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Background and Objectives: In patients with spontaneous intracranial hypotension (SIH), microsurgical repair is recommended in Type 1 (ventral) dural leaks, when conservative measures fail. However, there is lacking consensus on the optimal surgical technique for permanent and safe closure of ventral leaks., Methods: We performed a retrospective analysis of surgically treated SIH patients with Type 1 leaks at our institution between 2013 and 2023. Patients were analyzed according to the type of surgical technique: (1) Microsurgical suture vs (2) extradural and intradural patching (sealing technique). End points were resolution of spinal longitudinal epidural cerebrospinal fluid collection (SLEC), change in brain SIH-Score (Bern-Score), headache resolution after 3 months, surgery time, complications, and reoperation rates., Results: In total, 85 (66% women) patients with consecutive SIH (mean age 47 ± 11 years) underwent transdural microsurgical repair. The leak was sutured in 53 (62%) patients (suture group) and patch-sealed in 32 (38%) patients (sealing group). We found no significant difference in the rates of residual SLEC and resolution of headache between suture and sealing groups (13% vs 22%, P = .238 and 89% vs 94%, P = .508). No changes were found in the postoperative Bern-Score between suture and sealing groups (1.4 [±1.6] vs 1.7 [±2.1] P = 1). Mean surgery time was significantly shorter in the sealing group than in the suture group (139 ± 48 vs 169 ± 51 minutes; P = .007). Ten patients of the suture and 3 of the sealing group had a complication (23% vs 9%, P = .212), whereas 6 patients of the suture and 2 patients of the sealing group required reoperation (11% vs 6%, P = .438)., Conclusion: Microsurgical suturing and patch-sealing of ventral dural leaks in patients with SIH are equally effective. Sealing alone is a significantly faster technique, requiring less spinal cord manipulation and may therefore minimize the risk of surgical complications., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc on behalf of Congress of Neurological Surgeons.)

Introduction: Spontaneous intracranial hypotension (SIH) is an important cause of devastating headaches and caused by CSF-leaks in the spine., Research Question: The aim of this analysis was to gain an overview of the progress of research on SIH over time. The global publication landscape relating to SIH was analyzed and comparisons between regions were made., Material and Methods: A bibliometric analysis was performed by searching for research articles on SIH in PubMed published between 1983 and 2022. Countries responsible for the publications were ranked by the sum of citations. An average annual growth rate was calculated and the density of SIH publications per 100 000 physicians was determined., Results: We identified 974 articles. In 1983 only one SIH patient was reported; in 2021 the number of patients had increased to 4230. The average annual growth rate of SIH publications during this period was 12.7%. The most common publication type were case reports (n = 570). The most common medical specialty of the first author was neurology (n = 251) followed by neurosurgery (n = 250) and radiology (n = 191). Although most publications originated from the United States of America (USA), South Korea had the highest density of SIH investigators (37.86 publications per 100 000 medical doctors). The most cited paper (296 citations) was published in 2006 in JAMA (USA)., Discussion and Conclusion: Research on SIH has increased exponentially over the past four decades. The international community of SIH researchers is growing, and with it the opportunities for global networks involved in research, treatment, and patient education., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Objective: The authors' aim was to assess the velocity and pattern of growth of meningiomas and to correlate the kinetics of tumor growth with their previously reported two-item radiological risk stratification and CNS WHO grade (5th edition, 2021)., Methods: The authors performed a serial volumetric analysis of meningiomas diagnosed radiologically at their institution between 2003 and 2015. The primary endpoint was velocity of diametric expansion (VDE), which represents the slope of the linear regression of the mean tumor diameter against time. For the secondary analysis, they categorized the growth patterns as linear or exponential by fitting time-volume curves to a linear and exponential function. Three radiological risk categories based on T2-weighted iso/hyperintensity and absence of calcifications were compared: low risk (T2-weighted hypointense), intermediate-risk (T2-weighted iso/hyperintense with calcifications), and high-risk (T2-weighted iso/hyperintense without calcifications) tumors., Results: For the entire cohort of 240 meningiomas, the median (IQR) VDE was 0.33 (0.00-0.71) mm/year. Distribution of VDE differed significantly among radiological risk categories (0.49 vs 0.35 vs 0.05 mm/year, p < 0.001). High-risk and intermediate-risk tumors more frequently tended to grow exponentially compared to low-risk tumors (43.8% vs 37.0% vs 8.3%, p = 0.067). The authors found no correlation of growth velocity with CNS WHO grade in their cohort (1.30 mm/year for CNS WHO grade 1 vs 4.01 mm/year for CNS WHO grade 2, p = 0.185)., Conclusions: A radiological risk assessment using two parameters-T2-weighted signal iso/hyperintensity and absence of calcifications-allows estimation of growth velocity and characteristics of untreated intracranial meningiomas. Only high-risk tumors exhibit the potential for rapid growth. However, rapid tumor growth does not indicate a higher CNS WHO grade per se.

Purpose: Spontaneous spinal epidural hematoma (SSEH) is a rare pathology characterized by a hemorrhage in the spinal epidural space without prior surgical or interventional procedure. Recent literature reported contradictory findings regarding the clinical, radiological and surgical factors determining the outcome, hence the objective of this retrospective analysis was to re-assess these outcome-determining factors., Methods: Patients surgically treated for SSEH at our institution from 2010 - 2022 were screened and retrospectively assessed regarding management including the time-to-treatment, the pre-and post-treatment clinical status, the radiological findings as well as other patient-specific parameters. The outcome was assessed using the modified McCormick Scale. Statistical analyses included binary logistic regression and Fisher's exact test., Results: In total, 26 patients (17 men [65%], 9 women [35%], median age 70 years [interquartile range 26.5]) were included for analysis. The SSEHs were located cervically in 31%, cervicothoracically in 42% and thoracically in 27%. Twenty-four patients (92%) improved after surgery. Fifteen patients (58%) had a postoperative modified McCormick Scale grade of I (no residual symptoms) and 8 patients (31%) had a grade of II (mild symptoms). Only 3 (12%) patients remained with a modified McCormick Scale grade of IV or V (severe motor deficits / paraplegic). Neither time-to-treatment, craniocaudal hematoma expansion, axial hematoma occupation of the spinal canal, anticoagulation or antiplatelet drugs, nor the preoperative clinical status were significantly associated with the patients' outcomes., Conclusion: Early surgical evacuation of SSEH generally leads to favorable clinical outcomes. Surgical hematoma evacuation should be indicated in all patients with symptomatic SSEH., (© 2024. The Author(s).)

