global guidelines on IPG choice may not represent regional or national differences in the healthcare systems.

A single-center, open-label trial on convenience and complications of rechargeable implantable pulse generators for spinal cord stimulation: The Recharge Pain Trial.

Rechargeable implantable pulse generators (r-IPGs) have been available for spinal cord stimulation (SCS) claiming to offer a longer service life but demanding continuous monitoring and regular recharging by the patients. The aim of the study (DRKS00021281; Apr 7th, 2020) was to assess the convenience, safety, and acceptance of r-IPGs and their effect on patient lives under long-term therapy. Standardized questionnaires were sent to all chronic pain patients with a r-IPG at the time of trial. Primary endpoint was the overall convenience of the charging process on an ordinal scale from "very hard" (1 point) to "very easy" (5 points). Secondary endpoints were charge burden (min/week), rates of user confidence and complications (failed recharges, interruptions of therapy). Endpoints were analyzed for several subgroups. Data sets n = 40 (42% return rate) were eligible for analysis. Patient age was 57.2 ± 12.6 (mean ± standard deviation) years with the r-IPG being implanted for 52.1 ± 32.6 months. The overall convenience of recharging was evaluated as "easy" (4 points). The charge burden was 112.7 ± 139 min/week. 92% of the patients felt confident recharging the neurostimulator. 37.5% of patients reported failed recharges. 28.9% of patients experienced unintended interruptions of stimulation. Subgroup analysis only showed a significant impact on overall convenience for different models of stimulators (p < 0.05). Overall, SCS patients feel confident handling a r-IPG at high rates of convenience and acceptable effort despite high rates of usage-related complications. Further technical improvements for r-IPGs are needed.

The molecular diagnostic yield of frame-based stereotactic biopsies in the age of precision neuro-oncology: a cross-sectional study.

PURPOSE: With the increasing role of molecular genetics in the diagnostics of intracranial tumors, delivering sufficient representative tissue for such analyses is of paramount importance. This study explored the rate of successful diagnosis after frame-based stereotactic biopsies of intracranial lesions. METHODS: Consecutive patients undergoing frame-based stereotactic biopsies in 2020 and 2021 were included in this retrospective analysis. Cases were classified into three groups: conclusive, diagnosis with missing molecular genetics (MG) data, and inconclusive neuropathological diagnosis. RESULTS: Of 145 patients, a conclusive diagnosis was possible in n = 137 cases (94.5%). For 3 cases (2.0%), diagnosis was established with missing MG data. In 5 cases (3.5%), an inconclusive (tumor) diagnosis was met. Diagnoses comprised mainly WHO 4 glioblastomas (n = 73, 56%), CNS lymphomas (n = 23, 16%), inflammatory diseases (n = 14, 10%), and metastases (n = 5, 3%). Methylomics were applied in 49% (n = 44) of tumor cases (panel sequencing in n = 28, 30% of tumors). The average number of specimens used for MG diagnostics was 5, while the average number of specimens provided was 15. In a univariate analysis, insufficient DNA was associated with an inconclusive diagnosis or a diagnosis with missing MG data (p < 0.001). Analyses of planned and implemented trajectories of cases with diagnosis with missing MG data or inconclusive diagnosis (n = 8) revealed that regions of interest were reached in almost all cases (n = 7). CONCLUSION: Although stereotactic frame-based biopsies deliver a limited amount of tissue, they bear high histopathological and molecular genetic diagnostic yields. Given the proven surgical precision of the planned biopsy trajectories, optimizing surveyed lesion regions could help improve the rate of conclusive diagnoses.

Routine ICU admission after brain tumor surgery: retrospective validation and critical appraisal of two prediction scores.

