Mild Systemic Inflammation Increases Erythrocyte Fragility.

There is growing evidence that inflammation impairs erythrocyte structure and function. We assessed the impact of mild systemic inflammation on erythrocyte fragility in three different settings. In order to investigate causation, erythrocyte osmotic fragility was measured in mice challenged with a live attenuated bacterial strain to induce low-grade systemic inflammation; a significant increase in erythrocyte osmotic fragility was observed. To gather evidence that systemic inflammation is associated with erythrocyte fragility in humans, two observational studies were conducted. First, using a retrospective study design, the relationship between reticulocyte-based surrogate markers of haemolysis and high-sensitivity C-reactive protein was investigated in 9292 healthy participants of the UK Biobank project. Secondly, we prospectively assessed the relationship between systemic inflammation (measured by the urinary neopterin/creatinine ratio) and erythrocyte osmotic fragility in a mixed population (n = 54) of healthy volunteers and individuals with long-term medical conditions. Both human studies were in keeping with a relationship between inflammation and erythrocyte fragility. Taken together, we conclude that mild systemic inflammation increases erythrocyte fragility and may contribute to haemolysis. Further research is needed to assess the molecular underpinnings of this pathway and the clinical implications in inflammatory conditions.

Systemic inflammation associates with and precedes cord atrophy in progressive multiple sclerosis.

In preclinical models of multiple sclerosis, systemic inflammation has an impact on the compartmentalized inflammatory process within the central nervous system and results in axonal loss. It remains to be shown whether this is the case in humans, specifically whether systemic inflammation contributes to spinal cord or brain atrophy in multiple sclerosis. Hence, an observational longitudinal study was conducted to delineate the relationship between systemic inflammation and atrophy using magnetic resonance imaging: the SIMS (Systemic Inflammation in Multiple Sclerosis) study. Systemic inflammation and progression were assessed in people with progressive multiple sclerosis (n = 50) over two and a half years. Eligibility criteria included: (i) primary or secondary progressive multiple sclerosis; (ii) age ≤ 70; and (iii) Expanded Disability Status Scale ≤ 6.5. First morning urine was collected weekly to quantify systemic inflammation by measuring the urinary neopterin-to-creatinine ratio using a validated ultra-performance liquid chromatography mass spectrometry technique. The urinary neopterin-to-creatinine ratio temporal profile was characterized by short-term responses overlaid on a background level of inflammation, so these two distinct processes were considered as separate variables: background inflammation and inflammatory response. Participants underwent MRI at the start and end of the study, to measure cervical spinal cord and brain atrophy. Brain and cervical cord atrophy occurred on the study, but the most striking change was seen in the cervical spinal cord, in keeping with the corticospinal tract involvement that is typical of progressive disease. Systemic inflammation predicted cervical cord atrophy. An association with brain atrophy was not observed in this cohort. A time lag between systemic inflammation and cord atrophy was evident, suggesting but not proving causation. The association of the inflammatory response with cord atrophy depended on the level of background inflammation, in keeping with experimental data in preclinical models where the effects of a systemic inflammatory challenge on tissue injury depended on prior exposure to inflammation. A higher inflammatory response was associated with accelerated cord atrophy in the presence of background systemic inflammation below the median for the study population. Higher background inflammation, while associated with cervical cord atrophy itself, subdued the association of the inflammatory response with cord atrophy. Findings were robust to sensitivity analyses adjusting for potential confounders and excluding cases with new lesion formation. In conclusion, systemic inflammation associates with, and precedes, multiple sclerosis progression. Further work is needed to prove causation since targeting systemic inflammation may offer novel treatment strategies for slowing neurodegeneration in multiple sclerosis.

A Case Study of Emphysematous Cystitis in a Non-diabetic Patient Following Empagliflozin Use: An Uncommon Presentation.

Emphysematous cystitis (EC), a rare urinary tract infection characterized by gas accumulation in the bladder walls, is predominantly seen in diabetic patients. This case study discusses an 83-year-old non-diabetic male with end-stage heart failure who presented with symptoms of EC after being administered empagliflozin. The unique presentation suggests a possible link between empagliflozin and EC in non-diabetic heart failure patients, a connection previously undocumented in medical literature, emphasizing the importance of vigilant monitoring and further research in this area.

