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Abstract Objective The piriform cortex is considered to be highly epileptogenic. Its resection during epilepsy surgery is a predictor for postoperative seizure freedom in temporal lobe epilepsy. Epilepsy is associated with a dysfunction of the blood–brain barrier. We investigated blood–brain barrier dysfunction in the piriform cortex of people with temporal lobe epilepsy using quantitative T1‐relaxometry. Methods Gadolinium‐based contrast agent was administered ictally and interictally in 37 individuals before undergoing quantitative T1‐relaxometry. Postictal and interictal images were co‐registered, and subtraction maps were created as biomarkers for peri‐ictal (∆qT1interictal‐postictal) and interictal (∆qT1noncontrast‐interictal) blood–brain barrier dysfunction. Values were extracted for the piriform cortex, hippocampus, amygdala, and the whole cortex. Results In temporal lobe epilepsy (n = 14), ∆qT1noncontrast‐interictal was significantly higher in the piriform cortex than in the whole cortex (p = 0.02). In extratemporal lobe epilepsy (n = 23), ∆qT1noncontrast‐interictal was higher in the hippocampus than in the whole cortex (p = 0.05). Across all individuals (n = 37), duration of epilepsy was correlated with ∆qT1noncontrast‐interictal (ß = 0.001, p

Abstract Objective Brain tumors and metastases account for approximately 10% of all status epilepticus (SE) cases. This study described the clinical characteristics, treatment, and short- and long-term outcomes of this population. Methods This retrospective, multi-center cohort study analyzed all brain tumor patients treated for SE at the university hospitals of Frankfurt and Marburg between 2011 and 2017. Results The 208 patients (mean 61.5 ± 14.7 years of age; 51% male) presented with adult-type diffuse gliomas (55.8%), metastatic entities (25.5%), intracranial extradural tumors (14.4%), or other tumors (4.3%). The radiological criteria for tumor progression were evidenced in 128 (61.5%) patients, while 57 (27.4%) were newly diagnosed with tumor at admission and 113 (54.3%) had refractory SE. The mean hospital length of stay (LOS) was 14.8 days (median 12.0, range 1–57), 171 (82.2%) patients required intensive care (mean LOS 8.9 days, median 5, range 1–46), and 44 (21.2%) were administered mechanical ventilation. All patients exhibited significant functional status decline (modified Rankin Scale) post-SE at discharge (p

Abstract Background Novel treatments are needed to control refractory status epilepticus (SE). This study aimed to assess the potential effectiveness of fenfluramine (FFA) as an acute treatment option for SE. We present a summary of clinical cases where oral FFA was used in SE. Methods A case of an adult patient with Lennox–Gastaut syndrome (LGS) who was treated with FFA due to refractory SE is presented in detail. To identify studies that evaluated the use of FFA in SE, we performed a systematic literature search. Results Four case reports on the acute treatment with FFA of SE in children and adults with Dravet syndrome (DS) and LGS were available. We report in detail a 30-year-old woman with LGS of structural etiology, who presented with generalized tonic and dialeptic seizures manifesting at high frequencies without a return to clinical baseline constituting the diagnosis of SE. Treatment with anti-seizure medications up to lacosamide 600 mg/d, brivaracetam 300 mg/d, valproate 1,600 mg/d, and various benzodiazepines did not resolve the SE. Due to ongoing refractory SE and following an unremarkable echocardiography, treatment was initiated with FFA, with an initial dose of 10 mg/d (0.22 mg/kg body weight [bw]) and fast up-titration to 26 mg/d (0.58 mg/kg bw) within 10 days. Subsequently, the patient experienced a resolution of SE within 4 days, accompanied by a notable improvement in clinical presentation and regaining her mobility, walking with the assistance of physiotherapists. In the three cases reported in the literature, DS patients with SE were treated with FFA, and a cessation of SE was observed within a few days. No treatment-emergent adverse events were observed during FFA treatment in any of the four cases. Conclusions Based on the reported cases, FFA might be a promising option for the acute treatment of SE in patients with DS and LGS. Observational data show a decreased SE frequency while on FFA, suggesting a potentially preventive role of FFA in these populations. Key points We summarize four cases of refractory status epilepticus (SE) successfully treated with fenfluramine. Refractory SE resolved after 4–7 days on fenfluramine. Swift fenfluramine up-titration was well-tolerated during SE treatment. Treatment-emergent adverse events on fenfluramine were not observed. Fenfluramine might be a valuable acute treatment option for SE in Dravet and Lennox–Gastaut syndromes.

Abstract Background Epilepsy surgery is an established treatment for drug-resistant focal epilepsy (DRFE) that results in seizure freedom in about 60% of patients. Correctly identifying an epileptogenic lesion in magnetic resonance imaging (MRI) is challenging but highly relevant since it improves the likelihood of being referred for presurgical diagnosis. The epileptogenic lesion’s etiology directly relates to the surgical intervention’s indication and outcome. Therefore, it is vital to correctly identify epileptogenic lesions and their etiology presurgically. Methods We compared the final histopathological diagnoses of all patients with DRFE undergoing epilepsy surgery at our center between 2015 and 2021 with their MRI diagnoses before and after presurgical diagnosis at our epilepsy center, including MRI evaluations by expert epilepsy neuroradiologists. Additionally, we analyzed the outcome of different subgroups. Results This study included 132 patients. The discordance between histopathology and MRI diagnoses significantly decreased from 61.3% for non-expert MRI evaluations (NEMRIs) to 22.1% for epilepsy center MRI evaluations (ECMRIs; p

Abstract Background Whether and how psychotherapies change brain structure and function is unknown. Its study is of great importance for contemporary psychotherapy, as it may lead to discovery of neurobiological mechanisms that predict and mediate lasting changes in psychotherapy, particularly in severely mentally ill patients, such as those with chronic depression. Previous studies have shown that psychoanalytic psychotherapies produce robust and enduring improvements in not only symptom severity but also personality organization in patients who have chronic depression and early life trauma, especially if therapy is delivered at a high weekly frequency. Methods/design Patients with chronic major depression and a history of early life trauma will be recruited, assessed, and treated across 3 international sites: Germany, Switzerland, and the United States. They will be randomized to one of two treatment arms: either (1) once weekly psychoanalytic psychotherapies, or (2) 3–4 times weekly psychoanalytic psychotherapies. They will have full clinical characterization as well as undergo MRI scanning at study baseline prior to randomization and again one year later. A group of matched healthy controls will undergo similar assessments and MRI scanning at the same time points to help discern whether study treatments induce brain changes toward or away from normal values. Primary study outcomes will include anatomical MRI, functional MRI, and Diffusion Tensor Imaging measures. Study hypotheses will be tested using the treatment-by-time interaction assessed in multiple general linear models with repeated measures analyses in an intent-to-treat analysis. Discussion MODE may allow the identification of brain-based biomarkers that may be more sensitive than traditional behavioral and clinical measures in discriminating, predicting, and mediating treatment response. These findings could help to personalize care for patients who have chronic depression patients and early life trauma, and they will provide new therapeutic targets for both psychological and biological treatments for major depressive illness.

In addition to necrosis and apoptosis, the two forms of cell death that have been known for many decades, other non-apoptotic forms of cell death have been discovered, many of which also play a role in tumors. Starting with the description of autophagy more than 60 years ago, newer forms of cell death have become important for the biology of tumors, such as ferroptosis, pyroptosis, necroptosis, and paraptosis. In this review, all non-apoptotic and oncologically relevant forms of programmed cell death are presented, starting with their first descriptions, their molecular characteristics, and their role and their interactions in cell physiology and pathophysiology. Based on these descriptions, the current state of knowledge about their alterations and their role in gliomas will be presented. In addition, current efforts to therapeutically influence the molecular components of these forms of cell death will be discussed. Although research into their exact role in gliomas is still at a rather early stage, our review clarifies that all these non-apoptotic forms of cell death show significant alterations in gliomas and that important insight into understanding them has already been gained.

