Spreading depolarizations in ischaemia after subarachnoid haemorrhage, a diagnostic phase III study.

Focal brain damage after aneurysmal subarachnoid haemorrhage predominantly results from intracerebral haemorrhage, and early and delayed cerebral ischaemia. The prospective, observational, multicentre, cohort, diagnostic phase III trial, DISCHARGE-1, primarily investigated whether the peak total spreading depolarization-induced depression duration of a recording day during delayed neuromonitoring (delayed depression duration) indicates delayed ipsilateral infarction. Consecutive patients (n = 205) who required neurosurgery were enrolled in six university hospitals from September 2009 to April 2018. Subdural electrodes for electrocorticography were implanted. Participants were excluded on the basis of exclusion criteria, technical problems in data quality, missing neuroimages or patient withdrawal (n = 25). Evaluators were blinded to other measures. Longitudinal MRI, and CT studies if clinically indicated, revealed that 162/180 patients developed focal brain damage during the first 2 weeks. During 4.5 years of cumulative recording, 6777 spreading depolarizations occurred in 161/180 patients and 238 electrographic seizures in 14/180. Ten patients died early; 90/170 developed delayed infarction ipsilateral to the electrodes. Primary objective was to investigate whether a 60-min delayed depression duration cut-off in a 24-h window predicts delayed infarction with >0.60 sensitivity and >0.80 specificity, and to estimate a new cut-off. The 60-min cut-off was too short. Sensitivity was sufficient [= 0.76 (95% confidence interval: 0.65-0.84), P = 0.0014] but specificity was 0.59 (0.47-0.70), i.e. <0.80 (P < 0.0001). Nevertheless, the area under the receiver operating characteristic (AUROC) curve of delayed depression duration was 0.76 (0.69-0.83, P < 0.0001) for delayed infarction and 0.88 (0.81-0.94, P < 0.0001) for delayed ischaemia (reversible delayed neurological deficit or infarction). In secondary analysis, a new 180-min cut-off indicated delayed infarction with a targeted 0.62 sensitivity and 0.83 specificity. In awake patients, the AUROC curve of delayed depression duration was 0.84 (0.70-0.97, P = 0.001) and the prespecified 60-min cut-off showed 0.71 sensitivity and 0.82 specificity for reversible neurological deficits. In multivariate analysis, delayed depression duration (ß = 0.474, P < 0.001), delayed median Glasgow Coma Score (ß = -0.201, P = 0.005) and peak transcranial Doppler (ß = 0.169, P = 0.016) explained 35% of variance in delayed infarction. Another key finding was that spreading depolarization-variables were included in every multiple regression model of early, delayed and total brain damage, patient outcome and death, strongly suggesting that they are an independent biomarker of progressive brain injury. While the 60-min cut-off of cumulative depression in a 24-h window indicated reversible delayed neurological deficit, only a 180-min cut-off indicated new infarction with >0.60 sensitivity and >0.80 specificity. Although spontaneous resolution of the neurological deficit is still possible, we recommend initiating rescue treatment at the 60-min rather than the 180-min cut-off if progression of injury to infarction is to be prevented.

Benign peripheral nerve sheath tumors: an interdisciplinary diagnostic and therapeutic challenge.

A benign peripheral nerve sheath tumor (bPNST) is a rare lesion associated with peripheral nerval structures. Symptoms may be heterogeneous, complicating diagnosis finding. Additionally, management concepts of bPNST may vary. In some cases, initial misdiagnosis leads to mistreatment resulting in severe functional deficits and chronic pain syndromes. Therefore, we analyzed patients treated for bPNST in our specialized institution with a primary focus on prior misdiagnosis and possible mistreatment. Patients with bPNSTs (schwannomas, neurofibromas, hybrid nerve sheath tumors, and perineuriomas) treated at the Neurosurgical Department between January 1, 2015, and July 31, 2021, were included. Assessment of demographics, tumor entity, tumor location, symptoms, the interval between the onset of symptoms and surgery, involved medical specialties, and outpatients' treatment, with particular focus on initial misdiagnosis and inappropriate medical treatment, was performed. Eighty-five patients were included in the final analysis with schwannoma being the most prevalent histopathological diagnosis (schwannoma (75.3%, n=64), neurofibroma (12.9%, n=11), hybrid nerve sheath tumor (5.9%, n=5), and perineurioma (5.9%, n=5)). An incorrect primary diagnosis was detected in 44.7% (n=38), leading to suboptimal or insufficient treatment in these cases. Of those, 28.9% (n=11/38) were treated suboptimal, while 18.5% (n=7/38) underwent unnecessary invasive diagnostics. Inappropriate surgery based on prior misdiagnosis, which led to severe neurological deficits in all these cases, was reported in 26.3% (n=10/38). For the first time, our data shows the quantity and impact of incorrect initial diagnosis in bPNST causing a delay in causative treatment or resulting in unnecessary or potentially harmful treatment.

