Effect of short- versus long-term serum glucose levels on early ischemic water homeostasis and functional outcome in patients with large vessel occlusion stroke.

BACKGROUND AND PURPOSE: In ischemic stroke, the impact of short- versus long-term blood glucose level (BGL) on early lesion pathophysiology and functional outcome has not been assessed. The purpose of this study was to directly compare the effect of long-term blood glucose (glycated hemoglobin [HbA1c]) versus serum BGL on early edema formation and functional outcome. METHODS: Anterior circulation ischemic stroke patients who underwent mechanical thrombectomy after multimodal computed tomography (CT) on admission were analyzed. Endpoints were early ischemic cerebral edema, measured by quantitative net water uptake (NWU) on initial CT and functional independence at Day 90. RESULTS: A total of 345 patients were included. Patients with functional independence had significantly lower baseline NWU (3.1% vs. 8.3%; p < 0.001) and lower BGL (113 vs. 123 mg/dL; p < 0.001) than those without functional independence, while HbA1c levels did not differ significantly (5.7% vs. 5.8%; p = 0.15). A significant association was found for NWU and BGL (ß = 0.02, 95% confidence interval [CI] 0.006-0.03; p = 0.002), but not for HbA1c and NWU (ß = -0.16, 95% CI -0.53-0.21; p = 0.39). Mediation analysis showed that 67% of the effect of BGL on functional outcome was mediated by early edema formation. CONCLUSION: Aggravated early edema and worse functional outcome was associated with elevated short-term serum BGL, but not with HbA1c levels. Hence, the link between short-term BGL and early edema development might be used as a target for adjuvant therapy in patients with ischemic stroke.

Edema Reduction versus Penumbra Salvage: Investigating Treatment Effects of Mechanical Thrombectomy in Ischemic Stroke.

OBJECTIVE: Mechanical thrombectomy (MT) is of benefit to patients with ischemic stroke; however, the effect of recanalization on lesion pathophysiology is not yet well understood. The aim of this study was to quantitatively assess how the effect of vessel recanalization on clinical outcome is mediated by edema reduction versus penumbra salvage. METHODS: Consecutive analysis was made of anterior circulation ischemic stroke patients triaged by multimodal computed tomography (CT) undergoing MT. Edema reduction was defined using the difference of quantitative net water uptake (NWU) determined on baseline and follow-up CT (∆NWU). Penumbra salvage volume (PSV) was defined as the difference between admission penumbra and net infarct growth volumes to follow-up. Mediation analyses were performed with vessel recanalization as independent variable (modified Thrombolysis in Cerebral Infarction ≥ 2b) and ∆NWU/PSV as mediator variables. Modified Rankin Scale scores at 90 days served as endpoint. RESULTS: Of 422 included patients, 321 (76%) achieved successful recanalization. The median ∆NWU was 6.8% (interquartile range [IQR] = 3.9-10.4), and the median PSV was 66ml (IQR = 8-124). ∆NWU, PSV, and recanalization were significantly associated with functional outcome in logistic regression analysis. ∆NWU and PSV partially mediated the relationship between recanalization and outcome. Sixty-six percent of the relationship between recanalization and functional outcome could be explained by treatment-induced edema reduction, whereas 22% was mediated by PSV (p < 0.0001). INTERPRETATION: Compared to penumbra salvage, edema reduction was a stronger mediator of the effect of recanalization on functional outcome. Given the current trials on adjuvant neuroprotectants also targeting ischemic edema formation, combining reperfusion with antiedematous neuroprotectants may have synergistic effects resulting in better outcomes in patients with ischemic stroke. ANN NEUROL 2023.

Mapping the deficit dimension structure of the National Institutes of Health Stroke Scale.

