Delirium and long-term cognitive impairment after stroke: the role of the hypothalamic-pituitary-adrenal axis

Delirium is a severe neuropsychiatric syndrome, characterised by the acute onset of inattention, altered level of arousal, and other mental status abnormalities. Delirium is extremely common in acute stroke, affecting at least 1 in 5 such patients admitted to hospital. It is a serious complication of stroke, being associated with higher mortality, longer length of hospital stay and higher dependency at discharge. The pathophysiology of delirium is not completely understood, and there are no specific treatments. This thesis investigated the role of cortisol in the development of delirium after stroke and also investigated the role of delirium and of cortisol in the development of cognitive impairment in the 12 months after stroke. The thesis specifically investigated whether levels of cortisol in saliva are elevated in delirium and also whether there is a loss of the normal diurnal rhythm in delirium, evidenced by elevated afternoon salivary cortisol levels and reduced morning level to afternoon level ratio. The thesis also investigated whether cortisol levels are persistently elevated in the year after stroke in those who developed delirium and whether cortisol levels are associated with cognitive decline. Finally it investigated whether acute and/or chronic changes seen on Computed Tomography (CT) brain scans taken around the time of stroke onset are associated with the development of delirium after stroke A longitudinal cohort study was conducted in 95 participants aged 60 years or over, who were admitted to hospital with a clinically confirmed stroke. Participants gave informed consent, or proxy consent was obtained if they lacked capacity to consent. At baseline participants underwent brief cognitive testing and were then assessed for the presence of delirium, using DSM IV criteria, at regular intervals during the first two weeks after stroke. At each assessment a saliva sample was collected in the morning and in the afternoon, to measure cortisol. Participants were then visited at 1 month, 4 months and 12 months after stroke onset, at which point they were assessed for the presence of delirium, further saliva samples were taken and a cognitive test battery was completed. 26 (27%) participants developed delirium during the course of the study period. The study found elevated salivary cortisol levels in those with delirium at up to 4 months after stroke, but at 12 months there was no difference between the delirium and no delirium group. A loss of the diurnal rhythm was seen in those who developed delirium at 5 days after stroke, but the diurnal variation had returned to a normal pattern at follow-up. However, in a multivariate analysis, controlling for age, sex, stroke severity (NIHSS), current illness burden (APACHE II), chronic illness burden (CCI) and prior cognitive impairment (IQCODE), neither median salivary cortisol levels in the first two weeks after stroke, nor the ratio of morning to afternoon cortisol levels were independent predictors of delirium diagnosis, although median 9am cortisol approached significance (OR=0.95, 95% confidence interval (CI) 0.89-1.01, p=0.08). In a random effects logistic regression analysis, the probability of developing delirium decreased over time from stroke onset and increased per unit increase in salivary cortisol (nmol/L), however this effect was not statistically significant (OR 1.02, CI 0.84-1.19 P=0.70 for morning cortisol and OR 1.05, CI 0.82-1.25 p=0.46 for afternoon cortisol). Global cognition, measured by the MoCA, was significantly poorer in the delirium group at each time point throughout the 12 months after stroke. However, there was a trend towards improvement in MoCA scores in the whole cohort throughout the 12 month follow-up, with the exception of those who developed the most severe delirium. The presence of delirium at any point during the 12 month follow-up did not affect the rate of change of the MoCA scores over the 12 months after stroke. The presence of brain atrophy identified on admission CT brain scans was independently associated with delirium (OR 3.7, CI 1.15-11.88, p=0.02), however the presence of a visible acute or chronic stroke lesion and the presence of white matter lesions were not. Finally, those who developed delirium had a worse functional outcome, longer length of hospital stay and were more likely to require institutional care or a package of care at home, compared with those who did not develop delirium. This thesis has contributed to our understanding of the mechanisms and phenomenology of delirium after stroke, and has also highlighted areas for further research which will be required to unpick the complex pathophysiology of delirium

Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) might theoretically reduce post‐stroke disability by direct effects on the brain. This Cochrane Review was first published in 2012 and last updated in 2019. OBJECTIVES: To determine if SSRIs are more effective than placebo or usual care at improving outcomes in people less than 12 months post‐stroke, and to determine whether treatment with SSRIs is associated with adverse effects. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched 7 January 2021), Cochrane Controlled Trials Register (CENTRAL, Issue 7 of 12, 7 January 2021), MEDLINE (1946 to 7 January 2021), Embase (1974 to 7 January 2021), CINAHL (1982 to 7 January 2021), PsycINFO (1985 to 7 January 2021), and AMED (1985 to 7 January 2021). PsycBITE had previously been searched (16 July 2018). We searched clinical trials registers. SELECTION CRITERIA: We included randomised controlled trials (RCTs) recruiting stroke survivors within the first year. The intervention was any SSRI, at any dose, for any period, and for any indication. The comparator was usual care or placebo. Studies reporting at least one of our primary (disability score or independence) or secondary outcomes (impairments, depression, anxiety, quality of life, fatigue, cognition, healthcare cost, death, adverse events and leaving the study early) were included in the meta‐analysis. The primary analysis included studies at low risk of bias. DATA COLLECTION AND ANALYSIS: We extracted data on demographics, stroke type and, our pre‐specified outcomes, and bias sources. Two review authors independently extracted data. We used mean difference (MD) or standardised mean differences (SMDs) for continuous variables, and risk ratios (RRs) for dichotomous variables, with 95% confidence intervals (CIs). We assessed bias risks and applied GRADE criteria. MAIN RESULTS: We identified 76 eligible studies (13,029 participants); 75 provided data at end of treatment, and of these two provided data at follow‐up. Thirty‐eight required participants to have depression to enter. The duration, drug, and dose varied. Six studies were at low risk of bias across all domains; all six studies did not need participants to have depression to enter, and all used fluoxetine. Of these six studies, there was little to no difference in disability between groups SMD ‐0.0; 95% CI ‐0.05 to 0.05; 5 studies, 5436 participants, high‐quality evidence) or in independence (RR 0.98; 95% CI 0.93 to 1.03; 5 studies, 5926 participants; high‐quality evidence) at the end of treatment. In the studies at low risk of bias across all domains, SSRIs slightly reduced the average depression score (SMD 0.14 lower, 95% CI 0.19 lower to 0.08 lower; 4 studies; 5356 participants, high‐quality evidence) and there was a slight reduction in the proportion with depression (RR 0.75, 95% CI 0.65 to 0.86; 3 studies, 5907 participants, high‐quality evidence). Cognition was slightly better in the control group (MD ‐1.22, 95% CI ‐2.37 to ‐0.07; 4 studies, 5373 participants, moderate‐quality evidence). Only one study (n = 30) reported neurological deficit score (SMD ‐0.39, 95% CI ‐1.12 to 0.33; low‐quality evidence). SSRIs resulted in little to no difference in motor deficit (SMD 0.03, ‐0.02 to 0.08; 6 studies, 5518 participants, moderate‐quality evidence). SSRIs slightly increased the proportion leaving the study early (RR 1.57, 95% CI 1.03 to 2.40; 6 studies, 6090 participants, high‐quality evidence). SSRIs slightly increased the outcome of a seizure (RR 1.40, 95% CI 1.00 to 1.98; 6 studies, 6080 participants, moderate‐quality evidence) and a bone fracture (RR 2.35, 95% CI 1.62 to 3.41; 6 studies, 6080 participants, high‐quality evidence). One study at low risk of bias across all domains reported gastrointestinal side effects (RR 1.71, 95% CI 0.33, to 8.83; 1 study, 30 participants). There was no difference in the total number of deaths between SSRI and placebo (RR 1.01, 95% CI 0.82 to 1.24; 6 studies, 6090 participants, moderate quality evidence). SSRIs probably result in little to no difference in fatigue (MD ‐0.06; 95% CI ‐1.24 to 1.11; 4 studies, 5524 participants, moderate‐quality of evidence), nor in quality of life (MD 0.00; 95% CI ‐0.02 to 0.02, 3 studies, 5482 participants, high‐quality evidence). When all studies, irrespective of risk of bias, were included, SSRIs reduced disability scores but not the proportion independent. There was insufficient data to perform a meta‐analysis of outcomes at end of follow‐up. Several small ongoing studies are unlikely to alter conclusions. AUTHORS' CONCLUSIONS: There is high‐quality evidence that SSRIs do not make a difference to disability or independence after stroke compared to placebo or usual care, reduced the risk of future depression, increased bone fractures and probably increased seizure risk

