Human stem cell-derived neurons and astrocytes to detect novel auto-reactive IgG response in immune-mediated neurological diseases.

Background and objectives: Up to 46% of patients with presumed autoimmune limbic encephalitis are seronegative for all currently known central nervous system (CNS) antigens. We developed a cell-based assay (CBA) to screen for novel neural antibodies in serum and cerebrospinal fluid (CSF) using neurons and astrocytes derived from human-induced pluripotent stem cells (hiPSCs). Methods: Human iPSC-derived astrocytes or neurons were incubated with serum/CSF from 99 patients [42 with inflammatory neurological diseases (IND) and 57 with non-IND (NIND)]. The IND group included 11 patients with previously established neural antibodies, six with seronegative neuromyelitis optica spectrum disorder (NMOSD), 12 with suspected autoimmune encephalitis/paraneoplastic syndrome (AIE/PNS), and 13 with other IND (OIND). IgG binding to fixed CNS cells was detected using fluorescently-labeled antibodies and analyzed through automated fluorescence measures. IgG neuronal/astrocyte reactivity was further analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMCs) were used as CNS-irrelevant control target cells. Reactivity profile was defined as positive using a Robust regression and Outlier removal test with a false discovery rate at 10% following each individual readout. Results: Using our CBA, we detected antibodies recognizing hiPSC-derived neural cells in 19/99 subjects. Antibodies bound specifically to astrocytes in nine cases, to neurons in eight cases, and to both cell types in two cases, as confirmed by microscopy single-cell analyses. Highlighting the significance of our comprehensive 96-well CBA assay, neural-specific antibody binding was more frequent in IND (15 of 42) than in NIND patients (4 of 57) (Fisher's exact test, p = 0.0005). Two of four AQP4+ NMO and four of seven definite AIE/PNS with intracellular-reactive antibodies [1 GFAP astrocytopathy, 2 Hu+, 1 Ri+ AIE/PNS)], as identified in diagnostic laboratories, were also positive with our CBA. Most interestingly, we showed antibody-reactivity in two of six seronegative NMOSD, six of 12 probable AIE/PNS, and one of 13 OIND. Flow cytometry using hiPSC-derived CNS cells or PBMC-detected antibody binding in 13 versus zero patients, respectively, establishing the specificity of the detected antibodies for neural tissue. Conclusion: Our unique hiPSC-based CBA allows for the testing of novel neuron-/astrocyte-reactive antibodies in patients with suspected immune-mediated neurological syndromes, and negative testing in established routine laboratories, opening new perspectives in establishing a diagnosis of such complex diseases.

Complications of Intracranial Multimodal Monitoring for Neurocritical Care: A Systematic Review and Meta-Analysis.

Intracranial multimodal monitoring (iMMM) is increasingly used for neurocritical care. However, concerns arise regarding iMMM invasiveness considering limited evidence in its clinical significance and safety profile. We conducted a synthesis of evidence regarding complications associated with iMMM to delineate its safety profile. We performed a systematic review and meta-analysis (PROSPERO Registration Number: CRD42021225951) according to the Preferred Reporting Items for Systematic Review and Meta-Analysis and Peer Review of Electronic Search Strategies guidelines to retrieve evidence from studies reporting iMMM use in humans that mention related complications. We assessed risk of bias using the Newcastle-Ottawa Scale and funnel plots. The primary outcomes were iMMM complications. The secondary outcomes were putative risk factors. Of the 366 screened articles, 60 met the initial criteria and were further assessed by full-text reading. We included 22 studies involving 1206 patients and 1434 iMMM placements. Most investigators used a bolt system (85.9%) and a three-lumen device (68.8%), mainly inserting iMMM into the most injured hemisphere (77.9%). A total of 54 postoperative intracranial hemorrhages (pooled rate of 4%; 95% confidence interval [CI] 0-10%; I2 86%, p < 0.01 [random-effects model]) was reported, along with 46 misplacements (pooled rate of 6%; 95% CI 1-12%; I2 78%, p < 0.01) and 16 central nervous system infections (pooled rate of 0.43%; 95% CI 0-2%; I2 64%, p < 0.01). We found 6 system breakings, 18 intracranial bone fragments, and 5 cases of pneumocephalus. Currently, iMMM systems present a similar safety profile as intracranial devices commonly used in neurocritical care. Long-term outcomes of prospective studies will complete the benefit-risk assessment of iMMM in neurocritical care. Consensus-based reporting guidelines on iMMM use are needed to bolster future collaborative efforts.

Case report: Serious unexpected vascular events in two patients with lymphocytic variant hypereosinophilic syndrome.