BACKGROUND: Routine admission to an intensive care unit (ICU) following brain tumor surgery has been a common practice for many years. Although this practice has been challenged by many authors, it has still not changed widely, mainly due to the lack of reliable data for preoperative risk assessment. Motivated by this dilemma, risk prediction scores for postoperative complications following brain tumor surgery have been developed recently. In order to improve the ICU admission policy at our institution, we assessed the applicability, performance, and safety of the two most appropriate risk prediction scores. METHODS: One thousand consecutive adult patients undergoing elective brain tumor resection within 19 months were included. Patients with craniotomy for other causes, i.e., cerebral aneurysms and microvascular decompression, were excluded. The decision for postoperative ICU-surveillance was made by joint judgment of the operating surgeon and the anesthesiologist. All data and features relevant to the scores were extracted from clinical records and subsequent ICU or neurosurgical floor documentation was inspected for any postoperative adverse events requiring ICU admission. The CranioScore derived by Cinotti et al. (Anesthesiology 129(6):1111-20, 5) and the risk assessment score of Munari et al. (Acta Neurochir (Wien) 164(3):635-641, 15) were calculated and prognostic performance was evaluated by ROC analysis. RESULTS: In our cohort, both scores showed only a weak prognostic performance: the CranioScore reached a ROC-AUC of 0.65, while Munari et al.'s score achieved a ROC-AUC of 0.67. When applying the recommended decision thresholds for ICU admission, 64% resp. 68% of patients would be classified as in need of ICU surveillance, and the negative predictive value (NPV) would be 91% for both scores. Lowering the thresholds in order to increase patient safety, i.e., 95% NPV, would lead to ICU admission rates of over 85%. CONCLUSION: Performance of both scores was limited in our cohort. In practice, neither would achieve a significant reduction in ICU admission rates, whereas the number of patients suffering complications at the neurosurgical ward would increase. In future, better risk assessment measures are needed.

Mapping autonomic, mood and cognitive effects of hypothalamic region deep brain stimulation.

Because of its involvement in a wide variety of cardiovascular, metabolic and behavioural functions, the hypothalamus constitutes a potential target for neuromodulation in a number of treatment-refractory conditions. The precise neural substrates and circuitry subserving these responses, however, are poorly characterized to date. We sought to retrospectively explore the acute sequelae of hypothalamic region deep brain stimulation and characterize their neuroanatomical correlates. To this end we studied-at multiple international centres-58 patients (mean age: 68.5 ± 7.9 years, 26 females) suffering from mild Alzheimer's disease who underwent stimulation of the fornix region between 2007 and 2019. We catalogued the diverse spectrum of acutely induced clinical responses during electrical stimulation and interrogated their neural substrates using volume of tissue activated modelling, voxel-wise mapping, and supervised machine learning techniques. In total 627 acute clinical responses to stimulation-including tachycardia, hypertension, flushing, sweating, warmth, coldness, nausea, phosphenes, and fear-were recorded and catalogued across patients using standard descriptive methods. The most common manifestations during hypothalamic region stimulation were tachycardia (30.9%) and warmth (24.6%) followed by flushing (9.1%) and hypertension (6.9%). Voxel-wise mapping identified distinct, locally separable clusters for all sequelae that could be mapped to specific hypothalamic and extrahypothalamic grey and white matter structures. K-nearest neighbour classification further validated the clinico-anatomical correlates emphasizing the functional importance of identified neural substrates with area under the receiving operating characteristic curves between 0.67 and 0.91. Overall, we were able to localize acute effects of hypothalamic region stimulation to distinct tracts and nuclei within the hypothalamus and the wider diencephalon providing clinico-anatomical insights that may help to guide future neuromodulation work.

The use of quantitative pupillometry in patients with pituitary tumors: a technical note.

BACKGROUND: Pituitary tumors may cause compression of the optic chiasm, resulting in decreased visual acuity. Therefore, decompression of the optic chiasm is a major goal of surgical treatment in such patients. Quantitative pupillometry has been used in various clinical settings for assessing the optic system but has not been applied in patients with pituitary tumors. This study aimed to evaluate the potential of this technique to improve treatment modalities in patients undergoing surgical resection of pituitary tumors. METHOD: Pupillometry using the automated NPi 200® Pupillometer was performed in seven patients who underwent surgical resection of large pituitary tumors at the University of Heidelberg in 2018. The neurological pupil index (NPi) was assessed preoperatively and postoperatively, and correlations with visual acuity and magnetic resonance imaging (MRI) findings regarding optic chiasm compression were determined. RESULTS: All patients experienced visual disturbance due to a large pituitary tumor. The NPi was < 4.0 in all patients in at least one pupil. Intraoperative MRI demonstrated successful decompression of the optic chiasm in all cases. Postoperatively, the NPi values increased, and this increase was correlated with improved visual acuity. CONCLUSIONS: We found that quantitative pupillometry can detect optic chiasm compression in patients with pituitary tumors. Furthermore, postoperative improvement of NPi values may indicate sufficient decompression of the optic chiasm. Further studies are warranted to substantiate the granularity of this technique to gain valuable information for patients with pituitary tumors who are indicated for surgery.