Objective: Spontaneous intracranial hypotension (SIH) is an important cause of orthostatic headaches caused by spinal CSF leaks. It has a strong negative impact on patients' socioeconomic status and health-related quality of life (HRQOL). This study aimed to analyze the impact of surgical and endovascular treatments on patients' HRQOL., Methods: The authors conducted a prospective, observational cohort study that included all patients treated for SIH with microsurgery or embolization, depending on the type of CSF leak, at their institution between April 2022 and May 2023. Patients were asked to complete a specifically designed questionnaire, as well as the 15D HRQOL questionnaire, before and 3 months after treatment., Results: A total of 21 patients (14 female; mean age 51.7 years) were treated in the study period. There were 12 (57%) type 1 leaks, 3 (14%) type 2, and 6 (29%) type 3. While 20 (95.2%) leaks were localized in the thoracic spine, only 1 (4.8%) was found in the lumbar spine. All patients completed the questionnaires. Fifteen (71.4%) patients underwent microsurgery and 6 (28.6%) endovascular embolization. The mean 15D score improved from 0.802 before to 0.889 after treatment (p = 0.013). Compared with an age- and sex-matched general population, HRQOL was significantly impaired in patients with SIH before treatment. After treatment, the authors found no significant difference in the overall HRQOL between patients and the healthy population. Mean headache intensity on a numeric rating scale improved from 8.1 before treatment to 2.3 after treatment (p = 0.003). Patients reported that SIH had a notable impact on their social and working life., Conclusions: SIH has a considerable negative impact on HRQOL. Microsurgery or embolization can dramatically improve HRQOL, subjective perception of health, and headache intensity. Therefore, surgical or endovascular treatment should be considered given the improvement observed in HRQOL for patients with SIH.

Retrospective cohort study. To assess the utility of the LACE index for predicting death and readmission in patients with spinal infections (SI). SIs are severe conditions, and their incidence has increased in recent years. The LACE (Length of stay, Acuity of admission, Comorbidities, Emergency department visits) index quantifies the risk of mortality or unplanned readmission. It has not yet been validated for SIs. LACE indices were calculated for all adult patients who underwent surgery for spinal infection between 2012 and 2021. Data were collected from a single academic teaching hospital. Outcome measures included the LACE index, mortality, and readmission rate within 30 and 90 days. In total, 164 patients were analyzed. Mean age was 64.6 (± 15.1) years, 73 (45%) were female. Ten (6.1%) patients died within 30 days and 16 (9.8%) died within 90 days after discharge. Mean LACE indices were 13.4 (± 3.6) and 13.8 (± 3.0) for the deceased patients, compared to 11.0 (± 2.8) and 10.8 (± 2.8) for surviving patients (p = 0.01, p < 0.001), respectively. Thirty-seven (22.6%) patients were readmitted ≤ 30 days and 48 (29.3%) were readmitted ≤ 90 days. Readmitted patients had a significantly higher mean LACE index compared to non-readmitted patients (12.9 ± 2.1 vs. 10.6 ± 2.9, < 0.001 and 12.8 ± 2.3 vs. 10.4 ± 2.8, p < 0.001, respectively). ROC analysis for either death or readmission within 30 days estimated a cut-off LACE index of 12.0 points (area under the curve [AUC] 95% CI, 0.757 [0.681-0.833]) with a sensitivity of 70% and specificity of 69%. Patients with SI had high LACE indices that were associated with high mortality and readmission rates. The LACE index can be applied to this patient population to predict the risk of early death or unplanned readmission., (© 2024. The Author(s).)

Objective: Although orthostatic headache is the hallmark symptom of spontaneous intracranial hypotension (SIH), patients can present with a wide range of different complaints and thereby pose a diagnostic challenge for clinicians. Our aim was to describe and group the different symptoms associated with SIH and their course over time., Methods: We retrospectively surveyed consecutive patients diagnosed and treated for SIH at our institution from January 2013 to May 2020 with a specifically designed questionnaire to find out about their symptomatology and its course., Results: Of 112 eligible patients, 79 (70.5%) returned the questionnaire and were included in the analysis. Of those, 67 (84.8%) reported initial orthostatic headaches, whereas 12 (15.2%) denied having this initial symptom. All except one (98.7%) patients reported additional symptoms: most frequently cephalic pressure (69.6%), neck pain (68.4%), auditory disturbances (59.5%), nausea (57%), visual disturbances (40.5%), gait disturbance (20.3%), confusion (10.1%) or sensorimotor deficits (21.5%). Fifty-seven (72.2%) patients reported a development of the initial symptoms predominantly in the first three months after symptom onset. Age and sex were not associated with the symptomatology or its course (p > 0.1)., Conclusion: Although characteristic of SIH, a relevant amount of patients present without orthostatic headaches. In addition, SIH can manifest with non-orthostatic headaches at disease onset or during the course of the disease. Most patients report a wide range of associated complaints. A high degree of suspicion is crucial for an early diagnosis and targeted treatment., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Deep perforator arteriolopathy (DPA) causes intracerebral haemorrhage (ICH) and lacunar strokes (LS). We compare patient characteristics, MRI findings and clinical outcomes among patients with deep ICH and LS., Patients and Methods: We included patients with MRI-confirmed LS or ICH in the basal ganglia, thalamus, internal capsule or brainstem from the Bernese Stroke Registry. We assessed MRI small vessel disease (SVD) markers, SVD burden score, modified Rankin Scale (mRS) and ischaemic stroke or ICH at 3 months., Results: We included 716 patients, 117 patients (16.3%) with deep ICH (mean age (SD) 65.1 (±15.2) years, 37.1% female) and 599 patients (83.7%) with LS (mean age (SD) 69.7 (±13.6) years, 39.9% female). Compared to LS, deep ICH was associated with a higher SVD burden score (median (IQR) 2 (1-2) vs 1 (0-2)), aOR shift 3.19, 95%CI 2.15-4.75). Deep ICH patients had more often cerebral microbleeds (deep ICH: 71.6% vs LS: 29.2%, p  < 0.001, median count (IQR) 4(2-12) vs 2(1-6)) and a higher prevalence of lacunes (deep ICH: 60.5% vs LS: 27.4% p  < 0.001). At 3 months, deep ICH was associated with higher mRS (aOR shift 2.16, 95%CI 1.21-3.87). Occurrence of ischaemic stroke was numerically but not significantly higher in deep ICH (4.3% vs 2.9%; p  = 0.51). One patient (1.1%) with ICH but none with LS suffered ICH recurrence., Discussion/conclusion: DPA manifesting as ICH is associated with more severe MRI SVD burden and worse outcome compared to LS. The short-term risks of subsequent ischaemic stroke and recurrent ICH are similar in ICH and LS patients. This implies potential consequences for future secondary prevention strategies., Competing Interests: Declaration of conflicting interestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Goeldlin: Grants from Swiss Academy of Medical Sciences/Bangerter-Rhyner-Foundation, Mittelbauvereinigung der Universität Bern (outside the submitted work), Swiss Stroke Society (Förderpreis), European Stroke Organisation (department to department visit grant), Insel Gruppe, and Pfizer congress grant (outside the submitted work). Dr. Siepen: Funding by the Bangerter-Rhyner-Foundation (outside the submitted work). Dr. Fischer: research support from Swiss National Science Foundation, Swiss Heart Foundation, Medtronic (BEYOND SWIFT, SWIFT DIRECT), Stryker, Rapid medical, Penumbra, Phenox (DISTAL), consultancies for Medtronic, Stryker, and CSL Behring (fees paid to institution), participation in an advisory board for Alexion/Portola and Boehringer Ingelheim (fees paid to institution).Dr. Seiffge: Advisory board for Bayer and Portola/Alexion, Research grant from the Bangerter-Rhyner Foundation. All other authors do not report conflicts of interest.