Abstract Background Large vessel occlusion (LVO) is a severe condition that carries a high risk of morbidity and mortality, underscoring the importance of effective prevention strategies. This retrospective study aimed to analyze the intake of preventive medication at the time of hospitalization in a cohort of recurrent stroke patients presenting with acute LVO. Methods The study assessed the intake of either platelet aggregation inhibitors (PAI), oral anticoagulants (OAC) or statins at admission in patients with recurrent stroke and correlated it with the final classification of LVO. The frequency of those secondary preventive medication in recurrent stroke patients was defined as primary endpoint. The Modified Rankin Scale (mRS) at discharge was used as a functional outcome and defined as a secondary outcome measure. Results This study included 866 patients who were treated for LVO between 2016 and 2020, of whom 160 (18.5%) had a recurrent ischemic stroke. OAC (25.6% vs. 14.1%, p

Abstract Objective This study was performed to identify coexisting structural lesions in patients with epilepsy and known temporal encephaloceles (TEs). Methods Forty‐seven structural magnetic resonance imaging (MRI) scans of patients with epilepsy and radiologically diagnosed TEs were retrospectively reviewed visually and using an automated postprocessing software, the Morphometric Analysis Program v2018 (MAP18), to depict additional subtle, potentially epileptogenic lesions in the 3D T1‐weighted MRI data. All imaging findings were evaluated in the context of clinical and electroencephalographical findings. Results The study population consisted of 47 epilepsy patients (38.3% female, n = 18). The median age at the time of the scan was 40 years (range 12–81 years). Twenty‐one out of 47 MRI scans (44.7%) showed coexisting lesions in the initial MRI evaluation; in 38.3% (n = 18) of patients, those lesions were considered probably epileptogenic. After postprocessing, probable epileptogenic lesions were identified in 53.2% (n = 25) of patients. Malformations of cortical development had initially been reported in 17.0% (n = 8) of patients with TEs, which increased to 38.3% (n = 18) after postprocessing. TEs and other epileptogenic lesions were considered equally epileptogenic in 21.3% (n = 10) of the cases in the initial MR reports and 25.5% (n = 12) of the cases after postprocessing. Significance Temporal encephaloceles are a potential cause of MRI‐negative temporal lobe epilepsy. According to our data, TEs can occur with other lesions, suggesting that increased awareness is also required in patients with lesional epilepsy. TEs may not always be epileptogenic; hence, their occurrence with other structural pathologies may influence the presurgical evaluation and surgical approach. Finally, TEs can be associated with malformations of cortical development, which may indicate a common developmental etiology of those lesions.

Abstract Acute brain injuries such as intracerebral hemorrhage (ICH) and ischemic stroke have been reported in critically ill COVID-19 patients as well as in patients treated with veno-venous (VV)-ECMO independently of their COVID-19 status. The purpose of this study was to compare critically ill COVID-19 patients with and without VV-ECMO treatment with regard to acute neurological symptoms, pathological neuroimaging findings (PNIF) and long-term deficits. The single center study was conducted in critically ill COVID-19 patients between February 1, 2020 and June 30, 2021. Demographic, clinical and laboratory parameters were extracted from the hospital’s databases. Retrospective imaging modalities included head computed tomography (CT) and magnetic resonance imaging (MRI). Follow-up MRI and neurological examinations were performed on survivors > 6 months after the primary occurrence. Of the 440 patients, 67 patients received VV-ECMO treatment (15%). Sixty-four patients (24 with VV-ECMO) developed acute neurological symptoms (pathological levels of arousal/brain stem function/motor responses) during their ICU stay and underwent neuroimaging with brain CT as the primary modality. Critically ill COVID-19 patients who received VV-ECMO treatment had a significantly lower survival during their hospital stay compared to those without (p

Background Collaterals are the main determinants of the severity of cerebral ischemia and control the pace of the ischemic tissue damage in acute ischemic stroke. Assessment of collateral status remains a major challenge in stroke imaging. We evaluated a signal variance–based collateral vessel index in perfusion‐weighted imaging (CVIPWI) in terms of its association with initial stroke severity, presence of a mismatch for endovascular thrombectomy (EVT), and early functional outcome in patients with large‐vessel occlusion. Methods T2*‐weighted time series from dynamic susceptibility contrast perfusion imaging were processed to calculate the CVIPWI. Ischemic cores were segmented automatically on apparent diffusion coefficient maps. The relationship between collateral status and the fulfilment of mismatch criteria for EVT as well as the association between the CVIPWI and functional outcome in patients undergoing EVT were analyzed. Furthermore, spatial patterns of pial collateralization were investigated. Results A total of 156 patients with large‐vessel occlusion were included in the final analysis. Higher CVIPWI and thus better collateral supply was associated with lower baseline National Institutes of Health Stroke Scale and smaller baseline infarct volumes (P=0.022 and P=0.002, respectively), and the CVIPWI varied significantly among groups according to fulfillment of mismatch criteria for EVT (P

A generation ago, the molecular properties of tumor cells were the focus of scientific interest in oncology research. Since then, it has become increasingly apparent that the tumor environment (TEM), whose major components are non-neoplastic cell types, is also of utmost importance for our understanding of tumor growth, maintenance and resistance. In this review, we present the current knowledge concerning all cellular components within the TEM in gliomas, focusing on their molecular properties, expression patterns and influence on the biological behavior of gliomas. Insight into the TEM of gliomas has expanded considerably in recent years, including many aspects that previously received only marginal attention, such as the phenomenon of phagocytosis of glioma cells by macrophages and the role of the thyroid-stimulating hormone on glioma growth. We also discuss other topics such as the migration of lymphocytes into the tumor, phenotypic similarities between chemoresistant glioma cells and stem cells, and new clinical approaches with immunotherapies involving the cells of TEM.

Abstract Background The ongoing expansion of the cosmetic armamentarium of facial rejuvenation fails to uncover the inherent risks of cosmetic interventions. Informed consent to all risks of cosmetic filler injections and potential sequelae, including ocular and neurological complications, should be carefully ensured. We present two cases of complications following facial hyaluronic acid filler injections. Case presentations Case 1: A 43-year-old woman presented with monocular vision loss of the left eye, associated ptosis, ophthalmoplegia, periocular pain and nausea, cutaneous changes of the glabella region and forehead, and sensory impairment in the left maxillary branch dermatome (V2) after receiving a hyaluronic acid (HA) filler injection into the left glabellar area. On ophthalmological examination, an ophthalmic artery occlusion (OAO) was diagnosed upon identification of a “cherry-red spot”. Magnetic resonance imaging (MRI) revealed a left ischemic optic neuropathy. Supportive therapy and hyaluronidase injections were initiated. A follow-up MRI of the head performed two months after presentation corresponded to stable MRI findings. The patient had irreversible and complete vision loss of the left eye, however, the ptosis resolved. Case 2: A 29-year-old woman was admitted to hospital a few hours after a rhinoplasty and cheek augmentation with hyaluronic acid, presenting with acute monocular vision loss in the right eye, retrobulbar pain, fatigue and vomiting. In addition, the patient presented a harbinger of impending skin necrosis and a complete oculomotor nerve palsy on the right side, choroidal ischemia and vision impairment. Supportive treatment and hyaluronidase injections into the ischemic tissue were initiated. A small scar at the tip of the nose, vision impairment and an irregular pupillary margin on the right side persisted at follow-up. Conclusion These two case reports and the literature review emphasize the pathophysiological mechanisms leading to potentially devastating complications. In order to reduce the risk of vision loss secondary to cosmetic filler injections, practitioners should possess a thorough knowledge of anatomy and preventive strategies.