Wireless Subcutaneous Trigeminal Nerve Field Stimulation for Refractory Trigeminal Pain: A Single Center Experience.

INTRODUCTION: Subcutaneous trigeminal nerve field stimulation (sTNFS) is a neuromodulatory treatment for neuropathic trigeminal pain with the ability to reduce the intensity and frequency of pain attacks. However, hardware issues including lead migration, skin erosion, infection, so-called pocket pain at the site of the implanted neurostimulator are reported. Implantable wireless neurostimulation technology promises not only an even less invasive sTNFS treatment and thinner and more flexible electrodes better suited for facial implants, but also provides further advantages such as lack of an implantable neurostimulator and 3T magnetic resonance imaging compatibility. MATERIAL AND METHODS: All patients who had received trial stimulation with a partially implantable sTNFS system were analyzed for ICHD-3 (3rd edition of the International Classification of Headache Disorders) diagnosis, success of trial stimulation, pre- and postoperative pain intensity, frequency of attacks, complications, and side-effects of sTNFS. RESULTS: All patients (N = 3) responded to sTNFS (≥50% pain reduction) during the trial period. According to ICHD-3, N = 2 of the patients were classified with trigeminal neuralgia (TN) with concomitant persistent facial pain and N = 1 patient with multiple sclerosis associated TN. The time of the test period was 44 ± 31.24 days (mean ± SD). The average daily duration of stimulation per patient amounted 2.5 ± 2.2 hours (range 1-5). The pain intensity (defined on a visual analog scale) was reduced by 80% ± 17% (mean ± SD). Reduction or cessation in pain medication was observed in all patients. No surgical complications occurred in the long-term follow-up period of 18.84 ± 6 (mean ± SD) months. CONCLUSION: The partially implantable sTNFS device seems to be safe, effective, and reliable. Compared to conventional devices, the equipment is not limited to the length of trial stimulation. Furthermore, the daily stimulation duration was much shorter compared to previous reports.

Location and Volume of MRI Artifacts in Patients With Implanted Sphenopalatine Ganglion Neurostimulators for Treatment of Chronic Cluster Headache.

INTRODUCTION: Sphenopalatine ganglion stimulation (SPG-S) is an invasive form of neuromodulation by which a neurostimulator is implanted into the pterygopalatine fossa to treat refractory chronic cluster headache. The implant is MRI conditional, up to 3 T, however there is no clinical data on the shape, size, and location of the artifact produced by the implant. MATERIALS AND METHODS: Records of patients with SPG-S were analyzed for postoperative cranial MRI scans. MRI and intraoperative CT scans for visualization of the implant were fused and volumetry was performed for both the implant and the MRI artifact in different MRI sequences. RESULTS: In total, n = 3 patients with postoperative MRI scans were identified. The mean CT artifact volume was 0.73 cm3 (±0.15 cm3 ). MRI artifact volume differed between sequences (range: 25.2-220.7 cm3 ). The intracranial space was largely unaffected besides the pole of the ipsilateral temporal lobe and the basal frontal gyrus. MRI artifacts affected the extracranial space (orbit, maxillary and ethmoid sinuses, and parts of the parotid gland). No adverse events occurred during or after MRI scans. CONCLUSIONS: Cranial MRI scans with SPG-S implants were safely performed in three patients following the manufacturer's MRI conditions. MRI artifacts were mostly located in the extracranial space. Brain MRI imaging is largely unaffected. CONFLICT OF INTEREST: The authors declare no potential conflicts of interest with respect to research, authorship, and/or publication of this article.

Rechargeable Internal Pulse Generators as Initial Neurostimulators for Deep Brain Stimulation in Patients With Movement Disorders.

