COVID-19 Pandemic and Neurocognitive Process: New Scenarios for Understanding and Treatment

COVID-19 disease was defined as a disease of primary respiratory system. However, symptoms associated with central nervous system were detected in approximately 2/3 of the hospitalized patients. The rate of ischemic cerebrovascular diseases is higher in central nervous system. In addition, hemorrhagic cerebrovascular diseases, encephalitis and/or encephalopathy are the other diseases. Complex pathogenesis was demonstrated in the central nervous system diseases associated with SARS-CoV-2. It was reported that SARS-CoV-2 virus could directly invade the central nervous system, especially via the olfactory nerves or the haematological pathway. As a result, endothelial cells, pericytes and/or neurons can be infected (direct pathway). Another mechanism is central nervous system deficit resulting from peripheral immune reactivation (indirect pathway). All these etiopathogenetic results support that COVID-19 disease is associated with cognitive dysfunction. Cerebral hypoperfusion associated with vascular endothelial structures is the main factor in the etiopathogenesis. It was reported that COVID-19 disease induced amyloid-β (Aβ) and α-synuclein phosphorylation. Besides, it was detected that this process was associated with tau and TDP-43 pathology. “Cognitive COVID-19” is a term that describes acute and long-term cognitive changes in people infected with SARS-CoV-2. Encephalopathy, delirium and cognitive disorders are most frequently detected. In this chapter, the clinical and etiopathogenetic processes of cognitive dysfunction after COVID-19 disease were evaluated. In addition, the disease, disease process and treatment were evaluated in general

Relationship between race and outcome in Asian, Black and Caucasian patients with spontaneous intracerebral haemorrhage: data from the Virtual International Stroke Trials Archive (VISTA) and Efficacy of Nitric Oxide in Stroke trial (ENOS)

Background and purpose: Although poor prognosis after intracerebral haemorrhage relates to risk factors and haematoma characteristics, there is limited evidence for the effect of race-ethnicity. Methods: Data from 1011 patients with intracerebral haemorrhage enrolled into hyperacute trials and randomised to control were obtained from the Virtual International Stroke Trials Archive (VISTA) and Efficacy of Nitric Oxide in Stroke (ENOS) Trial. Clinical characteristics and functional outcome were compared among three racial groups – Asians, Blacks and Caucasians. Results: The majority of patients were Caucasian (78.1%) followed by Asians (14.5%) and Blacks (5.5%). At baseline, Caucasians were older and had larger haematoma volumes; Blacks had lower Glasgow Coma Scale and higher systolic blood pressure (all p<0.05). Although the primary outcome of modified Rankin scale (mRS) did not differ at 90 days (p=0.14), there were significant differences in mortality (p<0.0001) and quality of life (EQ-5D p<0.0001; EQ-VAS p 0.015). In test of multiple comparisons, Caucasians were more likely to die (p=0.0003) and had worse quality of life (EQ-5D p=0.003; EQ-VAS p<0.0001) as compared to Asians. Conclusion: Race-ethnicity appears to explain some of the variation in clinical characteristics and outcomes after acute intracerebral haemorrhage. Factors that explain this variation need to be identified

Predictors and outcomes of neurological deterioration in intracerebral hemorrhage: results from the TICH-2 randomised controlled trial

Neurological deterioration is common after intracerebral hemorrhage (ICH). We aimed to identify the predictors and effects of neurological deterioration and whether tranexamic acid reduced the risk of neurological deterioration. Data from the Tranexamic acid in IntraCerebral Hemorrhage-2 (TICH-2) randomized controlled trial were analyzed. Neurological deterioration was defined as an increase in National Institutes of Health Stroke Scale (NIHSS) of ≥ 4 or a decline in Glasgow Coma Scale of ≥ 2. Neurological deterioration was considered to be early if it started ≤ 48 h and late if commenced between 48 h and 7 days after onset. Logistic regression was used to identify predictors and effects of neurological deterioration and the effect of tranexamic acid on neurological deterioration. Of 2325 patients, 735 (31.7%) had neurological deterioration: 590 (80.3%) occurred early and 145 (19.7%) late. Predictors of early neurological deterioration included recruitment from the UK, previous ICH, higher admission systolic blood pressure, higher NIHSS, shorter onset-to-CT time, larger baseline hematoma, intraventricular hemorrhage, subarachnoid extension and antiplatelet therapy. Older age, male sex, higher NIHSS, previous ICH and larger baseline hematoma predicted late neurological deterioration. Neurological deterioration was independently associated with a modified Rankin Scale of > 3 (aOR 4.98, 3.70–6.70; p [less than] 0.001). Tranexamic acid reduced the risk of early (aOR 0.79, 0.63–0.99; p = 0.041) but not late neurological deterioration (aOR 0.76, 0.52–1.11; p = 0.15). Larger hematoma size, intraventricular and subarachnoid extension increased the risk of neurological deterioration. Neurological deterioration increased the risk of death and dependency at day 90. Tranexamic acid reduced the risk of early neurological deterioration and warrants further investigation in ICH

