Isosorbide Mononitrate and Cilostazol Treatment in Patients With Symptomatic Cerebral Small Vessel Disease: The Lacunar Intervention Trial-2 (LACI-2) Randomized Clinical Trial.

Importance: Cerebral small vessel disease (cSVD) is a common cause of stroke (lacunar stroke), is the most common cause of vascular cognitive impairment, and impairs mobility and mood but has no specific treatment. Objective: To test the feasibility, drug tolerability, safety, and effects of 1-year isosorbide mononitrate (ISMN) and cilostazol treatment on vascular, functional, and cognitive outcomes in patients with lacunar stroke. Design, Setting, and Participants: The Lacunar Intervention Trial-2 (LACI-2) was an investigator-initiated, open-label, blinded end-point, randomized clinical trial with a 2 × 2 factorial design. The trial aimed to recruit 400 participants from 26 UK hospital stroke centers between February 5, 2018, and May 31, 2021, with 12-month follow-up. Included participants had clinical lacunar ischemic stroke, were independent, were aged older than 30 years, had compatible brain imaging findings, had capacity to consent, and had no contraindications to (or indications for) the study drugs. Data analysis was performed on August 12, 2022. Interventions: All patients received guideline stroke prevention treatment and were randomized to ISMN (40-60 mg/d), cilostazol (200 mg/d), ISMN-cilostazol (40-60 and 200 mg/d, respectively), or no study drug. Main Outcomes: The primary outcome was recruitment feasibility, including retention at 12 months. Secondary outcomes were safety (death), efficacy (composite of vascular events, dependence, cognition, and death), drug adherence, tolerability, recurrent stroke, dependence, cognitive impairment, quality of life (QOL), and hemorrhage. Results: Of the 400 participants planned for this trial, 363 (90.8%) were recruited. Their median age was 64 (IQR, 56.0-72.0) years; 251 (69.1%) were men. The median time between stroke and randomization was 79 (IQR, 27.0-244.0) days. A total of 358 patients (98.6%) were retained in the study at 12 months, with 257 of 272 (94.5%) taking 50% or more of the allocated drug. Compared with those participants not receiving that particular drug, neither ISMN (adjusted hazard ratio [aHR], 0.80 [95% CI, 0.59 to 1.09]; P = .16) nor cilostazol (aHR, 0.77 [95% CI, 0.57 to 1.05]; P = .10) alone reduced the composite outcome in 297 patients. Isosorbide mononitrate reduced recurrent stroke in 353 patients (adjusted odds ratio [aOR], 0.23 [95% CI, 0.07 to 0.74]; P = .01) and cognitive impairment in 308 patients (aOR, 0.55 [95% CI, 0.36 to 0.86]; P = .008). Cilostazol reduced dependence in 320 patients (aHR, 0.31 [95% CI, 0.14 to 0.72]; P = .006). Combination ISMN-cilostazol reduced the composite (aHR, 0.58 [95% CI, 0.36 to 0.92]; P = .02), dependence (aOR, 0.14 [95% CI, 0.03 to 0.59]; P = .008), and any cognitive impairment (aOR, 0.44 [95% CI, 0.23 to 0.85]; P = .02) and improved QOL (adjusted mean difference, 0.10 [95% CI, 0.03 to 0.17]; P = .005) in 153 patients. There were no safety concerns. Conclusions and Relevance: These results show that the LACI-2 trial was feasible and ISMN and cilostazol were well tolerated and safe. These agents may reduce recurrent stroke, dependence, and cognitive impairment after lacunar stroke, and they could prevent other adverse outcomes in cSVD. Therefore, both agents should be tested in large phase 3 trials. Trial Registration: ClinicalTrials.gov Identifier: NCT03451591.

Late onset AMACR deficiency with metabolic stroke-like episodes and seizures.

