Economic Evaluation of Stem Cell Therapies in Neurological Diseases: A Systematic Review.

OBJECTIVES: To examine economic evaluation studies of stem cell therapies (SCTs) in neurological disorders and to provide an overview of the quality of the economic evidence available on this topic. METHODS: The review examined studies that performed an economic evaluation of the use of stem cells in adult patients with neurological diseases and that were published in English during the period 2007 to 2017. Data analyzed and reported included study population, disease indication, main analytical approaches for the economic analysis and perspective, key assumptions made or tested in sensitivity analyses, cost outcomes, estimates of incremental cost effectiveness, and approaches to quantifying decision uncertainty. RESULTS: A total of three studies reporting on the findings of the economic evaluation of the use of SCT in stroke, Parkinson disease, and secondary progressive multiple sclerosis, respectively, were identified. All three studies conducted a cost-utility analysis using decision-analytic models and reported an incremental cost per quality-adjusted life-years gained (incremental cost-effectiveness ratio) versus standard care. These studies reported meaningful cost savings in stroke, Parkinson disease, and secondary progressive multiple sclerosis in the base-case scenarios. CONCLUSIONS: Despite significant progress in clinical research in the use of SCT in neurological diseases, economic evaluation of these therapies is still at a nascent stage. Given the early stage of research inputs (clinical and cost outcomes data) into the models per se, further research is urgently needed to enable meaningful assessment of the cost effectiveness of these advanced therapies and to ensure sustainable access for population groups most likely to benefit in clinical practice.

Efficacy of botulinum toxin in modifying spasticity to improve walking and quality of life in post-stroke lower limb spasticity - a randomized double-blind placebo controlled study.

BACKGROUND: Post-stroke lower limb spasticity (PSLLS) has a prevalence of 28-37%. PSLLS can cause difficulty in walking and reduce quality of life (QOL). Post stroke spasticity impairs the ability to intervene to improve walking ability. Botulinum Toxin A (BT) is an effective intervention for focal spasticity, but its use is currently restricted in many countries by their reimbursement system stating that the evidence for improvement in walking and quality of life (QOL) is not robust for treatment in the lower limb. This randomized control trial (RCT) will investigate the effectiveness of BT in modifying spasticity, and improving functioning (mobility, walking, activities of daily living (ADL's) and QOL. METHODS/DESIGN: A double-blind placebo-controlled trial injection will assess the effect of BT compared with a placebo (normal saline) in a sample of n = 94 patients. Following treatment of spasticity measured by Modified Ashworth Scale (MAS), the primary outcome of gait velocity will be measured by i) Gait Rite (Electronic Walkway); ii) walking by 2 Min Walk Test; iii) balance by Berg Balance Scale; mobility by iv) Timed Up and Go (TUG); v) lower limb function by ABILICO; vi) patient related goal by Goal Attainment Scale (GAS); vii) QOL by SF 12 (Rand version); viii) activities of daily living by the Functional Autonomy Measurement System (SMAF). There will be an associated health economic analysis. DISCUSSION: The study methodology is based on our systematic review 2026 studies, which concluded the evidence for improving mobility following use of BT to reduce spasticity was not robust. The results of this study could establish the use of BT in improving gait and lower limb function in PSLLS. This study could provide the evidence needed for reimbursement schemes to consider and changes to its funding policy for BT in PSLLS. TRIAL REGISTRATION: The trial is registered with the Australia New Zealand Clinical Trails Registry (ANZCTR)- ANZCTRN12617001603303 . Registered 07/12/2017.

PERSPECTIVES: Stroke survivors' views on the design of an early-phase cell therapy trial for patients with chronic ischaemic stroke.

