Moyamoya Disease with Non-Functional Pituitary Macroadenoma: A Case Report of a Rare Presentation.

Moyamoya disease (MMD) is a rare neurological condition characterized by brain blood vessel narrowing, leading to collateral vessel formation. Diagnosis typically involves cerebral angiography and magnetic resonance angiography (MRA), with surgical revascularization often providing superior outcomes. Here, we present the case of a 55-year-old woman with hypertension, diabetes, and a history of ischemic stroke. She recently experienced a hemorrhagic stroke due to MMD, compounded by a non-functional pituitary macroadenoma. Recognizing signs of a hemorrhagic stroke is crucial to prevent future occurrences and ensure optimal outcomes. However, our understanding of the connection between MMD and pituitary macroadenoma remains incomplete. Further research is essential to refine diagnostic techniques and treatment strategies. Through continued research and awareness, we can strive for improved outcomes and an enhanced quality of life for individuals affected by MMD and its complications.

Loganin exerts neuroprotective effect by inhibiting neuronal pyroptosis in rat with cerebral haemorrhage.

Intracerebral haemorrhage (ICH) presents significant challenges in clinical management because of the high morbidity and mortality, necessitating novel therapeutic approaches. This study aimed to assess the neuroprotective effects of loganin in a rat ICH model. Sprague-Dawley rats were used, subjected to a collagenase-induced ICH model, followed by loganin treatment at doses of 2.5, 5 and 10 mg/kg. Neurological functions were evaluated using the modified neurological severity score (mNSS) and a rotarod test. Results indicated a significant improvement in neurological functions in loganin-treated groups, evident from the mNSS and rotarod tests, suggesting dose-dependent neuroprotection. Loganin also effectively reduced the blood-brain barrier (BBB) permeability and cerebral oedema. Additionally, it mitigated cellular pyroptosis, as shown by terminal deoxynucleotidyl transferase dUTP nick-end labelling staining and western blot analysis, which indicated reduced levels of pyroptosis markers in treated rats. Furthermore, loganin's regulatory effects on the adenosine A2A receptor and myosin light chain kinase pathways were observed, potentially underpinning its protective mechanism against ICH. The study concludes that loganin exhibits significant neuroprotective properties in a rat ICH model, highlighting its potential as a novel therapeutic strategy. Despite promising results, the study needs further research to determine loganin's therapeutic potential in human ICH patients. This research paves the way for further exploration into loganin's clinical applications, potentially revolutionizing treatment strategies for patients suffering from intracerebral haemorrhage.

Cerebral tau pathology in cerebral amyloid angiopathy.

Tau, a hallmark of Alzheimer's disease, is poorly characterized in cerebral amyloid angiopathy. We aimed to assess the clinico-radiological correlations between tau positron emission tomography scans and cerebral amyloid angiopathy. We assessed cerebral amyloid and hyperphosphorylated tau in patients with probable cerebral amyloid angiopathy (n = 31) and hypertensive small vessel disease (n = 27) using 11C-Pittsburgh compound B and 18F-T807 positron emission tomography. Multivariable regression models were employed to assess radio-clinical features related to cerebral tau pathology in cerebral amyloid angiopathy. Cerebral amyloid angiopathy exhibited a higher cerebral tau burden in the inferior temporal lobe [1.25 (1.17-1.42) versus 1.08 (1.05-1.22), P < 0.001] and all Braak stage regions of interest (P < 0.05) than hypertensive small vessel disease, although the differences were attenuated after age adjustment. Cerebral tau pathology was significantly associated with cerebral amyloid angiopathy-related vascular markers, including cortical superficial siderosis (ß = 0.12, 95% confidence interval 0.04-0.21) and cerebral amyloid angiopathy score (ß = 0.12, 95% confidence interval 0.03-0.21) after adjustment for age, ApoE4 status and whole cortex amyloid load. Tau pathology correlated significantly with cognitive score (Spearman's ρ=-0.56, P = 0.001) and hippocampal volume (-0.49, P = 0.007), even after adjustment. In conclusion, tau pathology is more frequent in sporadic cerebral amyloid angiopathy than in hypertensive small vessel disease. Cerebral amyloid angiopathy-related vascular pathologies, especially cortical superficial siderosis, are potential markers of cerebral tau pathology suggestive of concomitant Alzheimer's disease.