Background and Objectives: Laser speckle contrast imaging (LSCI) has emerged as a promising tool for assessment of vessel flow during neurosurgery. We aimed to investigate the feasibility of visualizing vessel flow in the macrocirculation with a new fully microscope-integrated LSCI system and assess the validity and objectivity of findings compared with fluorescence angiography (FA)., Methods: This is a single-center prospective observational study enrolling adult patients requiring microsurgical treatment for brain vascular pathologies or brain tumors. Three independent raters, blinded toward findings of FA, reviewed regions of interest (ROIs) placed in exposed vessels and target structures. The primary end point was the validity of LSCI for assessment of vessel flow as measured by the agreement with FA. The secondary end point was objectivity, measured as the inter-rater agreement of LSCI findings., Results: During 18 surgical procedures, 23 observations using FA and LSCI were captured simultaneously. Using LSCI, vessel flow was assessable in 62 (86.1%) and not assessable in 10 (13.9%) ROIs. The agreement between LSCI and FA was 86.1%, with an agreement coefficient of 0.85 (95% CI: 0.75-0.94). Disagreement between LSCI and FA was observed in the 10 ROIs that were not assessable. The agreement between ROIs that were assessable using LSCI and FA was 100%. The inter-rater agreement of LSCI findings was 87.9%, with an agreement coefficient of 0.86 (95% CI: 0.79-0.94)., Conclusion: Fully microscope-integrated LSCI is feasible and has a high potential for clinical utility. Because of its characteristics, LSCI can be viewed as a full-field visual micro-Doppler that can be used as a complementary method to FA for assessing vessel flow during neurosurgery. Despite technical limitations related to the early development phase of the fully microscope-integrated system, we demonstrated reasonable validity and objectivity of findings compared with FA. Further research and refinement of the system may enhance its value in neurosurgical applications., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Spontaneous intracranial hypotension (SIH) is a serious medical condition caused by loss of cerebrospinal fluid at the level of the spine, which, when not treated, may cause substantial long-term disability and increase morbidity. The following video summarizes the necessary steps for successful diagnosis and treatment of SIH, starting with a brain and spine magnetic resonance imaging, followed by dynamic myelography. Because an epidural bloodpatch did not provide a lasting relief, the patient underwent surgery which demonstrated a ventral dural slit caused by an osteodiscogenic microspur. In the 1-month follow up, the patient was symptom free. This video is meant to raise awareness of SIH among clinicians in order to increase general sensitivity for this diagnosis., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background:  Anterior lumbar interbody fusion (ALIF) is an effective surgical technique for treating various lumbar pathologies, but its use in elderly patients is controversial. Data concerning complications and effectiveness are sparse. We investigated peri- and postoperative complications, radiographic parameters, and clinical outcome in elderly patients., Methods:  Patients ≥65 years who underwent ALIF between January 2008 and August 2020 were included in the study. All surgeries were performed through a retroperitoneal approach. Clinical and surgical data as well as radiologic parameters were collected prospectively and analyzed retrospectively., Results:  A total of 39 patients were included; the mean age was 72.6 (±6.3) years (range: 65-90 years); and the mean American Society of Anesthesiologists (ASA) risk classification was 2.3 (±0.6). A laceration of the left common iliac vein was the only major complication recorded (2.6%). Minor complications occurred in 20.5% of patients. Fusion rate was 90.9%. Reoperation rate at the index level was 12.8 and 7.7% in adjacent segments. The multidimensional Core Outcome Measures Index (COMI) improved from 7.4 (±1.4) to 3.9 (±2.7) after 1 year and to 3.3 (±2.6) after 2 years. Oswestry disability index (ODI) improved from 41.2 (±13.7) to 20.9 (±14.9) after 1 year and to 21.5 (±18.8) after 2 years. Improvements of at least the minimal clinically important change score of 2.2 and 12.9 points in the ODI and COMI after 2 years were noted in 75 and 56.3% of the patients, respectively., Conclusion:  With careful patient selection, ALIF is safe and effective in elderly patients., Competing Interests: O.S. is the designing surgeon for Biedermann Motech GmbH & Co. KG, Villingen-Schwenningen, Germany. All other authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: Idiopathic spinal cord herniations (ISCH) are rare defects of the ventromedial or mediolateral dura mater with herniation of the spinal cord through the defect with approximately 350 described cases worldwide. Patients usually become symptomatic with motor or sensory neurological deficits and gait disturbances., Objective: To describe characteristic symptoms and clinical findings and to evaluate the postoperative course and outcomes of ISCH., Methods: We present a single-center data analysis of a case series of 11 consecutive patients who were diagnosed with ISCH and underwent surgery in our department between 2009 and 2021., Results: All herniations were located in the thoracic spine between T2 and T9. In most cases, gait ataxia and dysesthesia led to further workup and subsequently to the diagnosis of ISCH. A "far-enough" posterior-lateral surgical approach, hemilaminectomy or laminectomy with a transdural approach, was performed under intraoperative neurophysiological monitoring which was followed by adhesiolysis, repositioning of the spinal cord and sealing using a dura patch. After surgery, clinical symptoms improved in 9 of 11 patients (81.8%), while only 1 patient experienced deterioration of symptoms (9.1%) and 1 patient remained equal (9.1%). The median preoperative McCormick grade was 3 (±0.70), while the median postoperative grade was 2 (±0.98) ( P = .0047)., Conclusion: In our case series of ISCH, we found that in most patients, neurological deficits improved postoperatively. This indicates that surgery in ISCH should not be delayed in symptomatic patients., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc on behalf of Congress of Neurological Surgeons.)

