Stratifying quality of life outcome in subthalamic stimulation for Parkinson's disease.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) for Parkinson's disease (PD) improves quality of life (QoL), motor and non-motor symptoms (NMS). However, in previous studies, 43%-49% of patients did not experience clinically relevant postoperative QoL improvement. To inform individualised prediction of postoperative QoL improvement, we developed a stratification analysis of QoL outcomes based on preoperative non-motor total burden, severity of motor progression and motor response in levodopa challenge tests. METHODS: This was a prospective, open-label, multicentre, international study with a 6-month follow-up. A distribution-based threshold identified 'QoL responders' in the PDQuestionnaire-8 Summary Index (PDQ-8 SI). After baseline stratification based on the NMS Scale, Hoehn and Yahr Scale and levodopa response assessed with the Unified PD Rating Scale-III, we compared postoperative QoL response between these strata. To assess the clinical usefulness and statistical feasibility of stratifications, we compared cumulative distribution function curves, respectively PDQ-8 within-stratum variation. RESULTS: All main outcomes improved postoperatively. Based on the 8.1 points threshold for clinically meaningful PDQ-8 SI improvement, only 80/161 patients were classified as 'QoL responders'. The absolute risk reductions for QoL non-response among respective non-motor, motor progression and levodopa response strata were 23%, 8% and 3%, respectively. Only non-motor stratification reduced PDQ-8 within-stratum variation compared with the overall cohort. CONCLUSIONS: Non-motor stratification, but not motor progression or levodopa response stratification, is clinically useful and statistically feasible for personalised preoperative prediction of postoperative QoL outcome of STN-DBS for PD. Our findings highlight that non-motor assessments are necessary components of a case-based, holistic approach of DBS indication evaluations geared towards optimising postoperative QoL outcomes. TRIAL REGISTRATION NUMBER: GermanClinicalTrialsRegister: #6735.

Botulism after intragastric botulinum toxin injections for weight reduction.

Although-considering the risk-benefit ratio-botulinum neurotoxin A (BoNT/A) is unequivocally recommended to treat severe neurological diseases such as dystonia, this has not yet been determined for its endoscopic intragastric injection aimed at weight reduction in obesity. However, severe adverse effects of intragastric BoNT/A had not yet been reported, prompting some European countries to endorse its (off-label) use and treat patients transnationally. We here present three cases of botulism after intragastric BoNT/A injections for obesity treatment in a Turkish hospital. Patients presented with cranial nerve affection, bulbar symptoms, and descending paresis, and benefited from treatment with BoNT antitoxin and pyridostigmine. We assume that iatrogenic botulism was induced by overdosing in combination with toxin spread via the highly vascularized gastric tissue. Of note, within a few weeks, more than 80 cases of iatrogenic botulism were reported across Europe after identical intragastric BoNT/A injections. These cases demonstrate the risks of BoNT/A injections if they are not applied within the limits of evidence-based medicine. There is a need for international guidelines to define the indication and a safe dosing scheme, especially in the context of medical tourism.

The manifestation of affective symptoms in multiple sclerosis and discussion of the currently available diagnostic assessment tools.

INTRODUCTION: In addition to physical and cognitive symptoms, patients with multiple sclerosis (MS) have an increased risk of experiencing mental health problems. METHODS: This narrative review provides an overview of the appearance and epidemiology of affective symptoms in MS such as depression, anxiety, bipolar disorder, euphoria, and pseudobulbar affect. Furthermore, the association between affective symptoms and quality of life and the currently used diagnostic instruments for assessing these symptoms are considered whereby relevant studies published between 2009 and 2021 were included in the review. RESULTS: Patients with mild and moderate disability more frequently reported severe problems with depression and anxiety than severe mobility problems. Apart from the occurrence of depression, little is known about the association of other affective symptoms such as anxiety, bipolar disorder, euphoria, and pseudobulbar affect and subsyndromal symptoms, which fail to meet the diagnostic criteria but are nevertheless a significant source of distress. Although there are a few recommendations in the research to perform routine screenings for diagnosable affective disorders, a standardized diagnostic procedure to assess subsyndromal symptoms is still lacking. As the applied measurements are diverse and show low accuracy to detect these symptoms, patients who experience affective symptoms are less likely to be identified. DISCUSSION: In addition to the consideration of definite psychiatric diagnoses, there is an unmet need for a common definition and assessment of disease-related affective symptoms in MS. Future studies should focus on the improvement and standardization of a common diagnostic procedure for subsyndromal affective symptoms in MS to enable integrated and optimal care for patients.