INTRODUCTION: Rechargeable internal pulse generators (r-IPGs) for deep brain stimulation (DBS) promise a longer battery life and cost effectiveness compared to non-rechargeable IPGs. However, patients need to learn to check the battery capacity and perform the recharging process to ensure continuous therapy. METHODS: n = 35 consecutive adult patients with movement disorders that underwent DBS electrode placement with implantation of a r-IPG were assessed with a questionnaire. They were asked to report on their recharging routine, user confidence, satisfaction, and adverse events. Patients were asked to assess the level of difficulty of the individual steps and the overall recharging process on an ordinal scale awarding 1-5 points. RESULTS: 89% (n = 31) patients responded and were available for data analysis. n = 21 patients received DBS for Parkinson's Disease, n = 8 for essential tremor and n = 2 for dystonia at a mean age of 63.3 years. The mean follow-up was 21.2 months. n = 7 patients have partners or nursing services check and recharge the IPG. The recharging takes an average of 57.6 min. 90.3% felt confident using their IPG after a mean of 2.1 weeks and 1.6 training sessions. 97% of patients prefer their r-IPG over a conventional one. n = 3 patients experienced inability to recharge their IPG at some point. One patient experienced battery depletion and interruption of stimulation because of inability to recharge. The overall recharging process was rated as "easy" with a score of 4.0 out of 5 points. Each individual step was also rated as "easy" with a median score of 4.0 out of 5. Old age was not associated with more adverse events or a lower rating for the recharging process. CONCLUSIONS: Choosing a r-IPG during initial DBS surgery is safe and associated with a low number of adverse events even in older patients. The vast majority of patients consider handling and recharging the IPG as "easy." Most of the patients undergoing DBS for movement disorders will benefit from the advantages of r-IPGs.

Subcutaneous trigeminal nerve field stimulation for refractory trigeminal pain: a cohort analysis.

BACKGROUND: Neurosurgical pain management of drug-resistant trigeminal neuralgia (TN) is highly challenging. Microvascular decompression is a first-line neurosurgical approach for classical TN with neurovascular conflict, but can show clinical relapse despite proper decompression. Second-line destructive techniques like radiofrequency thermocoagulation have become reluctantly used due to their potential for irreversible side effects. Subcutaneous peripheral nerve field stimulation (sPNFS) is a minimally invasive neuromodulatory technique which has been shown to be effective for chronic localised pain conditions. Reports on sPNFS for the treatment of trigeminal pain (sTNFS) are still sparse and primarily focused on pain intensity as outcome measure. Detailed data on the impact of sTNFS on attack frequency are currently not available. METHODS: Patients were classified according to the International Headache Society classification (ICHD-3-beta). Three patients had classical TN without (n = 3) and another three TN with concomitant persistent facial pain (n = 3). Two patients suffered from post-herpetic trigeminal neuropathy (n = 2). All eight patients underwent a trial stimulation of at least 7 days with subcutaneous leads in the affected trigeminal area connected to an external neurostimulator. Of those, six patients received permanent implantation of a neurostimulator. During the follow-up (6-29 months, mean 15.2), VAS-scores, attack frequencies, oral drug intake, complications and side effects were documented. RESULTS: Seven out of eight patients responded to sTNFS (i.e. ≥50 % pain reduction) during the test trial. The pain intensity (according to VAS) was reduced by 83 ± 16 % (mean ± SD) and the number of attacks decreased by 73 ± 26 % (mean ± SD). Five out of six patients were able to reduce or stop pain medication. One patient developed device infection. Two patients developed stimulation-related side effects which could be resolved by reprogramming. CONCLUSIONS: Treatment by sTNFS is a beneficial option for patients with refractory trigeminal pain. Prospective randomised trials are required to systematically evaluate efficacy rates and safety of this low-invasive neurosurgical technique.

Rapid bedside coagulometry prior to urgent neurosurgical procedures in anticoagulated patients.