BACKGROUND: Stem cell research holds the potential for a paradigm shift in the management of diseases such as stroke. Patient and public involvement in research (PPIR) can bring a focus to issues of clinical relevance and accelerate translation to real-world clinical practice. OBJECTIVE: A qualitative thematic analysis of the perspectives of stroke survivors regarding the conduct and design aspects of a proposed phase I clinical cell therapy study in stroke. DESIGN: Twelve stroke survivors were purposively recruited in July 2016-August 2017 and participated in semi-structured, face-to-face interviews for input into the design of a proposed phase I clinical study of autologous dental pulp stem cells. Concurrent thematic analysis was conducted until data saturation was achieved. DISCUSSION AND CONCLUSIONS: Participants conveyed that the most relevant outcomes to them were regaining participation, decreased dependence on caregivers and improvement in cognition, memory, mood, pain and fatigue. The perception of risk vs. benefit was likely influenced by the time elapsed since stroke, with participants being more willing to accept a higher level of risk early in the post-stroke disease course. They believed that all stroke survivors should be given an opportunity to participate in research, irrespective of their cognitive capacity. A relatively small sample population of 12 stroke survivors was studied as thematic saturation was achieved. PERSPECTIVES study applied principles of PPIR to early-phase cell research. Incorporation of outcomes relevant to patients' need within the study design is critical to generate data that will enable personalized application of regenerative medicine in stroke.

Early glycogen synthase kinase-3ß and protein phosphatase 2A independent tau dephosphorylation during global brain ischaemia and reperfusion following cardiac arrest and the role of the adenosine monophosphate kinase pathway.

Abnormal tau phosphorylation (p-tau) has been shown after hypoxic damage to the brain associated with traumatic brain injury and stroke. As the level of p-tau is controlled by Glycogen Synthase Kinase (GSK)-3ß, Protein Phosphatase 2A (PP2A) and Adenosine Monophosphate Kinase (AMPK), different activity levels of these enzymes could be involved in tau phosphorylation following ischaemia. This study assessed the effects of global brain ischaemia/reperfusion on the immediate status of p-tau in a rat model of cardiac arrest (CA) followed by cardiopulmonary resuscitation (CPR). We reported an early dephosphorylation of tau at its AMPK sensitive residues, Ser(396) and Ser(262) after 2 min of ischaemia, which did not recover during the first two hours of reperfusion, while the tau phosphorylation at GSK-3ß sensitive but AMPK insensitive residues, Ser(202) /Thr(205) (AT8), as well as the total amount of tau remained unchanged. Our data showed no alteration in the activities of GSK-3ß and PP2A during similar episodes of ischaemia of up to 8 min and reperfusion of up to 2 h, and 4 weeks recovery. Dephosphorylation of AMPK followed the same pattern as tau dephosphorylation during ischaemia/reperfusion. Catalase, another AMPK downstream substrate also showed a similar pattern of decline to p-AMPK, in ischaemic/reperfusion groups. This suggests the involvement of AMPK in changing the p-tau levels, indicating that tau dephosphorylation following ischaemia is not dependent on GSK-3ß or PP2A activity, but is associated with AMPK dephosphorylation. We propose that a reduction in AMPK activity is a possible early mechanism responsible for tau dephosphorylation.

Differences in Common Genetic Predisposition to Ischemic Stroke by Age and Sex.

BACKGROUND AND PURPOSE: Evidence from epidemiological studies points to differences in factors predisposing to stroke by age and sex. Whether these arise because of different genetic influences remained untested. Here, we use data from 4 genome-wide association data sets to study the relationship between genetic influence on stroke with both age and sex. METHODS: Using genomic-relatedness-matrix restricted maximum likelihood methods, we performed 4 analyses: (1) we calculated the genetic correlation between groups divided by age and (2) by sex, (3) we calculated the heritability of age-at-stroke-onset, and (4) we evaluated the evidence that heritability of stroke is greater in women than in men. RESULTS: We found that genetic factors influence age at stroke onset (h2 [SE]=18.0 [6.8]; P=0.0038), with a trend toward a stronger influence in women (women: h2 [SE]=21.6 [3.5]; Men: h2 [SE]=13.9 [2.8]). Although a moderate proportion of genetic factors was shared between sexes (rG [SE]=0.68 [0.16]) and between younger and older cases (rG [SE]=0.70 [0.17]), there was evidence to suggest that there are genetic susceptibility factors that are specific to sex (P=0.037) and to younger or older groups (P=0.056), particularly for women (P=0.0068). Finally, we found a trend toward higher heritability of stroke in women although this was not significantly greater than in men (P=0.084). CONCLUSIONS: Our results indicate that there are genetic factors that are either unique to or have a different effect between younger and older age groups and between women and men. Performing large, well-powered genome-wide association study analyses in these groups is likely to uncover further associations.