Purpose: Epidural blood patch (EBP) is a minimally invasive treatment for spontaneous intracranial hypotension (SIH). Follow-up after EBP primarily relies on clinical presentation and data demonstrating successful sealing of the underlying spinal cerebrospinal fluid (CSF) leak are lacking. Our aim was to evaluate the rate of successfully sealed spinal CSF leaks in SIH patients after non-targeted EBP., Methods: Patients with SIH and a confirmed spinal CSF leak who had been treated with non-targeted EBP were retrospectively analyzed. Primary outcome was persistence of CSF leak on spine MRI or intraoperatively. Secondary outcome was change in clinical symptoms after EBP., Results: In this study 51 SIH patients (mean age, 47 ± 13 years; 33/51, 65% female) treated with non-targeted EBP (mean, 1.3 EBPs per person; range, 1-4) were analyzed. Overall, 36/51 (71%) patients had a persistent spinal CSF leak after EBP on postinterventional imaging and/or intraoperatively. In a best-case scenario accounting for missing data, the success rate of sealing a spinal CSF leak with an EBP was 29%. Complete or substantial symptom improvement in the short term was reported in 45/51 (88%), and in the long term in 17/51 (33%) patients., Conclusion: Non-targeted EBP is an effective symptomatic treatment providing short-term relief in a substantial number of SIH patients; however, successful sealing of the underlying spinal CSF leak by EBP is rare, which might explain the high rate of delayed symptom recurrence. The potentially irreversible and severe morbidity associated with long-standing intracranial hypotension supports permanent closure of the leak., (© 2022. The Author(s).)

Low Back Pain - When Is Surgical Therapy Promising? Abstract. Low back pain is the number one widespread disease and leads to a high socioeconomic burden. In most cases, low back pain has a non-specific cause, which can be treated conservatively. For low back pain with specific pathoanatomical causes, surgery is usually only indicated for cases refractory to conservative measures or for patients presenting with neurological deficits or mechanical instability. Especially in patients with herniated discs, spinal canal stenosis and spondylolisthesis, surgical treatment has been shown to lead to good or very good long-term patient outcomes. However, careful patient selection and education are critical for successful postoperative patient outcome.

Background and Purpose: Spontaneous intracranial hypotension (SIH) is an important etiology of infratentorial superficial siderosis (iSS) of the central nervous system. However, the prevalence of iSS amongst patients with SIH is unknown and the imaging findings of iSS might represent a late stage of disease. The aim was to identify cerebrospinal fluid (CSF) biomarkers of iSS in patients with SIH., Methods: Consecutive patients evaluated for SIH at our institution between May 2017 and January 2019 were included. Lumbar CSF samples were analyzed for the presence of ferritin and bilirubin. Magnetic resonance imaging was assessed for the presence of iSS., Results: Twenty-four patients with SIH were included. CSF samples were positive for bilirubin in 2/19 (10.5%). CSF ferritin was elevated in 7/23 (30.4%). Signs of iSS on imaging were present in four patients (16.7%). All patients with imaging signs of iSS demonstrated elevated CSF ferritin. Ferritin level was significantly higher amongst patients demonstrating iSS compared to those without (median 45.0 vs. 11.0 μg/l; p = 0.003). Symptom duration was longer in patients with iSS than in patients without iSS (median 40 months vs. 9 months, p = 0.018)., Conclusion: Cerebrospinal fluid alterations indicative of iSS are prevalent amongst patients with SIH. It is speculated that a preclinical phase without symptoms or imaging signs but during which elevated biomarkers of the disease are apparent from CSF analysis might exist. It is suggested that measurement of CSF ferritin is incorporated in the work-up of patients with SIH to identify those at risk of developing iSS., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background:  Surgery for intra-/extraforaminal disk herniations (IEDH) is technically demanding due to the hidden location of the compressed nerve root section. Ipsilateral approaches (medial and lateral) are accompanied by extended resection of the facet joint and inadequate visualization of the pathology, especially at the L5-S1 level., Methods:  We describe a microsurgical interlaminar contralateral approach (MICA) suitable for IEDH at the lumbosacral junction that can also be used at L4-L5 and L3-L4., Conclusion:  The MICA provides access and sufficient intraforaminal visualization for IEDH in the lumbosacral region without resection of stability-relevant structures or manipulation of the nerve root ganglion., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: Spontaneous intracranial hypotension (SIH), which is often caused by a spinal cerebrospinal fluid leak, is an important cause of disabling headaches. Many patients report devastating changes in their quality of life because of their symptoms. This study aimed to evaluate the impact of SIH on patients' social/ working life and health-related quality of life (HRQoL)., Methods: We included consecutive patients with proven SIH treated at our institution from January 2013 to May 2020. Patients were contacted and asked to complete the 15D questionnaire for the collection of HRQoL data and to provide additional information on their social life status., Results: Of 112 patients, 79 (70.5%) returned the questionnaire and were included in the analysis. Of those, 69 were treated surgically (87.3%), and 10 were managed non-operatively (12.7%). Twenty-five (31.6%) patients reported a severe impact on their partnership, 32 (41.5%) reported a moderate or severe impact on their social life. Forty (54.8%) patients reported sick leave for more than 3 months. The mean 15D score was 0.890 (± 0.114) and significantly impaired compared to an age- and sex-matched general population (p = 0.001), despite treatment. Patients with residual SIH-symptoms (36, 45.6%) had significantly impaired HRQoL compared to those without any residual symptoms (41, 51.9%) (p < 0.001)., Conclusion: SIH had a notable impact on the patients' social life and HRQoL. It caused long periods of incapacity for work, and is therefore, associated with high economic costs. Although all patients were appropriately treated, reduced HRQoL persisted after treatment, underlining the chronic character of this disease., (© 2022. The Author(s).)

Data on intraoperative neurophysiological monitoring (IOM) during spinal meningioma (SM) surgery are scarce. The aim of this study was to assess the role of IOM and its impact on post-operative functional outcome. Eighty-six consecutive surgically treated SM patients were included. We assessed pre and post-operative Modified McCormick Scale (mMCS), radiological and histopathological data and IOM findings. Degree of cord compression was associated with preoperative mMCS and existence of motor or sensory deficits (p < 0.001). IOM was used in 51 (59.3%) patients (IOM-group). Median pre and post-operative mMCS was II and I, respectively (p < 0.001). Fifty-seven (66.3%) patients showed an improvement of at least one grade in the mMCS one year after surgery. In the IOM group, only one patient had worsened neurological status, and this was correctly predicted by alterations in evoked potentials. Analysis of both groups found no significantly better neurological outcome in the IOM group, but IOM led to changes in surgical strategy in complex cases. Resection of SM is safe and leads to improved neurological outcome in most cases. Both complication and tumor recurrence rates were low. We recommend the use of IOM in surgically challenging cases, such as completely ossified or large ventrolateral SM.

