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ObjectiveSpinal 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.MethodsWe 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.ResultsSixty-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.ConclusionShorter 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.

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.

Spontaneous intracranial hypotension (SIH) has gained more attention in the eyes of clinicians in the past years and is now recognized as an important cause of headaches. While usually self-limiting and benign, some patients suffer from debilitating symptoms that interfere significantly with their social and professional life. Thus, recognition and adequate treatment of SIH is of paramount importance. Recent refinements in imaging techniques combined with modern microneurosurgical techniques offer many diagnostic and therapeutic possibilities today. The aim of this review is to give the reader an updated review on the state-of-the art in the challenging diagnosis and treatment of SIH as well as an insight into recent developments of pathophysiological concepts and affiliations with other enigmatic diseases.

ObjectiveSpontaneous 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).MethodsWe 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.ResultsOf 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).ConclusionSIH 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.

PurposeSpontaneous 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.MethodsPatients 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.ResultsIn 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.ConclusionEarly surgical evacuation of SSEH generally leads to favorable clinical outcomes. Surgical hematoma evacuation should be indicated in all patients with symptomatic SSEH.

Background Spinal arachnoid cysts (SAC) and spinal arachnoid webs (SAW) are intradural pathologies, often presenting with pain and/or myelopathic symptoms. Reports on postoperative outcomes for SAC and SAW are scarce. This study aims to assess the surgical outcomes of SAC and SAW. Methods Patients who underwent surgical treatment for SAC or SAW at our institution between 2011 and 2023 were retrospectively reviewed. Demographic data, radiological findings, surgical management, and clinical outcomes were evaluated using the modified McCormick (mMC) scale. Outcomes were categorized as \"favorable\" (mMC I-II) or \"unfavorable\" (mMC III-V). Results A total of 35 patients (29 SAC, 6 SAW) were analyzed. Mean age was 50.9 (SD ± 9.8) years. Males comprised 70.3% of cases (SAC: 64.5%, SAW: 100%). Most common symptoms were local or radiating pain (SAC 77.4%; SAW 100%), gait-disturbance (SAC 45.2%; SAW 16.7%), sensory-deficits (SAC 32.3%; SAW 66.7%) and impaired motor function (SAC 20%; SAW 16.7%). Median preoperative mMC was 2 in both groups (SAC IQR: 1; SAW IQR: 1). Median postoperative mMC was 1 in both groups (SAC CI 1.07–1.34; SAW CI 0.74–1.60). Favorable outcome (postoperative mMC I-II) was achieved in 26 SAC patients (90%) and 5 SAW patients (83%) respectively. Surgical complications occurred in 14.7%, all in the SAC group, without lasting deficits. Conclusion Surgical treatment for SAC and SAW appears to have an overall favorable outcome, though larger cohort analyses are needed. Surgery should be considered in symptomatic patients.

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.

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. 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. 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). 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. •Spontaneous intracranial hypotension can present with a wide range of symptoms.•A significant amount (15.2%) of patients present without initial orthostatic headaches.•Orthostatic headaches can change over the course of the disease.•Most patients report a wide range of associated complaints.

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.

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.