Real-world persistence of multiple sclerosis disease-modifying therapies.

BACKGROUND AND PURPOSE: Treatment persistence is the continuation of therapy over time. It reflects a combination of treatment efficacy and tolerability. We aimed to describe real-world rates of persistence on disease-modifying therapies (DMTs) for people with multiple sclerosis (pwMS) and reasons for DMT discontinuation. METHODS: Treatment data on 4366 consecutive people with relapse-onset multiple sclerosis (MS) were pooled from 13 UK specialist centres during 2021. Inclusion criteria were exposure to at least one MS DMT and a complete history of DMT prescribing. PwMS in blinded clinical trials were excluded. Data collected included sex, age at MS onset, age at DMT initiation, DMT treatment dates, and reasons for stopping or switching DMT. For pwMS who had received immune reconstituting therapies (cladribine/alemtuzumab), discontinuation date was defined as starting an alternative DMT. Kaplan-Meier survival analyses were used to express DMT persistence. RESULTS: In 6997 treatment events (1.6 per person with MS), median time spent on any single maintenance DMT was 4.3 years (95% confidence interval = 4.1-4.5 years). The commonest overall reasons for DMT discontinuation were adverse events (35.0%) and lack of efficacy (30.3%). After 10 years, 20% of people treated with alemtuzumab had received another subsequent DMT, compared to 82% of people treated with interferon or glatiramer acetate. CONCLUSIONS: Immune reconstituting DMTs may have the highest potential to offer a single treatment for relapsing MS. Comparative data on DMT persistence and reasons for discontinuation are valuable to inform treatment decisions and in personalizing treatment in MS.

A Systematic Review and Meta-Analysis of the Pathology Underlying Aneurysm Enhancement on Vessel Wall Imaging.

Intracranial aneurysms are common, but only a minority rupture and cause subarachnoid haemorrhage, presenting a dilemma regarding which to treat. Vessel wall imaging (VWI) is a contrast-enhanced magnetic resonance imaging (MRI) technique used to identify unstable aneurysms. The pathological basis of MR enhancement of aneurysms is the subject of debate. This review synthesises the literature to determine the pathological basis of VWI enhancement. PubMed and Embase searches were performed for studies reporting VWI of intracranial aneurysms and their correlated histological analysis. The risk of bias was assessed. Calculations of interdependence, univariate and multivariate analysis were performed. Of 228 publications identified, 7 met the eligibility criteria. Individual aneurysm data were extracted for 72 out of a total of 81 aneurysms. Univariate analysis showed macrophage markers (CD68 and MPO, p = 0.001 and p = 0.002), endothelial cell markers (CD34 and CD31, p = 0.007 and p = 0.003), glycans (Alcian blue, p = 0.003) and wall thickness (p = 0.030) were positively associated with enhancement. Aneurysm enhancement therefore appears to be associated with inflammatory infiltrate and neovascularisation. However, all these markers are correlated with each other, and the literature is limited in terms of the numbers of aneurysms analysed and the parameters considered. The data are therefore insufficient to determine if these associations are independent of each other or of aneurysm size, wall thickness and rupture status. Thus, the cause of aneurysm-wall enhancement currently remains unknown.

An assistive listening device improves hearing following aneurysmal subarachnoid haemorrhage.