Alpha-methylacyl-CoA racemase (AMACR) deficiency is a rare peroxisomal disorder causing pristanic acid accumulation. Only 16 cases have been described so far. A female in her seventh decade presented with episodes of dysphasia, headache and sensory disturbance inconsistent with migraine, epilepsy or transient ischaemic attack. An MRI demonstrated unusual changes in the pons, red nuclei, thalami and white matter. Mitochondrial disease was suspected but detailed testing was negative. After eight years of symptoms, she developed a febrile encephalopathy with hemispheric dysfunction, focal convulsive seizures and coma. Her condition stabilised after one month. Lacosamide was continued for seizure prevention. The diagnosis remained elusive until whole genome sequencing revealed AMACR deficiency. Pristanic acid levels were highly elevated and dietary modification was recommended. Genetic peroxisomal disorders can present in older age; our patient is the oldest in the AMACR deficiency literature. Novel features in our case include central apnoea, dystonia and rapid eye movement behaviour disorder.

Oxfordshire Community Stroke Project Classification: A proposed automated algorithm.

INTRODUCTION: The Oxfordshire Community Stroke Project (OCSP) proposed a clinical classification for Stroke patients. This classification has proved helpful to predict the risk of neurological complications. However, the OCSP was initially based on findings on the neurological assesment, which can pose difficulties for classifying patients. We aimed to describe the development and the validation step of a computer-based algorithm based on the OCSP classification. MATERIALS AND METHODS: A flow-chart was created which was reviewed by five board-certified vascular neurologists from which a computer-based algorithm (COMPACT) was developed. Neurology residents from 12 centers were invited to participate in a randomized trial to assess the effect of using COMPACT. They answered a 20-item questionnaire for classifying the vignettes according to the OCSP classification. Each correct answer has been attributed to 1-point for calculating the final score. RESULTS: Six-two participants agreed to participate and answered the questionnaire. Thirty-two were randomly allocated to use our algorithm, and thirty were allocated to adopt a list of symptoms alone. The group who adopted our algorithm had a median score of correct answers of 16.5[14.5, 17]/20 versus 15[13, 16]/20 points, p = 0.014. The use of our algorithm was associated with the overall rate of correct scores (p = 0.03). DISCUSSION: Our algorithm seemed a useful tool for any postgraduate year Neurology resident. A computer-based algorithm may save time and improve the accuracy to classify these patients. CONCLUSION: An easy-to-use computer-based algorithm improved the accuracy of the OCSP classification, with the possible benefit of further improvement of the prediction of neurological complications and prognostication.

Prevention of mood disorder after stroke: a randomised controlled trial of problem solving therapy versus volunteer support.

BACKGROUND: Mood disorder after stroke is common but drug and psychosocial treatments have been assessed with disappointing results. Preventing mood disorder from developing in the first place could be a better approach and might reduce the need for pharmacotherapy in this predominantly older patient group. We used a brief problem-solving therapy and evaluated its effect in reducing mood disorder in the 12 months after stroke. METHODS: A 3-group, parallel, randomised controlled trial. Four hundred fifty patients with stroke were randomised within 1 month of hospital admission to problem-solving therapy from a psychiatric nurse, non-specific support given by volunteers or treatment-as-usual. Follow up took place at 6 and 12 months after stroke. Standardised measures of mood (Present State Examination, GHQ-28), cognitive state (mini-mental state examination) and function (Barthel ADL index, Frenchay Activities Index) were taken at baseline, 6 and 12 months after randomisation. Satisfaction with care was recorded at follow up. RESULTS: At 6 months, all psychological and activity measures favoured problem-solving therapy. At 12 months, patients in the problem-solving therapy group had significantly lower GHQ-28 scores and lower median Present State Examination symptom scores. There were no statistically significant differences in activity. The problem-solving therapy group were more satisfied with some aspects of care. CONCLUSIONS: The results are encouraging and suggest it is possible to prevent mood disorder in stroke patients using a psychological intervention. The differences between the groups at 12 months may indicate a sustained impact of psychological therapies, by comparison with non-specific support. TRIAL REGISTRATION: ISRCTN: ISRCTN33773710 Registered: 23/01/2004 (Retrospectively).