The Role of the Neuroprotective Factor Npas4 in Cerebral Ischemia.

Stroke is one of the leading causes of death and adult disability in the world. Although many molecules have been documented to have a neuroprotective effect, the majority of these molecules failed to improve the neurological outcomes for patients with brain ischemia. It has been proposed that neuroprotection alone may, in fact, not be adequate for improving the prognosis of ischemic stroke. Neuroprotectants that can regulate other processes which occur in the brain during ischemia could potentially be targets for the development of effective therapeutic interventions in stroke. Neuronal Per-Arnt-Sim domain protein 4 (Npas4) is an activity-dependent transcription factor whose expression is induced in various brain insults, including cerebral ischemia. It has been shown that Npas4 plays an important role in protecting neurons against many types of neurodegenerative insult. Recently, it was demonstrated that Npas4 indeed has a neuroprotective role in ischemic stroke and that Npas4 might be involved in modulating the cell death pathway and inflammatory response. In this review, we summarize the current knowledge of the roles that Npas4 may play in neuroinflammation and ischemia. Understanding how ischemic lesion size in stroke may be reduced through modulation of Npas4-dependent apoptotic and inflammatory pathways could lead to the development of new stroke therapies.

Polygenic overlap between kidney function and large artery atherosclerotic stroke.

BACKGROUND AND PURPOSE: Epidemiological studies show strong associations between kidney dysfunction and risk of ischemic stroke (IS), the mechanisms of which are incompletely understood. We investigated whether these associations may reflect shared heritability because of a common polygenic basis and whether this differed for IS subtypes. METHODS: Polygenic models were derived using genome-wide association studies meta-analysis results for 3 kidney traits: estimated glomerular filtration rate using serum creatinine (eGFRcrea: n=73 998), eGFR using cystatin C (eGFRcys: n=22 937), and urinary albumin to creatinine ratio (n=31 580). For each, single nucleotide polymorphisms passing 10 P value thresholds were used to form profile scores in 4561 IS cases and 7094 controls from the United Kingdom, Germany, and Australia. Scores were tested for association with IS and its 3 aetiological subtypes: large artery atherosclerosis, cardioembolism, and small vessel disease. RESULTS: Polygenic scores correlating with higher eGFRcrea were associated with reduced risk of large artery atherosclerosis, with 5 scores reaching P<0.05 (peak P=0.004) and all showing the epidemiologically expected direction of effect. A similar pattern was observed for polygenic scores reflecting higher urinary albumin to creatinine ratio, of which 3 associated with large artery atherosclerosis (peak P=0.01) and all showed the expected directional association. One urinary albumin to creatinine ratio-based score also associated with small vessel disease (P=0.03). The global pattern of results was unlikely to have occurred by chance (P=0.02). CONCLUSIONS: This study suggests possible polygenic correlation between renal dysfunction and IS. The shared genetic components may be specific to stroke subtypes, particularly large artery atherosclerotic stroke. Further study of the genetic relationships between these disorders seems merited.

Concise review: Preclinical studies on human cell-based therapy in rodent ischemic stroke models: where are we now after a decade?