BACKGROUND AND PURPOSE: Hearing impairment is common following aneurysmal subarachnoid haemorrhage (aSAH). Previous studies have demonstrated that auditory processing disorder (APD) is the primary underlying pathology. Assistive listening devices (ALDs) can be used to manage APD but have not been explored in aSAH. The aim of this study was to assess the benefit of an ALD for patients reporting hearing difficulty after aSAH. METHODS: This was a prospective pilot single-arm intervention study of an ALD for APD following aSAH. Patients who reported subjective hearing difficulty following aSAH were identified from the Wessex Neurological Centre aSAH database. Speech-in-noise was evaluated using the Bamford-Kowal-Bench (BKB) test under 60 and 65 dB noise conditions. BKB performance was compared with and without an ALD. Cognition was assessed using the Addenbrooke's Cognitive Examination-III. RESULTS: Fourteen aSAH patients with self-reported hearing loss were included in the analysis. Under both noise conditions the ALD significantly improved BKB performance (60 dB, Z = -3.30, p < 0.001; 65 dB, Z = -3.33, p < 0.001). There was no relationship between cognition and response to the ALD. CONCLUSIONS: This study demonstrates the marked benefit of ALDs to manage APD following aSAH, regardless of cognitive status. This finding has implications for the management of this common yet disabling deficit which impacts quality of life and employment. A further trial of ALDs in this patient group is needed to test whether these large, short-term benefits can be practically translated to the community for long-term benefit when used at home.

Red Blood Cells in the Cerebrospinal Fluid Compartment After Subarachnoid Haemorrhage: Significance and Emerging Therapeutic Strategies.

Subarachnoid haemorrhage (SAH) is a subtype of stroke that predominantly impacts younger individuals. It is associated with high mortality rates and can cause long-term disabilities. This review examines the contribution of the initial blood load and the dynamics of clot clearance to the pathophysiology of SAH and the risk of adverse outcomes. These outcomes include hydrocephalus and delayed cerebral ischaemia (DCI), with a particular focus on the impact of blood located in the cisternal spaces, as opposed to ventricular blood, in the development of DCI. The literature described underscores the prognostic value of haematoma characteristics, such as volume, density, and anatomical location. The limitations of traditional radiographic grading systems are discussed, compared with the more accurate volumetric quantification techniques for predicting patient prognosis. Further, the significance of red blood cells (RBCs) and their breakdown products in secondary brain injury after SAH is explored. The review presents novel interventions designed to accelerate clot clearance or mitigate the effects of toxic byproducts released from erythrolysis in the cerebrospinal fluid following SAH. In conclusion, this review offers deeper insights into the complex dynamics of SAH and discusses the potential pathways available for advancing its management.

Sphingosine-1-phosphate Signalling in Aneurysmal Subarachnoid Haemorrhage: Basic Science to Clinical Translation.

Sphingosine-1-phosphate (S1P) is generated intracellularly and, when transported to the extracellular compartment, predominantly signals through S1P receptors. The S1P signalling pathway has been implicated in the pathophysiology of neurological injury following aneurysmal subarachnoid haemorrhage (aSAH). In this review, we bring together all the available data regarding the role of S1P in neurological injury following aSAH. There is agreement in the literature that S1P increases in the cerebrospinal fluid following aSAH and leads to cerebral artery vasospasm. On the other hand, the role of S1P in the parenchyma is less clear cut, with different studies arguing for beneficial and deleterious effects. A parsimonious interpretation of this apparently conflicting data is presented. We discuss the potential of S1P receptor modulators, in clinical use for multiple sclerosis, to be repurposed for aSAH. Finally, we highlight the gaps in our knowledge of S1P signalling in humans, the clinical challenges of targeting the S1P pathway after aSAH and other research priorities.

Dehydration associates with lower urinary tract symptoms in progressive multiple sclerosis.

BACKGROUND: Lower urinary tract symptoms (LUTS) are common in persons with progressive multiple sclerosis (pwPMS), who may consequently limit their fluid intake. We aimed to investigate the hypothesis that LUTS associate with objective evidence of inadequate hydration status in pwPMS. METHODS: In this prospective study, 55 pwPMS were studied over 2 years. A 6-monthly first-morning urine specimen was analysed for urinary osmolality and sodium as hydration markers. LUTS symptom severity in three categories (urgency, voiding and discomfort) was assessed and quantified using a questionnaire. Correlation between LUTS severity and hydration was assessed within subjects and between subjects, controlling for age. RESULTS: Some 274 urine samples with accompanying LUTS data from 55 participants were analysed. Biochemical data showed the expected loss of urine-concentrating capacity with increasing age. Inadequate hydration was observed in 47% of participants. LUTS were very common (87% reported urgency and 89% voiding symptoms). Voiding and discomfort, but not urgency severity, were correlated with hydration markers, both within and between participants. CONCLUSIONS: LUTS are very common in pwPMS, and associate with inadequate hydration. The causes and consequences of inadequate hydration in MS need further study, since (i) this will focus greater attention on LUTS management in pwPMS and (ii) dehydration has been associated with reversible cognitive dysfunction and physical underperformance.