Objective: Well-defined risk factors for cerebrospinal fluid leakage (CSFL) after intradural spine surgery are scarce in the literature. The aim of the present study was to identify patient- and surgery-related risk factors and the incidence of CSFL., Methods: For the present retrospective cohort study, we identified consecutive patients who had undergone intradural spine surgery between 2009 and 2021 at our department. The primary endpoint was the incidence of clinically or radiologically proven CSFL. The effects of the clinical and surgical factors on the occurrence of CSFL were analyzed., Results: A total of 375 patients (60.3% women; mean age, 54 ± 16.5 years) were included. Of the 375 patients, 30 (8%) had experienced postoperative CSFL and, thus, a significantly greater risk of wound healing disorders (odds ratio [OR], 24.9; 95% confidence interval [CI], 9.3-66.7) and surgical site infections (OR, 8.4; 95% CI, 2.6-27.7; P < 0.01 for each). No patient-related factors were associated with the development of CSFL. Previous surgery at the index level correlated significantly with the occurrence of postoperative CSFL (OR, 2.76; 95% CI, 1.1-6.8; P = 0.03) on multivariate analysis. Furthermore, patients with intradural tumors tended to have a greater risk of CSFL (OR, 2.3; 95% CI, 0.9-5.8; P = 0.07). Surgery-related factors did not influence the occurrence of CSFL. Surgery on the thoracic spine had resulted in a significantly lower postoperative CSFL rate compared with surgery on the cervical or lumbar spine (OR, -2.5; 95% CI, 1.3-4.9; P = 0.02)., Conclusions: Our study found no modifiable risk factors for preventing CSFL after intradural spine surgery. Patients with previous surgery at the index level had a greater risk of CSFL. The occurrence of CSFL resulted in significantly more wound healing disorders and surgical site infections, necessitating further therapy., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: The management of asymptomatic intracranial meningiomas is controversial. Through the assessment of growth predictors, the authors aimed to create the basis for practicable clinical pathways for the management of these tumors., Methods: The authors volumetrically analyzed meningiomas radiologically diagnosed at their institution between 2003 and 2015. The primary endpoint was growth of tumor volume. The authors used significant variables from the multivariable regression model to construct a decision tree based on the exhaustive Chi-Square Automatic Interaction Detection (CHAID) algorithm., Results: Of 240 meningiomas, 159 (66.3%) demonstrated growth during a mean observation period of 46.9 months. On multivariable logistic regression analysis, older age (OR 0.979 [95% CI 0.958-1.000], p = 0.048) and presence of calcification (OR 0.442 [95% CI 0.224-0.872], p = 0.019) had a negative predictive value for tumor growth, while T2-signal iso-/hyperintensity (OR 4.415 [95% CI 2.056-9.479], p < 0.001) had a positive predictive value. A decision tree model yielded three growth risk groups based on T2 signal intensity and presence of calcifications. The median tumor volume doubling time (Td) was 185.7 months in the low-risk, 100.1 months in the intermediate-risk, and 51.7 months in the high-risk group (p < 0.001). Whereas 0% of meningiomas in the low- and intermediate-risk groups had a Td of ≤ 12 months, the percentage was 8.9% in the high-risk group (p = 0.021)., Conclusions: Most meningiomas demonstrated growth during follow-up. The absence of calcifications and iso-/hyperintensity on T2-weighted imaging offer a practical way of stratifying meningiomas as low, intermediate, or high risk. Small tumors in the low- or intermediate-risk categories can be monitored with longer follow-up intervals.

Objective: Spinal cerebrospinal fluid (CSF) leaks cause spontaneous intracranial hypotension (SIH). Microsurgery can sufficiently seal spinal CSF leaks. Yet, some patients suffer from residual symptoms. Aim of the study was to assess predictors for favorable outcome after surgical treatment of SIH., Methods: We included consecutive patients with SIH treated surgically from January 2013 to May 2020. Subjects were surveyed by a questionnaire. Primary outcome was resolution of symptoms as rated by the patient. Secondary outcome was postoperative headache intensity on the numeric rating scale (NRS). Association between variables and outcome was assessed using univariate and multivariate regression. A cut-off value for continuous variables was calculated by a ROC analysis., Results: Sixty-nine out of 86 patients (80.2%) returned the questionnaire and were analyzed. Mean age was 46.7 years and 68.1% were female. A significant association with the primary and secondary outcome was found only for preoperative symptom duration (p = 0.001 and p < 0.001), whereby a shorter symptom duration was associated with a better outcome. Symptom duration remained a significant predictor in a multivariate model (p = 0.013). Neither sex, age, type of pathology, lumbar opening pressure, nor initial presentation were associated with the primary outcome. ROC analysis yielded treatment within 12 weeks as a cut-off for better outcome., Conclusion: Shorter duration of preoperative symptoms is the most powerful predictor of favorable outcome after surgical treatment of SIH. While an initial attempt of conservative treatment is justified, we advocate early definitive treatment within 12 weeks in case of persisting symptoms., (© 2021. The Author(s).)