INTRODUCTION: With the increased use of oral anticoagulation with vitamin K antagonists, emergency physicians encounter a growing number of patients requiring a rapid reversal of anticoagulant effects in order to perform urgent surgical procedures. Initiation of these procedures can be delayed because the coagulation status has to be assessed through examination of blood samples in central laboratories (CL). This delay may lead to negative effects, especially in potentially life-threatening conditions such as intracranial haemorrhage. Point-of-care (POC) devices for assessment of international normalized ratio (POC INR) have improved the management of anticoagulation therapy in the outpatient setting. The use of these devices may also have beneficial effects in the treatment of anticoagulated patients requiring urgent neurosurgical procedures. The primary aim of this study was to analyse the potential of POC-guided assessment of INR to reduce time to potentially life-saving neurosurgery in this setting. Feasibility and accuracy as well as the gain of time through the use of this device were analysed. MATERIALS AND METHODS: The POC coagulometer CoaguChek XS(®) was used in 17 patients with a history of anticoagulant use and a condition requiring urgent anticoagulant reversal prior to neurosurgical procedures (burr-hole trepanation: n = 8, craniotomy: n = 7, laminectomy: n = 2). RESULTS: No technical difficulties occurred and rapid assessment of INR was achieved in all cases within 2 min. POC INR values correlated well with CL INR assessment with a mean INR deviation of 0.036 ± 0.12. The mean gain of time through the use of the POC INR device compared with CL assessment of INR was 47 ± 6 min (range: 37-61 min). CONCLUSION: Our initial experiences with a POC INR device in anticoagulated patients undergoing urgent neurosurgical procedures demonstrate that its use may contribute to an improved management of these patients.

Deep learning aided preoperative diagnosis of primary central nervous system lymphoma.

The preoperative distinction between glioblastoma (GBM) and primary central nervous system lymphoma (PCNSL) can be difficult, even for experts, but is highly relevant. We aimed to develop an easy-to-use algorithm, based on a convolutional neural network (CNN) to preoperatively discern PCNSL from GBM and systematically compare its performance to experienced neurosurgeons and radiologists. To this end, a CNN-based on DenseNet169 was trained with the magnetic resonance (MR)-imaging data of 68 PCNSL and 69 GBM patients and its performance compared to six trained experts on an external test set of 10 PCNSL and 10 GBM. Our neural network predicted PCNSL with an accuracy of 80% and a negative predictive value (NPV) of 0.8, exceeding the accuracy achieved by clinicians (73%, NPV 0.77). Combining expert rating with automated diagnosis in those cases where experts dissented yielded an accuracy of 95%. Our approach has the potential to significantly augment the preoperative radiological diagnosis of PCNSL.

Recharge PSYCH: A Study on Rechargeable Implantable Pulse Generators in Deep Brain Stimulation for Psychiatric Disorders.

BACKGROUND: Rechargeable implantable pulse generators (r-IPGs) for deep brain stimulation (DBS) promise longer battery life and fewer replacement surgeries versus non-rechargeable systems. Long-term data on the effects of recharging in patients who received DBS for psychiatric indications is limited. The Recharge PSYCH trial is the first study that included DBS patients with psychiatric disorders treated with different r-IPG models. METHODS: Standardized questionnaires were sent to all psychiatric DBS patients with an r-IPG implanted at the time of the study. The primary endpoint was convenience of recharging. Secondary endpoints were rate of user confidence and rate of usage-related complications, as well as charge burden (defined as minutes per week needed to recharge). RESULTS: Data sets of n = 21 patients were eligible for data analysis. At the time of the survey patients were implanted with the r-IPG for a mean 31.8 ± 22.4 months. Prior to being implanted with an r-IPG, patients had undergone a median of 3 IPG replacements. The overall convenience of the charging process was rated as "easy" with a median of 8.0 out of 10.0 points. 33.3% of patients experienced situations in which the device could not be successfully recharged. In 38.1% of patients, therapy with the r-IPG was interrupted unintentionally. The average charge burden was 286 ± 22.4 minutes per week. CONCLUSIONS: Patients with psychiatric disorders rated the recharging process as "easy", but with a significantly higher charge burden and usage-related complication rates compared to published data on movement disorder DBS patients.

Deep brain stimulation of the nucleus accumbens in treatment-resistant alcohol use disorder: a double-blind randomized controlled multi-center trial.

Treatment resistance in alcohol use disorders (AUD) is a major problem for affected individuals and for society. In the search of new treatment options, few case studies using deep brain stimulation (DBS) of the nucleus accumbens have indicated positive effects in AUD. Here we report a double-blind randomized controlled trial comparing active DBS ("DBS-EARLY ON") against sham stimulation ("DBS-LATE ON") over 6 months in n = 12 AUD inpatients. This 6-month blind phase was followed by a 12-month unblinded period in which all patients received active DBS. Continuous abstinence (primary outcome), alcohol use, alcohol craving, depressiveness, anxiety, anhedonia and quality of life served as outcome parameters. The primary intention-to-treat analysis, comparing continuous abstinence between treatment groups, did not yield statistically significant results, most likely due to the restricted number of participants. In light of the resulting limited statistical power, there is the question of whether DBS effects on secondary outcomes can nonetheless be interpreted as indicative of an therapeutic effect. Analyses of secondary outcomes provide evidence for this, demonstrating a significantly higher proportion of abstinent days, lower alcohol craving and anhedonia in the DBS-EARLY ON group 6 months after randomization. Exploratory responder analyses indicated that patients with high baseline alcohol craving, depressiveness and anhedonia responded to DBS. The results of this first randomized controlled trial are suggestive of beneficial effects of DBS in treatment-resistant AUD and encourage a replication in larger samples.