Glia from the central and peripheral nervous system are differentially affected by paclitaxel chemotherapy via modulating their neuroinflammatory and neuroregenerative properties.

Glia are critical players in defining synaptic contacts and maintaining neuronal homeostasis. Both astrocytes as glia of the central nervous system (CNS), as well as satellite glial cells (SGC) as glia of the peripheral nervous system (PNS), intimately interact with microglia, especially under pathological conditions when glia regulate degenerative as well as regenerative processes. The chemotherapeutic agent paclitaxel evokes peripheral neuropathy and cognitive deficits; however, the mechanisms underlying these diverse clinical side effects are unclear. We aimed to elucidate the direct effects of paclitaxel on the function of astrocytes, microglia, and SGCs, and their glia-glia and neuronal-glia interactions. After intravenous application, paclitaxel was present in the dorsal root ganglia of the PNS and the CNS of rodents. In vitro, SGC enhanced the expression of pro-inflammatory factors and reduced the expression of neurotrophic factor NT-3 upon exposure to paclitaxel, resulting in predominantly neurotoxic effects. Likewise, paclitaxel induced a switch towards a pro-inflammatory phenotype in microglia, exerting neurotoxicity. In contrast, astrocytes expressed neuroprotective markers and increasingly expressed S100A10 after paclitaxel exposure. Astrocytes, and to a lesser extent SGCs, had regulatory effects on microglia independent of paclitaxel exposure. Data suggest that paclitaxel differentially modulates glia cells regarding their (neuro-) inflammatory and (neuro-) regenerative properties and also affects their interaction. By elucidating those processes, our data contribute to the understanding of the mechanistic pathways of paclitaxel-induced side effects in CNS and PNS.

Transcranial-Direct-Current-Stimulation Accelerates Motor Recovery After Cortical Infarction in Mice: The Interplay of Structural Cellular Responses and Functional Recovery.

BACKGROUND: Transcranial direct current stimulation (tDCS) promotes recovery after stroke in humans. The underlying mechanisms, however, remain to be elucidated. Animal models suggest tDCS effects on neuroinflammation, stem cell proliferation, neurogenesis, and neural plasticity. OBJECTIVE: In a longitudinal study, we employed tDCS in the subacute and chronic phase after experimental focal cerebral ischemia in mice to explore the relationship between functional recovery and cellular processes. METHODS: Mice received photothrombosis in the right motor cortex, verified by Magnetic Resonance Imaging. A composite neuroscore quantified subsequent functional deficits. Mice received tDCS daily: either 5 sessions from day 5 to 9, or 10 sessions with days 12 to 16 in addition. TDCS with anodal or cathodal polarity was compared to sham stimulation. Further imaging to assess proliferation and neuroinflammation was performed by immunohistochemistry at different time points and Positron Emission Tomography at the end of the observation time of 3 weeks. RESULTS: Cathodal tDCS at 198 kC/m2 (220 A/m2) between days 5 and 9 accelerated functional recovery, increased neurogenesis, decreased microglial activation, and mitigated CD16/32-expression associated with M1-phenotype. Anodal tDCS exerted similar effects on neurogenesis and microglial polarization but not on recovery of function or microglial activation. TDCS on days 12 to 16 after stroke did not induce any further effects, suggesting that the therapeutic time window was closed by then. CONCLUSION: Overall, data suggest that non-invasive neuromodulation by tDCS impacts neurogenesis and microglial activation as critical cellular processes influencing functional recovery during the early phase of regeneration from focal cerebral ischemia.

Status epilepticus during the COVID-19 pandemic in Cologne, Germany: data from a retrospective, multicentre registry.