BACKGROUND: The National Institutes of Health Stroke Scale (NIHSS) is the most frequently applied clinical rating scale for standardized assessment of neurological deficits in acute stroke in both clinical and research settings. Notwithstanding this prominent role, important questions regarding its validity remain insufficiently addressed: Investigations of the underlying dimensional structure of the NIHSS yielded inconsistent results that are largely not generalizable across studies. Neurobiological validations by linking measured deficit dimensions to brain anatomy and function are missing. METHODS: We, therefore, employ advanced machine learning to identify an optimal representation of the dimensional structure of the NIHSS across two independent and heterogeneous stroke datasets (N = 503 and N = 690). Associated lesion locations are identified by multivariate lesion-deficit mapping (LDM) and their functional relevance is profiled based on a-priori task activation meta-data analysis, to provide an independent link to the behavioural level. FINDINGS: A five-factor structure of the NIHSS was identified as the most robust and generalizable representation of stroke deficit dimensions across study populations, settings, and clinical phenotypes. Specifically, the identified dimensions comprised NIHSS items for (F1) left motor deficits, (F2) right motor deficits, (F3) dysarthria and facial palsy, (F4) language, and (F5) deficits in spatial attention and gaze. LDM linked four of these factors to differentially localized, eloquent neuroanatomical areas. Functional characterization of LDM results aligned with detected deficit dimensions, revealing associations with motor functions, language processing, and various functions in the perception domain. INTERPRETATION: By cross-validating machine learning in heterogeneous multi-site stroke cohorts, we report evidence on the validity of the NIHSS: We identified an overarching structure of the NISHS containing a five-dimensional representation of stroke deficits. We provide an anatomical map of the NIHSS that is of value for future applications of individualized stroke treatment and rehabilitation. FUNDING: This research was supported by the National Key R&D Program of China (Grant No. 2021YFC2502200), the National Human Brain Project of China (Grant No. 2022ZD0214000)", the German Research Foundation (Deutsche Forschungsgemeinschaft), Project 178316478 (A1, C1, C2), and Project 454012190 of the SPP 2041, the Helmholtz Portfolio Theme "Supercomputing and Modelling for the Human Brain" and Helmholtz Imaging Platform grant NimRLS (ZT-I-PF-4-010).

Recurrent amnesia caused by early seizures after hippocampal infarction: a case report.

BACKGROUND: We report the case of a patient with recurrent episodes of disturbed memory suggestive of transient epileptic amnesia, and a focal hippocampal lesion typically associated with transient global amnesia. We argue how careful consideration of clinical, electrophysiological and imaging findings can resolve this apparent contradiction and lead to a diagnosis of early symptomatic post-stroke seizures that links brain structure to function in a new, clinically relevant way. CASE PRESENTATION: A 70-year-old patient was identified in clinical practice in our tertiary care centre and was evaluated clinically as well as by repeated electroencephalography and magnetic resonance imaging. The presenting complaint were recurrent episodes of short-term memory disturbance which manifested as isolated anterograde amnesia on neurocognitive evaluation. EEG and MRI revealed predominantly right frontotemporal spikes and a punctate diffusion-restricted lesion in the left hippocampus, respectively. Both symptoms and EEG changes subsided under anticonvulsant treatment with levetiracetam. CONCLUSIONS: Our report contributes to the current discussion of clinical challenges in the differential diagnosis of transient memory disturbance. It suggests that focal diffusion-restricted hippocampal lesions, as seen in TGA, might be ischemic and thus highlights the importance of considering post-stroke seizures as a possible cause of transient memory disturbance.

Myocardial rupture after percutaneous coronary intervention of an unstable RCA lesion in myocardial infarction and concomitant stroke treated with intravenous fibrinolytic agents: A case report.

Myocardial rupture after thrombolysis is an often fatal consequence. For patients with myocardial infarction and ischemic stroke within a short timeframe, a catheter-based therapy to retrieve emboli poses a valid therapeutic option in case of a treatment target in CT-Angiography.

HDAC6 as a target for antileukemic drugs in acute myeloid leukemia.

Inhibition of histone deacetylases (HDACs) by drugs such as vorinostat or depsipeptide has become treatment strategy under study in acute myeloid leukemia. Most preclinically and clinically investigated HDACi target classes I, II and IV, but only few are selective in inhibiting specific HDACs. Here we analyzed the in vitro antileukemic activity of three novel hydroxamate derivatives, the pan-HDAC-inhibitors ST13, ST34 and the known HDAC6 inhibitor ST80, treating leukemia cell lines HL60, Kasumi-1, NB-4, THP-1, K562, U937, Jurkat as well as primary AML blasts. In cell lines all three compounds exerted a strong growth-inhibitory effect at low micromolar concentrations. ST13 increased acetylation of H3, H4 and α-tubulin, while ST34 preferentially acetylated histones H3 and H4. Interestingly, ST80 preferentially induced α-tubulin acetylation at low micromolar doses, confirming a selective inhibition of HDAC6 by ST80 in leukemic cells. These observations were also confirmed in primary AML blasts cultured ex vivo. Growth-inhibition by ST80 was independent of pre-treatment HDAC6 protein expression and in contrast to ST13 and ST34, ST80 did not result in induction of p21/WAF. Immunofluorescence imaging confirmed that ST80 treatment both increased the abundance and resulted in unilateral local accumulation of acetylated α-tubulin. In conclusion, the three novel HDACi show potent antileukemic activity in myeloid cell lines and primary AML blasts at low micromolar concentrations. Preferential acetylation of α-tubulin implies that ST80 might exert its antileukemic effect not through histone reacetylation but rather through inhibition of HDAC6.