IntroductionDespite current clinical guidelines recommending suboccipital decompressive craniectomy (SDC) in cerebellar infarction when patients present with neurological deterioration, the precise definition of neurological deterioration remains unclear and accurate timing of SDC can be challenging. The current study aimed at characterizing whether clinical outcomes can be predicted by the GCS score immediately prior to SDC and whether higher GCS scores are associated with better clinical outcomes.MethodsIn a single-center, retrospective analysis of 51 patients treated with SDC for space-occupying cerebellar infarction, clinical and imaging data were evaluated at the time points of symptom onset, hospital admission, and preoperatively. Clinical outcomes were measured by the mRS. Preoperative GCS scores were stratified into three groups (GCS, 3–8, 9–11, and 12–15). Univariate and multivariate Cox regression analyses were performed using clinical and radiological parameters as predictors of clinical outcomes.ResultsIn cox regression analysis GCS scores of 12–15 at surgery were significant predictors of positive clinical outcomes (mRS, 1–2). For GCS scores of 3–8 and 9–11, no significant increase in proportional hazard ratios was observed. Negative clinical outcomes (mRS, 3–6) were associated with infarct volume above 6.0 cm3, tonsillar herniation, brainstem compression, and a preoperative GCS score of 3–8 [HR, 2.386 (CI, 1.160–4.906); p = 0.018].ConclusionOur preliminary findings suggest that SDC should be considered in patients with infarct volumes above 6.0 cm3 and with GCS between 12 and 15, as these patients may show better long-term outcomes than those in whom surgery is delayed until a GCS score below 11.

Abstract Importance The entry of artificial intelligence into medicine is pending. Several methods have been used for the predictions of structured neuroimaging data, yet nobody compared them in this context. Objective Multi-class prediction is key for building computational aid systems for differential diagnosis. We compared support vector machine, random forest, gradient boosting, and deep feed-forward neural networks for the classification of different neurodegenerative syndromes based on structural magnetic resonance imaging. Design, setting, and participants Atlas-based volumetry was performed on multi-centric T1-weighted MRI data from 940 subjects, i.e., 124 healthy controls and 816 patients with ten different neurodegenerative diseases, leading to a multi-diagnostic multi-class classification task with eleven different classes. Interventions N.A. Main outcomes and measures Cohen’s kappa, accuracy, and F1-score to assess model performance. Results Overall, the neural network produced both the best performance measures and the most robust results. The smaller classes however were better classified by either the ensemble learning methods or the support vector machine, while performance measures for small classes were comparatively low, as expected. Diseases with regionally specific and pronounced atrophy patterns were generally better classified than diseases with widespread and rather weak atrophy. Conclusions and relevance Our study furthermore underlines the necessity of larger data sets but also calls for a careful consideration of different machine learning methods that can handle the type of data and the classification task best.

Background: We aimed to investigate whether combined phosphorous (31P) magnetic resonance spectroscopic imaging (MRSI) and quantitative T2′ mapping are able to detect alterations of the cerebral oxygen extraction fraction (OEF) and intracellular pH (pHi) as markers the of cellular energy metabolism in cerebral small vessel disease (SVD). Materials and methods: 32 patients with SVD and 17 age-matched healthy control subjects were examined with 3-dimensional 31P MRSI and oxygenation-sensitive quantitative T2′ mapping (1/T2′ = 1/T2* - 1/T2) at 3 Tesla (T). PHi was measured within the white matter hyperintensities (WMH) in SVD patients. Quantitative T2′ values were averaged across the entire white matter (WM). Furthermore, T2′ values were extracted from normal-appearing WM (NAWM) and the WMH and compared between patients and controls. Results: Quantitative T2′ values were significantly increased across the entire WM and in the NAWM in patients compared to control subjects (149.51 ± 16.94 vs. 138.19 ± 12.66 ms and 147.45 ± 18.14 vs. 137.99 ± 12.19 ms, p

Introduction When evaluating MRIs for glioblastoma progression, previous scans are usually included into the review. Nowadays dynamic susceptibility contrast (DSC)-perfusion is an essential component in MR-diagnostics of gliomas, since the extent of hyperperfusion upon first diagnosis correlates with gene expression and survival. We aimed to investigate if this initial perfusion signature also characterizes the glioblastoma at time of progression. If so, DSC-perfusion data from the initial diagnosis could be of diagnostic benefit in follow-up assessments. Methods We retrospectively identified 65 patients with isocitrate dehydrogenase wildtype glioblastoma who had received technically identical DSC-perfusion measurements at initial diagnosis and at time of first progression. We determined maximum relative cerebral blood volume values (rCBVmax) by standardized re-evaluation of the data including leakage correction. In addition, the corresponding tissue samples from 24 patients were examined histologically for the maximum vessel density within the tumor. Differences (paired t-test/ Wilcoxon matched pairs test) and correlations (Spearman) between the measurements at both timepoints were calculated. Results The rCBVmax was consistently lower at time of progression compared to rCBVmax at time of first diagnosis (p < .001). There was no correlation between the rCBVmax values at both timepoints (r = .12). These findings were reflected in the histological examination, with a lower vessel density in progressive glioblastoma (p = .01) and no correlation between the two timepoints (r = -.07). Conclusion Our results suggest that the extent of hyperperfusion in glioblastoma at first diagnosis is not a sustaining tumor characteristic. Hence, the rCBVmax at initial diagnosis should be disregarded when reviewing MRIs for glioblastoma progression.

Abstract Background More patients with left-hemispheric than right-hemispheric strokes are admitted to hospitals. This is due to the easier recognition of cortical symptoms of the dominant-hemisphere. The thalamus constitutes a “micro-model” of the brain cortex with structure-function relationships known to be asymmetric, especially for language, memory, and visuo-spatial neurocognitive functions. The goal of this study was to characterize clinical symptoms and lesion distribution patterns of patients with acute isolated thalamic stroke (ITS) and to evaluate whether left-sided lesions are overrepresented in the hospital. Methods We performed a radiological database search including all brain scans performed in the Center of Neurology and Neurosurgery of the University Hospital Frankfurt between 2010 and 2019. A total of 5733 patients presenting with acute ischemic stroke were screened for ITS. Based on the MRI data, a lesion-overlap map was then generated to visualize the ITS lesion distribution. Results Fifty-eight patients with unilateral ITS were identified. A majority of 38 patients (65.5%) showed left-sided ITS, whereas only 20 patients (34.5%) had right-sided ITS (p = 0.012). A particular difference was found for ITS lesions in the anterior thalamus of the anterolateral (n = 10) and anteromedian (n = 3) vascular territory, which were located in the left thalamus in 85% of patients (p = 0.011). No distribution difference was found for ITS lesions in the inferomedial (n = 7), central (n = 8), inferolateral (n = 23) and posterior (n = 7) vascular territories. The neuropsychological symptoms of thalamic aphasia (n = 8), neurocognitive impairment (n = 6), behavioral changes (n = 2), neglect (n = 2) and memory deficits (n = 3) were described predominantly in patients with left-sided ITS (p

Abstract Objective Using multimodal imaging, we tested the hypothesis that patients after hemispherotomy recruit non‐primary motor areas and non‐pyramidal descending motor fibers to restore motor function of the impaired limb. Methods Functional and structural MRI data were acquired in a group of 25 patients who had undergone hemispherotomy and in a matched group of healthy controls. Patients’ motor impairment was measured using the Fugl‐Meyer Motor Assessment. Cortical areas governing upper extremity motor‐control were identified by task‐based functional MRI. The resulting areas were used as nodes for functional and structural connectivity analyses. Results In hemispherotomy patients, movement of the impaired upper extremity was associated to widespread activation of non‐primary premotor areas, whereas movement of the unimpaired one and of the control group related to activations prevalently located in the primary motor cortex (all p ≤ 0.05, FWE‐corrected). Non‐pyramidal tracts originating in premotor/supplementary motor areas and descending through the pontine tegmentum showed relatively higher structural connectivity in patients (p