BACKGROUND: The "coronavirus disease 2019" (COVID-19) pandemic, caused by the "severe-acute-respiratory-syndrome-coronavirus 2" (SARS-CoV-2), challenges healthcare systems worldwide and impacts not only COVID-19 patients but also other emergencies. To date, data are scarce on the extent to which the COVID-19 pandemic impacted status epilepticus (SE) and its treatment. OBJECTIVE: To assess the influence of the COVID-19 pandemic on the incidence, management and outcome of SE patients. STUDY DESIGN: This is a retrospective, multicentre trial, approved by the University of Cologne (21-1443-retro). METHODS: All SE patients from the urban area of Cologne transmitted to all acute neurological departments in Cologne between 03/2019 and 02/2021 were retrospectively analysed and assessed for patient characteristics, SE characteristics, management, and outcome in the first pandemic year compared to the last pre-pandemic year. RESULTS: 157 pre-pandemic (03/2019-02/2020) and 171 pandemic (from 03/2020 to 02/2021) SE patients were included in the analyses. Acute SARS-CoV-2 infections were rarely detected. Patient characteristics, management, and outcome did not reveal significant groupwise differences. In contrast, regarding prehospital management, a prolonged patient transfer to the hospital and variations in SE aetiologies compared to the last pre-pandemic year were observed with less chronic vascular and more cryptogenic and anoxic SE cases. No infections with SARS-CoV-2 occurred during inpatient stays. CONCLUSIONS: SARS-CoV-2 infections did not directly affect SE patients, but the transfer of SE patients to emergency departments was delayed. Interestingly, SE aetiology rates shifted, which warrants further exploration. Fears of contracting an in-hospital SARS-CoV-2-infection were unfounded due to consequent containment measures.

Meaningful use of imaging resources to rule out cerebral venous sinus thrombosis after ChAdOx1 COVID-19 vaccination: Evaluation of the AHA diagnostic algorithm with a clinical cohort and a systematic data review.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) with cerebral venous thrombosis (CVST) is an improbable (0.0005%), however potentially lethal complication after ChAdOx1 vaccination. On the other hand, headache is among the most frequent side effects of ChAdOx1 (29.3%). In September 2021, the American Heart Association (AHA) suggested a diagnostic workflow to facilitate risk-adapted use of imaging resources for patients with neurological symptoms after ChAdOx1. We aimed to evaluate the AHA workflow in a retrospective patient cohort presenting at four primary care hospitals in Germany for neurological complaints after ChAdOx1. Scientific literature was screened for case reports of VITT with CVST after ChAdOx1, published until September 1st, 2021. One-hundred-thirteen consecutive patients (77 female, mean age 38.7 +/- 11.9 years) were evaluated at our institutes, including one case of VITT with CVST. Further 228 case reports of VITT with CVST are published in recent literature, which share thrombocytopenia (225/227 reported) and elevated d-dimer levels (100/101 reported). The AHA workflow would have recognized all VITT cases with CVST (100% sensitivity), the number needed to diagnose (NND) was 1:113. Initial evaluation of thrombocytopenia or elevated d-dimer levels would have lowered the NND to 1:68, without cost of sensitivity. Hence, we suggest that in case of normal thrombocyte and d-dimer levels, the access to further diagnostics should be limited by the established clinical considerations regardless of vaccination history.

Osteopontin regulates proliferation, migration, and survival of astrocytes depending on their activation phenotype.

The glycoprotein osteopontin is highly upregulated in central nervous system (CNS) disorders such as ischemic stroke. Osteopontin regulates cell growth, cell adhesion, homeostasis, migration, and survival of various cell types. Accordingly, osteopontin is considered an essential regulator of regeneration and repair in the ischemic milieu. Astrocytes are the most abundant cells in the CNS and play significant roles in health and disease. Astrocytes are involved in homeostasis, promote neuroprotection, and regulate synaptic plasticity. Upon activation, astrocytes may adopt different phenotypes, termed A1 and A2. The direct effects of osteopontin on astrocytes, especially in distinct activation states, are yet unknown. The current study aimed to elucidate the impact of osteopontin on resting and active astrocytes. We established an inflammatory in vitro model of activated (A1) primary astrocytes derived from neonatal wistar rats by exposure to a distinct combination of proinflammatory cytokines. To model ischemic stroke in vitro, astrocytes were subjected to oxygen and glucose deprivation (OGD) in the presence or absence of osteopontin. Osteopontin modulated the activation phenotype by attenuating A1- and restoring A2-marker expression without compromising the active astrocytes' immunocompetence. Osteopontin promoted the proliferation of active and the migration of resting astrocytes. Following transient OGD, osteopontin mitigated the delayed ongoing death of primary astrocytes, promoting their survival. Data suggest that osteopontin differentially regulates essential functions of resting and active astrocytes and confirm a significant regulatory role of osteopontin in an in vitro ischemia model. Furthermore, the data suggest that osteopontin constitutes a promising target for experimental therapies modulating neuroregeneration and repair.

