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

Routine versus As-Needed Bevacizumab with 12-Weekly Assessment Intervals for Neovascular Age-Related Macular Degeneration 92-Week Results of the GMAN Trial

PurposeTo evaluate the efficacy and safety of intravitreal bevacizumab (Avastin; Genentech, South San Francisco, CA) in patients with neovascular age-related macular degeneration (nAMD) using 2 different treatment regimens in which patients were assessed clinically at up to 12-week intervals.DesignRandomized, controlled, noninferiority trial.ParticipantsA total of 331 patients with nAMD.MethodsPatients were treated with 1.25 mg intravitreal bevacizumab and followed up to 92 weeks. They were randomized into 2 arms. All patients received 3 loading doses 4 weeks apart and thereafter were assessed every 12 weeks until the end of the study. One arm received a routine treatment at each 12-week assessment, and the other arm was treated at these assessments on an as-needed basis. After the loading doses, patients in either arm who showed signs of disease activity had an additional assessment after 6 weeks and at that visit had top-up treatments on an as-needed basis.Main Outcome MeasuresMean best-corrected visual acuity (BCVA) at 92 weeks.ResultsAt 92 weeks, patients who had treatments every 12 weeks had superior BCVA to those treated on an as-needed basis every 12 weeks (P = 0.008), with the regular treatment arm gaining a mean BCVA of 5.5 letters and the as-needed treatment arm gaining 0.6 letters. The regular treatment arm of the study showed significantly improved outcomes with respect to 5-, 10-, and 15-letter changes in BCVA from baseline compared with the as-needed treatment arm, as well as superior reading speed. In patients who completed the study, up to but not including week 92, the mean number of treatments was 10.8 for the regular treatment arm and 9.1 for the as-needed treatment arm.ConclusionsA treatment regimen with regular bevacizumab injections every 12 weeks after loading doses supplemented with as-needed top-up treatments produced a stable improvement in BCVA from baseline. The improvement in BCVA was broadly similar to that obtained in other studies using anti-vascular endothelial growth factor drugs with more frequent assessments and treatments

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

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

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

Environmental Education to Promote Peace and Cooperation: A Case Study of Tree Nurseries in Nakuru, Kenya

This field report describes a peace education program in the Nakuru district of Kenya, focusing on environmental education tree nurseries. The peace clubs introduced tree nurseries as a way of equipping children to take care of their environment. The interaction required to maintain these nurseries strengthens these relationships and promotes cooperation. By planting and caring for tree nurseries, children are able to express their commitment to their community and to the lasting health of their environment.sch_iih23pub2969pub

Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial

Background Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects. Methods FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762. Findings Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months. Interpretation Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function. Funding UK Stroke Association and NIHR Health Technology Assessment Programme

The power to propose: An analysis of the government's financial veto

This paper explores the financial veto procedure established in the Standing Orders of the House of Representatives of New Zealand. The paper historically situates the financial veto by considering the traditional division of authorising power in public finance. It then sketches an outline of the financial veto, while noting that the scope of the financial veto is not entirely clear. The paper finds that the financial veto runs contrary to democratic principles; a proportionality analysis is used to determine that the procedure is an unjustified limitation on those principles. The abolition of the financial veto procedure is recommended, but alternative options for reform are also briefly considered