Background In patients with covert cerebrovascular disease or proximal source of embolism, embolic silent brain infarction may precede major stroke events. Therefore, characterization of particularly cortical silent brain infarction is essential for identifying affected patients and commencing adequate secondary prevention. This study aimed to investigate differences in the distribution pattern of cortical ischemic stroke lesions to assess potential predilection sites of cortical silent brain infarction. Methods and Results We prospectively included all consecutive patients with stroke presenting from January 1 to December 31, 2018. Diffusion‐weighted imaging lesions were used to generate voxel‐based lesion maps and assigned to atlas‐based cortical regions of interest in middle cerebral artery territories. Each region‐of‐interest lesion frequency was related to the respective region‐of‐interest volume to identify frequently affected and underrepresented cerebral cortex areas. Diffusion‐weighted imaging data for voxel‐based lesion maps were available in 334 out of 633 patients. Primary analysis revealed that small‐ (

During the last 20 years, molecular alterations have gained increasing significance in the diagnosis and biological assessment of tumors. Gliomas represent the largest group of tumors of the central nervous system, and the main aim of this review is to present the current knowledge on molecular pathways and their alterations in gliomas. A wide range of new insights has been gained, including evidence for the involvement of the WNT pathway or the hippo pathway in the pathobiology of gliomas, indicating a broad involvement of different pathways formerly not considered to play a central role in gliomas. Even new aspects of angiogenic, apoptotic, and metabolic pathways are presented, as well as the rapidly growing field of epigenetic processes, including non-coding RNAs. The two major conclusions drawn from the present review are the distinct interconnectivity of the whole spectrum of molecular pathways and the prominent role of non-coding RNAs, especially circular RNAs, in the regulation of specific targets. All these new insights are discussed, even considering the topic of the resistance to therapy of gliomas, along with aspects that are still incompletely understood, like the role of hydroxymethylation, or even ferroptosis, in the pathobiology of gliomas.

Purpose:Hypertrophic olivary degeneration (HOD) is a pathology of the inferior olivary nucleus (ION) that occurs after injuries to the Guillain-Mollaret triangle (GMT). Lacking a diagnostic gold standard, diagnosis is usually based on T2 or FLAIR imaging and expert rating. To facilitate precise HOD diagnosis in future studies, we assessed the reliability of this rater-based approach and explored alternative, quantitative analysis.MethodsPatients who had suffered strokes in the GMT and a matched control group prospectively underwent an MRI examination including T2, FLAIR, and proton density (PD). Diffusion tensor imaging (DTI) was additionally performed in the patient group. The presence of HOD was assessed on FLAIR, T2, and PD separately by 3 blinded reviewers. Employing an easily reproducible segmentation approach, relative differences in intensity, fractional anisotropy (FA), and mean diffusivity (MD) between both IONs were calculated.ResultsIn total, 15 patients were included in this study. The interrater reliability was best for FLAIR, followed by T2 and PD (Fleiss κ = 0.87 / 0.77 / 0.65). The 3 raters diagnosed HOD in 38–46% (FLAIR), 40–47% (T2), and 53–67% (PD) of patients. False-positive findings in the control group were less frequent in T2 than in PD and FLAIR (2.2% / 8.9% / 6.7%). In 53% of patients, the intensity difference between both IONs on PD was significantly increased in comparison with the control group. These patients also showed significantly decreased FA and increased MD.ConclusionWhile the rater-based approach yielded the best performance on T2 imaging, a quantitative, more sensitive HOD diagnosis based on ION intensities in PD and DTI imaging seems possible.

Abstract Patient care in a neurointensive care unit (neuro-ICU) is challenging. Multidrug-resistant organisms (MDROs) are increasingly common in the routine clinical practice. We evaluated the impact of infection with MDROs on outcomes in patients with subarachnoid hemorrhage (SAH). A single-center retrospective analysis of SAH cases involving patients treated in the neuro-ICU was performed. The outcome was assessed 6 months after SAH using the modified Rankin Scale [mRS, favorable (0–2) and unfavorable (3–6)]. Data were compared by matched-pair analysis. Patient characteristics were well matched in the MDRO (n = 61) and control (n = 61) groups. In this center, one nurse was assigned to a two-bed room. If a MDRO was detected, the patient was isolated, and the nurse was assigned to the patient infected with the MDRO. In the MDRO group, 29 patients (48%) had a favorable outcome, while 25 patients (41%) in the control group had a favorable outcome; the difference was not significant (p > 0.05). Independent prognostic factors for unfavorable outcomes were worse status at admission (OR = 3.1), concomitant intracerebral hematoma (ICH) (OR = 3.7), and delayed cerebral ischemia (DCI) (OR = 6.8). Infection with MRDOs did not have a negative impact on the outcome in SAH patients. Slightly better outcomes were observed in SAH patients infected with MDROs, suggesting the benefit of individual care.

Abstract Background Epileptic seizures are common clinical features in patients with acute subdural hematoma (aSDH); however, diagnostic feasibility and therapeutic monitoring remain limited. Surface electroencephalography (EEG) is the major diagnostic tool for the detection of seizures but it might be not sensitive enough to detect all subclinical or nonconvulsive seizures or status epilepticus. Therefore, we have planned a clinical trial to evaluate a novel treatment modality by perioperatively implanting subdural EEG electrodes to diagnose seizures; we will then treat the seizures under therapeutic monitoring and analyze the clinical benefit. Methods In a prospective nonrandomized trial, we aim to include 110 patients with aSDH. Only patients undergoing surgical removal of aSDH will be included; one arm will be treated according to the guidelines of the Brain Trauma Foundation, while the other arm will additionally receive a subdural grid electrode. The study’s primary outcome is the comparison of incidence of seizures and time-to-seizure between the interventional and control arms. Invasive therapeutic monitoring will guide treatment with antiseizure drugs (ASDs). The secondary outcome will be the functional outcome for both groups as assessed via the Glasgow Outcome Scale and modified Rankin Scale both at discharge and during 6 months of follow-up. The tertiary outcome will be the evaluation of chronic epilepsy within 2–4 years of follow-up. Discussion The implantation of a subdural EEG grid electrode in patients with aSDH is expected to be effective in diagnosing seizures in a timely manner, facilitating treatment with ASDs and monitoring of treatment success. Moreover, the occurrence of epileptiform discharges prior to the manifestation of seizure patterns could be evaluated in order to identify high-risk patients who might benefit from prophylactic treatment with ASDs. Trial registration ClinicalTrials.gov identifier no. NCT04211233 .

Excluding persons from magnetic resonance imaging (MRI) research studies based on their medical history or because they have tattoos, can create bias and compromise the validity and generalizability of study results. In the population-based Rhineland Study, we limited exclusion criteria for MRI and allowed participants with passive medical implants, tattoos or permanent make-up to undergo MRI. Thereby, we could include 16.6% more people than would have been possible based on common recommendations. We observed no adverse events or artifacts. This supports that most passive medical implants, tattoos and permanent make-up are MRI suitable and can be scanned in research settings.