Assessment of Affective-Behavioral States in Parkinson's Disease Patients: Towards a New Screening Tool.

BACKGROUND: Assessment of affective-behavioral states in patients with Parkinson's disease (PD) undergoing deep brain stimulation (DBS) is essential. OBJECTIVE: To analyze well-established questionnaires as a pilot-study with the long term aim to develop a screening tool evaluating affective-behavioral dysfunction, including depression, anxiety, apathy, mania, and impulse control disorders, in PD patients screened for DBS. METHODS: Two hundred ninety-seven inpatients with PD underwent standardized neuropsychiatric testing including German versions of Beck Depression Inventory-II, Hospital Anxiety and Depression Scale, Apathy Evaluation Scale, Self-Report Manic Inventory, and Questionnaire for Impulsive-Compulsive Disorders in PD-Rating Scale, to assess appropriateness for DBS. Statistical item reduction was based on exploratory factor analysis, Cronbach's alpha, item-total correlations, item difficulty, and inter-item correlations. Confirmatory factor analysis was conducted to assess factorial validity. An expert rating was performed to identify clinically relevant items in the context of PD and DBS, to maintain content validity. We compared the shortened subscales with the original questionnaires using correlations. To determine cutoff points, receiver operating characteristics analysis was performed. RESULTS: The items of the initial questionnaires were reduced from 129 to 38 items. Results of confirmatory factor analyses supported the validity of the shortened pool. It demonstrated high internal consistency (Cronbach's alpha = 0.72-0.83 across subscales), and the individual subscales were correlated with the corresponding original scales (rs = 0.84-0.95). Sensitivities and specificities exceeded 0.7. CONCLUSION: The shortened item pool, including 38 items, provides a good basis for the development of a screening tool, capturing affective-behavioral symptoms in PD patients before DBS implantation. Confirmation of the validity of such a screening tool in an independent sample of PD patients is warranted.

Mental symptoms in MS (MeSyMS): Development and validation of a new assessment.

BACKGROUND: Patients with Multiple Sclerosis (MS) have an increased risk of suffering from mental and neuropsychiatric symptoms. So far, a fundamental problem in the clinical care of MS patients is that these symptoms are underdiagnosed and, as a consequence, often remain untreated. Present assessment tools have not been developed to be applied in patients with MS. This study aims to develop and validate a new questionnaire to identify disease-related mental symptoms in MS patients. METHODS: A questionnaire has been developed by including the following subscales: social and emotional health problems, anxiety, and depression. To evaluate test quality and internal consistency, an item analysis has been conducted. After matching MS patients and control subjects on age and gender, we conducted group comparisons, a Receiver Operating Characteristic (ROC) Curve analysis and a binary logistic regression model. RESULTS: In total, 314 MS patients and 100 matched control subjects were analysed. After performed item analysis, the questionnaire revealed an excellent internal consistency (α=0.94). Compared to control subjects, MS patients showed significant mental health problems in all three dimensions. In comparison to the subscales, the dimension of social and emotional health problems revealed the highest accuracy (AUC = 0.75; d = 0.948) and turned out to be the only scale that reliably differentiated between the groups. CONCLUSIONS: MeSyMS constitutes a valid screening instrument to detect mental symptoms in MS. Social and emotional health problems turned out to be the most important aspect when identifying disease-related mental health symptoms in MS.

Comparison of Accuracy of Arrival-Time-Insensitive and Arrival-Time-Sensitive CTP Algorithms for Prediction of Infarct Tissue Volumes.