Development and validation of a nomogram to predict intracranial haemorrhage in neonates.

BACKGROUND: The aim of this study was to establish and validate a Susceptibility-weighted imaging (SWI)-based predictive model for neonatal intracranial haemorrhage (ICH). METHODS: A total of 1190 neonates suspected of ICH after cranial ultrasound screening in a tertiary hospital were retrospectively enrolled. The neonates were randomly divided into a training cohort and a internal validation cohort by a ratio of 7:3. Univariate analysis was used to analyze the correlation between risk factors and ICH, and the prediction model of neonatal ICH was established by multivariate logistic regression based on minimum Akaike information criterion (AIC). The nomogram was externally validated in another tertiary hospital of 91 neonates. The performance of the nomogram was evaluated in terms of discrimination by the area under the curve (AUC), calibration by the calibration curve and clinical net benefit by the decision curve analysis (DCA). RESULTS: Univariate analysis and min AIC-based multivariate logistic regression screened the following variables to establish a predictive model for neonatal ICH: Platelet count (PLT), gestational diabetes, mode of delivery, amniotic fluid contamination, 1-min Apgar score. The AUC was 0.715, 0.711, and 0.700 for the training cohort, internal validation cohort, and external validation cohort, respectively. The calibration curve showed a good correlation between the nomogram prediction and actual observation for ICH. DCA showed the nomogram was clinically useful. CONCLUSION: We developed and validated an easy-to-use nomogram to predict ICH for neonates. This model could support individualized risk assessment and healthcare.

Prevalence and epidemiology of stroke in patients with multiple sclerosis: a systematic review and meta-analysis.

BACKGROUND: Epidemiological data are sparse regarding the risk of stroke in patients with multiple sclerosis (MS). OBJECTIVE: To estimate the following: (1) the pooled prevalence of all-cause stroke, acute ischaemic stroke (AIS) and intracerebral haemorrhage (ICH) in MS patients; (2) the relative risk for all-cause stroke, AIS and ICH in MS patients compared to the general population; (3) associations between patient characteristics and the risk for AIS and ICH in MS patients. METHODS: Systematic review and meta-analysis of registry-based and cohort studies. RESULTS: Thirteen observational studies comprising 146,381 MS patients were included. The pooled prevalence of all-cause stroke was 2.7% (95% confidence interval [CI] 1.3-4.6%), with the relative risk of all-cause stroke being higher in MS patients compared to the general population (RR: 2.55; 95% CI 1.97-3.29). Subgroup analyses per stroke subtype revealed a pooled AIS prevalence of 2.1% (95% CI 0.8-4.1%) and a pooled ICH prevalence of 0.6% (95% CI 0.2-1.2%). Compared to the general population, patients with MS were found to harbour an increased risk for AIS (RR: 2.79; 95% CI 2.27-3.41) and ICH (RR: 2.31; 95% CI 1.04-5.11), respectively. The pooled prevalence of cardiovascular risk factors in MS patients was 11.5% (95% CI 2.9-24.7%) for dyslipidaemia, 18.2% (95% CI 5.9-35.3%) for hypertension and 5.4% (95% CI 2.1-10.2%) for diabetes. In meta-regression, age was negatively associated with AIS risk (ß = - .03, p = 0.04), with a 1-year increase in age resulting in a significant 3% (95%CI 0-5) attenuation of the risk of AIS. CONCLUSION: The findings of the present meta-analysis indicate that MS is associated with an increased risk for ischaemic and haemorrhagic stroke. Future well-designed epidemiological studies are warranted to corroborate the robustness of the present findings in the MS population.

A case of early intraventricular haemorrhage following ventriculoperitoneal shunt: An entity requiring consideration.