The design and validation of a parent-report questionnaire for assessing the characteristics and quality of early intervention over time.

This article concerns a parent-report repeat questionnaire to evaluate the quality of multiprofessional early intervention following early identification of deafness. It discusses the rationale for the design of the instrument, its theoretical underpinnings, its psychometric properties, and its usability. Results for the validity and reliability of the instrument are based on completion by 82 parents. The questionnaire is divided into four sections. "The description of the structure of professional services" demonstrated good face and content validity; the "content of intervention scale" yielded high internal consistency (Cronbach's alpha = 0.88) and reliability (6-month test-retest correlations, rho = 0.88, r = .68; 12-month test-retest correlations, rho = 0.60, r = .82); the "process of intervention" scale yielded high internal consistency (Cronbach's alpha = 0.93) and high reliability on test-retest administration (6-month test-retest correlations, r = 0.64; 12 month test-retest correlations, r = .82); and the short "overall impact" questions were answered well. The Trait Emotional Intelligence Questionnaire was used to control for influence of parental disposition on ratings of quality of intervention. Evaluating the goodness of fit between early intervention and parental priorities/values is discussed as a vital component in improving child and family outcomes.

Elevated C-reactive protein and long-term mortality after ischaemic stroke: relationship with markers of endothelial cell and platelet activation.

BACKGROUND AND PURPOSE: Inflammatory biomarkers predict development of atherothrombotic events. In the present study we examined the relationships between C-reactive protein (CRP), complement C3, and long-term mortality after acute ischemic stroke. METHODS: CRP and C3 were analyzed by in-house enzyme-linked immunosorbent assay in 394 subjects with acute ischemic stroke who survived for >30 days, followed-up for a median of 7.4 years. RESULTS: CRP was higher in subjects who died (10.8 mg/L; 95% CI, 9.1-12.8) compared with survivors (3.8 mg/L; 95% CI, 3.1-4.7), whereas C3 was similar in both groups (P=0.26). CRP remained predictive for mortality after adjusting for conventional clinical and demographic risk factors (the adjusted hazard ratio for those with CRP in the highest compared with the lowest quartile was 2.0; 95% CI, 1.3-3.1). However, CRP was no longer independently predictive of mortality after additionally adjusting for beta-thromboglobulin or von Willebrand factor. CONCLUSIONS: Our data suggest that the relationship between CRP and poststroke mortality may in part reflect inflammation-induced endothelial cell dysfunction and platelet activation.

Acceptance, effectiveness and safety of continuous positive airway pressure in acute stroke: a pilot study.

OBJECTIVES: To evaluate the acceptance, effectiveness in preventing upper airways obstruction, and haemodynamic effects of continuous positive airway pressure (CPAP) in acute stroke. METHODS: Twelve patients (4 M, and 8 F; mean (SD), 75.2 (5.5) years) within 48 h of acute stroke onset underwent: (1) sleep studies (1st night: auto-CPAP mode; 2nd night: diagnostic); (2) nocturnal non-invasive blood pressure studies (1st night during CPAP; 2nd night during spontaneous breathing (SB)); and (3) daytime cerebral blood flow velocity measurement in middle cerebral artery (FV) with transcranial Doppler during SB and with CPAP (5, 10, 15 cm H(2)O). RESULTS: Ninety percent, 60% and 50% of stroke patients had a respiratory disturbance index (RDI) of >or=5, >or=10 and >or=15 events per hour, respectively (18.2 (11.3)). CPAP acceptance was 84%; 42% used CPAP more than 6h and 42% between 1-3h with a mean use of CPAP of 5.2h (4.0). Compared to SB, CPAP reduced, though not significantly, RDI, time with SaO(2)<90%, mean blood pressure and mean blood pressure dips (10 mm Hg)/h. Compared with SB, any level of CPAP progressively and significantly reduced systolic and mean FV; drop in diastolic FV was significant at CPAP10 and CPAP15. The partial pressure of end-tidal CO(2) was significantly lowered by all levels of CPAP. CONCLUSIONS: According to this pilot study, CPAP is reasonably well tolerated by patients with acute stroke for at least one night. Despite its possible beneficial effect on obstructive sleep-disordered breathing and blood pressure variability, CPAP use in acute stroke should be still considered with caution due to possible harmful haemodynamic effects at higher pressures.