Diagnosis and treatment of meralgia paresthetica between 2005 and 2018: a national cohort study.

The prevalence of meralgia paresthetica (MP), which is caused by compression of the lateral femoral cutaneous nerve (LFCN), has been increasing over recent decades. Since guidelines and large-scale studies are lacking, there are substantial regional differences in diagnostics and management in MP care. Our study aims to report on current diagnostic and therapeutic strategies as well as time trends in clinical MP management in Germany. Patients hospitalized in Germany between January 1, 2005, and December 31, 2018, with MP as their primary diagnosis were identified using the International Classification of Disease (ICD-10) code G57.1 and standardized operations and procedures codes (OPS). A total of 5828 patients with MP were included. The rate of imaging studies increased from 44% in 2005 to 79% in 2018 (p < 0.001) and that of non-imaging diagnostic studies from 70 to 93% (p < 0.001). Among non-imaging diagnostics, the rates of evoked potentials and neurography increased from 20%/16% in 2005 to 36%/23% in 2018 (p < 0.001, respectively). Rates of surgical procedures for MP decreased from 53 to 37% (p < 0.001), while rates of non-surgical procedures increased from 23 to 30% (p < 0.001). The most frequent surgical interventions were decompressive procedures at a mean annual rate of 29% (± 5) throughout the study period, compared to a mean annual rate of 5% (± 2) for nerve transection procedures. Between 2005 and 2018, in-hospital MP care in Germany underwent significant changes. The rates of imaging, evoked potentials, neurography, and non-surgical management increased. The decompression of the LFCN was substantially more frequent than that of the LFCN transection, yet both types of intervention showed a substantial decrease in in-hospital prevalence over time.

Skeletal muscle provides the immunological micro-milieu for specific plasma cells in anti-synthetase syndrome-associated myositis.

Anti-synthetase syndrome (ASyS)-associated myositis is a major subgroup of the idiopathic inflammatory myopathies (IIM) and is characterized by disease chronicity with musculoskeletal, dermatological and pulmonary manifestations. One of eight autoantibodies against the aminoacyl-transferase RNA synthetases (ARS) is detectable in the serum of affected patients. However, disease-specific therapeutic approaches have not yet been established.To obtain a deeper understanding of the underlying pathogenesis and to identify putative therapeutic targets, we comparatively investigated the most common forms of ASyS associated with anti-PL-7, anti-PL-12 and anti-Jo-1. Our cohort consisted of 80 ASyS patients as well as healthy controls (n = 40), diseased controls (n = 40) and non-diseased controls (n = 20). We detected a reduced extent of necrosis and regeneration in muscle biopsies from PL-12+ patients compared to Jo-1+ patients, while PL-7+ patients had higher capillary dropout in biopsies of skeletal muscle. Aside from these subtle alterations, no significant differences between ASyS subgroups were observed. Interestingly, a tissue-specific subpopulation of CD138+ plasma cells and CXCL12+/CXCL13+CD20+ B cells common to ASyS myositis were identified. These cells were localized in the endomysium associated with alkaline phosphatase+ activated mesenchymal fibroblasts and CD68+MHC-II+CD169+ macrophages. An MHC-I+ and MHC-II+ MxA negative type II interferon-driven milieu of myofiber activation, topographically restricted to the perifascicular area and the adjacent perimysium, as well as perimysial clusters of T follicular helper cells defined an extra-medullary immunological niche for plasma cells and activated B cells. Consistent with this, proteomic analyses of muscle tissues from ASyS patients demonstrated alterations in antigen processing and presentation. In-depth immunological analyses of peripheral blood supported a B-cell/plasma-cell-driven pathology with a shift towards immature B cells, an increase of B-cell-related cytokines and chemokines, and activation of the complement system. We hypothesize that a B-cell-driven pathology with the presence and persistence of a specific subtype of plasma cells in the skeletal muscle is crucially involved in the self-perpetuating chronicity of ASyS myositis. This work provides the conceptual framework for the application of plasma-cell-targeting therapies in ASyS myositis.