The ventriculoperitoneal shunt (VP shunt) is one of the most common neurosurgical procedures performed in daily practice. Various complications following a VP shunt are as follows: post-procedure shunt-related infections, shunt block, shunt displacement or exteriorisation and haemorrhage associated with it. Delayed intraventricular haemorrhage is a relatively uncommon complication following the aforementioned procedure. Here we present an atypical case of a 72-year-old male who presented with subarachnoid haemorrhage with hydrocephalus and underwent a VP shunt, following which the patient had early intraventricular haemorrhage (eIVH) with an unfortunate outcome. Here, we propose pathophysiology and risk factors for eIVH.

m6A reader YTHDC2 mediates NCOA4 mRNA stability affecting ferritinophagy to alleviate secondary injury after intracerebral haemorrhage.

Oxidative stress and neuronal dysfunction caused by intracerebral haemorrhage (ICH) can lead to secondary injury. The m6A modification has been implicated in the progression of ICH. This study aimed to investigate the role of the m6A reader YTHDC2 in ICH-induced secondary injury. ICH models were established in rats using autologous blood injection, and neuronal cell models were induced with Hemin. Experiments were conducted to overexpress YTH domain containing 2 (YTHDC2) and examine its effects on neuronal dysfunction, brain injury, and neuronal ferritinophagy. RIP-qPCR and METTL3 silencing were performed to investigate the regulation of YTHDC2 on nuclear receptor coactivator 4 (NCOA4). Finally, NCOA4 overexpression was used to validate the regulatory mechanism of YTHDC2 in ICH. The study found that YTHDC2 expression was significantly downregulated in the brain tissues of ICH rats. However, YTHDC2 overexpression improved neuronal dysfunction and reduced brain water content and neuronal death after ICH. Additionally, it reduced levels of ROS, NCOA4, PTGS2, and ATG5 in the brain tissues of ICH rats, while increasing levels of FTH and FTL. YTHDC2 overexpression also decreased levels of MDA and Fe2+ in the serum, while promoting GSH synthesis. In neuronal cells, YTHDC2 overexpression alleviated Hemin-induced injury, which was reversed by Erastin. Mechanistically, YTHDC2-mediated m6A modification destabilized NCOA4 mRNA, thereby reducing ferritinophagy and alleviating secondary injury after ICH. However, the effects of YTHDC2 were counteracted by NCOA4 overexpression. Overall, YTHDC2 plays a protective role in ICH-induced secondary injury by regulating NCOA4-mediated ferritinophagy.

Mechanical Thrombectomy for Aseptic, Atraumatic, Medically Refractory Cerebral Venous Sinus Thrombosis: a Systematic Review.

BACKGROUND: Cerebral venous sinus thrombosis (CVST) follows a severe clinical course in 13.5% of cases. Practice guidelines recommend endovascular therapy (EVT); no randomised control trials (RCTs) exist comparing EVTs. PURPOSE: To determine whether specific EVTs are superior to alternatives. DATA SOURCES: CENTRAL, Medline, Embase, five other databases and four clinical trials registers. Grey literature searches, reference checking, citation searching, and author contact. STUDY SELECTION: All CVST cases treated with mechanical thrombectomy (MT) were includible. Paediatric, and trauma-related or infection-related thromboses were excluded. DATA ANALYSIS: Standard Cochrane review procedures. Primary outcome measures; clinical efficacy (modified Rankin Score, mRS), technical efficacy (recanalisation), and clinical safety (procedure-related complications and death). Subgroup analyses were performed, comparing outcome measures between demographic groups, clinico-radiological severity, interventional strategies, and degrees of recanalisation. DATA SYNTHESIS: In this study 124 papers were included (n = 486). All patients underwent MT, with 69.5% of patients receiving concomitant chemolysis. New/expanding intracerebral haemorrhage (ICH) occurred in 5.1%; non-haemorrhagic complications in 1.4%; 10.7% died. Predictors of poor efficacy included age ≥ 55 years, altered mental status (AMS), Glasgow Coma Scale (GCS) < 8. Predictive of poor safety outcomes included pre-existing ICH, deep system thrombosis, and AMS. Complete recanalisation was associated with improved clinical efficacy and safety outcomes. LIMITATIONS: The review is based on case reports/series, increasing bias-risk. Myriad of potentially includible studies were necessarily excluded due to lack of requisite details. CONCLUSION: Predictors of poor outcomes with medical therapy predict poor outcomes with MT; these measures should not dictate candidacy. Complete recanalisation predicts favorable clinical and safety outcomes. Local chemolysis is safe, improves recanalisation, and should be recommended, provided there is no contraindication. Clot maceration strategies and stent-retriever thrombectomy are associated with superior clinical efficacy and safety endpoints, as compared with balloon angioplasty and rheolysis.

