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IntroductionPersistent spine pain syndrome type 2 (PSPS2) represents a significant burden to the individual and society. Treatment options include revision surgery, stabilisation surgery of the spine, neuromodulation, analgesics and cognitive behavioural therapy. Nevertheless, structured treatment algorithms are missing as high-level evidence on the various treatments is sparse. The aim of this study is to compare higher frequency neuromodulation with instrumentation surgery in patients suffering from PSPS2.Methods and analysisThe sPinal coRd stimulatiOn coMpared with lumbar InStrumEntation for low back pain after previous lumbar decompression (PROMISE) trial is a prospective randomised rater blinded multicentre study. Patients suffering from PSPS2 with a functional burden of Oswestry Disability Index (ODI) >20 points are randomised to treatment via spinal cord stimulation or spinal instrumentation. Primary outcome is back-related functional outcome according to the ODI 12 months after treatment. Secondary outcomes include pain perception (visual analogue scale), Short Form-36, EuroQOL5D, the amount of analgesics, the length of periprocedural hospitalisation and adverse events. Follow-up visits are planned at 3 and 12 months after treatment. Patients with previous lumbar instrumentation, symptomatic spinal stenosis, radiographical apparent spinal instability or severe psychiatric or systemic comorbidities are excluded from the study. In order to detect a significant difference of ≥10 points (ODI) with a power of 80%, n=72 patients need to be included. The recruitment period will be 24 months with a subsequent 12 months follow-up. The beginning of enrolment is planned for October 2022.Ethics and disseminationThe PROMISE trial is the first randomised rater blinded multicentre study comparing the functional effectiveness of spinal instrumentation versus neuromodulation in patients with PSPS2 in order to achieve high-level evidence for these commonly used treatment options in this severely disabling condition. Patient recruitment will be performed at regular outpatient clinic visits. No further (print, social media) publicity is planned. The study is approved by the local ethics committee (LMU Munich, Germany) and will be conducted according to the Declaration of Helsinki.Trial registration numberNCT05466110.

One of the main obstacles of electrode implantation in epilepsy surgery is the electrode shift between implantation and the day of explantation. We evaluated this possible electrode displacement using intraoperative MRI (iopMRI) data and CT/MRI reconstruction.Thirteen patients (nine female, four male, median age 26 ± 9.4 years) suffering from drug-resistant epilepsy were examined. After implantation, the position of subdural electrodes was evaluated by 3.0 T-MRI and thin-slice CCT for 3D reconstruction. Localization of electrodes was performed with the volume-rendering technique. Post-implantation and pre-explantation 1.5 T-iopMRI scans were coregistered with the 3D reconstructions to determine the extent of electrode dislocation.Intraoperative MRI at the time of explantation revealed a relevant electrode shift in one patient (8%) of 10 mm. Median electrode displacement was 1.7 ± 2.6 mm with a coregistration error of 1.9 ± 0.7 mm. The median accuracy of the neuronavigation system was 2.2 ± 0.9 mm. Six of twelve patients undergoing resective surgery were seizure free (Engel class 1A, median follow-up 37.5 ± 11.8 months).Comparison of pre-explantation and post-implantation iopMRI scans with CT/MRI data using the volume-rendering technique resulted in an accurate placement of electrodes. In one patient with a considerable electrode dislocation, the surgical approach and extent was changed due to the detected electrode shift.ECoG: electrocorticography; EZ: epileptogenic zone; iEEG: invasive EEG; iopMRI: intraoperative MRI; MEG: magnetoencephalography; PET: positron emission tomography; SPECT: single photon emission computed tomography; 3D: three-dimensional.

Background In patients with subarachnoid hemorrhage (SAH), vasospasm remains one of the major complications. The application of intravenous magnesium sulfate (MgSO4) has been under discussion to prevent cerebral ischemia. Our aim was to examine the impact of early MgSO4 administration on local cerebral microcirculation during microsurgical clipping of SAH-related aneurysms. Methods The non-invasive laser-Doppler spectrophotometry system “Oxygen-to-See (O2C)” was used in 14 consecutive patients (11 female, 3 male, median age 56.5±9.7 yrs) with aneurysmatic SAH. A subdural probe measured capillary venous oxygenation (SO2), relative hemoglobin content (rHb), blood cell velocity (velo) and blood flow (flow) in 7 mm tissue depth. Data samples were recorded as baseline immediately before intraoperative application of MgSO4 10% 50 mg/kg body weight and 10 min thereafter. The continuous MgSO4 infusion rate depended on blood pressure (mean arterial pressure > 60-65 mmHg) and lasted a maximum of 60 min. Results MgSO4 was administered 2.8 (min. 1.6, max. 15.5) hours after onset of symptoms. Median flow increased significantly by 20.8% (5–68%, p = 0.001). Velo increased 4.9% (1–17%), rHb decreased 1.5% (3–34%) and SO2 decreased 9.4% (8–38%) by trend compared to the baseline values. FiO2 correlated positively with velo (rs = 0.712, p = 0.004), whereas arterial HCO3 correlated negatively with SO2 (rs = −0.599, p = 0.024). Of 14 patients, 2 had symptomatic vasospasm. Conclusions Our data suggest an increased cerebral blood flow after early intraoperative administration of MgSO4 in patients with SAH. Using a non-invasive laser-Doppler spectrophotometry system, this technique is feasible for continuous real-time monitoring of cerebral microcirculation. Trial registration DRKS (German Clinical Trial Registry), DRKS00013047 , retrospectively registered on September 21st, 2017.