The purpose of this study was to compare the performance of arrival-time-insensitive (ATI) and arrival-time-sensitive (ATS) computed tomography perfusion (CTP) algorithms in Philips IntelliSpace Portal (v9, ISP) and to investigate optimal thresholds for ATI regarding the prediction of final infarct volume (FIV). Retrospective, single-center study with 54 patients (mean 67.0 ± 13.1 years, 68.5% male) who received Stroke-CT/CTP-imaging between 2010 and 2018 with occlusion of the middle cerebral artery in the M1-/proximal M2-segment or terminal internal carotid artery. FIV was determined on short-term follow-up imaging in two patient groups: A) not attempted or failed mechanical thrombectomy (MT) and B) successful MT. ATS (default settings) and ATI (full-range of threshold settings regarding FIV prediction) maps were coregistered in 3D with FIV using voxel-wise overlap measurement. Based on an average imaging follow-up of 2.6 ± 2.1 days, the estimation regarding penumbra (group A, ATI: r = 0.63/0.69, ATS: r = 0.64) and infarct core (group B, ATI: r = 0.60/0.68, ATS: r = 0.63) was slightly higher in ATI but the effect was not significant (p > 0.05). Regarding ATI, Tmax (AUC 0.9) was the best estimator of the penumbra (group A), CBF relative to the contralateral hemisphere (AUC 0.80) showed the best estimation of the infarct core (group B). There was a broad range of thresholds of optimal ATI settings in both groups. Prediction of FIV with ATI was slightly better compared to ATS. However, this difference was not significant. Since ATI showed a broad range of optimal thresholds, exact thresholds regarding the ATI algorithm should be evaluated in further prospective, clinical studies.

A prospective, controlled study of non-motor effects of subthalamic stimulation in Parkinson's disease: results at the 36-month follow-up.

OBJECTIVE: To examine 36-month effects of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) on non-motor symptoms (NMS) compared with standard-of-care medical treatment (MED) in Parkinson's disease (PD). METHODS: Here we report the 36-month follow-up of a prospective, observational, controlled, international multicentre study of the NILS cohort. Assessments included NMSScale (NMSS), PDQuestionnaire-8 (PDQ-8), Scales for Outcomes in PD (SCOPA)-motor examination, -activities of daily living, and -complications, and levodopa equivalent daily dose (LEDD). Propensity score matching resulted in a pseudo-randomised sub-cohort balancing baseline demographic and clinical characteristics between the STN-DBS and MED groups. Within-group longitudinal outcome changes were analysed using Wilcoxon signed-rank and between-group differences of change scores with Mann-Whitney U test. Strength of clinical responses was quantified with Cohen's effect size. In addition, bivariate correlations of change scores were explored. RESULTS: Propensity score matching applied on the cohort of 151 patients (STN-DBS n=67, MED n=84) resulted in a well-balanced sub-cohort including 38 patients per group. After 36 months, STN-DBS significantly improved NMSS, PDQ-8, SCOPA-motor examination and -complications and reduced LEDD. Significant between-group differences, all favouring STN-DBS, were found for NMSS, SCOPA-motor complications, LEDD (large effects), motor examination and PDQ-8 (moderate effects). Furthermore, significant differences were found for the sleep/fatigue, urinary (large effects) and miscellaneous NMSS domains (moderate effects). NMSS total and PDQ-8 change scores correlated significantly. CONCLUSIONS: This study provides Class IIb evidence for beneficial effects of STN-DBS on NMS at 36-month follow-up which also correlated with quality of life improvements. This highlights the importance of NMS for DBS outcomes assessments.

The impact of hyperpolarization-activated cyclic nucleotide-gated (HCN) and voltage-gated potassium KCNQ/Kv7 channels on primary microglia function.