Persistent convex ST-segment elevation in a patient with a history of prior intracerebral haemorrhage.

Management of patients with acute chest pain poses a significant challenge in identifying those requiring urgent coronary reperfusion. Electrocardiogram (ECG) constitutes the cornerstone in making prompt clinical decisions by identifying ST-segment elevation, commonly associated with ST-segment elevation myocardial infarction. It is important to note that ST-segment elevation can also be a manifestation of various cardiac and non-cardiac conditions, from acute myocarditis, early repolarization syndrome, acute pericarditis, and left bundle branch block to unknown origins. The similarity of ECG changes among these conditions complicates clinical differential diagnosis, necessitating a detailed medical history and thorough examinations. Here, we presented a case of a 52-year-old female with chest pain and unidentified convex ST-segment elevation. Considering the negative emergent coronary angiography results, normal echocardiography, and long-lasting ST-segment elevation for the following 1 year, the final diagnosis was non-myocardial infarction, probably related to a prior cerebral haemorrhage.

Long-term headache after spontaneous intracerebral haemorrhage.

BACKGROUND: Though headache is commonly observed after stroke and may affect survivors' quality of life, it has rarely been studied after spontaneous intracerebral haemorrhage (ICH). In a cohort of ICH survivors, we assessed the long-term prevalence and determinants of headache. METHODS: We screened consecutive ICH survivors enrolled in the prospective, single-centre Prognosis of Intracerebral Haemorrhage study for headache 1, 3, and 6 years after ICH, according to the International Headache Society's criteria. Depressive and anxiety symptoms severity was measured at 1-year follow-up. Variables associated with the presence of headache 1 year after ICH were analyzed using univariate and multivariable models. RESULTS: Among the 146 patients included in this study, 31 (21%), 25 (19%), and 14 (20%) patients reported headache at 1-, 3-, and 6-year follow-up, respectively. In an age-adjusted model, patients with headache at ICH onset (adjusted odds ratio [aOR] 2.75; 95% CI 1.02-7.42) and previous history of headache (aOR 4.60; 95% CI 1.74-12.1) were associated with headache at 1-year follow-up. Patients with headache were more likely to report depressive and anxiety symptoms at 1-year follow-up (both p < 0.02). CONCLUSIONS: One in five ICH survivors suffered from headache and patients who reported headache at ICH onset were especially at risk.

Swiss trial of decompressive craniectomy versus best medical treatment of spontaneous supratentorial intracerebral haemorrhage (SWITCH): an international, multicentre, randomised-controlled, two-arm, assessor-blinded trial.

RATIONALE: Decompressive craniectomy (DC) is beneficial in people with malignant middle cerebral artery infarction. Whether DC improves outcome in spontaneous intracerebral haemorrhage (ICH) is unknown. AIM: To determine whether DC without haematoma evacuation plus best medical treatment (BMT) in people with ICH decreases the risk of death or dependence at 6 months compared to BMT alone. METHODS AND DESIGN: SWITCH is an international, multicentre, randomised (1:1), two-arm, open-label, assessor-blinded trial. Key inclusion criteria are age ⩽75 years, stroke due to basal ganglia or thalamic ICH that may extend into cerebral lobes, ventricles or subarachnoid space, Glasgow coma scale of 8-13, NIHSS score of 10-30 and ICH volume of 30-100 mL. Randomisation must be performed <66 h after onset and DC <6 h after randomisation. Both groups will receive BMT. Participants randomised to the treatment group will receive DC of at least 12 cm in diameter according to institutional standards. SAMPLE SIZE: A sample of 300 participants randomised 1:1 to DC plus BMT versus BMT alone provides over 85% power at a two-sided alpha-level of 0.05 to detect a relative risk reduction of 33% using a chi-squared test. OUTCOMES: The primary outcome is the composite of death or dependence, defined as modified Rankin scale score 5-6 at 6 months. Secondary outcomes include death, functional status, quality of life and complications at 180 days and 12 months. DISCUSSION: SWITCH will inform physicians about the outcomes of DC plus BMT in people with spontaneous deep ICH, compared to BMT alone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02258919.