Understanding the role of genetics in disease has become a central part of medical research. Non-synonymous single nucleotide variants (nsSNVs) in coding regions of human genes frequently lead to pathological phenotypes. Beyond single variations, the individual combination of nsSNVs may add to pathogenic processes. We developed a multiscale pipeline to systematically analyze the existence of quantitative effects of multiple nsSNVs and gene combinations in single individuals on pathogenicity. Based on this pipeline, we detected in a data set of 842 nsSNVs discovered in 76 genes related to cardiomyopathies, associated nsSNV combinations in seven genes present in at least 70% of all 639 patient samples, but not in a control cohort of healthy humans. Structural analyses of these revealed primarily an influence on the protein stability. For amino acid substitutions located at the protein surface, we generally observed a proximity to putative binding pockets. To computationally analyze cumulative effects and their impact, pathogenicity methods are currently being developed. Our approach supports this process, as shown on the example of a cardiac phenotype but can be likewise applied to other diseases such as cancer.

Hypothalamic harmartomas (HHs) are either occasionally associated with medically intractable epileptic syndromes or precocious puberty. Due to the extraordinary location and the expansive intra-axial growth, surgical resection is difficult and challenging without causing severe neurological, hypothalamic or endocrinological deficits, which account for higher mortality and morbidity.We present a series of five adult patients with drug-resistant epilepsy who had been operated on for HH using neuronavigation and intraoperative 1.5-T magnetic resonance imaging (MRI). In this retrospective investigation, we compared our surgical strategy and postoperative results to existing series.During surgery, we identified remnant HH in the first intraoperative MRI control scan in three out of five patients. After re-segmentation of the residual lesion using neuronavigation, complete resection was achieved in two of the three patients as confirmed by final intraoperative and late follow-up MRI, raising the rate of total resections to four out of five patients. Two patients died during the observation period. One patient suffered from a permanent third nerve palsy and one from a transient monoparesis of the left arm. New endocrinological disturbances included diabetes insipidus centralis in two and secondary hypothyroidism and hypogonadism in one patient. Four out of five patients had favourable seizure control (Engel I or II) after 64.8 (34-83) months of mean follow-up.Neuronavigation and intraoperative MRI are valuable tools to encounter difficulties while performing surgery in patients with HHs. Intraoperative resection control increases the amount of maximum resection.

Purpose To evaluate the value of magnetoencephalography (MEG) source localization in localization of epileptic activities and predicting surgical outcome in frontal lobe epilepsies (FLE). Methods Forty-six patients with presurgical MEG evaluation and intractable FLE surgery (28 male patients) were analyzed retrospectively with a mean follow-up of 5 years. Dipole analysis was performed for MEG source imaging (MSI). The localization of dipole clusters in relation to the dominant hemisphere, lesions, resection cavity and functional cortex were analyzed. The predictive value of MSI in respect to clinical outcome with long-term postoperative follow up was evaluated. Results Interictal focal epileptic activities were found in 82.6% (38/46) patients with monofocal activity 81.6% (31/38) and multifocal activities 18.4% (7/38). Seizure free rate was 47.9% at the mean follow-up of 5.0±4.0 years (median 11.5, range 2–57). Seizure recurrence mainly occurred in the first 1 year after surgery. In the monofocal epileptic activity group, 58.1% (18/31) of the patients were seizure free, predicitng postoperative seizure freedom better than multifocal localization 0% (0/7) ( p =0.028). Dipole clusters were completely resected in 70.9% of monofocal activity patients, which had higher seizure free rates compared to partial resection ( p =0.002). In patients with surgery in the dominant hemisphere, seizure control was less likely ( p =0.006). Conclusion MSI contributes to the clinical prediction of postoperative outcome in FLE patients. MSI may non-invasively disclose early epileptogenic lesions, pointing to a resectable lesion, and it then facilitates shortcut route of presurgical evaluation.

Background: In dominant temporal lobe epilepsy surgery, speech, memory and visual systems are at risk. Objective: Functional magnetic resonance imaging (fMRI) and diffusion tensor imaging combined with intraoperative neuronavigation and MRI were investigated retrospectively regarding risk reductions for favorable neurological and seizure outcome. Methods: Functional imaging risk maps were generated for 14 patients suffering from dominant temporal lobe epilepsy [7 with hippocampal sclerosis (HS), 7 with various lesions] and used for neuronavigation-guided tailored resection. Postoperative neurological and seizure outcome and complications were evaluated. Results: None of the patients had postoperative speech dysfunction despite 2.3/3.6-cm mean hippocampal/neocortical resection. Verbal memory decline was found in 2 of the 14 (14.3%) patients, correlating with surgical lesions in fMRI memory-activated functional areas in the dominant posterior parahippocampal gyrus. Verbal memory scores did not statistically differ between the HS and the lesional group, neither pre- nor postoperatively. A contralateral visual field defect occurred in 1 patient (7.1%). An Engel class I seizure outcome was found in 12 patients (85.7%), and 11 were completely seizure free (78.6%) at a mean follow-up of 19.5 months. Conclusion: This retrospectively investigated protocol led to an excellent neurological and seizure outcome and a low complication rate in dominant temporal lobe epilepsy surgery.