Risk of subarachnoid haemorrhage reduces with blood pressure values below hypertensive thresholds.

BACKGROUND: Hypertension is a known risk factor for subarachnoid haemorrhage (SAH). The aim of this study was to describe the relationship between blood pressure and SAH using a large cohort study and perform a meta-analysis of the published literature. METHODS: Participants in the UK Biobank were followed up via electronic records until 31 March 2017. Cox proportional hazards models were used to analyse the association between baseline blood pressure (systolic blood pressure [SBP], diastolic blood pressure [DBP] and MABP [mean arterial blood pressure]) and subsequent aneurysmal SAH. Linearity was assessed by comparing models including and excluding cubic splines. Electronic databases were searched from inception until 11 February 2022 for studies reporting on blood pressure and SAH. RESULTS: A total of 500,598 individuals were included with 539 (0.001%) suffering from aneurysmal SAH. Nonlinear models including cubic splines visually appeared linear between SBP of 110 and 180 mmHg and there was minimal difference in fit between linear and nonlinear models. When values were stratified, those with SBP 120-130 mmHg were at higher risk compared to those with SBP <120 mmHg (hazard ratio [HR] 1.41 [1.02, 1.95]). The meta-analysis demonstrated a similar increased risk of SAH in individuals with SBP 120-130 mmHg relative to those with <120 mmHg (HR 1.41 [1.17, 1.72]). A stepwise increase in risk was also seen at each subsequent threshold (130-140 mmHg: HR 1.85 [1.53, 2.24], 140-160 mmHg: HR 2.16 [1.57, 2.98], 160-180 mmHg: HR 2.81 [1.85, 4.29], >180 mmHg: HR 5.84 [1.94, 17.54]). CONCLUSIONS: The rate of SAH increases linearly with higher SBP in the general population and specifically appears lower in those with SBP <120 mmHg.

The Haptoglobin Response after Aneurysmal Subarachnoid Haemorrhage.

Haptoglobin is the body's first line of defence against the toxicity of extracellular haemoglobin released following a subarachnoid haemorrhage (SAH). We investigated the haptoglobin response after SAH in cerebrospinal fluid (CSF) and serum. Paired CSF and serum samples from 19 controls and 92 SAH patients were assayed as follows: ultra-performance liquid chromatography for CSF haemoglobin and haptoglobin, immunoassay for serum haptoglobin and multiplexed CSF cytokines, and colorimetry for albumin. There was marked CSF haptoglobin deficiency: 99% of extracellular haemoglobin was unbound. The quotients for both CSF/serum albumin (qAlb) and haptoglobin (qHp) were used to compute the CSF haptoglobin index (qHp/qAlb). CSF from SAH patients had a significantly lower haptoglobin index compared to controls, especially in Haptoglobin-1 allele carriers. Serum haptoglobin levels increased after SAH and were correlated with CSF cytokine levels. Haptoglobin variables were not associated with long-term clinical outcomes post-SAH. We conclude that: (1) intrathecal haptoglobin consumption occurs after SAH, more so in haptoglobin-1 allele carriers; (2) serum haptoglobin is upregulated after SAH, in keeping with the liver acute phase response to central inflammation; (3) haptoglobin in the CSF is so low that any variation is too small for this to affect long-term outcomes, emphasising the potential for therapeutic haptoglobin supplementation.

Cryptococcal meningoencephalitis in multiple sclerosis treated with fingolimod.