Background: Lymphocytic-variant hypereosinophilic syndrome (L-HES) is a form of reactive hypereosinophilia, most commonly associated with interleukin-5 over-production by clonal, most commonly CD3-CD4+CD2hiCD5hiCD45RO+ T-cells. Patients often present with predominant cutaneous and soft-tissue manifestations, while cardiovascular involvement is uncommon. Methods: We reviewed the medical files of two L-HES patients followed in our center who developed serious vascular complications and performed a literature review for similar cases. Results: Patient 1, a 52-year-old female, presented with an ischemic stroke secondary to left middle cerebral artery dissection after 10 years of indolent L-HES. Blood eosinophilia was controlled with oral corticosteroids (OCS), but OCS-tapering attempts with hydroxyurea and pegylated interferon failed, prompting the introduction of mepolizumab with rapid normalization. Patient 2, a 62-year-old female, had been asymptomatic for 10 years without treatment when a NSTEMI occurred, due to coronary artery occlusion secondary to a large cauliflower-aneurysm of the proximal aorta and aneurysmal dilatation of several coronary arteries, requiring semi-urgent surgical management. Aortic wall staining for eosinophil major basic protein showed eosinophils in the adventitia. Blood eosinophilia was controlled with OCS. Conclusions: Patients with apparently clinically benign L-HES may develop arterial complications, consisting in dissection and/or aneurysm dilatation of medium-to-large vessels with serious consequences. The value of performing regular vascular imaging and monitoring during follow-up has yet to be determined.

Crossed Cerebellar Diaschisis Worsens the Clinical Presentation in Acute Large Vessel Occlusion.

INTRODUCTION: Initial NIHSS in anterior large vessel occlusion (LVO) correlates partially with the hypoperfusion volume. We aimed at assessing the contribution of crossed cerebellar diaschisis (CCD) from the hypoperfused territory on LVO initial clinical deficit. METHODS: CCD was retrospectively identified by brain CT perfusion imaging (CTP) in patients with anterior LVO treated by mechanical thrombectomy from January 2017 to July 2021. CCD was defined by CTP parameter alteration in the contralateral cerebellar hemisphere to the LVO. NIHSS, clinical/perfusion variables, and CCD were included in regression models to assess their interrelationships. RESULTS: 206 patients were included. CCD was present in 90 patients (69%). NIHSS scores were higher on admission and at stroke discharge among patients with CCD (17.90 ± 6.1 vs. 11.4 ± 8.4, p < 0.001; 9.6 ± 7.7 vs. 6.6 ± 7.9, p = 0.049; respectively). Patients with a CCD had higher stroke volumes (118.2 ± 60.3 vs. 69.3 ± 59.7, p < 0.001) and lower rate of known atrial fibrillation (22% vs. 41%, p = 0.021). On multivariable logistic regression, CCD independently worsened the initial NIHSS (OR 4.85 [2.37-7.33]; p < 0.001). CONCLUSION: CCD is found in 69% of LVO on admission CTP, correlates with stroke volumes, and independently worsens initial NIHSS.

Brain Tissue Oxygenation-Guided Therapy and Outcome in Traumatic Brain Injury: A Single-Center Matched Cohort Study.

Brain tissue oxygenation (PbtO2)-guided therapy can improve the neurological outcome of traumatic brain injury (TBI) patients. With several Phase-III ongoing studies, most of the existing evidence is based on before-after cohort studies and a phase-II randomized trial. The aim of this study was to assess the effectiveness of PbtO2-guided therapy in a single-center cohort. We performed a retrospective analysis of consecutive severe TBI patients admitted to our center who received either intracranial pressure (ICP) guided therapy (from January 2012 to February 2016) or ICP/PbtO2-guided therapy (February 2017 to December 2019). A genetic matching was performed based on covariates including demographics, comorbidities, and severity scores on admission. Intracranial hypertension (IH) was defined as ICP > 20 mmHg for at least 5 min. Brain hypoxia (BH) was defined as PbtO2 < 20 mmHg for at least 10 min. IH and BH were targeted by specific interventions. Mann−Whitney U and Fisher's exact tests were used to assess differences between groups. A total of 35 patients were matched in both groups: significant differences in the occurrence of IH (ICP 85.7% vs. ICP/PbtO2 45.7%, p < 0.01), ICU length of stay [6 (3−13) vs. 16 (9−25) days, p < 0.01] and Glasgow Coma Scale at ICU discharge [10 (5−14) vs. 13 (11−15), p = 0.036] were found. No significant differences in ICU mortality and Glasgow Outcome Scales at 3 months were observed. This study suggests that the role of ICP/PbtO2-guided therapy should await further confirmation in well-conducted large phase III studies.