BackgroundPrevious studies reported decreased volumes of acute stroke admissions during the COVID-19 pandemic. We aimed to examine whether aneurysmal subarachnoid hemorrhage (aSAH) volumes demonstrated similar declines in our department. Furthermore, the impact of the pandemic on disease progression should be analyzed.MethodsWe conducted a retrospective study in the neurosurgical department of the university hospital Frankfurt including patients with the diagnosis of aSAH during the first year of the COVID pandemic. One year cumulative volume for aSAH hospitalization procedures was compared to the year before (03/2020 – 02/2021 vs. 03/2019 – 02/2020) and the last 5 pre-COVID-pandemic years (2015-2020). All relevant patient characteristics concerning family history, disease history, clinical condition at admission, active/past COVID-infection, treatment management, complications, and outcome were analyzed.ResultsCompared to the 84 hospital admissions during the pre-pandemic years, the number of aSAH hospitalizations (n = 56) declined during the pandemic without reaching significance. No significant difference in the analyzed patient characteristics including clinical condition at onset, treatment, complications, and outcome, between 56 patients with aSAH admitted during the COVID pandemic and the treated patients in the last 5 years in the pre-COVID period were found. In our multivariable analysis, we detected young age (p < 0.05; OR 4.2) and no existence of early hydrocephalus (p < 0.05; OR 0.13) as important factors for a favorable outcome (mRS ≤ 0–2) after aSAH during the COVID pandemic. A past COVID-infection was detected in young patients suffering from aSAH (Age

BackgroundThe inclusion of immune checkpoint inhibitors (ICIs) in therapeutic algorithms has led to significant survival benefits in patients with various metastatic cancers. Concurrently, an increasing number of neurological immune related adverse events (IRAE) has been observed. In this retrospective analysis, we examine the ICI-induced incidence of cerebral pseudoprogression and propose a classification system.MethodsWe screened our hospital information system to identify patients with any in-house ICI treatment for any tumor disease during the years 2007-2019. All patients with cerebral MR imaging (cMRI) of sufficient diagnostic quality were included. cMRIs were retrospectively analyzed according to immunotherapy response assessment for neuro-oncology (iRANO) criteria.ResultsWe identified 12 cases of cerebral pseudoprogression in 123 patients treated with ICIs and sufficient MRI. These patients were receiving ICI therapy for lung cancer (n=5), malignant melanoma (n=4), glioblastoma (n=1), hepatocellular carcinoma (n=1) or lymphoma (n=1) when cerebral pseudoprogression was detected. Median time from the start of ICI treatment to pseudoprogression was 5 months. All but one patient developed neurological symptoms. Three different patterns of cerebral pseudoprogression could be distinguished: new or increasing contrast-enhancing lesions, new or increasing T2 predominant lesions and cerebral vasculitis type pattern.ConclusionCerebral pseudoprogression followed three distinct patterns and was detectable in 3.2% of all patients during ICI treatment and in 9.75% of the patients with sufficient brain imaging follow up. The fact that all but one of the affected patients developed neurological symptoms, which would be classified as progressive disease according to iRANO criteria, mandates vigilance in the diagnosis and treatment of ICI-induced cerebral lesions.

(1) Background and Purpose: The aim of this study was to retrospectively characterize WMSAs in an unselected patient cohort at a large pediatric neuroimaging facility, in order to learn more about the spectrum of the underlying disorders encountered in everyday clinical practice. (2) Materials and Methods: Radiology reports of 5166 consecutive patients with standard brain MRI (2006–2018) were searched for predefined keywords describing WMSAs. A neuroradiology specialist enrolled patients with WMSAs following a structured approach. Imaging characteristics, etiology (autoimmune disorders, non-genetic hypoxic and ischemic insults, traumatic white matter injuries, no final diagnosis due to insufficient clinical information, “non-specific” WMSAs, infectious white matter damage, leukodystrophies, toxic white matter injuries, inborn errors of metabolism, and white matter damage caused by tumor infiltration/cancer-like disease), and age/gender distribution were evaluated. (3) Results: Overall, WMSAs were found in 3.4% of pediatric patients scanned at our and referring hospitals within the ten-year study period. The majority were found in the supratentorial region only (87%) and were non-enhancing (78% of CE-MRI). WMSAs caused by autoimmune disorders formed the largest group (23%), followed by “non-specific” WMSAs (18%), as well as non-genetic hypoxic and ischemic insults (17%). The majority were therefore acquired as opposed to inherited. Etiology-based classification of WMSAs was affected by age but not by gender. In 17% of the study population, a definite diagnosis could not be established due to insufficient clinical information (mostly external radiology consults). (4) Conclusions: An “integrated diagnosis” that combines baseline demographics, including patient age as an important factor, clinical characteristics, and additional diagnostic workup with imaging patterns can be made in the majority of cases.

Introduction: Ischemic and hemorrhagic strokes in the brainstem and cerebellum with injury to the functional loop of the Guillain-Mollaret triangle (GMT) can trigger a series of events that result in secondary trans-synaptic neurodegeneration of the inferior olivary nucleus. In an unknown percentage of patients, this leads to a condition called hypertrophic olivary degeneration (HOD). Characteristic clinical symptoms of HOD progress slowly over months and consist of a rhythmic palatal tremor, vertical pendular nystagmus, and Holmes tremor of the upper limbs. Diffusion Tensor Imaging (DTI) with tractography is a promising method to identify functional pathway lesions along the cerebello-thalamo-cortical connectivity and to generate a deeper understanding of the HOD pathophysiology. The incidence of HOD development following stroke and the timeline of clinical symptoms have not yet been determined in prospective studies—a prerequisite for the surveillance of patients at risk.Methods and Analysis: Patients with ischemic and hemorrhagic strokes in the brainstem and cerebellum with a topo-anatomical relation to the GMT are recruited within certified stroke units of the Interdisciplinary Neurovascular Network of the Rhine-Main. Matching lesions are identified using a predefined MRI template. Eligible patients are prospectively followed up and present at 4 and 8 months after the index event. During study visits, a clinical neurological examination and brain MRI, including high-resolution T2-, proton-density-weighted imaging, and DTI tractography, are performed. Fiberoptic endoscopic evaluation of swallowing is optional if palatal tremor is encountered.Study Outcomes: The primary endpoint of this prospective clinical multicenter study is to determine the frequency of radiological HOD development in patients with a posterior fossa stroke affecting the GMT at 8 months after the index event. Secondary endpoints are identification of (1) the timeline and relevance of clinical symptoms, (2) lesion localizations more prone to HOD occurrence, and (3) the best MR-imaging regimen for HOD identification. Additionally, (4) DTI tractography data are used to analyze individual pathway lesions. The aim is to contribute to the epidemiological and pathophysiological understanding of HOD and hereby facilitate future research on therapeutic and prophylactic measures.Clinical Trial Registration: HOD-IS is a registered trial at https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00020549.

Magnetic resonance imaging (MRI) is the gold standard imaging technique for diagnosis and monitoring of many neurological diseases. However, the application of conventional MRI in clinical routine is mainly limited to the visual detection of macroscopic tissue pathology since mixed tissue contrasts depending on hardware and protocol parameters hamper its application for the assessment of subtle or diffuse impairment of the structural tissue integrity. Multiparametric quantitative (q)MRI determines tissue parameters quantitatively, enabling the detection of microstructural processes related to tissue remodeling in aging and neurological diseases. In contrast to measuring tissue atrophy via structural imaging, multiparametric qMRI allows for investigating biologically distinct microstructural processes, which precede changes of the tissue volume. This facilitates a more comprehensive characterization of tissue alterations by revealing early impairment of the microstructural integrity and specific disease-related patterns. So far, qMRI techniques have been employed in a wide range of neurological diseases, including in particular conditions with inflammatory, cerebrovascular and neurodegenerative pathology. Numerous studies suggest that qMRI might add valuable information, including the detection of microstructural tissue damage in areas appearing normal on conventional MRI and unveiling the microstructural correlates of clinical manifestations. This review will give an overview of current qMRI techniques, the most relevant tissue parameters and potential applications in neurological diseases, such as early (differential) diagnosis, monitoring of disease progression, and evaluating effects of therapeutic interventions.

