Case fatality and functional outcome after spontaneous subarachnoid haemorrhage: A systematic review and meta-analysis of time trends and regional variations in population-based studies.

INTRODUCTION: A previous systematic review of population-based studies from 1973 to 2002 found a decrease in case fatality for spontaneous subarachnoid haemorrhage, but could not find a sufficient number of studies to assess changes in functional outcome. Since then, treatment has advanced distinctly. We assessed whether case fatality has decreased further and whether functional outcome has improved. PATIENTS AND METHODS: We searched PubMed and Web of Science for new population-based studies using the same criteria as in our previous systematic review. We assessed changes in case fatality and functional outcome over time using linear regression. RESULTS: We included 24 new studies with 827 patients and analysed 9542 patients described in 62 study periods between 1973 and 2017. Case fatality decreased by 0.3% (95% CI: -0.7 to 0.1) per year. In a sensitivity analysis excluding studies that did not provide 1-month outcome and outliers, the age and sex-adjusted decrease was 0.1% per year (95% CI: -0.9 to 0.6). The mean case fatality rate decreased from 47% (95% CI: 31-63) in the 1970s to 35% (95% CI: 30-39) in the 1990s, and remained stable in the 2000s (34%; 95% CI: 27-41) and 2010s (38%; 95% CI: 15-60). In 15 studies, the mean proportion of patients living independently increased by 0.2% per year (95%CI: -0.7 to 1.1) and the mean was 45% (95% CI: 39-50) in six studies that reported outcome after 12 months. DISCUSSION AND CONCLUSION: From 1973 to 2017, the case-fatality rate of spontaneous subarachnoid haemorrhage declined overall by 13.5%, but remained stable over the last two decades. The data on time trends in functional outcome were inconclusive.

Vagus nerve stimulation for the treatment of narcolepsy.

BACKGROUND AND OBJECTIVE: No study on neurostimulation in narcolepsy is available until now. Arousal- and wake-promoting effects of vagus nerve stimulation (VNS) have been demonstrated in animal experiments and are well-known as side effects of VNS therapy in epilepsy and depression. The objective was to evaluate the therapeutic effect of VNS on daily sleepiness and cataplexies in narcolepsy. METHODS: In our open-label prospective comparative study, we included narcolepsy patients who were treated with VNS because of depression or epilepsy and compared them to controls without narcolepsy treated with VNS for depression or epilepsy (18 patients in each group, aged 31.5 ± 8.2 years). We evaluated daily sleepiness (Epworth Sleepiness Scale, ESS) and the number of cataplexies per week before the implantation of VNS and at three and six month follow-ups. RESULTS: Compared to baseline (ESS: 15.9 ± 2.5) patients with narcolepsy showed a significant improvement on ESS after three months (11.2 ± 3.3, p < 0.05) and six months (9.6 ± 2.8, p < 0.001) and a trend to reduction of cataplexies. No significant ESS-improvement was observed in patients without narcolepsy (14.9 ± 3.9, 13.6 ± 3.7, 13.2 ± 3.5, p = 0.2 at baseline, three and six months, correspondingly). Side effects did not differ between the study groups. CONCLUSION: In this first evaluation of VNS in narcolepsy, we found a significant improvement of daily sleepiness due to this type of neurostimulation. VNS could be a promising non-medical treatment in narcolepsy.

Synergistic effects of vagus nerve stimulation and antiseizure medication.