A 21-year-old woman with multiple sclerosis (taking regular fingolimod) developed sudden-onset severe headache with nausea and malaise. Neurological examination was normal and she was afebrile. Blood results showed lymphocytes 0.53 x 109/L and C reactive protein 19 mg/L. CT scan of head and venogram were normal. CSF showed an opening pressure of 33 cm H2O and an incidental light growth of Cryptococcus neoformans, confirmed with positive India Ink stain and a positive cryptococcal antigen (1:100). She was treated for cryptococcal meningoencephalitis with amphotericin and flucytosine. Her presenting symptoms had closely mimicked subarachnoid haemorrhage. This atypical presentation of cryptococcal CNS infection highlights the need for vigilance in immunosuppressed patients.

Functional effects of haemoglobin can be rescued by haptoglobin in an in vitro model of subarachnoid haemorrhage.

During subarachnoid haemorrhage, a blood clot forms in the subarachnoid space releasing extracellular haemoglobin (Hb), which causes oxidative damage and cell death in surrounding tissues. High rates of disability and cognitive decline in SAH survivors are attributed to loss of neurons and functional connections during secondary brain injury. Haptoglobin sequesters Hb for clearance, but this scavenging system is overwhelmed after a haemorrhage. Whilst exogenous haptoglobin application can attenuate cytotoxicity of Hb in vitro and in vivo, the functional effects of sub-lethal Hb concentrations on surviving neurons and whether cellular function can be protected with haptoglobin treatment remain unclear. Here we use cultured neurons to investigate neuronal health and function across a range of Hb concentrations to establish the thresholds for cellular damage and investigate synaptic function. Hb impairs ATP concentrations and cytoskeletal structure. At clinically relevant but sub-lethal Hb concentrations, we find that synaptic AMPAR-driven currents are reduced, accompanied by a reduction in GluA1 subunit expression. Haptoglobin co-application can prevent these deficits by scavenging free Hb to reduce it to sub-threshold concentrations and does not need to be present at stoichiometric amounts to achieve efficacy. Haptoglobin itself does not impair measures of neuronal health and function at any concentration tested. Our data highlight a role for Hb in modifying synaptic function in surviving neurons, which may link to impaired cognition or plasticity after SAH and support the development of haptoglobin as a therapy for subarachnoid haemorrhage.

Haptoglobin Treatment for Aneurysmal Subarachnoid Hemorrhage: Review and Expert Consensus on Clinical Translation.

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating form of stroke frequently affecting young to middle-aged adults, with an unmet need to improve outcome. This special report focusses on the development of intrathecal haptoglobin supplementation as a treatment by reviewing current knowledge and progress, arriving at a Delphi-based global consensus regarding the pathophysiological role of extracellular hemoglobin and research priorities for clinical translation of hemoglobin-scavenging therapeutics. After aneurysmal subarachnoid hemorrhage, erythrocyte lysis generates cell-free hemoglobin in the cerebrospinal fluid, which is a strong determinant of secondary brain injury and long-term clinical outcome. Haptoglobin is the body's first-line defense against cell-free hemoglobin by binding it irreversibly, preventing translocation of hemoglobin into the brain parenchyma and nitric oxide-sensitive functional compartments of cerebral arteries. In mouse and sheep models, intraventricular administration of haptoglobin reversed hemoglobin-induced clinical, histological, and biochemical features of human aneurysmal subarachnoid hemorrhage. Clinical translation of this strategy imposes unique challenges set by the novel mode of action and the anticipated need for intrathecal drug administration, necessitating early input from stakeholders. Practising clinicians (n=72) and scientific experts (n=28) from 5 continents participated in the Delphi study. Inflammation, microvascular spasm, initial intracranial pressure increase, and disruption of nitric oxide signaling were deemed the most important pathophysiological pathways determining outcome. Cell-free hemoglobin was thought to play an important role mostly in pathways related to iron toxicity, oxidative stress, nitric oxide, and inflammation. While useful, there was consensus that further preclinical work was not a priority, with most believing the field was ready for an early phase trial. The highest research priorities were related to confirming haptoglobin's anticipated safety, individualized versus standard dosing, timing of treatment, pharmacokinetics, pharmacodynamics, and outcome measure selection. These results highlight the need for early phase trials of intracranial haptoglobin for aneurysmal subarachnoid hemorrhage, and the value of early input from clinical disciplines on a global scale during the early stages of clinical translation.