Stroke, a debilitating brain insult, afflicts millions of individuals globally each year. In the last decade, researchers have investigated cell-based therapy as an alternative strategy to improve neurological outcome following stroke. This concise review critically examines preclinical reports using human adult and fetal stem/progenitor cells in rodent models of ischemic stroke. As we enter the second decade of study, we should aim to optimize our collective likelihood to translational success for stroke victims worldwide. We advocate international consensus recommendations be developed for future preclinical research.

Safety of varenicline tartrate and counseling versus counseling alone for smoking cessation: a randomized controlled trial for inpatients (STOP study).

INTRODUCTION: Inpatient medical settings offer an opportunistic environment for initiating smoking cessation interventions to patients reflecting on their health. Current evidence has shown the superior efficacy of varenicline tartrate (VT) for smoking cessation compared with other tobacco cessation therapies; however, recent evidence also has highlighted concerns about the safety and tolerability of VT. Given these apprehensions, we aimed to evaluate the safety and effectiveness of VT plus quitline-counseling compared to quitline-counseling alone in the inpatient medical setting. METHODS: Adult patients (n = 392, 20-75 years) admitted with a smoking-related illnesses to 3 hospitals were randomized to receive either 12 weeks of varenicline tartrate (titrated from 0.5mg daily to 1mg twice daily) plus quitline-counseling (VT+C), (n = 196) or quitline-counseling alone (n = 196). RESULTS: VT was well tolerated in the inpatient setting among subjects admitted with acute smoking-related illnesses (mean age 52.8±2.89 and 53.7±2.77 years in the VT+C and counseling alone groups, respectively). The most common self-reported adverse event during the 12-week treatment phase was nausea (16.3% in the VT+C group compared with 1.5% in the counseling alone group). Thirteen deaths occurred during the study period (n = 6 were in the VT+C arm compared with n = 7 in the counseling alone arm). All of these subjects had known comorbidities or developed underlying comorbidities. CONCLUSIONS: VT appears to be a safe and well-tolerated opportunistic treatment for inpatient smokers who have related chronic disease. Based on the proven efficacy of varenicline from outpatient studies and our recent inpatient evidence, we suggest it be considered as part of standard care in the hospital setting.

Upregulation of the neuronal Per-Arnt-Sim domain protein 4 (Npas4) in the rat corticolimbic system following focal cerebral ischemia.

The neuronal Per-Arnt-Sim domain protein 4 (Npas4) is an important transcriptional regulator of synaptic plasticity and cognition. The present study characterises the in vivo neuroanatomical expression pattern of the Npas4 protein in a rat model of focal cerebral ischemia. Animals were subjected to unilateral middle cerebral artery occlusion for 2 h, after which the spatiotemporal and neuronal profiles of Npas4 protein expression were analysed by immunohistochemistry at different time points post-reperfusion. Focal cerebral ischemia induced an early, transient and robust upregulation of Npas4 in a brain region-dependent manner involving predominantly principal neurons. Interestingly, we observed a unique differential induction of Npas4 protein expression in corticolimbic regions of the rat brain that are critically linked to cognition and emotion. These findings suggest that stroke-induced Npas4 upregulation may be involved in a transcriptional regulatory program within the corticolimbic circuitry following an ischemic insult.

Smoking Termination Opportunity for inPatients (STOP): superiority of a course of varenicline tartrate plus counselling over counselling alone for smoking cessation: a 12-month randomised controlled trial for inpatients.

RATIONALE: Smoking cessation interventions in outpatient settings have been demonstrated to be cost effective. Given this evidence, we aimed to evaluate the effectiveness of varenicline tartrate plus Quitline-counselling compared with Quitline-counselling alone when initiated in the inpatient setting. METHODS: Adult patients (18-75 years) admitted with a smoking-related illness to three hospitals, were randomised to receive either 12-weeks of varenicline tartrate plus Quitline-counselling, (n=196) or Quitline-counselling alone, (n=196), with 12-months follow-up. RESULTS: For the primary analysis population (intention-to-treat), the proportion of subjects who remained continuously abstinent were significantly greater in the varenicline plus counselling arm (31.1%, n=61) compared with counselling alone (21.4%, n=42; RR 1.45, 95% CI 1.03 to 2.03, p=0.03). CONCLUSIONS: The combined use of varenicline plus counselling when initiated in the inpatient setting has produced a sustained smoking cessation benefit at 12-months follow-up, indicating a successful opportunistic treatment for smokers admitted with smoking related illnesses. TRIAL REGISTRATION: http://www.clinicaltrials.gov/ ClinicalTrials.gov identification number: NCT01141855.