Mitoxantrone-iron oxide biodistribution in blood, tumor, spleen, and liver--magnetic nanoparticles in cancer treatment.

BACKGROUND: Magnetic drug targeting is a new treatment principle for tumors using cytostatics coupled to ferromagnetic nanoparticles and extracorporeal magnets. Higher concentrations in tumor tissue with lower systemic concentrations and without damage of healthy organs should be achieved. MATERIALS AND METHODS: n = 42 adult Wag/Rij rats were transfected with rhabdomyosarcoma R(1)H in their right gastrocnemius muscle. In the biodistribution trial (n = 36) concentrations of mitoxantrone-iron oxide with and without an extracorporeal 0.6 tesla magnet and regular mitoxantrone were measured in plasma and tumor tissue for one- and two-dose administration. In the plasma iron trial (n = 6) iron concentrations were measured in plasma before, during, and up to 30 min after drug administration. Seven days after the trial liver, spleen and tumor samples were obtained and histologically assessed. RESULTS: Mitoxantrone iron-oxide concentration in plasma was significantly (P < 0.05) lower when a magnet was placed over the tumor area and as low as uncoupled mitoxantrone. Mitoxantrone concentration in tumor tissue was always significantly higher with magnetic drug targeting when compared with uncoupled mitoxantrone. Two doses resulted in drug accumulation in tumor tissue. Plasma iron concentrations rose when the drug was first administered. Plasma levels fell below the starting level with a magnet applied. A rebound phenomenon with rising iron concentrations was observed after the magnet was removed. Tumors showed fresh necrosis and liver and spleen had detectable iron depositions but no necrosis 7 d after treatment. No allergies or toxic reactions were observed. CONCLUSIONS: We showed that magnetic drug targeting achieves higher concentrations of cytostatics in tumor tissue compared with blood. During magnetic drug targeting, iron particles are quickly sliced and kept in the tumor area. Organs of the reticuloendothelial system are not affected by cytostatic damage.

Questionnaire-based approach to evaluate the convenience of rechargeable extracorporeal pulse generators for wireless spinal cord stimulation.

Spinal cord stimulation (SCS) has been utilized for more than 50 years to treat refractory neuropathic pain. Currently, SCS systems with fully implantable pulse generators (IPGs) represent the standard. New wireless extracorporeal SCS (wSCS) devices without IPGs promise higher levels of comfort and convenience for patients. However, to date there are no studies on how charging and using this wSCS system affects patients and their therapy. This study is the first questionnaire-based survey on this topic focusing on patient experience. The trial was a single arm, open-label and mono-centric phase IV study. Standardized questionnaires were sent to all patients with a wSCS device in use at the time of trial. The primary endpoint was the convenience of the charging and wearing process scored on an ordinal scale from "very hard" (1) to "very easy" (5). Secondary endpoints included time needed for charging, the duration of stimulation per day and complication rates. Questionnaires of 6 out of 9 patients were returned and eligible for data analysis. The mean age of patients was 61.3 ± 6.7 (± SD) years. The duration of therapy was 20.3 ± 15.9 months (mean ± SD). The mean duration of daily stimulation was 17 ± 5.9 h (mean ± SD). n = 5 patients rated the overall convenience as "easy" (4) and n = 3 patients evaluated the effort of the charging process and wearing of the wSCS device as "low" (4). n = 5 patients considered the wearing and charging process as active participation in their therapy. n = 5 patients would choose an extracorporeal device again over a conventional SCS system. Early or late surgical complications did not occur in this patient collective. Overall, patients felt confident using extracorporeal wSCS devices without any complications. Effort to maintain therapy with this system was rated as low.

Modifying the progression of Alzheimer's and Parkinson's disease with deep brain stimulation.