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.

Aspirin and Subarachnoid Haemorrhage in the UK Biobank.

Previous studies investigating the relationship between aspirin use and subarachnoid haemorrhage (SAH) have yielded conflicting results. In this study, we aimed to clarify the association between aspirin and SAH in the general population. The UK Biobank is a prospective population-based cohort study. Sex, age, smoking, alcohol, medication use, hypertension, blood pressure, ischaemic heart disease and stroke were recorded at baseline assessments. Follow-up is conducted through linkages to National Health Service data including electronic, coded death certificate, hospital and primary care data. Cox proportional hazards modelling was used to analyse the association between aspirin use and SAH. Of the 501,060 participants included in the analysis, a total of 579 suffered from spontaneous SAH after their baseline assessment. There was no relationship between aspirin and SAH of all causes (HR, 1.16 [0.92-1.46]), aneurysmal SAH (HR, 1.15 [0.91-1.47]) or non-aneurysmal SAH (HR, 1.29 [0.54-3.09]). Aspirin use was associated with SAH resulting in death (HR, 1.69 [1.14-2.51]), especially out of hospital death (HR, 2.10 [1.13-3.91]). Despite reports of a protective association between aspirin and SAH in patients with known unruptured aneurysms, this study has not demonstrated the same effect in the general population. However, aspirin users were more likely to suffer SAH resulting in death, especially out of hospital.

Genetic variation in NFE2L2 is associated with outcome following aneurysmal subarachnoid haemorrhage.

BACKGROUND AND PURPOSE: Nuclear factor erythroid 2-related factor 2 (NRF2; encoded by the NFE2L2 gene) has been implicated in outcome following aneurysmal subarachnoid haemorrhage (aSAH) through its activity as a regulator of inflammation, oxidative injury and blood breakdown product clearance. The aim of this study was to identify whether genetic variation in NFE2L2 is associated with clinical outcome following aSAH. METHODS: Ten tagging single nucleotide polymorphisms (SNPs) in NFE2L2 were genotyped and tested for association with dichotomized clinical outcome, assessed by the modified Rankin scale, in both a discovery and a validation cohort. In silico functional analysis was performed using a range of bioinformatic tools. RESULTS: One SNP, rs10183914, was significantly associated with outcome following aSAH in both the discovery (n = 1007) and validation cohorts (n = 466). The risk of poor outcome was estimated to be 1.33-fold (95% confidence interval 1.12-1.58) higher in individuals with the T allele of rs10183914 (pmeta-analysis  = 0.001). In silico functional analysis identified rs10183914 as a potentially regulatory variant with effects on transcription factor binding in addition to alternative splicing with the T allele, associated with a significant reduction in the NFE2L2 intron excision ratio (psQTL  = 1.3 × 10-7 ). CONCLUSIONS: The NFE2L2 SNP, rs10183914, is significantly associated with outcome following aSAH. This is consistent with a clinically relevant pathophysiological role for oxidative and inflammatory brain injury due to blood and its breakdown products in aSAH. Furthermore, our findings support NRF2 as a potential therapeutic target following aSAH and other forms of intracranial haemorrhage.

Fewer COVID-19 Neurological Complications with Dexamethasone and Remdesivir.