INTRODUCTION: Vagus nerve stimulation (VNS) is an effective, non-pharmacological therapy for epileptic seizures. Until now, favorable combinations of different groups of antiseizure medication (ASM) and VNS have not been sufficiently addressed. The aim of this study was to identify the synergistic effects between VNS and different ASMs. METHODS: We performed an observational study of patients with epilepsy who were implanted with VNS and had a stable ASM therapy during the first 2 years after the VNS implantation. Data were collected from the Mainz Epilepsy Registry. The efficacy of VNS depending on the concomitantly used ASM group/individual ASMs was assessed by quantifying the responder rate (≥ 50% seizure reduction compared to the time of VNS implantation) and seizure freedom (absence of seizures during the last 6 months of the observation period). RESULTS: One hundred fifty one patients (mean age 45.2 ± 17.0 years, 78 females) were included in the study. Regardless of the used ASM, the responder rate in the whole cohort was 50.3% and the seizure freedom was 13.9%. Multiple regression analysis showed that combination of VNS with synaptic vesicle glycoprotein (SV2A) modulators (responder rate 64.0%, seizure freedom 19.8%) or slow sodium channel inhibitors (responder rate 61.8%, seizure freedom 19.7%) was associated with a statistically significant better responder rate and seizure freedom than combinations of VNS and ASM with other mechanism of action. Within these ASM groups, brivaracetam showed a more favorable effect than levetiracetam, whereas lacosamide and eslicarbazepine were comparable in their effects. CONCLUSION: Our data suggest that the combination of VNS with ASMs belonging to either SV2A modulators or slow sodium channel inhibitors could be optimal to achieve a better seizure control following VNS. However, these preliminary data require further validation under controlled conditions.

Validation of the German version of the subarachnoid haemorrhage outcome tool (SAHOT).

Objective: The subarachnoid haemorrhage (SAH) outcome tool (SAHOT) is the first SAH-specific patient reported outcome measure, and was developed in the UK. We aimed to validate the SAHOT outside the UK, and therefore endeavored to adapt the SAHOT into German and to test its psychometric properties. Methods: We adapted and pilot tested the German version. We applied the SAHOT, Quality of Life after Brain Injury, Hospital Anxiety and Depression Scale, and EuroQol questionnaires in a cohort of 89 patients with spontaneous SAH after discharge. We assessed internal consistency by Cronbach's α, test-retest reliability by intraclass correlation, and validity by Pearson correlations with established measures. Sensitivity to change was evaluated following neurorehabilitation by effect sizes. Results: The translation of SAHOT resulted in a German version that is semantically and conceptually equivalent to the English version. Internal consistency was good regarding the physical domain (α = 0.83) and excellent for the other domains (α = 0.92-0.93). Test-retest reliability indicated a high level of stability with an intraclass correlation of 0.85 (95% CI: 0.83-0.86). All domains correlated moderately or strongly with established measures (r = 0.41-0.74; p < 0.01). SAHOT total scores showed moderate sensitivity to change (Cohen's d = -0.68), while mRS and GOSE showed no significant sensitivity to change. Conclusion: The SAHOT can be adapted to other health care systems and societies than the UK. The German version of the SAHOT is a reliable and valid instrument, and can be used in future clinical studies and individual assessment after spontaneous SAH.

Deep Neural Network for Differentiation of Brain Tumor Tissue Displayed by Confocal Laser Endomicroscopy.

BACKGROUND: Reliable on site classification of resected tumor specimens remains a challenge. Implementation of high-resolution confocal laser endoscopic techniques (CLEs) during fluorescence-guided brain tumor surgery is a new tool for intraoperative tumor tissue visualization. To overcome observer dependent errors, we aimed to predict tumor type by applying a deep learning model to image data obtained by CLE. METHODS: Human brain tumor specimens from 25 patients with brain metastasis, glioblastoma, and meningioma were evaluated within this study. In addition to routine histopathological analysis, tissue samples were stained with fluorescein ex vivo and analyzed with CLE. We trained two convolutional neural networks and built a predictive level for the outputs. RESULTS: Multiple CLE images were obtained from each specimen with a total number of 13,972 fluorescein based images. Test accuracy of 90.9% was achieved after applying a two-class prediction for glioblastomas and brain metastases with an area under the curve (AUC) value of 0.92. For three class predictions, our model achieved a ratio of correct predicted label of 85.8% in the test set, which was confirmed with five-fold cross validation, without definition of confidence. Applying a confidence rate of 0.999 increased the prediction accuracy to 98.6% when images with substantial artifacts were excluded before the analysis. 36.3% of total images met the output criteria. CONCLUSIONS: We trained a residual network model that allows automated, on site analysis of resected tumor specimens based on CLE image datasets. Further in vivo studies are required to assess the clinical benefit CLE can have.