Burden of intracerebral haemorrhage in Europe: forecasting incidence and mortality between 2019 and 2050.

Background: Anticipating the burden of intracerebral haemorrhage is crucial for proactive management and building resilience against future health challenges. Prior forecasts are based on population demography and to a lesser extent epidemiological trends. This study aims to utilise selected modifiable risk factors and socio-demographic indicators to forecast the incidence and mortality of intracerebral haemorrhage in Europe between 2019 and 2050. Methods: Three intracerebral haemorrhage risk factors identified in the Global Burden of Diseases, Injuries, and Risk Factors study (GBD 2019)-high systolic blood pressure, high fasting plasma glucose, and high body mass index-were utilised to predict the risk-attributable fractions between 2019 and 2050. Disease burden not attributable to these risk factors was then forecasted using time series models (autoregressive integrated moving average [ARIMA]), incorporating the Socio-demographic Index (SDI) as an external predictor. The optimal parameters of ARIMA models were selected for each age-sex-country group based on the Akaike Information Criterion (AIC). Different health scenarios were constructed by extending the past 85th and 15th percentiles of annualised rates of change in risk factors and SDI across all location-years, stratified by age and sex groups. A decomposition analysis was performed to assess the relative contributions of population size, age composition, and intracerebral haemorrhage risk on the projected changes. Findings: Compared with observed figures in 2019, our analysis predicts an increase in the burden of intracerebral haemorrhage in Europe in 2050, with a marginal rise of 0.6% (95% uncertainty interval [UI], -7.4% to 9.6%) in incident cases and an 8.9% (-2.8% to 23.6%) increase in mortality, reaching 141.2 (120.6-166.5) thousand and 144.2 (122.9-172.2) thousand respectively. These projections may fluctuate depending on trajectories of the risk factors and SDI; worsened trends could result in increases of 16.7% (8.7%-25.3%) in incidence and 31.2% (17.7%-48%) in mortality, while better trajectories may lead to a 10% (16.4%-2.3%) decrease in intracerebral haemorrhage cases with stabilised mortality. Individuals aged ≥80 years are expected to contribute significantly to the burden, comprising 62.7% of the cases in 2050, up from 40% in 2019, and 72.5% of deaths, up from 50.5%. Country-wide variations were noted in the projected changes, with decreases in the standardised rates across all nations but varying crude rates. The largest relative reductions in counts for both incidence and mortality are expected in Latvia, Bulgaria, and Hungary-ranging from -38.2% to -32.4% and -37.3% to -30.2% respectively. In contrast, the greatest increases for both measures were forecasted in Ireland (45.7% and 74.4%), Luxembourg (45% and 70.7%), and Cyprus (44.5% and 74.2%). The modelled increase in the burden of intracerebral haemorrhage could largely be attributed to population ageing. Interpretation: This study provides a comprehensive forecast of intracerebral haemorrhage in Europe until 2050, presenting different trajectories. The potential increase in the number of people experiencing and dying from intracerebral haemorrhage could have profound implications for both caregiving responsibilities and associated costs. However, forecasts were divergent between different scenarios and among EU countries, signalling the pivotal role of public health initiatives in steering the trajectories. Funding: The European Union's Horizon 2020 Research and Innovation Programme under grant agreement No. 754517. The National Institute for Health and Care Research (NIHR) under its Programme Grants for Applied Research (NIHR202339).

Diagnostic accuracy of dual-energy computed tomography in the diagnosis of neurological complications after endovascular treatment of acute ischaemic stroke: a systematic review and meta-analysis.