Cerebral lesions may cause degeneration and neuroplastic reorganization in both the ipsi- and the contralesional hemisphere, presumably creating an imbalance of primarily inhibitory interhemispheric influences produced via transcallosal pathways. The two hemispheres are thought to mutually hamper neuroplastic reorganization of the other hemisphere. The results of preceding degeneration and neuroplastic reorganization of white matter may be reflected by Diffusion Tensor Imaging-derived diffusivity parameters such as fractional anisotropy (FA). In this study, we applied Diffusion Tensor Imaging (DTI) to contrast the white matter status of the contralesional hemisphere of young lesioned brains with and without contralateral influences by comparing patients after hemispherotomy to those who had not undergone neurosurgery. DTI was applied to 43 healthy controls (26 females, mean age ± SD: 25.07 ± 11.33 years) and two groups of in total 51 epilepsy patients with comparable juvenile brain lesions (32 females, mean age ± SD: 25.69 ± 12.77 years) either after hemispherotomy (30 of 51 patients) or without neurosurgery (21 of 51 patients), respectively. FA values were compared between these groups using the unbiased tract-based spatial statistics approach. A voxel-wise ANCOVA controlling for age at scan yielded significant group differences in FA. A post hoc t-test between hemispherotomy patients and healthy controls revealed widespread supra-threshold voxels in the contralesional hemisphere of hemispherotomy patients indicating comparatively higher FA values (p < 0.05, FWE-corrected). The non-surgery group, in contrast, showed extensive supra-threshold voxels indicating lower FA values in the contralesional hemisphere as compared to healthy controls (p < 0.05, FWE-corrected). Whereas lower FA values are suggestive of pronounced contralesional degeneration in the non-surgery group, higher FA values in the hemispherotomy group may be interpreted as a result of preceding plastic remodeling. We conclude that, whether juvenile brain lesions are associated with contralesional degeneration or reorganization partly depends on the ipsilesional hemisphere. Contralesional reorganization as observed in hemispherotomy patients was most likely enabled by the complete neurosurgical deafferentation of the ipsilesional hemisphere and, thereby, the disinhibition of the neuroplastic potential of the contralesional hemisphere. The main argument of this study is that hemispherotomy may be seen as a major plastic stimulus and as a prerequisite for contralesional neuroplastic remodeling in patients with juvenile brain lesions.

PurposeIn the clinical routine, detection of focal cortical dysplasia (FCD) by visual inspection is challenging. Still, information about the presence and location of FCD is highly relevant for prognostication and treatment decisions. Therefore, this study aimed to develop, describe and test a method for the calculation of synthetic anatomies using multiparametric quantitative MRI (qMRI) data and surface-based analysis, which allows for an improved visualization of FCD.Materials and MethodsQuantitative T1-, T2- and PD-maps and conventional clinical datasets of patients with FCD and epilepsy were acquired. Tissue segmentation and delineation of the border between white matter and cortex was performed. In order to detect blurring at this border, a surface-based calculation of the standard deviation of each quantitative parameter (T1, T2, and PD) was performed across the cortex and the neighboring white matter for each cortical vertex. The resulting standard deviations combined with measures of the cortical thickness were used to enhance the signal of conventional FLAIR-datasets. The resulting synthetically enhanced FLAIR-anatomies were compared with conventional MRI-data utilizing regions of interest based analysis techniques.ResultsThe synthetically enhanced FLAIR-anatomies showed higher signal levels than conventional FLAIR-data at the FCD sites (p = 0.005). In addition, the enhanced FLAIR-anatomies exhibited higher signal levels at the FCD sites than in the corresponding contralateral regions (p = 0.005). However, false positive findings occurred, so careful comparison with conventional datasets is mandatory.ConclusionSynthetically enhanced FLAIR-anatomies resulting from surface-based multiparametric qMRI-analyses have the potential to improve the visualization of FCD and, accordingly, the treatment of the respective patients.

PurposeDiffuse cortical damage in relapsing–remitting multiple sclerosis (RRMS) is clinically relevant but cannot be directly assessed with conventional MRI. In this study, it was aimed to use diffusion tensor imaging (DTI) techniques with optimized intrinsic eddy current compensation to quantify and characterize cortical mean diffusivity (MD) and fractional anisotropy (FA) changes in RRMS and to analyze the distribution of these changes across the cortex.Materials and MethodsThree-Tesla MRI acquisition, mapping of the MD providing information about the integrity of microstructural barriers and of the FA reflecting axonal density and surface-based analysis with Freesurfer were performed for 24 RRMS patients and 25 control subjects.ResultsAcross the whole cortex, MD was increased in patients (p < 0.001), while surface-based analysis revealed focal cortical FA decreases. MD and FA changes were distributed inhomogeneously across the cortex, the MD increase being more widespread than the FA decrease. Cortical MD correlated with the Expanded Disability Status Scale (EDSS, r = 0.38, p = 0.03).ConclusionDamage of microstructural barriers occurs inhomogeneously across the cortex in RRMS and might be spatially more widespread than axonal degeneration. The results and, in particular, the correlation with the clinical status indicate that DTI might be a promising technique for the monitoring of cortical damage under treatment in larger clinical studies.

Background: Quantitative MRI (qMRI) techniques allow assessing cerebral tissue properties. However, previous studies on the accuracy of quantitative T1 and T2 mapping reported a scanner model bias of up to 10% for T1 and up to 23% for T2. Such differences would render multi-centre qMRI studies difficult and raise fundamental questions about the general precision of qMRI. A problem in previous studies was that different methods were used for qMRI parameter mapping or for measuring the transmitted radio frequency field B1 which is critical for qMRI techniques requiring corrections for B1 non-uniformities. Aims: The goal was to assess the intra- and inter-scanner reproducibility of qMRI data at 3 ​T, using two different scanner models from the same vendor with exactly the same multiparametric acquisition protocol. Methods: Proton density (PD), T1, T2* and T2 mapping was performed on healthy subjects and on a phantom, performing each measurement twice for each of two scanner models. Although the scanners had different hardware and software versions, identical imaging sequences were used for PD, T1 and T2* mapping, adapting the codes of an existing protocol on the older system line by line to match the software version of the newer scanner. For T2-mapping, the respective manufacturer’s sequence was used which depended on the software version. However, system-dependent corrections were carried out in this case. Reproducibility was assessed by average values in regions of interest. Results: Mean scan-rescan variations were not exceeding 2.14%, with average values of 1.23% and 1.56% for the new and old system, respectively. Inter-scanner model deviations were not exceeding 5.21% with average values of about 2.2–3.8% for PD, 2.5–3.0% for T2*, 1.6–3.1% for T1 and 3.3–5.2% for T2. Conclusions: Provided that identical acquisition sequences are used, discrepancies between qMRI data acquired with different scanner models are low. The level of systematic differences reported in this work may help to interpret multi-centre data.