BACKGROUND: Microglia are essential to maintain cell homeostasis in the healthy brain and are activated after brain injury. Upon activation, microglia polarize towards different phenotypes. The course of microglia activation is complex and depends on signals in the surrounding milieu. Recently, it has been suggested that microglia respond to ion currents, as a way of regulating their activity and function. METHODS AND RESULTS: Under the hypothesis that HCN and KCNQ/Kv7 channels impact on microglia, we studied primary rat microglia in the presence or absence of specific pharmacological blockade or RNA silencing. Primary microglia expressed the subunits HCN1-4, Kv7.2, Kv7.3, and Kv7.5. The expression of HCN2, as well as Kv7.2 and Kv7.3, varied among different microglia phenotypes. The pharmacological blockade of HCN channels by ZD7288 resulted in cell depolarization with slowly rising intracellular calcium levels, leading to enhanced survival and reduced proliferation rates of resting microglia. Furthermore, ZD7288 treatment, as well as knockdown of HCN2 RNA by small interfering RNA, resulted in an attenuation of later microglia activation-both towards the anti- and pro-inflammatory phenotype. However, HCN channel inhibition enhanced the phagocytic capacity of IL4-stimulated microglia. Blockade of Kv7/KCNQ channel by XE-991 exclusively inhibited the migratory capacity of resting microglia. CONCLUSION: These observations suggest that the HCN current contributes to various microglia functions and impacts on the course of microglia activation, while the Kv7/KCNQ channels affect microglia migration. Characterizing the role of HCN channels in microglial functioning may offer new therapeutic approaches for targeted modulation of neuroinflammation as a hallmark of various neurological disorders.

Crosstalk between stressed brain cells: direct and indirect effects of ischemia and aglycemia on microglia.

BACKGROUND: In cerebral ischemia, microglia have a dichotomous role in keeping the balance between pro- and anti-inflammatory mediators to avoid deleterious chronic inflammation and to leverage repair processes. METHODS: We examined functional and inflammatory markers in primary rat microglia in vitro after oxygen-glucose deprivation (OGD) or glucose deprivation (aglycemia). We then investigated the preconditioning effect of OGD or aglycemia upon a subsequent strong inflammatory stimulus, here lipopolysaccharides (LPS). Moreover, an "in vitro brain model" of neurons and glia, differentiated from primary rat neural stem cells, was exposed to OGD or aglycemia. Conditioned medium (CM) of this neuronal/glial co-culture was then used to condition microglia, followed by LPS as a "second hit." RESULTS: OGD or aglycemia at sublethal doses did not significantly affect microglia function, including the expression of inflammatory markers. However, preconditioning with either OGD or aglycemia led to a decreased pro-inflammatory response to a subsequent stimulus with LPS. Interestingly, the anti-inflammatory markers IGF-1 and IL-10 were additionally reduced after such preconditioning, while expression of CD206 remained unaffected. Treatment with CM from the neuronal/glial co-culture alone did not affect the expression of inflammatory markers in microglia. In contrast, treatment with CM increased the expression of both pro- and anti-inflammatory markers in microglia upon a second hit with LPS. Interestingly, this effect could be attenuated in microglia treated with CM from neuronal/glia co-cultures preconditioned with OGD or aglycemia. CONCLUSIONS: Data suggest specific and distinct microglia signatures in response to metabolic stress. While metabolic stress directly and indirectly applied to microglia did not mitigate their subsequent response to inflammation, preconditioning with metabolic stress factors such as OGD and aglycemia elicited a decreased inflammatory response to a subsequent inflammation stimulus.

Transcranial Current Stimulation Alters the Expression of Immune-Mediating Genes.

Despite its extensive use in clinical studies, the molecular mechanisms underlying the effects of transcranial direct current stimulation (tDCS) remain to be elucidated. We previously described subacute effects of tDCS on immune- and stem cells in the rat brain. To investigate the more immediate effects of tDCS regulating those cellular responses, we treated rats with a single session of either anodal or cathodal tDCS, and analyzed the gene expression by microarray; sham-stimulated rats served as control. Anodal tDCS increased expression of several genes coding for the major histocompatibility complex I (MHC I), while cathodal tDCS increased the expression of the immunoregulatory protein osteopontin (OPN). We confirmed the effects of gene upregulation by immunohistochemistry at the protein level. Thus, our data show a novel mechanism for the actions of tDCS on immune- and inflammatory processes, providing a target for future therapeutic studies.

Heparin for prophylaxis of venous thromboembolism in intracerebral haemorrhage.