Aneurysmal subarachnoid hemorrhage in Germany between 2005 and 2018: A nationwide observational study.

BACKGROUND AND PURPOSE: In recent decades, the global incidence of aneurysmal subarachnoid hemorrhage (aSAH) has declined. However, significant regional differences exist. We present the first comprehensive analysis of time trends in the incidence of aSAH and case fatality in Germany. METHODS: All patients hospitalized with aSAH in Germany between 2005 and 2018 were identified using International Classification of Disease, 10th Revision codes I60.0-I60.7. RESULTS: A total of 101,105 cases were included. The incidence of aSAH in Germany decreased at a mean annual rate of 0.5% (p = 0.003) from 8.9 per 100,000 population in 2005 to 8.2 in 2018. Over time, incidences of aSAH declined among patients younger than 55 years and patients aged 70-79 years, increased among ages 60-64 years, and remained stable in age groups 65-69 and 85-89 years. This corresponded to an increase in the mean age of aSAH onset from 55.6 (±14.3) to 59.0 (±14.0) years. Throughout the study period, the mean age of aSAH onset was higher in women compared to men (58.3 ± 14.4 years vs. 56.1 ± 14.1 years). There were no changes in in-hospital case fatality (16.2 vs. 16.6%, p = 0.18), but the duration of hospital stay increased significantly from 19.7 to 24.8 days (p < 0.001). The most frequent aSAH-associated aneurysm location was the anterior circulation throughout the entire study period. CONCLUSIONS: In Germany, the incidence of aSAH decreased between 2005 and 2018, especially in younger parts of the population. This may reflect effects of lifestyle adjustments most pronounced in younger age groups.

Clinical implementation of a 3D4K-exoscope (Orbeye) in microneurosurgery.

Exoscopic surgery promises alleviation of physical strain, improved intraoperative visualization and facilitation of the clinical workflow. In this prospective observational study, we investigate the clinical usability of a novel 3D4K-exoscope in routine neurosurgical interventions. Questionnaires on the use of the exoscope were carried out. Exemplary cases were additionally video-documented. All participating neurosurgeons (n = 10) received initial device training. Changing to a conventional microscope was possible at all times. A linear mixed model was used to analyse the impact of time on the switchover rate. For further analysis, we dichotomized the surgeons in a frequent (n = 1) and an infrequent (n = 9) user group. A one-sample Wilcoxon signed rank test was used to evaluate, if the number of surgeries differed between the two groups. Thirty-nine operations were included. No intraoperative complications occurred. In 69.2% of the procedures, the surgeon switched to the conventional microscope. While during the first half of the study the conversion rate was 90%, it decreased to 52.6% in the second half (p = 0.003). The number of interventions between the frequent and the infrequent user group differed significantly (p = 0.007). Main reasons for switching to ocular-based surgery were impaired hand-eye coordination and poor depth perception. The exoscope investigated in this study can be easily integrated in established neurosurgical workflows. Surgical ergonomics improved compared to standard microsurgical setups. Excellent image quality and precise control of the camera added to overall user satisfaction. For experienced surgeons, the incentive to switch from ocular-based to exoscopic surgery greatly varies.

Large Size Hemicraniectomy Reduces Early Herniation in Malignant Middle Cerebral Artery Infarction.