Temporal lobe adult-onset seizures (TAOS) related to autoimmunity represent an increasingly recognized disease syndrome within the spectrum of epilepsies. In this context, certain autoantibodies (autoABs) were often associated with limbic encephalitis (LE). Here, we aimed to gain insights into (a) the distribution of 'neurological' autoABs (neuroABs, defined as autoABs targeting neuronal surface structures or 'onconeuronal' ABs or anti-glutamate acid decarboxylase 65 (GAD65) autoABs) in a large consecutive TAOS patient cohort, to characterize (b) clinical profiles of seropositive versus seronegative individuals and to find (c) potential evidence for other autoABs. Blood sera/cerebrospinal fluid (CSF) of TAOS patients (n = 800) and healthy donors (n = 27) were analyzed for neuroABs and screened for other autoABs by indirect immunofluorescence on hippocampal/cerebellar sections and immunoblots of whole brain and synaptosome lysates. Serological results were correlated with clinico-neuropsychological features. 13% of TAOS patients (n = 105) were neuroAB+, with anti-GAD65 and anti-N-methyl-D-aspartate receptors (NMDAR) as most frequent autoABs in this group. In our screening tests 25% of neuroAB- patients (n = 199) were positive (screening+), whereas all control samples were negative (n = 27). Intriguingly, key clinico-neuropsychological characteristics including magnetic resonance imaging (MRI) findings, epileptiform electroencephalographic (EEG) activity, and inflammatory cellular infiltrates in CSF were shared to a greater extent by neuroAB+ with neuroAB-/screening+ patients than with neuroAB-/screening- patients. Serological testing in a large consecutive TAOS patient series revealed seropositivity for anti-GAD65 autoABs as the most frequent neuroAB. Intriguingly, neuroAB+ individuals were virtually indistinguishable from neuroAB-/screening+ patients in several major clinical features. In contrast, neuroAB-/screening- TAOS patients differed in many parameters. These data support the potential presence of so far unrecognized autoABs in patients with TAOS.

Limbic encephalitis (LE) is an autoimmune syndrome often associated with temporal lobe epilepsy. Recent research suggests that particular structural changes in LE depend on the type of the associated antibody and occur in both mesiotemporal gray matter and white matter regions. However, it remains questionable to what degree conventional diffusion tensor imaging (DTI)-methods reflect alterations in white matter microstructure, since these methods do not account for crossing fibers. To address this methodological shortcoming, we applied fixel-based analysis as a novel technique modeling distinct fiber populations. For our study, 19 patients with LE associated with autoantibodies against glutamic acid decarboxylase 65 (GAD-LE, mean age = 35.9 years, 11 females), 4 patients with LE associated with autoantibodies against leucine-rich glioma-inactivated 1 (LGI1-LE, mean age = 63.3 years, 2 females), 5 patients with LE associated with contactin-associated protein-like 2 (CASPR2, mean age = 57.4, 0 females), 20 age- and gender-matched control patients with hippocampal sclerosis (19 GAD-LE control patients: mean age = 35.1 years, 11 females; 4 LGI1-LE control patients: mean age = 52.6 years, 2 females; 5 CASPR2-LE control patients: mean age = 42.7 years, 0 females; 10 patients are included in more than one group) and 33 age- and gender-matched healthy control subjects (19 GAD-LE healthy controls: mean age = 34.6 years, 11 females; 8 LGI1-LE healthy controls: mean age = 57.0 years, 4 females, 10 CASPR2-LE healthy controls: mean age = 57.2 years, 0 females; 4 subjects are included in more than one group) underwent structural imaging and DTI at 3 T and neuropsychological testing. Patient images were oriented according to lateralization in EEG resulting in an affected and unaffected hemisphere. Fixel-based metrics fiber density (FD), fiber cross-section (FC), and fiber density and cross-section (FDC = FD · FC) were calculated to retrieve information about white matter integrity both on the micro- and the macroscale. As compared to healthy controls, patients with GAD-LE showed significantly (family-wise error-corrected, p

Introduction: Acute stroke care delivered by interdisciplinary teams is time-sensitive. Simulation-based team training is a promising tool to improve team performance in medical operations. It has the potential to improve process times, team communication, patient safety, and staff satisfaction. We aim to assess whether a multi-level approach consisting of a stringent workflow revision based on peer-to-peer review and 2–3 one-day in situ simulation trainings can improve acute stroke care processing times in high volume neurocenters within a 6 months period.Methods and Analysis: The trial is being carried out in a pre-test-post-test design at 7 tertiary care university hospital neurocenters in Germany. The intervention is directed at the interdisciplinary multiprofessional stroke teams. Before and after the intervention, process times of all direct-to-center stroke patients receiving IV thrombolysis (IVT) and/or endovascular therapy (EVT) will be recorded. The primary outcome measure will be the “door-to-needle” time of all consecutive stroke patients directly admitted to the neurocenters who receive IVT. Secondary outcome measures will be intervention-related process times of the fraction of patients undergoing EVT and effects on team communication, perceived patient safety, and staff satisfaction via a staff questionnaire.Interventions: We are applying a multi-level intervention in cooperation with three “STREAM multipliers” from each center. First step is a central meeting of the multipliers at the sponsor's institution with the purposes of algorithm review in a peer-to-peer process that is recorded in a protocol and an introduction to the principles of simulation training and debriefing as well as crew resource management and team communication. Thereafter, the multipliers cooperate with the stroke team trainers from the sponsor's institution to plan and execute 2–3 one-day simulation courses in situ in the emergency department and CT room of the trial centers whereupon they receive teaching materials to perpetuate the trainings.Clinical Trial Registration: STREAM is a registered trial at https://clinicaltrials.gov/ct2/show/NCT03228251.

Inflammatory nontraumatic atlantoaxial rotatory subluxation (AAS) in children is an often-missed diagnosis, especially in the early stages of disease. Abscess formation and spinal cord compression are serious risks that call for immediate surgical attention. Neither radiographs nor non-enhanced computed tomography (CT) images sufficiently indicate inflammatory processes. Magnetic resonance imaging (MRI) allows a thorough evaluation of paraspinal soft tissues, joints, and ligaments. In addition, it can show evidence of vertebral distraction and spinal cord compression. After conducting a scoping review of the literature, along with scientific and practical considerations, we outlined a standardized pediatric MRI protocol for suspected inflammatory nontraumatic AAS. We recommend contrast-enhanced MRI as the primary diagnostic imaging modality in children with signs of torticollis in combination with nasopharyngeal inflammatory or ear nose and throat (ENT) surgical history.

Background: Due to the difficulties in the definite diagnosis, data on brain imaging in pediatric patients with central nervous system (CNS)-invasive mold infection (IMD) are scarce. Our aim was to describe brain imaging abnormalities seen in immunocompromised children with CNS-IMD, and to analyze retrospectively whether specific imaging findings and sequences have a prognostic value. Methods: In a retrospective study of 19 pediatric patients with proven or probable CNS-IMD, magnetic resonance imaging (MRI)-findings were described and analyzed. The results were correlated with outcome, namely death, severe sequelae, or no neurological sequelae. Results: 11 children and 8 adolescents (11/8 with proven/probable CNS-IMD) were included. Seven of the patients died and 12/19 children survived (63%): seven without major neurological sequelae and five with major neurological sequelae. Multifocal ring enhancement and diffusion restriction were the most common brain MRI changes. Diffusion restriction was mostly seen at the core of the lesion. No patient with disease limited to one lobe died. Perivascular microbleeding seen on susceptibility weighted imaging (SWI) and/or gradient-echo/T2* images, as well as infarction, were associated with poor prognosis. Conclusions: The presence of infarction was related to poor outcome. As early microbleeding seems to be associated with poor prognosis, we suggest including SWI in routine diagnostic evaluation of immunocompromised children with suspected CNS-IMD.