Introduction: Surgical management of isthmic spondylolisthesis is controversial and reports on anterior approaches in the literature are scarce., Research Question: To evaluate the safety and efficacy of stand-alone anterior lumbar interbody fusion (ALIF) in patients with symptomatic low-grade L5-S1 isthmic spondylolisthesis., Material and Methods: All adult patients with isthmic spondylolisthesis of the lumbosacral junction treated in a single institution between 2008 and 2019 with stand-alone ALIF were screened. A titan cage was inserted at L5-S1 with vertebral anchoring screws. Prospectively collected surgical, clinical and radiographic data were analyzed retrospectively., Results: 34 patients (19 men, 15 women, mean age 52.5 ​± ​11.5 years) with a mean follow-up of 3.2 (±2.5) years were analyzed. 91.2% (n ​= ​31) of patients had a low-grade spondylolisthesis and 8.8% (n ​= ​3) grade III according to Meyerding classification. Mean COMI and ODI scores improved significantly from 6.9 (±1.5) and 35.5 (±13.0) to 2.0 (±2.5) and 10.2 (±13.0), respectively after one year, and to 1.7 (±2.5) and 8.2 (±9.6), respectively, after two years. The COMI and ODI scores improved in 86.4% and 80%, respectively, after one year and 92.9% of patients after two years by at least the minimal clinically important difference. No intraoperative complications were recorded. 8.8% (n ​= ​3) of patients needed a reoperation., Discussion and Conclusion: After stand-alone ALIF for symptomatic isthmic spondylolisthesis, the patients improved clinically important after one and two years. Stand-alone ALIF is a safe and effective surgical treatment option for low-grade isthmic spondylolisthesis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Background: Intrawound vancomycin powder is an emerging strategy to reduce surgical site infections (SSIs) in spine surgery. However, there are concerns relating to its safety profile and toxicity. Data on systemic uptake of suprafascially administered vancomycin powder following instrumented spinal fusion is lacking., Objective: To study the systemic uptake and safety of suprafascially administered vancomycin powder in the early postoperative phase following open instrumented posterior spinal fusion., Methods: This was a substudy of an ongoing randomized clinical trial. Eligible adult patients were randomized 1:1 to either receive suprafascial vancomycin powder before wound closure or not to receive vancomycin powder. Serum vancomycin levels were assessed on postoperative days 1 and 2, serum creatinine levels were measured pre- and post-operatively. Adverse events up to 6 wk following surgery were recorded., Results: Among 34 randomized patients (mean age 62 yr, range 31-84 yr; 18 [53%] women), 17 received vancomycin powder. No detectable serum vancomycin levels (>4.0 mg/L) were found. Proportion of adverse events per patient in the vancomycin and control group, respectively, were 29.4% (5/17) vs 11.8% (2/17) (OR 3.12; 95% CI, 0.52; 19.38; P = .398). No patient had nephrotoxicity or ototoxicity in either group., Conclusion: Suprafascial vancomycin powder in open instrumented spinal fusion surgery is safe and results in negligible systemic uptake. Final results of the VANCO Trial need to be awaited for conclusive data on the efficacy of vancomycin for SSI prevention and its impact on wound healing., (© Congress of Neurological Surgeons 2021.)

Objective: Spontaneous intracranial hypotension (SIH) is typically caused by CSF leakage from a spinal dural tear, a meningeal diverticulum, or a CSF venous fistula. However, some patients present with classic orthostatic symptoms and typical intracranial imaging findings without evidence of CSF leakage despite repeated diagnostic work-up. This article aims to elaborate a hypothesis that would explain a pathologically increased orthostatic shift of CSF from the cranial to the spinal compartment in the absence of a CSF leak. Medical Hypothesis: The symptoms of SIH are caused by a decrease in intracranial CSF volume, intracranial hypotension, and downward displacement of intracranial structures. A combination of pathologically increased spinal compliance, decreased intracranial CSF volume, low CSF outflow resistance, and decreased venous pressure might result in a pathological orthostatic cranial-to-spinal CSF shift. Thus, in rare cases, intracranial hypotension may occur in the absence of CSF leakage from the dural sac. Conclusion: We propose a pathophysiological concept for the subgroup of SIH patients with typical cranial imaging findings and no evidence of CSF leakage. In these patients, reducing the compliance or the volume of the spinal compartment seems to be the appropriate therapeutic strategy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Goldberg, Häni, Jesse, Zubak, Piechowiak, Gralla, Dobrocky, Beck and Raabe.)

Objective: CSF leaks are common complications of spinal and cranial surgeries. Several dural grafts and suture techniques are available to achieve watertight dural closure, but the effectiveness of these techniques remains unclear. The authors developed a standardized in vitro model to test available grafts and suture techniques alone or in combination to find the technique with the most watertight dural closure., Methods: A fluid chamber with a dural fixation device, infusion pump, pressure gauge, and porcine pericardium as a dural equivalent was assembled to provide the reusable device for testing. The authors performed dural closure in 4 different fashions, as follows: A) using running versus simple interrupted suture technique and different suture materials to close a 3-cm incision; B) selecting commonly used sealants and dural patches in combination with a running suture; C) performing duraplasty (1.5 × 1.5-cm square defect) with different dural substitutes in a stand-alone fashion; and D) performing duraplasty with different dural substitutes in a double-layer fashion. Each technique was tested 6 times. The hydrostatic burst pressure (BP) was measured and compared using the Kruskal-Wallis test or the Mann-Whitney U-test. Values are reported as mean ± SD., Results: There was no significant difference between the running and simple interrupted suture technique (p = 0.79). Adding a patch or sealant to a suture resulted in a 1.7- to 14-fold higher BP compared to solitary suture closure (36.2 ± 24.27 cm H2O and 4.58 ± 1.41 cm H2O, respectively; p < 0.001). The highest BP was achieved by adding DuraSeal or TachoSil (82.33 ± 12.72 cm H2O and 74.17 ± 12.64 cm H2O, respectively). For closing a square defect, using a double-layer duraplasty significantly increased BP by a factor of 4-12 compared to a single-layer duraplasty (31.71 ± 12.62 cm H2O vs 4.19 ± 0.88 cm H2O, respectively; p < 0.001). The highest BP was achieved with the combination of Lyomesh and TachoSil (43.67 ± 11.45 cm H2O)., Conclusions: A standardized in vitro model helps to objectify the watertightness of dural closure. It allows testing of sutures and dural grafts alone or in combination. In the authors' testing, a running 6-0 monofilament polypropylene suture combined with DuraSeal or TachoSil was the technique achieving the highest BP. For the duraplasty of square defects, the double-layer technique showed the highest efficacy.

Background: Spinal imaging is essential to identify and localize cerebrospinal fluid (CSF) leaks in spontaneous intracranial hypotension (SIH) patients when targeted treatment is necessary., Purpose: Provide an in-depth presentation of the conventional dynamic myelography (CDM) technique for localizing spinal CSF leaks in SIH patients., Material and Methods: Consecutive SIH patients with a CSF leak confirmed on CDM and postmyelography computed tomography (CT) investigated at our institution between 2013 and 2019 were retrospectively analyzed. Intraoperative reports were reviewed to confirm the accuracy of CDM., Results: In total, 62 patients (mean age 45 years) were included; 48 with a ventral dural tear, 12 with a meningeal diverticulum, and in 2 patients positive for spinal longitudinal extradural CSF collection the site remained unclear. The leak was identified during the first and the second CDM in 43 and 17 patients, respectively. The use of CDM correctly identified the site of the CSF leak in all but one patient undergoing surgical closure (45/46, 98%). The mean fluoroscopy time was 7.8 min (range 1.8-14.4 min) with a radiation dose for a single examination of 310 mGy (range 28-1237 mGy)., Conclusion: The CDM procedure has a high accuracy for spinal CSF leak localization including dural tears and spinal nerve diverticula. It is the technique with the highest temporal resolution, is robust to breathing artifacts, allows great flexibility regarding patient positioning, compares favorably to other dynamic examinations with respect to the radiation dose and does not require general anesthesia. For CSF venous fistulas, however, other dynamic examinations, such as digital subtraction myelography, seem more appropriate., (© 2020. The Author(s).)