BACKGROUND: Decompressive hemicraniectomy (DHC) reduces mortality and improves outcome after malignant middle cerebral artery infarction (MMI) but early in-hospital mortality remains high between 22 and 33%. Possibly, this circumstance is driven by cerebral herniation due to space-occupying brain swelling despite decompressive surgery. As the size of the removed bone flap may vary considerably between surgeons, a size too small could foster herniation. Here, we investigated the effect of the additional volume created by an extended DHC (eDHC) on early in-hospital mortality in patients suffering from MMI. METHODS: We performed a retrospective single-center cohort study of 97 patients with MMI that were treated either with eDHC (n = 40) or standard DHC (sDHC; n = 57) between January 2006 and June 2012. The primary study end point was defined as in-hospital mortality due to transtentorial herniation. RESULTS: In-hospital mortality due to transtentorial herniation was significantly lower after eDHC (0 vs. 11%; p = 0.04), which was paralleled by a significantly larger volume of the craniectomy (p < 0.001) and less cerebral swelling (eDHC 21% vs. sDHC 25%; p = 0.03). No statistically significant differences were found in surgical or non-surgical complications and postoperative intensive care treatment. CONCLUSION: Despite a more aggressive surgical approach, eDHC may reduce early in-hospital mortality and limit transtentorial herniation. Prospective studies are warranted to confirm our results and assess general safety of eDHC.

Moyamoya Vessel Pathology Imaged by Ultra-High-Field Magnetic Resonance Imaging at 7.0 T.

BACKGROUND: Prompt diagnosis of vessel pathology and appropriate treatment of moyamoya vasculopathy (MMV) are essential to improve long-term prognosis. The aims of our study were to explore the diagnostic value of ultra-high-field (UHF) magnetic resonance imaging at 7.0 T in MMV patients and to compare the applicability of two different 7.0 T vessel imaging modalities to 3.0 T magnetic resonance angiography (MRA) and digital subtraction angiography (DSA). METHODS: In a World Health Organization-registered and prospective imaging trial, patients were investigated at 7.0 T magnetization-prepared rapid-acquisition gradient echo (MPRAGE)-MRA and time-of-flight (TOF)-MRA, 3.0 T TOF-MRA, and by DSA. RESULTS: Six patients were included in our study and evaluated for MMV. 3.0 T TOF-MRA and 7.0 T MPRAGE-MRA were able to depict the complete major vascular tree and confirmed MMV-specific steno-occlusions of major intracranial arteries, as previously identified by DSA. 7.0 T TOF-MRA was limited to visualization of the circle of Willis as well as the internal carotid artery only. Donor vessels for bypass surgery (i.e., branches of superficial temporal artery) could be sufficiently visualized with all magnetic resonance modalities. CONCLUSIONS: Our results indicate that a specific 7.0 T vascular imaging protocol yields diagnostic information about vessel pathology in MMV that approximates conventional DSA. 7.0 T MPRAGE was superior to 7.0 T TOF-MRA due to shorter scanning times and better brain coverage. To date, however, limited availability of 7.0 T technology in medical facilities as well as technical and procedural constraints excludes a fair amount of patients from the clinical 7.0 T imaging process.

Health-related quality of life in patients with peripheral nerve tumors: results from the German multicentric Peripheral Nerve Tumor Registry.

Objective: Peripheral nerve tumors (PNTs) are rare diseases. So far, no multicenter data on diagnostics, the efficacy of treatment, long-term outcomes, and health-related quality of life (HRQoL) exist. The establishment of the Peripheral Nerve Tumor Registry (PNTR) in 2015 allows for the systematic analysis of patients with tumors associated with peripheral nerves. The present study aims to investigate the impact of PNT on an individual's HRQoL and the effect of surgery. Methods: HRQoL was pre- and postoperatively assessed by the Euro-Qol-5D-5L (EQ-5D-5L) and Euro-Qol visual analog scale (EQ-VAS) survey in the retrospective and prospective study arm in three active participating study centers. An index was calculated based on the EQ-5D-5L for the quantification of health state (0: worst possible state of health, 1: best possible state of health). The EQ-VAS ranges from 0% (worst imaginable health status) to 100% (best possible health status). Patient characteristics (age, sex), as well as disease (histopathological entity) and treatment (pre- and postoperative symptoms, type of treatment)-specific data, were analyzed. Results: Data from 171 patients from three high-volume centers were included, with schwannoma (70.8%, n = 121) and neurofibroma (15.8%, n = 27) being the most prevalent histopathological diagnoses. Both the median health index value (preoperative: 0.887, n = 167; postoperative: 0.910, n = 166) and the median EQ-VAS (preoperative: 75%, n = 167; postoperative: 85%, n = 166) of the entire cohort regarding all histopathological diagnosis improved significantly after surgical therapy (p < 0.001). Preoperatively, 12.3% (n = 21) reached the highest index score of 1.0 in EQ-5D-5L and 100% in the EQ-VAS score in 5.3% (n = 9) of all patients. Postoperatively, the highest index score of 1.0 and 100% in the EQ-VAS score increased significantly and were achieved in 33.3% (n = 57) and 11.1% (n = 19) of the patients, respectively (p < 0.001). Conclusion: For the first time, our study presents multicenter data on life quality and the effect of surgery in primarily benign peripheral nerve tumors. Early surgery at a specialized center could improve neurological outcomes and, in conclusion, better QoL. In summary, surgical therapy significantly improved the entire cohort's QoL, VAS, and analgesia.