Are myocardial infarction--associated single-nucleotide polymorphisms associated with ischemic stroke?

BACKGROUND AND PURPOSE: Ischemic stroke (IS) shares many common risk factors with coronary artery disease (CAD). We hypothesized that genetic variants associated with myocardial infarction (MI) or CAD may be similarly involved in the etiology of IS. To test this hypothesis, we evaluated whether single-nucleotide polymorphisms (SNPs) at 11 different loci recently associated with MI or CAD through genome-wide association studies were associated with IS. METHODS: Meta-analyses of the associations between the 11 MI-associated SNPs and IS were performed using 6865 cases and 11 395 control subjects recruited from 9 studies. SNPs were either genotyped directly or imputed; in a few cases a surrogate SNP in high linkage disequilibrium was chosen. Logistic regression was performed within each study to obtain study-specific ßs and standard errors. Meta-analysis was conducted using an inverse variance weighted approach assuming a random effect model. RESULTS: Despite having power to detect odds ratio of 1.09-1.14 for overall IS and 1.20-1.32 for major stroke subtypes, none of the SNPs were significantly associated with overall IS and/or stroke subtypes after adjusting for multiple comparisons. CONCLUSIONS: Our results suggest that the major common loci associated with MI risk do not have effects of similar magnitude on overall IS but do not preclude moderate associations restricted to specific IS subtypes. Disparate mechanisms may be critical in the development of acute ischemic coronary and cerebrovascular events.

FAST-IT: Find A Simple Test - In TIA (transient ischaemic attack): a prospective cohort study to develop a multivariable prediction model for diagnosis of TIA through proteomic discovery and candidate lipid mass spectrometry, neuroimaging and machine learning-study protocol.

INTRODUCTION: Transient ischaemic attack (TIA) may be a warning sign of stroke and difficult to differentiate from minor stroke and TIA-mimics. Urgent evaluation and diagnosis is important as treating TIA early can prevent subsequent strokes. Recent improvements in mass spectrometer technology allow quantification of hundreds of plasma proteins and lipids, yielding large datasets that would benefit from different approaches including machine learning. Using plasma protein, lipid and radiological biomarkers, our study will develop predictive algorithms to distinguish TIA from minor stroke (positive control) and TIA-mimics (negative control). Analysis including machine learning employs more sophisticated modelling, allowing non-linear interactions, adapting to datasets and enabling development of multiple specialised test-panels for identification and differentiation. METHODS AND ANALYSIS: Patients attending the Emergency Department, Stroke Ward or TIA Clinic at the Royal Adelaide Hospital with TIA, minor stroke or TIA-like symptoms will be recruited consecutively by staff-alert for this prospective cohort study. Advanced neuroimaging will be performed for each participant, with images assessed independently by up to three expert neurologists. Venous blood samples will be collected within 48 hours of symptom onset. Plasma proteomic and lipid analysis will use advanced mass spectrometry (MS) techniques. Principal component analysis and hierarchical cluster analysis will be performed using MS software. Output files will be analysed for relative biomarker quantitative differences between the three groups. Differences will be assessed by linear regression, one-way analysis of variance, Kruskal-Wallis H-test, χ2 test or Fisher's exact test. Machine learning methods will also be applied including deep learning using neural networks. ETHICS AND DISSEMINATION: Patients will provide written informed consent to participate in this grant-funded study. The Central Adelaide Local Health Network Human Research Ethics Committee approved this study (HREC/18/CALHN/384; R20180618). Findings will be disseminated through peer-reviewed publication and conferences; data will be managed according to our Data Management Plan (DMP2020-00062).