OBJECTIVES: To investigate dual-energy computed tomography's (DECT) diagnostic performance in detecting neurological complications following endovascular therapy (EVT) of acute ischaemic stroke (AIS). METHODS: We performed the literature search using Web of Science, Scopus, PubMed, EBSCO, and Science Direct databases for published related studies. The selected studies estimated the validity of DECT in the detection of neurological complications after EVT for AIS. Study quality assessment was performed utilizing the Quality of Diagnostic Accuracy Studies-2 Tool. Our meta-analysis calculated the pooled sensitivity, negative likelihood ratio, specificity, and positive likelihood ratio for each detected complication. The summary receiver operating characteristics (sROC) curve was utilized to estimate the area under the curve (AUC). RESULTS: Of 22 studies, 21 were included in the quantitative synthesis. In the detection of intracerebral haemorrhage (ICH), DECT pooled overall sensitivity and specificity were 69.9% (95% CI, 44.5%-86.8%) and 100% (95% CI, 92.1%-100%); whereas, in the detection of ischaemia, they were 85.9% (95% CI, 80.4%-90%) and 90.7% (95% CI, 87%-93.5%), respectively. On the sROC curve, AUC values of 0.954 and 0.952 were recorded for the detection of ICH and ischaemia, respectively. CONCLUSIONS: DECT demonstrated high accuracy and specificity in the detection of neurological complications post-endovascular treatment of AIS. However, further prospective studies with a standardized reference test and a larger sample size are recommended to support these findings. ADVANCES IN KNOWLEDGE: DECT is a rapid and valid imaging tool for the prediction of ICH and cerebral ischaemia after the EVT of AIS.

Prevalence, clinical characteristics, and risk factors of intracerebral haemorrhage in CADASIL: a case series and systematic review.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of stroke and is characterised by early onset stroke and dementia. Most strokes are lacunar ischaemic strokes, but intracerebral haemorrhage (ICH) has also been reported, although there are limited published data on its frequency and characteristics. METHODS: A retrospective review of a prospectively recruited CADASIL register from the British National Referral clinic was performed to identify acute ICH cases and their characteristics. In addition, a systematic review of ICH in CADASIL was performed. MEDLINE (Pubmed), Embase, and Web of Science were searched for articles published from inception until 31/05/2023. RESULTS: Ten cases of ICH were identified from the National clinic register of 516 symptomatic patients, giving an estimated point prevalence of 1.9%. An additional 119 cases were identified from the systematic review, comprising 129 cases and 142 ICH events in total. Including all identified cases, the mean age at onset of ICH was 56.6 ± 15.7 (SD) years, and 74 (57.4%) were male. ICH was the first manifestation of the disease in 32 patients (38.1%), and ICH recurrence occurred in 16 (12.4%). Most ICHs were subcortical, with the thalamus, 58 (40.8%), and basal ganglia, 34 (23.9%), being the commonest sites. Anticoagulation, but not antiplatelet agents, was associated with an increased risk of ICH (20.0% vs. 1.9%, p = 0.006). CONCLUSIONS: ICH is a relatively rare manifestation of CADASIL, occurring in about 2% of symptomatic cases. Most of the haemorrhages occurred in the subcortical regions.

Doctors and nurses subjective predictions of 6-month outcome compared to actual 6-month outcome for adult patients with spontaneous intracerebral haemorrhage (ICH) in neurocritical care: An observational study.

Background: Acute spontaneous intracerebral haemorrhage is a devastating form of stroke. Prognostication after ICH may be influenced by clinicians' subjective opinions. Purpose: To evaluate subjective predictions of 6-month outcome by clinicians' for ICH patients in a neurocritical care using the modified Rankin Scale (mRS) and compare these to actual 6-month outcome. Method: We included clinicians' predictions of 6-month outcome in the first 48 h for 52 adults with ICH and compared to actual 6-month outcome using descriptive statistics and multilevel binomial logistic regression. Results: 35/52 patients (66%) had a poor 6-month outcome (mRS 4-6); 19/52 (36%) had died. 324 predictions were included. For good (mRS 0-3) versus poor (mRS 4-6), outcome, accuracy of predictions was 68% and exact agreement 29%. mRS 6 and mRS 4 received the most correct predictions. Comparing job roles, predictions of death were underestimated, by doctors (12%) and nurses (13%) compared with actual mortality (36%). Predictions of vital status showed no significant difference between doctors and nurses: OR = 1.24 {CI; 0.50-3.05}; (p = 0.64) or good versus poor outcome: OR = 1.65 {CI; 0.98-2.79}; (p = 0.06). When predicted and actual 6-month outcome were compared, job role did not significantly relate to correct predictions of good versus poor outcome: OR = 1.13 {CI;0.67-1.90}; (p = 0.65) or for vital status: OR = 1.11 {CI; 0.47-2.61}; p = 0.81). Conclusions: Early prognostication is challenging. Doctors and nurses were most likely to correctly predict poor outcome but tended to err on the side of optimism for mortality, suggesting an absence of clinical nihilism in relation to ICH.