Core outcomes in nerve surgery: development of a core outcome set for ulnar neuropathy at the elbow.

OBJECTIVE: Ulnar neuropathy at the elbow (UNE) is common, affecting 1%-6% of the population. Despite this, there remains a lack of consensus regarding optimal treatment. This is primarily due to the difficulty one encounters when trying to assess the literature. Outcomes are inconsistently reported, which makes comparing studies or developing meta-analyses difficult or even impossible. Thus, there is a need for a core outcome set (COS) for UNE (COS-UNE) to help address this problem. The objective of this study was to utilize a modified Delphi method to develop COS-UNE. METHODS: A 5-stage approach was utilized to develop COS-UNE: stage 1, consortium development; 2, literature review to identify potential outcome measures; 3, Delphi survey to develop consensus on outcomes for inclusion; 4, Delphi survey to develop definitions; and 5, consensus meeting to finalize the COS and definitions. The study followed the Core Outcome Set-STAndards for Development (COS-STAD) recommendations. RESULTS: The Core Outcomes in Nerve Surgery (COINS) Consortium comprised 21 participants, all neurological surgeons representing 11 countries. The final COS-UNE consisted of 22 data points/outcomes covering the domains of demographic characteristics, diagnostics, patient-reported outcomes, motor/sensory outcomes, and complications. Appropriate instruments, methods of testing, and definitions were set. The consensus minimum duration of follow-up was 6 months, with the consensus optimal timepoints for assessment identified as preoperatively and 3, 6, and 12 months postoperatively. CONCLUSIONS: The authors identified consensus data points/outcomes and also provided definitions and specific scales to be utilized to help ensure that clinicians are consistent in their reporting across studies on UNE. This COS should serve as a minimum set of data to be collected in all future neurosurgical studies on UNE. The authors hope that clinicians evaluating ulnar neuropathy will incorporate this COS into routine practice and that future studies will consider this COS in the design phase.

Core outcomes in nerve surgery: development of a core outcome set for brachial plexus and upper extremity nerve injuries.

OBJECTIVE: When considering traumatic brachial plexus and upper extremity nerve injuries, iatrogenic nerve injuries, and nontraumatic nerve injuries, brachial plexus and upper extremity nerve injuries are commonly encountered in clinical practice. Despite this, data synthesis and comparison of available studies are difficult. This is at least in part due to the lack of standardization in reporting and a lack of a core outcome set (COS). Thus, there is a need for a COS for adult brachial plexus and upper extremity nerve injuries (COS-BPUE). The objective of this study was to develop a COS-BPUE using a modified Delphi approach. METHODS: A 5-stage approach was used to develop the COS-BPUE: 1) consortium development, 2) literature review to identify potential outcome measures, 3) Delphi survey to develop consensus on outcomes for inclusion, 4) Delphi survey to develop definitions, and 5) consensus meeting to finalize the COS and definitions. The study followed the Core Outcome Set-STAndards for Development (COS-STAD) recommendations. RESULTS: The Core Outcomes in Nerve Surgery (COINS) Consortium comprised 23 participants, all neurological surgeons, representing 13 countries. The final COS-BPUE consisted of 36 data points/outcomes covering demographic, diagnostic, patient-reported outcome, motor/sensory outcome, and complication domains. Appropriate instruments, methods of testing, and definitions were set. The consensus minimum duration of follow-up was 24 months, with the consensus optimal time points for assessment being preoperatively and 3, 6, 12, and 24 months postoperatively. CONCLUSIONS: The COINS Consortium developed a consensus COS and provided definitions, methods of implementation, and time points for assessment. The COS-BPUE should serve as a minimum set of data that should be collected in all future neurosurgical studies on adult brachial plexus and upper extremity nerve injuries. Incorporation of this COS should help improve consistency in reporting, data synthesis, and comparability, and should minimize outcome reporting bias.