Why don't health professionals check patient understanding? A questionnaire-based study.

Checking patient understanding, by asking questions about information presented in a medical consultation, is a core communication skill but its use is not frequently assessed. The newborn hearing screening commenced in England with a pilot of its implementation in January 2002. Because it is a new screening test, it provided an opportunity for studying the effective communication of novel information. A randomized controlled trial of training newborn hearing screeners to present information about the screening test and to ask questions to check understanding was commenced but had to be prematurely ended as the majority of the screeners did not ask the questions. The aim of this study was to understand why the screeners did not ask questions to check understanding of the information provided. Questionnaires were sent to screeners who participated in the study to elicit their responses to the use of the questions to check understanding. A response rate of 87% (26/30) was achieved. Screeners who reported not asking the questions were more likely to express a lack of confidence in their ability to ask questions, and to perceive asking questions as an ineffective way of increasing patient understanding. The study suggests that the ability and willingness of healthcare professionals to use simple communication skills may have been overestimated and training needs to target skills as well as beliefs about the effectiveness of using them.

Glucose-potassium-insulin infusions in the management of post-stroke hyperglycaemia: the UK Glucose Insulin in Stroke Trial (GIST-UK).

BACKGROUND: Hyperglycaemia after acute stroke is a common finding that has been associated with an increased risk of death. We sought to determine whether treatment with glucose-potassium-insulin (GKI) infusions to maintain euglycaemia immediately after the acute event reduces death at 90 days. METHODS: Patients presenting within 24 h of stroke onset and with admission plasma glucose concentration between 6.0-17.0 mmol/L were randomly assigned to receive variable-dose-insulin GKI (intervention) or saline (control) as a continuous intravenous infusion for 24 h. The purpose of GKI infusion was to maintain capillary glucose at 4-7 mmol/L, with no glucose intervention in the control group. The primary outcome was death at 90 days, and the secondary endpoint was avoidance of death or severe disability at 90 days. Additional planned analyses were done to determine any differences in residual disability or neurological and functional recovery. The trial was powered to detect a mortality difference of 6% (sample size 2355), with 83% power, at the 5% two-sided significance level. This study is registered as an International Standard Randomised Controlled Trial (number ISRCTN 31118803) FINDINGS: The trial was stopped due to slow enrolment after 933 patients were recruited. For the intention-to-treat data, there was no significant reduction in mortality at 90 days (GKI vs control: odds ratio 1.14, 95% CI 0.86-1.51, p=0.37). There were no significant differences for secondary outcomes. In the GKI group, overall mean plasma glucose and mean systolic blood pressure were significantly lower than in the control group (mean difference in glucose 0.57 mmol/L, p<0.001; mean difference in blood pressure 9.0 mmHg, p<0.0001). INTERPRETATION: GKI infusions significantly reduced plasma glucose concentrations and blood pressure. Treatment within the trial protocol was not associated with significant clinical benefit, although the study was underpowered and alternative results cannot be excluded.

Predictive variables for mortality after acute ischemic stroke.