OBJECTIVE: The objective of this study was to assess the impact of treatment with dexamethasone, remdesivir or both on neurological complications in acute coronavirus diease 2019 (COVID-19). METHODS: We used observational data from the International Severe Acute and emerging Respiratory Infection Consortium World Health Organization (WHO) Clinical Characterization Protocol, United Kingdom. Hospital inpatients aged ≥18 years with laboratory-confirmed severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection admitted between January 31, 2020, and June 29, 2021, were included. Treatment allocation was non-blinded and performed by reporting clinicians. A propensity scoring methodology was used to minimize confounding. Treatment with remdesivir, dexamethasone, or both was assessed against the standard of care. The primary outcome was a neurological complication occurring at the point of death, discharge, or resolution of the COVID-19 clinical episode. RESULTS: Out of 89,297 hospital inpatients, 64,088 had severe COVID-19 and 25,209 had non-hypoxic COVID-19. Neurological complications developed in 4.8% and 4.5%, respectively. In both groups, neurological complications were associated with increased mortality, intensive care unit (ICU) admission, worse self-care on discharge, and time to recovery. In patients with severe COVID-19, treatment with dexamethasone (n = 21,129), remdesivir (n = 1,428), and both combined (n = 10,846) were associated with a lower frequency of neurological complications: OR = 0.76 (95% confidence interval [CI] = 0.69-0.83), OR = 0.69 (95% CI = 0.51-0.90), and OR = 0.54 (95% CI = 0.47-0.61), respectively. In patients with non-hypoxic COVID-19, dexamethasone (n = 2,580) was associated with less neurological complications (OR = 0.78, 95% CI = 0.62-0.97), whereas the dexamethasone/remdesivir combination (n = 460) showed a similar trend (OR = 0.63, 95% CI = 0.31-1.15). INTERPRETATION: Treatment with dexamethasone, remdesivir, or both in patients hospitalized with COVID-19 was associated with a lower frequency of neurological complications in an additive manner, such that the greatest benefit was observed in patients who received both drugs together. ANN NEUROL 2023;93:88-102.

A Genome-Wide Association Study of Outcome After Aneurysmal Subarachnoid Haemorrhage: Discovery Analysis.

Candidate gene studies have identified genetic variants associated with clinical outcomes following aneurysmal subarachnoid haemorrhage (aSAH), but no genome-wide association studies have been performed to date. Here we report the results of the discovery phase of a two-stage genome-wide meta-analysis of outcome after aSAH. We identified 157 independent loci harbouring 756 genetic variants associated with outcome after aSAH (p < 1 × 10-4), which require validation. A single variant (rs12949158), in SPNS2, achieved genome-wide significance (p = 4.29 × 10-8) implicating sphingosine-1-phosphate signalling in outcome after aSAH. A large multicentre international effort to recruit samples for validation is required and ongoing. Validation of these findings will provide significant insight into the pathophysiology of outcomes after aSAH with potential implications for treatment.

Systemic infection drives urgent care needs and outcome in adults with long-term neurological conditions.

It is estimated that 1 in 6 people are living with a long-term neurological condition (LTNC). Although it is likely that systemic infections are a common trigger for urgent tertiary care needs in LTNCs, there is a lack of data. Yet this is important since systemic infections are a modifiable risk factor, and hence the motivation for a formal evaluation. We undertook case note review of 155 consecutive unselected adult patients with LTNC receiving urgent care at a tertiary hospital between November and December 2019. Data were collected on presenting symptoms, diagnosis, length of stay, complications, and change in social needs. The most common LTNCs were neurocognitive disorders (n = 68, 44%), cerebrovascular disorders (n = 65, 42%), and epilepsy (n = 19, 12%). Respiratory infections were most common (n = 40, 62.5%), followed by urinary (n = 16, 25%), skin (n = 4, 6%), gastrointestinal (n = 3, 5%) and bone (n = 1, 1.5%). Systemic infection was the trigger for urgent care in 41.3% of patients and in multivariable regression was associated with an increased likelihood of admission (p < 10-5, OR = 7.8, Nagelkerke R2 = 0.37), longer length of stay (p = 0.03, ß = 5.91, R2 = 0.06), and death (p = 0.045, OR = 4.3, Nagelkerke R2 = 0.22). Altered mental status was the presenting symptom most frequently associated with infection (p < 10-8, χ2 test). In conclusion, systemic infections are a major trigger of acute tertiary care needs in adults with LTNCs, and play a role in determining clinical outcome. Since systemic infections are preventable or can be treated if identified early, they may represent a modifiable target to improve quality of life, clinical outcomes and health service efficiency.