Purpose To investigate the value of intraoperative MR imaging (iopMRI) combined with neuronavigation to avoid intraoperative underestimation of the resection amount during surgery of lesional temporal lobe epilepsy (LTLE) patients. Methods We retrospectively investigated 88 patients (40 female, 48 male, mean age 37.2yrs, from 12 to 69yrs, 41 left sided lesions) with LTLE operated at our department, including 40.9% gangliogliomas (GG), 26.1% cavernomas (CM), 10.2% dysembryoplastic neuroepithelial tumours (DNT) and 11.4% focal cortical dysplasias (FCD), excluding hippocampal sclerosis. Results Complete resection was achieved in 85 of 88 patients (96.6%), as proven by postoperative MRI 6 months after surgery. In contrast, the routine first iopMR imaging before closure revealed radical resection in only 66 of these 88 patients (75%). After re-intervention, the second iopMR imaging demonstrated complete resection in 19 more patients. Thus, as a direct effect of iopMRI and neuronavigation, overall resection rate was increased by 21.6%. An excellent seizure outcome Engel Class I was found in 76.1% of patients during a mean follow-up of 26.4 months, irrespective of histological entity (74% in CM, 75% in GG, 78% in DNT and 60% in FCD). No severe postoperative complications occurred; permanent superior visual field defects were detected in 10.2% and permanent dysphasia/dyscalculia in 1.1%. Conclusion Refined surgery using neuronavigation combined with iopMR imaging in LTLE surgery led to radical resection in 96.6% of the patients, due to immediate correction of underestimated resection in 21.6% of patients. This protocol resulted in a favourable seizure outcome and a low complication rate.

OBJECTIVE Intraoperative overestimation of resection volume in epilepsy surgery is a well-known problem that can lead to an unfavorable seizure outcome. Intraoperative MRI (iMRI) combined with neuronavigation may help surgeons avoid this pitfall and facilitate visualization and targeting of sometimes ill-defined heterogeneous lesions or epileptogenic zones and may increase the number of complete resections and improve seizure outcome. METHODS To investigate this hypothesis, the authors conducted a retrospective clinical study of consecutive surgical procedures performed during a 10-year period for epilepsy in which they used neuronavigation combined with iMRI and functional imaging (functional MRI for speech and motor areas; diffusion tensor imaging for pyramidal, speech, and visual tracts; and magnetoencephalography and electrocorticography for spike detection). Altogether, there were 415 patients (192 female and 223 male, mean age 37.2 years; 41% left-sided lesions and 84.9% temporal epileptogenic zones). The mean preoperative duration of epilepsy was 17.5 years. The most common epilepsy-associated pathologies included hippocampal sclerosis (n = 146 [35.2%]), long-term epilepsy-associated tumor (LEAT) (n = 67 [16.1%]), cavernoma (n = 45 [10.8%]), focal cortical dysplasia (n = 31 [7.5%]), and epilepsy caused by scar tissue (n = 23 [5.5%]). RESULTS In 11.8% (n = 49) of the surgeries, an intraoperative second-look surgery (SLS) after incomplete resection verified by iMRI had to be performed. Of those incomplete resections, LEATs were involved most often (40.8% of intraoperative SLSs, 29.9% of patients with LEAT). In addition, 37.5% (6 of 16) of patients in the diffuse glioma group and 12.9% of the patients with focal cortical dysplasia underwent an SLS. Moreover, iMRI provided additional advantages during implantation of grid, strip, and depth electrodes and enabled intraoperative correction of electrode position in 13.0% (3 of 23) of the cases. Altogether, an excellent seizure outcome (Engel Class I) was found in 72.7% of the patients during a mean follow-up of 36 months (range 3 months to 10.8 years). The greatest likelihood of an Engel Class I outcome was found in patients with cavernoma (83.7%), hippocampal sclerosis (78.8%), and LEAT (75.8%). Operative revisions that resulted from infection occurred in 0.3% of the patients, from hematomas in 1.6%, and from hydrocephalus in 0.8%. Severe visual field defects were found in 5.2% of the patients, aphasia in 5.7%, and hemiparesis in 2.7%, and the total mortality rate was 0%. CONCLUSIONS Neuronavigation combined with iMRI was beneficial during surgical procedures for epilepsy and led to favorable seizure outcome with few specific complications. A significantly higher resection volume associated with a higher chance of favorable seizure outcome was found, especially in lesional epilepsy involving LEAT or diffuse glioma.