BACKGROUND AND PURPOSE: Stroke is a major healthcare issue worldwide with an incidence comparable to coronary events, highlighting the importance of understanding risk factors for stroke and subsequent mortality. METHODS: In the present study, we determined long-term (all-cause) mortality in 545 patients with ischemic stroke compared with a cohort of 330 age-matched healthy control subjects followed up for a median of 7.4 years. We assessed the effect of selected demographic, clinical, biochemical, hematologic, and hemostatic factors on mortality in patients with ischemic stroke. Stroke subtype was classified according to the Oxfordshire Community Stroke Project criteria. Patients who died 30 days or less after the acute event (n=32) were excluded from analyses because this outcome is considered to be directly attributable to the acute event. RESULTS: Patients with ischemic stroke were at more than 3-fold increased risk of death compared with the age-matched control cohort. In multivariate analyses, age, stroke subtype, atrial fibrillation, and previous stroke/transient ischemic attack were predictive of mortality in patients with ischemic stroke. Albumin and creatinine and the hemostatic factors von Willebrand factor and beta-thromboglobulin were also predictive of mortality in patients with ischemic stroke after accounting for demographic and clinical variables. CONCLUSIONS: The results indicate that subjects with acute ischemic stroke are at increased risk of all-cause mortality. Advancing age, large-vessel stroke, atrial fibrillation, and previous stroke/transient ischemic attack predict mortality; and analysis of albumin, creatinine, von Willebrand factor, and beta-thromboglobulin will aid in the identification of patients at increased risk of death after stroke.

A patient with neuro-Behçet's disease is successfully treated with etanercept: further evidence for the value of TNFalpha blockade.

Behçet's disease is a chronic relapsing multisystem vasculitis with 49% of cases involving the CNS. Recently there have been two reports of neuro-Behçet's disease (NB) successfully treated with the tumour necrosis factor alpha (TNFalpha) monoclonal antibody infliximab. We describe a patient with longstanding NB who was poorly responsive to azathioprine, cyclosporin, thalidomide and methotrexate. She showed a remarkable response when treated with the recombinant human TNFalpha receptor protein, etanercept. To the best of our knowledge this is the first report of NB successfully treated with etanercept.

Effectiveness of population-based newborn hearing screening in England: ages of interventions and profile of cases.

OBJECTIVE: The objective of this study was to determine the effectiveness in routine practice of the first phase of a national population-based newborn hearing screening and follow-up program that seeks to identify infants with bilateral permanent hearing loss of > or =40-dB hearing loss. METHODS: The study was a part of the independent evaluation of the 23 first phase sites (annual birth population approximately 120,000) of the national newborn hearing screening program in England. For each infant identified with the defined hearing loss, the measures of interest were degree and type of hearing loss, presence of risk factors, age of first audiologic assessment, age of identification of hearing loss, age of enrollment in an early support program, and age of hearing aid fitting. Data collection took place over the first 2 years of the program. RESULTS: Data were provided on 169 infants with permanent bilateral moderate or greater hearing loss identified through screening 169487 infants. Fifty-four percent of all cases were from an "at-risk" population. Three fourths of these "at-risk" infants spent > or =48 hours in the NICU. For the whole sample, the median age at first audiologic assessment was 5 weeks; the median age of identification of the hearing loss and of enrollment in early support program was 10 weeks irrespective of the degree of hearing loss; and the median age at hearing aid fitting was 16 weeks. Infants with moderate hearing loss were fitted with hearing aids significantly later than those with severe and profound hearing loss. CONCLUSIONS: Properly implemented, a newborn hearing screening program based on whole populations and routine service provision can deliver satisfactory outcomes in terms of age of referral, identification, and intervention. The distribution of degree and type of hearing loss and proportion with risk factors was similar to that expected. The numbers identified were such as to suggest that very few cases were missed by the screening program.

Maternal anxiety following newborn hearing screening: the moderating role of knowledge.