Anakinra in cerebral haemorrhage to target secondary injury resulting from neuroinflammation (ACTION): Study protocol of a phase II randomised clinical trial.

BACKGROUND: Inflammation plays a vital role in the development of secondary brain injury after spontaneous intracerebral haemorrhage (ICH). Interleukin-1 beta is an early pro-inflammatory cytokine and a potential therapeutic target. AIM: To determine the effect of treatment with recombinant human interleukin-1 receptor antagonist anakinra on perihematomal oedema (PHO) formation in patients with spontaneous ICH compared to standard medical management, and investigate whether this effect is dose-dependent. METHODS: ACTION is a phase-II, prospective, randomised, three-armed (1:1:1) trial with open-label treatment and blinded end-point assessment (PROBE) at three hospitals in The Netherlands. We will include 75 patients with a supratentorial spontaneous ICH admitted within 8 h after symptom onset. Participants will receive anakinra in a high dose (loading dose 500 mg intravenously, followed by infusion with 2 mg/kg/h over 72 h; n = 25) or in a low dose (loading dose 100 mg subcutaneously, followed by 100 mg subcutaneous twice daily for 72 h; n = 25), plus standard care. The control group (n = 25) will receive standard medical management. OUTCOMES: Primary outcome is PHO, measured as oedema extension distance on MRI at day 7 ± 1. Secondary outcomes include the safety profile of anakinra, the effect of anakinra on serum inflammation markers, MRI measures of blood brain barrier integrity, and functional outcome at 90 ± 7 days. DISCUSSION: The ACTION trial will provide insight into whether targeting interleukin-1 beta in the early time window after ICH onset could ameliorate secondary brain injury. This may contribute to the development of new treatment options to improve clinical outcome after ICH.

Microglial FoxO3a deficiency ameliorates ferroptosis-induced brain injury of intracerebral haemorrhage via regulating autophagy and heme oxygenase-1.

Microglial HO-1 regulates iron metabolism in the brain. Intracerebral haemorrhage (ICH) shares features of ferroptosis and necroptosis; hemin is an oxidized product of haemoglobin from lysed red blood cells, leading to secondary injury. However, little is known about the underlying molecular mechanisms attributable to secondary injury by hemin or ICH. In this study, we first show that FoxO3a was highly co-located with neurons and microglia but not astrocytes area of ICH model mice. Hemin activated FoxO3a/ATG-mediated autophagy and HO-1 signalling resulting in ferroptosis in vitro and in a mice model of brain haemorrhage. Accordingly, autophagy inhibitor Baf-A1 or HO-1 inhibitor ZnPP protected against hemin-induced ferroptosis. Hemin promoted ferroptosis of neuronal cells via FoxO3a/ATG-mediated autophagy and HO-1 signalling pathway. Knock-down of FoxO3a inhibited autophagy and prevented hemin-induced ferroptosis dependent of HO-1 signalling. We first showed that hemin stimulated microglial FoxO3a/HO-1 expression and enhanced the microglial polarisation towards the M1 phenotype, while knockdown of microglial FoxO3a inhibited pro-inflammatory cytokine production in microglia. Furthermore, the microglia activation in the striatum showed significant along with a high expression level of FoxO3a in the ICH mice. We found that conditional knockout of FoxO3a in microglia in mice alleviated neurological deficits and microglia activation as well as ferroptosis-induced striatum injury in the autologous blood-induced ICH model. We demonstrate, for the first time, that FoxO3a/ATG-mediated autophagy and HO-1 play an important role in microglial activation and ferroptosis-induced striatum injury of ICH, identifying a new therapeutic avenue for the treatment of ICH.