The authors present an illustrative technical note on microsurgical resection of ventrolateral completely ossified spinal meningiomas (OSMs) and a literature review of the surgical management of calcified spinal meningiomas or OSMs. These tumors are surgically demanding due to their solid consistency, especially when in a ventrolateral location with dislocation of the spinal cord. A challenging case with significant thoracic cord compression and displacement is described. Due to the firm consistency and the ventrolateral localization of the meningioma, a piecemeal resection was necessary. This could have resulted in a free-floating tumor remnant adherent to the spinal cord, impeding safe tumor resection. To avoid such a remnant, an anchoring burr hole was drilled at the border between the spinal cord and the adamantine tumor mass. Then, a microdissector was placed within the anchoring burr hole and the tumor was gently pulled laterally while drilling away the medial parts of the ossified tumor. This procedure was repeated until separation of the tumor from the spinal cord was possible and a gross-total resection (Simpson grade II) was manageable. Throughout the procedure, continuous intraoperative neurophysiological monitoring was performed.

Mutations in RNA binding proteins (RBPs) and in genes regulating autophagy are frequent causes of familial amyotrophic lateral sclerosis (fALS). The P56S mutation in vesicle-associated membrane protein-associated protein B (VAPB) leads to fALS (ALS8) and spinal muscular atrophy (SMA). While VAPB is primarily involved in the unfolded protein response (UPR), vesicular trafficking and in initial steps of the autophagy pathway, the effect of mutant P56S-VAPB on autophagy regulation in connection with RBP homeostasis has not been explored yet. Examining the muscle biopsy of our index ALS8 patient of European origin revealed globular accumulations of VAPB aggregates co-localised with autophagy markers LC3 and p62 in partially atrophic and atrophic muscle fibres. In line with this skin fibroblasts obtained from the same patient showed accumulation of P56S-VAPB aggregates together with LC3 and p62. Detailed investigations of autophagic flux in cell culture models revealed that P56S-VAPB alters both initial and late steps of the autophagy pathway. Accordingly, electron microscopy complemented with live cell imaging highlighted the impaired fusion of accumulated autophagosomes with lysosomes in cells expressing P56S-VAPB. Consistent with these observations, neuropathological studies of brain and spinal cord of P56S-VAPB transgenic mice revealed signs of neurodegeneration associated with altered protein quality control and defective autophagy. Autophagy and RBP homeostasis are interdependent, as demonstrated by the cytoplasmic mis-localisation of several RBPs including pTDP-43, FUS, Matrin 3 which often sequestered with P56S-VAPB aggregates both in cell culture and in the muscle biopsy of the ALS8 patient. Further confirming the notion that aggregation of the RBPs proceeds through the stress granule (SG) pathway, we found persistent G3BP- and TIAR1-positive SGs in P56S-VAPB expressing cells as well as in the ALS8 patient muscle biopsy. We conclude that P56S-VAPB-ALS8 involves a cohesive pathomechanism of aberrant RBP homeostasis together with dysfunctional autophagy.

Objective: To assess the pathophysiologic changes in patients with spontaneous intracranial hypotension (SIH) based on measures of CSF dynamics, and on the duration of symptoms, in a retrospective case-controlled study., Methods: We included consecutive patients investigated for SIH at our department from January 2012 to February 2018. CSF leak was considered confirmed if extrathecal contrast spillage was seen on imaging (CT or MRI) after intrathecal contrast application, or dural breach was detected by direct intraoperative visualization. We divided patients with a confirmed CSF leak into 3 groups depending on the symptom duration, as follows: ≤10, 11-52, and >52 weeks. Clinical characteristics and measures of CSF fluid dynamics obtained by computerized lumbar infusion testing were analyzed over time and compared with a reference population., Results: Among the 137 patients included, 69 had a confirmed CSF leak. Whereas 93.1% with <10 weeks of symptoms displayed typical orthostatic headache, only 62.5% with >10 weeks of symptoms did ( p = 0.004). Analysis of infusion tests revealed differences between groups with different symptom duration for CSF outflow resistance ( p < 0.001), lumbar baseline pressure ( p = 0.013), lumbar plateau pressure ( p < 0.001), baseline pressure amplitude ( p = 0.021), plateau pressure amplitude ( p = 0.001), pressure-volume index ( p = 0.001), elastance ( p < 0.001), and CSF production rate ( p = 0.001). Compared to the reference population, only patients with acute symptoms showed a significantly altered CSF dynamics profile., Conclusion: A CSF leak dramatically alters CSF dynamics acutely, but the pattern changes over time. There is an association between the clinical presentation and changes in CSF dynamics., (© 2020 American Academy of Neurology.)

Importance: Various signs may be observed on brain magnetic resonance imaging (MRI) in patients with spontaneous intracranial hypotension (SIH). However, the lack of a classification system integrating these findings limits decision making in clinical practice., Objective: To develop a probability score based on the most relevant brain MRI findings to assess the likelihood of an underlying spinal cerebrospinal fluid (CSF) leak in patients with SIH., Design, Setting, and Participants: This case-control study in consecutive patients investigated for SIH was conducted at a single hospital department from February 2013 to October 2017. Patients with missing brain MRI data were excluded. Three blinded readers retrospectively reviewed the brain MRI scans of patients with SIH and a spinal CSF leak, patients with orthostatic headache without a CSF leak, and healthy control participants, evaluating 9 quantitative and 7 qualitative signs. A predictive diagnostic score based on multivariable backward logistic regression analysis was then derived. Its performance was validated internally in a prospective cohort of patients who had clinical suspicion for SIH., Main Outcomes and Measures: Likelihood of a spinal CSF leak based on the proposed diagnostic score., Results: A total of 152 participants (101 female [66.4%]; mean [SD] age, 46.1 [14.3] years) were studied. These included 56 with SIH and a spinal CSF leak, 16 with orthostatic headache without a CSF leak, 60 control participants, and 20 patients in the validation cohort. Six imaging findings were included in the final scoring system. Three were weighted as major (2 points each): pachymeningeal enhancement, engorgement of venous sinus, and effacement of the suprasellar cistern of 4.0 mm or less. Three were considered minor (1 point each): subdural fluid collection, effacement of the prepontine cistern of 5.0 mm or less, and mamillopontine distance of 6.5 mm or less. Patients were classified into groups at low, intermediate, or high probability of having a spinal CSF leak, with total scores of 2 points or fewer, 3 to 4 points, and 5 points or more, respectively, on a scale of 9 points. The discriminatory ability of the proposed score could be demonstrated in the validation cohort., Conclusions and Relevance: This 3-tier predictive scoring system is based on the 6 most relevant brain MRI findings and allows assessment of the likelihood (low, intermediate, or high) of a positive spinal imaging result in patients with SIH. It may be useful in identifying patients with SIH who are leak positive and in whom further invasive myelographic examinations are warranted before considering targeted therapy.