Treatment of idiopathic meralgia paresthetica - is there reliable evidence yet?

OBJECTIVE: Meralgia paresthetica is a common condition that is usually diagnosed by its classical clinical presentation and by exclusion of a spinal origin of pain, sensory loss, and/or paresthesias in the anterolateral thigh. Treatment modalities include conservative management, local injections, and surgical therapy. To date, no level 1 evidence exists about treatment options for idiopathic meralgia paresthetica. This review article aims to give a structured overview of epidemiology, history, anatomy, diagnostics, and treatment. It focuses on the existing literature and current developments in clinical management. METHODS: A literature search on PubMed/MEDLINE was performed on 20 December 2021, yielding 1412 results. Abstracts were screened and classified in terms of epidemiology, anatomy, diagnostics, and treatment. RESULTS: High-quality observational data that was included in recent meta-analyses showed satisfactory results for conservative management, injections, and surgical decompression or neurectomy, but there is some major methodological criticism. For idiopathic meralgia paresthetica, the results of surgical decompression have never been compared to those of neurectomy in a randomized setup. The only study protocol published so far does not consider any extended decompression techniques (dynamic, circumferent, proximal, and distal to the inguinal ligament). A multicenter, prospective design has never been proposed. DISCUSSION: Reliable high-quality evidence on the treatment of idiopathic meralgia paresthetica is lacking at the current state, and challenges in clinical decision-making remain.

Meralgia Paresthetica: Relevance, Diagnosis, and Treatment.

BACKGROUND: Pain and sensory disturbance in the distribution of the lateral femoral cutaneous nerve in the ventrolateral portion of the thigh is called meralgia paresthetica (MP). The incidence of MP has risen along with the increasing prevalence of obesity and diabetes mellitus and was recently estimated at 32 new cases per 100 000 persons per year. In this review, we provide an overview of current standards and developments in the diagnosis and treatment of MP. METHODS: This review is based on publications retrieved by a selective literature search, with special attention to meta-analyses, systematic reviews, randomized and controlled trials (RCTs), and prospective observational studies. RESULTS: The diagnosis is mainly based on typical symptoms combined with a positive response to an infiltration procedure. In atypical cases, electrophysiological testing, neurosonography, and magnetic resonance imaging can be helpful in establishing the diagnosis. The literature search did not reveal any studies of high quality. Four prospective observational studies with small case numbers and partly inconsistent results are available. In a meta-analysis of 149 cases, pain relief was described after infiltration in 85% of cases and after surgery in 80%, with 1-38 months of follow-up. In another meta-analysis of 670 cases, there was pain relief after infiltration in 22% of cases, after surgical decompression in 63%, and after neurectomy in 85%. Hardly any data are available on more recent treatment options, such as radiofrequency therapy, spinal cord stimulation, or peripheral nerve stimulation. CONCLUSION: The state of the evidence is limited in both quantity and quality, corresponding to evidence level 2a for surgical and non-surgical methods. Advances in imaging and neurophysiological testing have made the diagnosis easier to establish. When intervention is needed, good success rates have been achieved with surgery (decompression, neurectomy), and variable success rates with infiltration.

Thoracic Outlet Syndrome Part II: Consensus on the Management of Neurogenic Thoracic Outlet Syndrome by the European Association of Neurosurgical Societies' Section of Peripheral Nerve Surgery.