Fluoxetine for stroke recovery: Meta-analysis of randomized controlled trials

Objective: To determine whether fluoxetine, at any dose, given within the first year after stroke to patients who did not have to have mood disorders at randomisation led to a reduction in disability, dependency, neurological deficits and fatigue; improved motor function, mood, and cognition at the end of treatment and follow-up, with the same number or fewer adverse effects. Methods: Searches in July 2018 included several databases, trials registers, reference lists, contact with experts. We excluded RCTs requiring patients to have mood disorder at randomisation. Co-primary outcomes were dependence and disability. Dichotomous data were synthesised using risk ratios (RR) and continuous data using standardised mean differences (SMD). Quality was appraised using Cochrane risk of bias methods. Sensitivity analyses explored influence of study quality. Results: The searches identified 3412 references of which 491 full texts were assessed for eligibility. Six new completed RCTs (n=3710) were eligible, making a total of 13 trials (n=4145). There was no difference in the proportion independent at the end of treatment (3 trials, n=3249, 36·6% fluoxetine vs 36·7% control; RR 1·00, 95% confidence interval 0·91 to 1.09, p=0·99, I2 78%) and no difference in disability (7 trials n=3404, SMD 0·05, -0·02 to 0·12 p=0·15, I2=81%). Fluoxetine was associated with better neurological scores and less depression but more seizures. Among the four (n=3283) high quality RCTs, the only difference between groups was lower depression scores with fluoxetine. Conclusion: Fluoxetine does not reduce disability and dependency after stroke. It improves depression scores but increases seizures. Ongoing RCTs will determine its effects in stroke vary depending on ethnicity, background treatment and other factors. Classification of evidence: meta-analysi

Predicting discharge to institutional long-term care after stroke: a systematic review & meta-analysis

Background/Objectives: Stroke is a leading cause of disability worldwide, and a significant proportion of stroke survivors require long-term institutional care. Understanding who cannot be discharged home is important for health and social care planning. Our aim was to establish predictive factors for discharge to institutional care after hospitalization for stroke. Design: We registered and conducted a systematic review and meta-analysis (PROSPERO: CRD42015023497) of observational studies. We searched MEDLINE, EMBASE, and CINAHL Plus to February 2017. Quantitative synthesis was performed where data allowed. Setting: Acute and rehabilitation hospitals. Participants: Adults hospitalized for stroke who were newly admitted directly to long-term institutional care at the time of hospital discharge. Measurements: Factors associated with new institutionalization. Results: From 10,420 records, we included 18 studies (n = 32,139 participants). The studies were heterogeneous and conducted in Europe, North America, and East Asia. Eight studies were at high risk of selection bias. The proportion of those surviving to discharge who were newly discharged to long-term care varied from 7% to 39% (median 17%, interquartile range 12%), and the model of care received in the long-term care setting was not defined. Older age and greater stroke severity had a consistently positive association with the need for long-term care admission. Individuals who had a severe stroke were 26 times as likely to be admitted to long-term care than those who had a minor stroke. Individuals aged 65 and older had a risk of stroke that was three times as great as that of younger individuals. Potentially modifiable factors were rarely examined. Conclusion: Age and stroke severity are important predictors of institutional long-term care admission directly from the hospital after an acute stroke. Potentially modifiable factors should be the target of future research. Stroke outcome studies should report discharge destination, defining the model of care provided in the long-term care setting

Selective Serotonin Reuptake Inhibitors for Stroke Recovery

Stroke is a major cause of adult disability. Selective serotonin reuptake inhibitors (SSRIs) have been used for many years to manage depression and other mood disorders after stroke. Small studies suggested that SSRIs might also promote motor recovery by direct effects on the brain. In this Cochrane review, we aimed to determine the effects of SSRIs in improving outcomes in people <12 months after stroke and to determine whether treatment with SSRIs is associated with adverse effects

New horizons in the pathogenesis, assessment and management of delirium

Delirium is one of the foremost unmet medical needs in healthcare. It affects one in eight hospitalised patients and is associated with multiple adverse outcomes including increased length of stay, new institutionalisation, and considerable patient distress. Recent studies also show that delirium strongly predicts future new-onset dementia, as well as accelerating existing dementia. The importance of delirium is now increasingly being recognised, with a growing research base, new professional international organisations, increased interest from policymakers, and greater prominence of delirium in educational and audit programmes. Nevertheless, the field faces several complex research and clinical challenges. In this article we focus on selected areas of recent progress and/or uncertainty in delirium research and practice. (i) Pathogenesis: recent studies in animal models using peripheral inflammatory stimuli have begun to suggest mechanisms underlying the delirium syndrome as well as its link with dementia. A growing body of blood and cerebrospinal fluid studies in humans have implicated inflammatory and stress mediators. (ii) Prevention: delirium prevention is effective in the context of research studies, but there are several unresolved issues, including what components should be included, the role of prophylactic drugs, and the overlap with general best care for hospitalised older people. (iii) Assessment: though there are several instruments for delirium screening and assessment, detection rates remain dismal. There are no clear solutions but routine screening embedded into clinical practice, and the development of new rapid screening instruments, offer potential. (iv) Management: studies are difficult given the heterogeneity of delirium and currently expert and comprehensive clinical care remains the main recommendation. Future studies may address the role of drugs for specific elements of delirium. In summary, though facing many challenges, the field continues to make progress, with several promising lines of enquiry and an expanding base of interest among researchers, clinicians and policymakers