Antiangiogenic treatment of glioblastomas with Bevacizumab lacks predictive markers. Myoinositol (MI) is an organic osmolyte, with intracellular concentration changes depending on the extracellular osmolality. Since Bevacizumab markedly reduces tumor edema and influences the tumor microenvironment, we investigated whether the MI concentration in the tumor changes during therapy.We used 1H-magnetic resonance spectroscopy to measure the MI concentrations in the tumor and contralateral control tissue of 39 prospectively recruited patients with recurrent glioblastomas before and 8-12 weeks after starting therapy. 30 patients received Bevacizumab and 9 patients were treated with CCNU/VM26 as control. We performed a survival analysis to evaluate MI as a predictive biomarker for Bevacizumab therapy.MI concentrations increased significantly during Bevacizumab therapy in tumor (p < .001) and control tissue (p = .001), but not during CCNU/VM26 treatment. For the Bevacizumab cohort, higher MI concentrations in the control tissue at baseline (p = .021) and higher differences between control and tumor tissue (delta MI, p = .011) were associated with longer survival. A Kaplan-Meier analysis showed a median OS of 164 days for patients with a deltaMI < 1,817 mmol/l and 275 days for patients with a deltaMI > 1,817 mmol/l. No differences were observed for the relative changes or the post treatment concentrations. Additionally calculated creatine concentrations showed no differences in between subgroups or between pre and post treatment measurements.Our data suggest that recurrent glioblastoma shows a strong metabolic reaction to Bevacizumab. Further, our results support the hypothesis that MI might be a marker for early tumor cell invasion. Pre-therapeutic MI concentrations are predictive of overall survival in patients with recurrent glioblastoma treated with Bevacizumab.

In secondary progressive Multiple Sclerosis (SPMS), global neurodegeneration as a driver of disability gains importance in comparison to focal inflammatory processes. However, clinical MRI does not visualize changes of tissue composition outside MS lesions. This quantitative MRI (qMRI) study investigated cortical and deep gray matter (GM) proton density (PD) values and T1 relaxation times to explore their potential to assess neuronal damage and its relationship to clinical disability in SPMS.11 SPMS patients underwent quantitative T1 and PD mapping. Parameter values across the cerebral cortex and deep GM structures were compared with 11 healthy controls, and correlation with disability was investigated for regions exhibiting significant group differences.PD was increased in the whole GM, cerebral cortex, thalamus, putamen and pallidum. PD correlated with disability in the whole GM, cerebral cortex, putamen and pallidum. T1 relaxation time was prolonged and correlated with disability in the whole GM and cerebral cortex.Our study suggests that the qMRI parameters GM PD (which likely indicates replacement of neural tissue with water) and cortical T1 (which reflects cortical damage including and beyond increased water content) are promising qMRI candidates for the assessment of disease status, and are related to disability in SPMS.

PURPOSE:Quantitative T2'-mapping detects regional changes of the relation of oxygenated and deoxygenated hemoglobin (Hb) by using their different magnetic properties in gradient echo imaging and might therefore be a surrogate marker of increased oxygen extraction fraction (OEF) in cerebral hypoperfusion. Since elevations of cerebral blood volume (CBV) with consecutive accumulation of Hb might also increase the fraction of deoxygenated Hb and, through this, decrease the T2'-values in these patients we evaluated the relationship between T2'-values and CBV in patients with unilateral high-grade large-artery stenosis. MATERIALS AND METHODS:Data from 16 patients (13 male, 3 female; mean age 53 years) with unilateral symptomatic or asymptomatic high-grade internal carotid artery (ICA) or middle cerebral artery (MCA) stenosis/occlusion were analyzed. MRI included perfusion-weighted imaging and high-resolution T2'-mapping. Representative relative (r)CBV-values were analyzed in areas of decreased T2' with different degrees of perfusion delay and compared to corresponding contralateral areas. RESULTS:No significant elevations in cerebral rCBV were detected within areas with significantly decreased T2'-values. In contrast, rCBV was significantly decreased (p

The multifunctional molecule netrin-1 is upregulated in various malignancies and has recently been presented as a major general player in tumorigenesis leading to tumor progression and maintenance in various animal models. However, there is still a lack of clinico-epidemiological data related to netrin-1 expression. Therefore, the aim of our study was to elucidate the association of netrin-1 expression and patient survival in brain metastases since those constitute one of the most limiting factors for patient prognosis. We investigated 104 brain metastases cases for netrin-1 expression using in-situ hybridization and immunohistochemistry with regard to clinical parameters such as patient survival and MRI data. Our data show that netrin-1 is strongly upregulated in most cancer subtypes. Univariate analyses revealed netrin-1 expression as a significant factor associated with poor patient survival in the total cohort of brain metastasis patients and in sub-entities such as non-small cell lung carcinomas. Interestingly, many cancer samples showed a strong nuclear netrin-1 signal which was recently linked to a truncated netrin-1 variant that enhances tumor growth. Nuclear netrin-1 expression was associated with poor patient survival in univariate as well as in multivariate analyses. Our data indicate both total and nuclear netrin-1 expression as prognostic factors in brain metastases patients in contrast to other prognostic markers in oncology such as patient age, number of brain metastases or Ki67 proliferation index. Therefore, nuclear netrin-1 expression constitutes one of the first reported molecular biomarkers for patient survival in brain metastases. Furthermore, netrin-1 may constitute a promising target for future anti-cancer treatment approaches in brain metastases.

PurposeMetabolic changes upon antiangiogenic therapy of recurrent glioblastomas (rGBMs) may provide new biomarkers for treatment efficacy. Since in vitro models showed that phospholipid membrane metabolism provides specific information on tumor growth we employed in-vivo MR-spectroscopic imaging (MRSI) of human rGBMs before and under bevacizumab (BVZ) to measure concentrations of phosphocholine (PCho), phosphoethanolamine (PEth), glycerophosphocholine (GPC), and glyceroethanolamine (GPE).Methods(1)H and (31)P MRSI was prospectively performed in 32 patients with rGBMs before and under BVZ therapy at 8 weeks intervals until tumor progression. Patients were dichotomized into subjects with long overall survival (OS) (>median OS) and short OS (ResultsBefore BVZ, (1)H-detectable choline signals (total GPC and PCho) in rGBMs were elevated but significance failed after dichotomizing. For metabolite ratios obtained by (31)P MRSI, the short-OS group showed higher PCho/GPC (p = 0.004) in rGBMs compared to control tissue before BVZ while PEth/GPE was elevated in rGBMs of both groups (long-OS p = 0.04; short-OS p = 0.003). Under BVZ, PCho/GPC and PEth/GPE in the tumor initially decreased (p = 0.04) but only PCho/GPC re-increased upon tumor progression (p = 0.02). Intriguingly, in normal-appearing tissue an initial PEth/GPE decrease (p = 0.047) was followed by an increase at the time of tumor progression (p = 0.031).ConclusionAn elevated PCho/GPC ratio in the short-OS group suggests that it is a negative predictive marker for BVZ efficacy. These gliomas may represent a malignant phenotype even growing under anti-VEGF treatment. Elevated PEth/GPE may represent an in-vivo biomarker more sensitive to GBM infiltration than MRI.

Mutations in the PINK1 gene cause autosomal recessive familial Parkinson's disease (PD). The gene encodes a mitochondrial protein kinase that plays an important role in maintaining mitochondrial function and integrity. However, the pathophysiological link between mutation-related bioenergetic deficits and the degenerative process in dopaminergic neurons remains to be elucidated. We performed phosphorous ((31)P) and proton ((1)H) 3-T magnetic resonance spectroscopic imaging (MRSI) in 11 members of a German family with hereditary PD due to PINK1 mutations (PARK6) compared to 23 age-matched controls. All family members had prior 18-Fluorodopa (FDOPA) positron emission tomography (PET). The striatal FDOPA uptake was correlated with quantified metabolic brain mapping in MRSI. At group level, the heterozygous PINK1 mutation carriers did not show any MRSI abnormalities relative to controls. In contrast, homozygous individuals with manifest PD had putaminal GPC, PCr, HEP and β-ATP levels well above the 2SD range of controls. Across all subjects, the FDOPA K(i) values correlated positively with MI (r = 0.879, p