Fatigue after spontaneous intracerebral haemorrhage: prevalence and associated factors.

BACKGROUND: Fatigue is a major complaint in stroke survivors, but data focusing on intracerebral haemorrhage (ICH) survivors are scarce. In a cohort of spontaneous ICH survivors, we assessed the long-term prevalence of fatigue and its associated factors. METHODS: We included consecutive 1-year ICH survivors from the prospective, observational, single-centre Prognosis of Intracerebral Haemorrhage (PITCH) study. We evaluated fatigue (defined as a score ≥ 4 in Chalder Fatigue Scale); the severity of neurological, depressive, and anxiety symptoms; and functional disability 1, 3, and 6 years after ICH. We performed univariable and multivariable models to evaluate clinical factors and brain magnetic resonance imaging (MRI) small vessel disease (SVD) markers associated with fatigue. RESULTS: Of 255 1-year ICH survivors, 153 (60%) underwent fatigue screening and were included in this study. Seventy-eight patients (51%) reported fatigue at 1-year, 56/110 (51%) at 3-year, and 27/67 (40%) at 6-year follow-up. Patients with fatigue exhibited more severe concomitant depressive/anxiety symptoms, but the severity of depressive symptoms was the only clinical factor significantly associated with 1-year fatigue in multivariable analysis (adjusted odds ratio 1.4 for one-point increase; 95% confidence interval 1.2-1.6). Patients with severe cortical atrophy at baseline had increased risk of fatigue at 1-year follow-up compared to patients with mild/no cortical atrophy (adjusted odds ratio 2.5; 95% confidence interval 1.1-5.8). CONCLUSIONS: Fatigue after ICH is frequent and long-lasting, and it is associated with cortical atrophy (but not with other MRI markers of cerebral SVD). The link between fatigue and depressive symptoms may represent a potential therapeutic target.

Prevention of infections and fever to improve outcome in older patients with acute stroke (PRECIOUS): a randomised, open, phase III, multifactorial, clinical trial with blinded outcome assessment.

Background: Infections and fever after stroke are associated with poor functional outcome or death. We assessed whether prophylactic treatment with anti-emetic, antibiotic, or antipyretic medication would improve functional outcome in older patients with acute stroke. Methods: We conducted an international, 2∗2∗2-factorial, randomised, controlled, open-label trial with blinded outcome assessment in patients aged 66 years or older with acute ischaemic stroke or intracerebral haemorrhage and a score on the National Institutes of Health Stroke Scale ≥ 6. Patients were randomly allocated (1:1) to metoclopramide (oral, rectal, or intravenous; 10 mg thrice daily) vs. no metoclopramide, ceftriaxone (intravenous; 2000 mg once daily) vs. no ceftriaxone, and paracetamol (oral, rectal, or intravenous; 1000 mg four times daily) vs. no paracetamol, started within 24 h after symptom onset and continued for four days. All participants received standard of care. The target sample size was 3800 patients. The primary outcome was the score on the modified Rankin Scale (mRS) at 90 days analysed with ordinal logistic regression and reported as an adjusted common odds ratio (an acOR < 1 suggests benefit and an acOR > 1 harm). This trial is registered (ISRCTN82217627). Findings: From April 2016 through June 2022, 1493 patients from 67 European sites were randomised to metoclopramide (n = 704) or no metoclopramide (n = 709), ceftriaxone (n = 594) or no ceftriaxone (n = 482), and paracetamol (n = 706) or no paracetamol (n = 739), of whom 1471 were included in the intention-to-treat analysis. Prophylactic use of study medication did not significantly alter the primary outcome at 90 days: metoclopramide vs. no metoclopramide (adjusted common odds ratio [acOR], 1.01; 95% CI 0.81-1.25), ceftriaxone vs. no ceftriaxone (acOR 0.99; 95% CI 0.77-1.27), paracetamol vs. no paracetamol (acOR 1.19; 95% CI 0.96-1.47). The study drugs were safe and not associated with an increased incidence of serious adverse events. Interpretation: We observed no sign of benefit of prophylactic use of metoclopramide, ceftriaxone, or paracetamol during four days in older patients with a moderately severe to severe acute stroke. Funding: This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No: 634809.