Relationship between nitrate headache and outcome in patients with acute stroke: results from the efficacy of nitric oxide in stroke (ENOS) trial

IntroductionNitrate-induced headache is common and may signify responsive cerebral vasculature. We assessed the relationship between nitrate-headache and outcome in patients with acute stroke.Materials and MethodsPatients were those randomised to glyceryl trinitrate (GTN) versus no GTN in the Efficacy of Nitric Oxide in Stroke trial. Development of headache by end of treatment (day 7), and functional outcome (modified Rankin Scale, mRS, primary outcome) at day 90, were assessed. Analyses are adjusted for baseline prognostic factors and give odds ratio (OR) and mean difference (MD) with 95% confidence intervals (95% CI).ResultsIn 4011 patients, headache was more common in GTN than control (360, 18.0% vs. 170, 8.5%; 2

Effects of blood pressure and tranexamic acid in spontaneous intracerebral haemorrhage: a secondary analysis of a large randomised controlled trial

BACKGROUND: Tranexamic acid reduced haematoma expansion and early death, but did not improve functional outcome in the tranexamic acid for hyperacute spontaneous intracerebral haemorrhage-2 (TICH-2) trial. In a predefined subgroup, there was a statistically significant interaction between prerandomisation baseline systolic blood pressure (SBP) and the effect of tranexamic acid on functional outcome (p=0.019). METHODS: TICH-2 was an international prospective double-blind placebo-controlled randomised trial evaluating intravenous tranexamic acid in patients with acute spontaneous intracerebral haemorrhage (ICH). Prerandomisation baseline SBP was split into predefined ≤170 and >170 mm Hg groups. The primary outcome at day 90 was the modified Rankin Scale (mRS), a measure of dependency, analysed using ordinal logistic regression. Haematoma expansion was defined as an increase in haematoma volume of >33% or >6 mL from baseline to 24 hours. Data are OR or common OR (cOR) with 95% CIs, with significance at p170 mm Hg. Tranexamic acid was associated with a favourable shift in mRS at day 90 in those with baseline SBP≤170 mm Hg (cOR 0.73, 95% CI 0.59 to 0.91, p=0.005), but not in those with baseline SBP>170 mm Hg (cOR 1.05, 95% CI 0.85 to 1.30, p=0.63). In those with baseline SBP≤170 mm Hg, tranexamic acid reduced haematoma expansion (OR 0.62, 95% CI 0.47 to 0.82, p=0.001), but not in those with baseline SBP>170 mm Hg (OR 1.02, 95% CI 0.77 to 1.35, p=0.90). CONCLUSIONS: Tranexamic acid was associated with improved clinical and radiological outcomes in ICH patients with baseline SBP≤170 mm Hg. Further research is needed to establish whether certain subgroups may benefit from tranexamic acid in acute ICH. TRIAL REGISTRATION NUMBER: ISRCTN93732214

Effect of glyceryl trinitrate on haemodynamics in acute stroke: data from the Efficacy of Nitric Oxide in Stroke trial

Background and Purpose: Increased blood pressure (BP), heart rate and their derivatives (variability, pulse pressure, rate-pressure product [RPP]) are associated with poor clinical outcome in acute stroke. We assessed the effects of glyceryl trinitrate (GTN) on haemodynamic parameters, and these on outcome in participants in the Efficacy of Nitric Oxide in Stroke trial.Methods: 4011 patients with acute stroke and raised BP were randomised within 48 hours of onset to transdermal GTN or no GTN for 7 days. Peripheral haemodynamics were measured at baseline (3 measures) and daily (2 measures) during treatment. Between-visit BP variability over days 1 to 7 (as standard deviation) was assessed in quintiles. Functional outcome was assessed as modified Rankin Scale (mRS) and cognition as telephone mini-mental state examination (t-MMSE) at day 90. Analyses were adjusted for baseline prognostic variables. Data are mean difference (MD) or odds ratios (OR) with 95% confidence intervals (CI).Results: Increased baseline BP (diastolic, variability), heart rate and RPP were each associated with unfavourable functional outcome at day 90. Increased between-visit systolic BP variability was associated with an unfavourable shift in mRS (highest quintile adjusted OR 1.65, 95% CI 1.37 to 1.99), worse cognitive scores (t-MMSE: highest quintile adjusted MD -2.03, 95% CI -2.84 to -1.22) and increased odds of death at day 90 (highest quintile adjusted OR 1.57, 95% CI 1.12 to 2.19). GTN lowered BP and RPP, and increased heart rate at day 1; and reduced between-visit systolic BP variability.Conclusions: Increased between-visit BP variability was associated with poor functional and cognitive outcomes and increased death 90 days after acute stroke. In addition to lowering BP and RPP, GTN reduced between-visit systolic BP variability. Agents that lower BP variability in acute stroke require further study