Adenosine-producing regulatory B cells in head and neck cancer.

BACKGROUND: Multiple mechanisms of immunosuppression have been identified in the tumor microenvironment including regulatory B cells (Breg). Recently, we have shown that Breg suppress T cell function by production of adenosine (ADO). However, the autocrine effect of ADO on B cells and the role of Breg in head and neck cancer remains unclear. METHODS: Blood (n = 42) and tumor tissue (n = 39) of head and neck cancer patients and healthy donors (n = 60) were analyzed by FACS. The effect of ADO on phenotype, intracellular signaling pathways, Ca2+ influx and ADO production was analyzed in Breg and effector B cells (Beff) by FACS, luminescence and mass spectrometry. The blockage of the ADO receptor A2A was analyzed in a murine head and neck cancer model. RESULTS: ADO-producing Breg were found in tumor tissue and peripheral blood. ADO inhibited the intracellular Bruton's tyrosine kinase (BTK) and Ca2+ influx only in Beff. The inhibition of BTK by ibrutinib mimicked the effect of ADO, and ibrutinib reduced the production of ADO by downregulation of CD39 in vitro. The inhibition of ADO receptor A2A significantly reduced tumor mass and increased B cell infiltration, in vivo. CONCLUSION: Our data demonstrate the presence of a novel ADO-producing Breg population within the tumor microenvironment in mice and humans. A new model is proposed on how ADO-producing Breg can influence the function of Beff cells in healthy donors and cancer patients. Thus, the modulation of the ADO pathway in B cells may serve as a therapeutic approach for cancer patients.

The influence of chemotherapy on adenosine-producing B cells in patients with head and neck squamous cell carcinoma.

INTRODUCTION: Head and neck squamous cell carcinoma (HNSCC) strongly suppresses the immune system, resulting in increased metastasis and recurrent disease. Chemotherapy is part of the multimodal treatment but may further immunosuppression. Recently, we demonstrated that regulatory B cells (Breg), defined as CD19+CD39+CD73+ B cells, play a significant role in the production of immunosuppressive, extracellular adenosine (ADO). Here, we tested the influence of chemotherapy on Breg function. RESULTS: In HNSCC patients, Breg were diminished in absolute number and frequency after chemotherapy (paired samples). Chemotherapeutic drugs had variable effects; while platinum-based chemotherapy decreased the expression of CD39, methotrexate led to a functional increase in CD39 expression and increased production of immunosuppressive ADO. These findings were confirmed in a second patient cohort. Surface expression of CD39 correlated strongly with the production of ADO as measured by mass spectrometry. CONCLUSIONS: Platinum-based anti-tumor-therapy reduces the number of adenosine-producing B cells and, consequently, potential immunosuppression within the tumor environment. Breg function in terms of ADO production and their potential capacity to suppress CD4+ T cells are promoted by methotrexate treatment amplifying anti-inflammatory therapeutic effects. Our results add to the understanding of how chemotherapeutic drugs can influence the human immune system and may therefore help to orchestrate standard oncologic therapy with new immune modulating approaches. METHODS: Mononuclear cells were collected prospectively from HNSCC patients before and after chemotherapy (n = 18), from healthy donors (n = 20), and an additional cohort sampled several months after chemotherapy (n = 14). Frequency, phenotype, and function of Breg were determined by multicolor flow cytometry, ATP luminescence assay as well as mass spectrometry measuring 5'-AMP, ADO, and inosine. Isolated B cells were incubated with chemotherapeutic drugs (cisplatin, methotrexate, paclitaxel, 5-fluorouracil) in vitro for functional studies.