OBJECTIVE: To determine the occurrence of intracranial haemorrhagic complications (IHC) on heparin prophylaxis (low-dose subcutaneous heparin, LDSH) in primary spontaneous intracerebral haemorrhage (ICH) (not oral anticoagulation-associated ICH, non-OAC-ICH), vitamin K antagonist (VKA)-associated ICH and non-vitamin K antagonist oral anticoagulant (NOAC)-associated ICH. METHODS: Retrospective cohort study (RETRACE) of 22 participating centres and prospective single-centre study with 1702 patients with VKA-associated or NOAC-associated ICH and 1022 patients with non-OAC-ICH with heparin prophylaxis between 2006 and 2015. Outcomes were defined as rates of IHC during hospital stay among patients with non-OAC-ICH, VKA-ICH and NOAC-ICH, mortality and functional outcome at 3 months between patients with ICH with and without IHC. RESULTS: IHC occurred in 1.7% (42/2416) of patients with ICH. There were no differences in crude incidence rates among patients with VKA-ICH, NOAC-ICH and non-OAC-ICH (log-rank p=0.645; VKA-ICH: 27/1406 (1.9%), NOAC-ICH 1/130 (0.8%), non-OAC-ICH 14/880 (1.6%); p=0.577). Detailed analysis according to treatment exposure (days with and without LDSH) revealed no differences in incidence rates of IHC per 1000 patient-days (LDSH: 1.43 (1.04-1.93) vs non-LDSH: 1.32 (0.33-3.58), conditional maximum likelihood incidence rate ratio: 1.09 (0.38-4.43); p=0.953). Secondary outcomes showed differences in functional outcome (modified Rankin Scale=4-6: IHC: 29/37 (78.4%) vs non-IHC: 1213/2048 (59.2%); p=0.019) and mortality (IHC: 14/37 (37.8%) vs non-IHC: 485/2048 (23.7%); p=0.045) in disfavour of patients with IHC. Small ICH volume (OR: volume <4.4 mL: 0.18 (0.04-0.78); p=0.022) and low National Institutes of Health Stroke Scale (NIHSS) score on admission (OR: NIHSS <4: 0.29 (0.11-0.78); p=0.014) were significantly associated with fewer IHC. CONCLUSIONS: Heparin administration for venous thromboembolism (VTE) prophylaxis in patients with ICH appears to be safe regarding IHC among non-OAC-ICH, VKA-ICH and NOAC-ICH in this observational cohort analysis. Randomised controlled trials are needed to verify the safety and efficacy of heparin compared with other methods for VTE prevention.

Substrate elasticity induces quiescence and promotes neurogenesis of primary neural stem cells-A biophysical in vitro model of the physiological cerebral milieu.

In the brain, neural stem cells (NSC) are tightly regulated by external signals and biophysical cues mediated by the local microenvironment or "niche." In particular, the influence of tissue elasticity, known to fundamentally affect the function of various cell types in the body, on NSC remains poorly understood. We, accordingly, aimed to characterize the effects of elastic substrates on critical NSC functions. Primary rat NSC were grown as monolayers on polydimethylsiloxane- (PDMS-) based gels. PDMS-coated cell culture plates, simulating the physiological microenvironment of the living brain, were generated in various degrees of elasticity, ranging from 1 to 50 kPa; additionally, results were compared with regular glass plates as usually used in cell culture work. Survival of NSC on the PDMS-based substrates was unimpaired. The proliferation rate on 1 kPa PDMS decreased by 45% compared with stiffer PMDS substrates of 50 kPa (p < 0.05) whereas expression of cyclin-dependent kinase inhibitor 1B/p27Kip1 increased more than two fold (p < 0.01), suggesting NSC quiescence. NSC differentiation was accelerated on softer substrates and favored the generation of neurons (42% neurons on 1 kPa PDMS vs. 25% on 50 kPa PDMS; p < 0.05). Neurons generated on 1 kPa PDMS showed 29% longer neurites compared with those on stiffer PDMS substrates (p < 0.05), suggesting optimized neuronal maturation and an accelerated generation of neuronal networks. Data show that primary NSC are significantly affected by the mechanical properties of their microenvironment. Culturing NSC on a substrate of brain-like elasticity keeps them in their physiological, quiescent state and increases their neurogenic potential.

Correction to: Mechanical Thrombectomy in Basilar Artery Occlusion : Presence of Bilateral Posterior Communicating Arteries is a Predictor of Favorable Clinical Outcome.

Correction to: Clin Neuroradiol 2017 https://doi.org/10.1007/s00062-017-0651-3 The original version of this article unfortunately contained a mistake. The presentation of Fig. 2 was incorrect. The corrected figure is given ….