General neurology: Current challenges and future implications

Background and purpose In the coming decades, the world will face an increasing burden of neurological disorders (ND) and an urgent need to promote brain health. These challenges contrast with an insufficient neurological workforce in most countries, as well as decreasing numbers of general neurologists and neurologists attracted to work in general neurology (GN). This white paper aims to review the current situation of GN and reflect on its future. Methods The European Academy of Neurology (EAN) task force (TF) met nine times between November 2021 and June 2023. During the 2023 EAN annual meeting, attendees were asked to answer five questions concerning the future of GN. The document was sent for suggestions and eventually approval to the board and the presidents of the 47 national societies of the EAN. Results The TF first identified four relevant current and future challenges related to GN: (i) definition, (ii) practice, (iii) education, and (iv) research. The TF then identified seven initiatives to further develop GN at both the academic and community level. Finally, the TF formulated 16 recommendations to promote GN in the future. Conclusions GN will remain essential in the coming decades to provide rapid, accessible, and comprehensive management of patients with ND that is affordable and cost-effective. There is also a need for research, education, and other initiatives aiming to facilitate improved working conditions, recognition, and prestige for those pursuing a career in GN

Central adjudication of serious adverse events did not affect trial's safety results: Data from the Efficacy of Nitric Oxide in Stroke (ENOS) trial

Background and Purpose: Central adjudication of serious adverse events (SAEs) can be undertaken in clinical trials, especially for open-label studies where outcome assessment may be at risk of bias. This study explored the effect of central adjudication of SAEs on the safety results of the Efficacy of Nitric Oxide in Stroke (ENOS) Trial. Methods: ENOS assigned patients with acute stroke at random to receive either transdermal glyceryl trinitrate (GTN) or no GTN and to Stop or Continue previous antihypertensive treatment. SAEs were reported by local investigators who were not blinded to treatment allocation. Central adjudicators blinded to treatment allocation, reviewed the investigators reports and used evidence available to confirm or re-categorise the classification of event, likely causality, diagnosis and expectedness of event. Results: Of 4011 patients enrolled in ENOS, 1473 SAEs were reported by local investigators; this was reduced to 1444 after the review by adjudicators, with 29 re-classified as not an SAE. There was fair agreement between investigators and adjudicators regarding likely causality, with 808 agreements and 644 disagreements (56% crude agreement, weighted kappa, κ = 0.31). Agreement increased upon dichotomisation of the causality categories, with 1432 agreements and 20 disagreements (99% crude agreement, kappa = 0.54). Repeating the main trial safety analysis with investigator reported events showed that adjudication had no effect on the main trial safety conclusions. Conclusions: In a large trial, with many SAEs reported, central adjudication of these events did not affect trial conclusions. This suggests that adjudication of SAEs in a clinical trial where the intervention already has a well-established safety profile may not be necessary. Potential efficiency savings (financial, logistical) can be made through not adjudicating SAEs

Route of feeding as a proxy for dysphagia after stroke and the effect of transdermal glyceryl trinitrate: data from the efficacy of nitric oxide in stroke randomised controlled trial

Post-stroke dysphagia is common, associated with poor outcome and often requires non-oral feeding/fluids. The relationship between route of feeding and outcome, as well as treatment with glyceryl trinitrate (GTN), was studied prospectively. The Efficacy of Nitric Oxide in Stroke (ENOS) trial assessed transdermal GTN (5 mg versus none for 7 days) in 4011 patients with acute stroke and high blood pressure. Feeding route (oral = normal or soft diet; nonoral = nasogastric tube, percutaneous endoscopic gastrostomy tube, parenteral fluids, no fluids) was assessed at baseline and day 7. The primary outcome was the modified Rankin Scale (mRS) measured at day 90. At baseline, 1331 (33.2%) patients had non-oral feeding, were older, had more severe stroke and more were female, than 2680 (66.8%) patients with oral feeding. By day 7, 756 patients had improved from non-oral to oral feeding, and 119 had deteriorated. Non-oral feeding at baseline was associated with more impairment at day 7 (Scandinavian Stroke Scale 29.0 versus 43.7; 2p < 0.001), and worse mRS (4.0 versus 2.7; 2p < 0.001) and death (23.6 versus 6.8%; 2p = 0.014) at day 90. Although GTN did not modify route of feeding overall, randomisation ≤6 hours of stroke was associated with a move to more oral feeding at day 7 (odds ratio = 0.61, 95% confidence intervals 0.38, 0.98; 2p = 0.040). As a proxy for dysphagia, non-oral feeding is present in 33% of patients with acute stroke and associated with more impairment, dependency and death. GTN moved feeding route towards oral intake if given very early after stroke