BACKGROUND: In the first part of this report, the European Association of Neurosurgical Societies' section of peripheral nerve surgery presented a systematic literature review and consensus statements on anatomy, classification, and diagnosis of thoracic outlet syndrome (TOS) along with a subclassification system of neurogenic TOS (nTOS). Because of the lack of level 1 evidence, especially regarding the management of nTOS, we now add a consensus statement on nTOS treatment among experienced neurosurgeons. OBJECTIVE: To document consensus and controversy on nTOS management, with emphasis on timing and types of surgical and nonsurgical nTOS treatment, and to support patient counseling and clinical decision-making within the neurosurgical community. METHODS: The literature available on PubMed/MEDLINE was systematically searched on February 13, 2021, and yielded 2853 results. Screening and classification of abstracts was performed. In an online meeting that was held on December 16, 2021, 14 recommendations on nTOS management were developed and refined in a group process according to the Delphi consensus method. RESULTS: Five RCTs reported on management strategies in nTOS. Three prospective observational studies present outcomes after therapeutic interventions. Fourteen statements on nonsurgical nTOS treatment, timing, and type of surgical therapy were developed. Within our expert group, the agreement rate was high with a mean of 97.8% (± 0.04) for each statement, ranging between 86.7% and 100%. CONCLUSION: Our work may help to improve clinical decision-making among the neurosurgical community and may guide nonspecialized or inexperienced neurosurgeons with initial patient management before patient referral to a specialized center.

Post-COVID exercise intolerance is associated with capillary alterations and immune dysregulations in skeletal muscles.

The SARS-CoV-2 pandemic not only resulted in millions of acute infections worldwide, but also in many cases of post-infectious syndromes, colloquially referred to as "long COVID". Due to the heterogeneous nature of symptoms and scarcity of available tissue samples, little is known about the underlying mechanisms. We present an in-depth analysis of skeletal muscle biopsies obtained from eleven patients suffering from enduring fatigue and post-exertional malaise after an infection with SARS-CoV-2. Compared to two independent historical control cohorts, patients with post-COVID exertion intolerance had fewer capillaries, thicker capillary basement membranes and increased numbers of CD169+ macrophages. SARS-CoV-2 RNA could not be detected in the muscle tissues. In addition, complement system related proteins were more abundant in the serum of patients with PCS, matching observations on the transcriptomic level in the muscle tissue. We hypothesize that the initial viral infection may have caused immune-mediated structural changes of the microvasculature, potentially explaining the exercise-dependent fatigue and muscle pain.

Rationale and design of the peripheral nerve tumor registry: an observational cohort study.

AIM: Peripheral nerve tumors (PNT) are rare lesions. To date, no systematic multicenter studies on epidemiology, clinical symptoms, treatment strategies and outcomes, genetic and histopathologic features, as well as imaging characteristics of PNT were published. The main goal of our PNT Registry is the systematic multicenter investigation to improve our understanding of PNT and to assist future interventional studies in establishing hypotheses, determining potential endpoints, and assessing treatment efficacy. METHODS: Aims of the PNT registry were set at the 2015 Meeting of the Section of Peripheral Nerve Surgery of the German Society of Neurosurgery. A study protocol was developed by specialists in PNT care. A minimal data set on clinical status, treatment types and outcomes is reported by each participating center at initial contact with the patient and after 1 year, 2 years, and 5 years. Since the study is coordinated by the Charité Berlin, the PNR Registry was approved by the Charité ethics committee (EA4/058/17) and registered with the German Trials Registry (www.drks.de). On a national level, patient inclusion began in June 2016. The registry was rolled out across Europe at the 2019 meeting of the European Association of Neurosurgery in Dublin. RESULTS: Patient recruitment has been initiated at 10 centers throughout Europe and 14 additional centers are currently applying for local ethics approval. CONCLUSION: To date, the PNT registry has grown into an international study group with regular scientific and clinical exchange awaiting the first results of the retrospective study arm.

Neurogenic Thoracic Outlet Syndrome.