OBJECTIVES: To describe the impact upon maternal anxiety of newborn hearing screening and examine the Possible moderating role of knowledge. METHODS: Questionnaires assessing maternal state anxiety, worry and certainty about the baby's hearing, and knowledge about screening, were sent to four groups of mothers three weeks after screening: Group 1 consisted of mothers whose babies had clear responses on a first or second screening test (n=103); Group 2 consisted of mothers whose babies had clear responses on the third screening test (n=81); Group 3 consisted of mothers whose babies did not have clear responses in one ear at the third screening test and were referred for audiological assessment (n=105); and Group 4 consisted of mothers whose babies did not have clear responses in either ear at the third hearing test and were referred for audiological assessment (n=55). RESULTS: Although mean anxiety levels were in the normal range, there was a significant trend for anxiety to rise as testing increased (F(1,327)=4.280, P<0.05). Worry increased significantly (F(1,337)=70.432, P<0.001) and certainty decreased significantly (F(1,339)=27.474, P=0.001) as the number of tests increased. Although total knowledge did not significantly moderate anxiety (R(2)=0.016, P=0.096), there was a significant interaction between mothers' group and one knowledge item, understanding that receipt of no clear responses was unlikely to mean that the baby had a hearing loss: mothers in Group 4 who understood this had lower anxiety (F(3,323)=4.791, P<0.01) and lower worry (F(3,332)=3.565, P<0.01) compared with mothers who did not. CONCLUSIONS: Understanding the meaning of being recalled following screening may avoid some of the anxiety associated with this.

Neonatal hearing screening: modelling cost and effectiveness of hospital- and community-based screening.

BACKGROUND: Children with congenital hearing impairment benefit from early detection and management of their hearing loss. These and related considerations led to the recommendation of universal newborn hearing screening. In 2001 the first phase of a national Newborn Hearing Screening Programme (NHSP) was implemented in England. Objective of this study was to assess costs and effectiveness for hospital and community-based newborn hearing screening systems in England based on data from this first phase with regard to the effects of alterations to parameter values. DESIGN: Clinical effectiveness analysis using a Markov Model. OUTCOME MEASURE: quality weighted detected child months (QCM). RESULTS: Both hospital and community programmes yielded 794 QCM at the age of 6 months with total costs of 3,690,000 pound sterling per 100,000 screened children in hospital and 3,340,000 pound sterling in community. Simulated costs would be lower in hospital in 48% of the trials. Any statistically significant difference between hospital and community in prevalence, test sensitivity, test specificity and costs would result in significant differences in cost-effectiveness between hospital and community. CONCLUSION: This modelling exercise informs decision makers by a quantitative projection of available data and the explicit and transparent statements about assumptions and the degree of uncertainty. Further evaluation of the cost-effectiveness should focus on the potential differences in test parameters and prevalence in these two settings.

Screening for hearing loss in childhood: issues, evidence and current approaches in the UK.

Until recently, screening for childhood hearing loss in the UK was based on two universal (i.e. whole population) screens: the infant distraction test screen at age eight months and the school entry hearing screen at age four to five years. Evidence reviewed in the 1990s indicated that the infant distraction test screen was seriously underperforming, but that (based on technology that had become available in the 1980s and 1990s) universal newborn hearing screening could be efficacious. At the same time, evidence was emerging on the importance and value of very early identification and intervention for permanent congenital childhood hearing loss. This led to the decision to implement a national newborn hearing screening programme (NHSP) in England and to phase out the distraction test at eight months. The initial implementation of the programme will be completed in 2005, and we summarize the evidence on the effectiveness of the first phase of the programme here. A number of important issues concerning childhood hearing loss and its management remain unresolved: the burden of late-onset and temporary childhood hearing losses, the most effective approaches to intervention and management, the case for screening for mild and/or unilateral hearing loss, and the role of the School entry screen. Some of the current research efforts to address these are outlined.

Interprofessional working in the context of newborn hearing screening: Education and Social Services compare challenges.

This article presents data from a study undertaken as part of the national evaluation of the introduction of the newborn hearing screening programme (NHSP) in England. It considers the impact on Education and Social Services of NHSP from the perspective of how each agency perceives each other's role in circumstances where NHSP is requiring a greater focus on interagency and interprofessional working. The qualitative interview study involved 27 education and 15 social services respondents from phase 1 NHSP sites. It reveals considerable agreement on the poorly developed nature of joint working but considerable disagreement about the roots of such. Education is more likely to focus on issues of role, value and skills; social services on conflicts of ethos and culture. The problem of social services' capacity to respond to referrals concerning deaf children was common to both. The findings are placed in the context of government guidance, in particular Early Support and Children's Trusts, both of which support a strategic and statutory basis for interprofessional working in this context.