At times of an aging population and increasing prevalence of neurodegenerative disorders, effective medical treatments remain limited. Therefore, there is an urgent need for new therapies to treat Alzheimer's disease (AD). Deep brain stimulation (DBS) is thought to address the neuronal network dysfunction of this disorder and may offer new therapeutic options. Preliminary evidence suggests that DBS of the fornix may have effects on cognitive decline, brain glucose metabolism, hippocampal volume and cortical grey matter volume in certain patients with mild AD. Rodent studies have shown that increase of cholinergic neurotransmitters, hippocampal neurogenesis, synaptic plasticity and reduction of amyloid plaques are associated with DBS. Currently a large phase III study of fornix DBS is assessing efficacy in patients with mild AD aged 65 years and older. The Nucleus basalis of Meynert has also been explored in a phase I study in of mild to moderate AD and was tolerated well regardless of the lack of benefit. Being an established therapy for Parkinson's Disease (PD), DBS may exert some disease-modifying traits rather than being a purely symptomatic treatment. There is evidence of dopaminergic neuroprotection in animal models and some suggestion that DBS may influence the natural progression of the disorder. Neuromodulation may possibly have beneficial effects on course of different neurodegenerative disorders compared to medical therapy alone. For dementias, functional neurosurgery may provide an adjunctive option in patient care. This article is part of the special issue entitled 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'.

Wireless, remote solution for home fetal and maternal heart rate monitoring.

BACKGROUND: Access to prenatal care can be challenging due to physician shortages and rural geography. The multiple prenatal visits performed to collect basic fetal measurements lead to significant patient burden as well. The standard of care tools for fetal monitoring, external fetal heart rate monitoring with cardiotocography, as used today, must be applied by a medical professional in a healthcare setting. Novel tools to enable a remote and self-administered fetal monitoring solution would significantly alleviate some of the current barriers to care. OBJECTIVE: To compare maternal and fetal heart rate monitoring data obtained by 'Invu system' (a wireless, wearable, self-administered, fixed-location device containing passive electrical and acoustic sensors) to cardiotocography, toward a true remote fetal monitoring solution. MATERIALS AND METHODS: A prospective, open-label, multicenter study evaluated concurrent use of Invu and cardiotocography in pregnant women, aged 18 to 50 years, with singleton pregnancies ≥32+0 weeks' gestation (NCT03504189). Simultaneous recording sessions from Invu and cardiotocography lasted for ≥30 minutes. Data from the 8 electrical sensors and 4 acoustic sensors in the Invu belt were acquired, digitized, and sent wirelessly for analysis by an algorithm on cloud-based servers. The algorithm validates the data, preprocesses the data to remove noise, detects heartbeats independently from the two data sources (electrical and acoustic), and fuses the detected heartbeat arrays to calculate fetal heart rate (FHR) and maternal heart rate (MHR). The primary performance endpoint was Invu FHR limit of agreement within ± 10 beats per minute (bpm) of FHR measured with cardiotocography. RESULTS: A total of 147 women were included in the study analysis. The mean (SD) maternal age was 31.8 ±6.9 years, and the mean gestational age was 37.7 ±2.3 weeks. There was a highly significant correlation between FHR measurements from Invu and cardiotocography (r = 0.92; P<0.0001). The 95% limits of agreement for the difference, the range within which most differences between the two measurements will lie, were -8.84 bpm to 8.24 bpm. Invu measurements of MHR were also very similar to cardiotocography and were highly significantly correlated (r = 0.97; P<0.0001). No adverse events were reported during the study. CONCLUSION: Although captured by very different methods, the FHR and MHR outputs wirelessly obtained by the Invu system through passive methods were very similar to those obtained by the current standard of care. The limits of agreement for FHR measured by Invu were within a clinically acceptable ± 8 bpm of cardiotocography FHR. The Invu device uses passive technology to allow for safe, non-invasive and convenient monitoring of patients in the clinic and remotely. Further work should investigate how remote perinatal monitoring could best address some of the recent challenges seen with prenatal care and maternal and fetal outcomes. CLINICAL TRIAL INFORMATION: Registration date: April 20, 2018; First participant enrollment: February 28, 2018; ClinicalTrials.gov registration NCT03504189; https://clinicaltrials.gov/ct2/show/NCT03504189.