Mechanical Thrombectomy in Basilar Artery Occlusion : Presence of Bilateral Posterior Communicating Arteries is a Predictor of Favorable Clinical Outcome.

BACKGROUND: Mechanical thrombectomy (MT) of basilar artery occlusions (BAO) is a subject of debate. We investigated the clinical outcome of MT in BAO and predictors of a favorable outcome. MATERIAL AND METHODS: A total of 104 MTs of BAO (carried out between 2010 and 2016) were analyzed. Favorable outcome as a modified Rankin scale (mRS) ≤ 2 at 90 days was the primary endpoint. The influence of the following variables on outcome was investigated: number of detectable posterior communicating arteries (PcoAs), patency of basilar tip, completeness of BAO and posterior circulation Alberta Stroke Program early computed tomography score (PC-ASPECTS). Secondary endpoints were technical periprocedural parameters including symptomatic intracranial hemorrhage (sICH). RESULTS: The favorable clinical outcome at 90 days was 25% and mortality was 43%. The rate of successful reperfusion, i.e. modified thrombolysis in cerebral infarction (mTICI) ≥ 2b was 82%. Presence of bilateral PcoAs (area under the curve, AUC: 0.81, odds ratio, OR: 4.2, 2.2-8.2; p < 0.0001), lower National Institute of Health Stroke Scale (NIHSS) on admission (AUC: 0.74, OR: 2.6, 1.3-5.2; p < 0.01), PC-ASPECTS ≥ 9 (AUC: 0.72, OR: 4.2, 1.5-11.9; p < 0.01), incomplete BAO (AUC: 0.66, OR: 2.6, 1.4-4.8; p < 0.001), and basilar tip patency (AUC: 0.66, OR: 2.5, 1.3-4.8; p < 0.01) were associated with a favorable outcome. Stepwise logistic regression analysis revealed that the strongest predictors of favorable outcome at 90 days were bilateral PcoAs, low NIHSS on admission, and incomplete BAO (AUC: 0.923, OR: 7.2, 3-17.3; p < 0.0001). CONCLUSION: The use of MT for BAO is safe with high rates of successful reperfusion. Aside from baseline NIHSS and incomplete vessel occlusion, both known predictors of favorable outcome in anterior circulation events, we found that collateral flow based on the presence or absence of PcoAs had a decisive prognostic impact.

Order of Treatment Matters in Ischemic Stroke: Mechanical Thrombectomy First, Then Carotid Artery Stenting for Tandem Lesions of the Anterior Circulation.

BACKGROUND: One endovascular treatment option of acute ischemic stroke due to tandem occlusion (TO) comprises intracranial thrombectomy and acute extracranial carotid artery stenting (CAS). In this setting, the order of treatment may impact the clinical outcome in this stroke subtype. METHODS: Retrospective analysis was performed on data prospectively collected in 4 international stroke centers between 2013 and 2017. One hundred sixty-five patients with anterior TO were treated by endovascular therapy. Clinical and procedural data were evaluated. Favorable clinical outcome was defined as modified Rankin Scale (mRS) ≤2 at 90 days. Propensity score matching was performed for different treatment strategies. RESULTS: Patients' mean age was 65 ± 11 years and 118 were male (69%). The median admission National Institutes of Health Stroke Scale was 15 (interquartile range 8). In 59% of the patients (n = 101), the antegrade strategy (first stenting, then thrombectomy) was -performed, in 41% (n = 70) retrograde treatment (first thrombectomy, then stenting). Successful reperfusion (mTICI ≥2b) was achieved in 128 patients (75%). Fifty-nine patients (39%) showed a favorable clinical outcome after 90 days. After propensity score matching, data of 100 patients could be analyzed. Analysis revealed that the retrograde strategy yielded a significantly higher rate of successful reperfusion compared to the antegrade strategy (92 vs. 56%; p < 0.001). The rate of favorable clinical outcome after 90 days (mRS ≤2) was consistently higher (44 vs. 30%; p < 0.05) in the retrograde strategy group. CONCLUSION: Mechanical thrombectomy prior to acute CAS in TO is a predictive factor for favorable clinical outcome at 90 days.