BACKGROUND: Thoracic outlet syndrome (TOS) refers to a group of disorders in which there is compression of and/or damage to the neurovascular structures at the thoracic outlet, i.e., at the transition from chest to neck. The incidence of neurogenic thoracic outlet syndrome (nTOS) is estimated to be 2-3 / 100 000 / year, with an estimated prevalence of 10 / 100 000. Patients present with upper extremity sensorimotor symptoms that are often related to movement. The aim of the present article is to highlight the clinical presentation patterns of nTOS and to provide an overview of its diagnosis and treatment. METHODS: Selective literature search for prospective observational studies and RCTs, including systematic reviews and metaanalyses. RESULTS: There is no multicenter randomized controlled trial available on the treatment of nTOS. Prospective observational studies with a hierarchical study design report a positive effect of physiotherapy in 27-59% of cases. After unsuccessful conservative treatment, up to 56-90% benefit from surgical management. Patients with nTOS are more severely affected compared with those with other forms of TOS and benefit less from transaxillary first rib resection. nTOS patients who underwent supraclavicular decompression without rib resection had excellent surgical outcomes in 27%, good outcomes in 36%, acceptable outcomes in 26%, and poor surgical outcomes in 11% of cases. There is no systematic comparison available of the types of surgical management involved. Also, there is currently no uniform classification available for all medical sub-disciplines. Therefore, interpretation, and comparability of the study results are limited. CONCLUSION: Although nTOS is the most common form of TOS, studies on its treatment are currently limited in terms of numbers and quality. The type of surgical management varies according to the experience and preference of the surgeon, treating specialty, special anatomic features, and clinical symptoms.

Endoplasmic reticulum-stress and unfolded protein response-activation in immune-mediated necrotizing myopathy.

Patients suffering from immune-mediated necrotizing myopathies (IMNM) harbor, the pathognomonic myositis-specific auto-antibodies anti-SRP54 or -HMGCR, while about one third of them do not. Activation of chaperone-assisted autophagy was described as being part of the molecular etiology of IMNM. Endoplasmic reticulum (ER)/sarcoplasmic reticulum (SR)-stress accompanied by activation of the unfolded protein response (UPR) often precedes activation of the protein clearance machinery and represents a cellular defense mechanism toward restoration of proteostasis. Here, we show that ER/SR-stress may be part of the molecular etiology of IMNM. To address this assumption, ER/SR-stress related key players covering the three known branches (PERK-mediated, IRE1-mediated, and ATF6-mediated) were investigated on both, the transcript and the protein levels utilizing 39 muscle biopsy specimens derived from IMNM-patients. Our results demonstrate an activation of all three UPR-branches in IMNM, which most likely precedes the activation of the protein clearance machinery. In detail, we identified increased phosphorylation of PERK and eIF2a along with increased expression and protein abundance of ATF4, all well-documented characteristics for the activation of the UPR. Further, we identified increased general XBP1-level, and elevated XBP1 protein levels. Additionally, our transcript studies revealed an increased ATF6-expression, which was confirmed by immunostaining studies indicating a myonuclear translocation of the cleaved ATF6-form toward the forced transcription of UPR-related chaperones. In accordance with that, our data demonstrate an increase of downstream factors including ER/SR co-chaperones and chaperones (e.g., SIL1) indicating an UPR-activation on a broader level with no significant differences between seropositive and seronegative patients. Taken together, one might assume that UPR-activation within muscle fibers might not only serve to restore protein homeostasis, but also enhance sarcolemmal presentation of proteins crucial for attracting immune cells. Since modulation of ER-stress and UPR via application of chemical chaperones became a promising therapeutic treatment approach, our findings might represent the starting point for new interventional concepts.

Initial pupil status is a strong predictor for in-hospital mortality after aneurysmal subarachnoid hemorrhage.

Prognosis of patients with high-grade aneurysmal subarachnoid hemorrhage (aSAH) is only insufficiently displayed by current standard prognostic scores. This study aims to evaluate the role of pupil status for mortality prediction and provide improved prognostic models. Anonymized data of 477 aSAH patients admitted to our medical center from November 2010 to August 2018 were retrospectively analyzed. Identification of variables independently predicting in-hospital mortality was performed by multivariable logistic regression analysis. Final regression models included Hunt & Hess scale (H&H), pupil status and age or in a simplified variation only H&H and pupil status, leading to the design of novel H&H-Pupil-Age score (HHPA) and simplified H&H-Pupil score (sHHP), respectively. In an external validation cohort of 402 patients, areas under the receiver operating characteristic curves (AUROC) of HHPA (0.841) and sHHP (0.821) were significantly higher than areas of H&H (0.794; p < 0.001) or World Federation of Neurosurgical Societies (WFNS) scale (0.775; p < 0.01). Accordingly, including information about pupil status improves the predictive performance of prognostic scores for in-hospital mortality in patients with aSAH. HHPA and sHHP allow simple, early and detailed prognosis assessment while predictive performance remained strong in an external validation cohort suggesting adequate generalizability and low interrater variability.