Alpha-motoneurons and muscle fibres are structurally and functionally interdependent. Both cell types particularly rely on endoplasmic reticulum (ER/SR) functions. Mutations of the ER proteins VAPB, SigR1 and HSP27 lead to hereditary motor neuron diseases (MNDs). Here, we determined the expression profile and localization of these ER proteins/chaperons by immunohistochemistry and immunoblotting in biopsy and autopsy muscle tissue of patients with amyotrophic lateral sclerosis (ALS) and other neurogenic muscular atrophies (NMAs) and compared these patterns to mouse models of neurogenic muscular atrophy. Postsynaptic neuromuscular junction staining for VAPB was intense in normal human and mouse muscle and decreased in denervated Nmd 2J mouse muscle fibres. In contrast, VAPB levels together with other chaperones and autophagy markers were increased in extrasynaptic regions of denervated muscle fibres of patients with MNDs and other NMAs, especially at sites of focal myofibrillar disintegration (targets). These findings did not differ between NMAs due to ALS and other causes. G93A-SOD1 mouse muscle fibres showed a similar pattern of protein level increases in denervated muscle fibres. In addition, they showed globular VAPB-immunoreactive structures together with misfolded SOD1 protein accumulations, suggesting a primary myopathic change. Our findings indicate that altered expression and localization of these ER proteins and autophagy markers are part of the dynamic response of muscle fibres to denervation. The ER is particularly prominent and vulnerable in both muscle fibres and alpha-motoneurons. Thus, ER pathology could contribute to the selective build-up of degenerative changes in the neuromuscular axis in MNDs., (© 2016 International Society of Neuropathology.)

Aim: Upon denervation, skeletal muscle fibres initiate complex changes in gene expression. Many of these genes are involved in muscle fibre remodelling and atrophy. Amyotrophic lateral sclerosis (ALS) leads to progressive neurodegeneration and neurogenic muscular atrophy (NMA). Disturbed calcium homeostasis and misfolded protein aggregation both in motor neurones and muscle fibres are key elements of ALS pathogenesis that are mutually interdependent. Therefore, we hypothesized that the calcium sensor STIM1 might be abnormally modified and involved in muscle fibre degeneration in ALS and other types of NMA., Methods: We examined ALS and NMA patient biopsy and autopsy tissue and tissue from G93A SOD1 mice by immunohistochemistry and immunoblotting., Results: In normal human and mouse muscle STIM1 was found to be differentially expressed in muscle fibres of different types and to concentrate at neuromuscular junctions, compatible with its known role in calcium sensing. Denervated muscle fibres of sALS and NMA cases and SOD1 mice showed diffusely increased STIM1 immunoreactivity along with ubiquitinated material. In addition, distinct focal accumulations of STIM1 were observed in target structures within denervated fibres of sALS and other NMA as well as SOD1 mouse muscles. Large STIM1-immunoreactive structures were found in ALS-8 patient muscle harbouring the P56S mutation in the ER protein VAPB., Conclusion: These findings suggest that STIM1 is involved in several ways in the reaction of muscle fibres to denervation, probably reflecting alterations in calcium homeostasis in denervated muscle fibres., (© 2014 British Neuropathological Society.)

Intracellular accumulations of altered, misfolded proteins in neuronal and other cells are pathological hallmarks shared by many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Mutations in several genes give rise to familial forms of ALS. Mutations in Sigma receptor 1 have been found to cause a juvenile form of ALS and frontotemporal lobar degeneration (FTLD). We recently described altered localization, abnormal modification and loss of function of SigR1 in sporadic ALS. In order to further elucidate the molecular mechanisms underlying SigR1-mediated alterations in sporadic and familial ALS, we extended our previous studies using neuronal SigR1 knockdown cell lines. We found that loss of SigR1 leads to abnormal ER morphology, mitochondrial abnormalities and impaired autophagic degradation. Consistent with these results, we found that endosomal trafficking of EGFR is impaired upon SigR1 knockdown. Furthermore, in SigR1-deficient cells the transport of vesicular stomatitis virus glycoprotein is inhibited, leading to the accumulation of this cargo protein in the Golgi apparatus. Moreover, depletion of SigR1 destabilized lipid rafts and associated calcium mobilization, confirming the crucial role of SigR1 in lipid raft and intracellular calcium homeostasis. Taken together, our results support the notion that loss of SigR1 function contributes to ALS pathology by causing abnormal ER morphology, lipid raft destabilization and defective endolysosomal pathways.

Marinesco-Sjögren syndrome (MSS) features cerebellar ataxia, mental retardation, cataracts, and progressive vacuolar myopathy with peculiar myonuclear alterations. Most MSS patients carry homozygous or compound heterozygous SIL1 mutations. SIL1 is a nucleotide exchange factor for the endoplasmic reticulum resident chaperone BiP which controls a plethora of essential processes in the endoplasmic reticulum. In this study we made use of the spontaneous Sil1 mouse mutant woozy to explore pathomechanisms leading to Sil1 deficiency-related skeletal muscle pathology. We found severe, progressive myopathy characterized by alterations of the sarcoplasmic reticulum, accumulation of autophagic vacuoles, mitochondrial changes, and prominent myonuclear pathology including nuclear envelope and nuclear lamina alterations. These abnormalities were remarkably similar to the myopathy in human patients with MSS. In particular, the presence of perinuclear membranous structures which have been reported as an ultrastructural hallmark of MSS-related myopathy could be confirmed in woozy muscles. We found that these structures are derived from the nuclear envelope and nuclear lamina and associate with proliferations of the sarcoplasmic reticulum. In line with impaired function of BiP secondary to loss of its nucleotide exchange factor Sil1, we observed activation of the unfolded protein response and the endoplasmic-reticulum-associated protein degradation-pathway. Despite initiation of the autophagy-lysosomal system, autophagic clearance was found ineffective which is in agreement with the formation of autophagic vacuoles. This report identifies woozy muscle as a faithful phenocopy of the MSS myopathy. Moreover, we provide a link between two well-established disease mechanisms in skeletal muscle, dysfunction of chaperones and nuclear envelope pathology.