Ischaemic stroke among young people aged 15 to 50 years in Adelaide, South Australia.

OBJECTIVES: To report risk factors, aetiology and neuroimaging features among a large series of young Australian patients who were admitted to hospital for a first-ever occurrence of ischaemic stroke; to analyse the effect of age, sex and ethnicity on the presence of risk factors; and to compare Australian and overseas data. DESIGN, SETTING AND PATIENTS: Retrospective evaluation of data for all patients aged from 15 to 50 years who were admitted to a public hospital in Adelaide, South Australia, from January 2006 to June 2010 with a primary diagnosis of ischaemic stroke. RESULTS: Among 326 patients (184 males), the most frequent stroke risk factors overall were dyslipidaemia (187), smoking (161), hypertension (105) and obesity (92). Fifty-one patients used illicit drugs, mostly comprising marijuana and amphetamines. The most frequent stroke aetiologies overall were cardioembolism (85), arterial dissection (49), and small-vessel occlusion (31). Cardioembolism was highly prevalent among our study population compared with patients in other countries. Neuroimaging showed that more patients in our study had strokes that involved both vascular territories concurrently (9%) compared with patients in other countries. CONCLUSIONS: Risk factors, aetiology and features of ischaemic stroke among young people in Adelaide differ significantly from published data for young patients around the world. Patients in Adelaide are more likely to be obese, to be misusing marijuana and amphetamines, to suffer a cardioembolic event and to have a stroke that concurrently affects both the anterior and posterior cerebral circulation.

Clinical Translation of Cell Therapies in Stroke (CT2S) Checklist-a pragmatic tool to accelerate development of cell therapy products.

BACKGROUND: Cell therapies present an exciting potential but there is a long history of expensive translational failures in stroke research. Researchers engaged in cell therapy research would benefit from a practical framework that can help in planning research and development of investigational cell therapies into viable medical products. METHODS: We developed a checklist using a mixed methodology approach to evaluate the impact of study design, regulatory policy, ethical, and health economic considerations for efficient implementation of early phase cell therapy studies. RESULTS: The checklist comprises a series of questions arranged under four domains: the first concerns study design such as characterization of target study population, trial design, endpoints and operational fit of dosage, time, and route of administration to target populations. A second domain addresses the data package required for regulatory approval relevant to the intended use (allogeneic/autologous; homologous/non-homologous; nature of cell processing). The third domain comprises patient involvement to ensure relevant data is collected via targeted study design. The final domain requires the team to determine the critical data elements that could be built into study design to enable health economic data collection to be started at an early phase of the study. CONCLUSIONS: The CT2S checklist can help to determine areas of expertise gaps and enable research groups to appropriately allocate resources for capacity building. Use of this checklist will allow identification of key areas where trial planning needs to be optimized, as well as helping to identify resources that need to be secured. The CT2S checklist can also serve as a general cell therapy research decision aid to improve research output and accelerate new cell therapy development.

Delayed Treatment with Human Dental Pulp Stem Cells Accelerates Functional Recovery and Modifies Responses of Peri-Infarct Astrocytes Following Photothrombotic Stroke in Rats.

Dental pulp contains multipotent mesenchymal stem cells that improve outcomes when administered early after temporary middle cerebral artery occlusion in rats. To further assess the therapeutic potential of these cells, we tested whether functional recovery following stroke induced by photothrombosis could be modified by a delayed treatment that was initiated after the infarct attained maximal volume. Photothrombosis induces permanent focal ischemia resulting in tissue changes that better reflect key aspects of the many human strokes in which early restoration of blood flow does not occur. Human dental pulp stem cells (approximately 400 × 103 viable cells) or vehicle were injected into the infarct and adjacent brain tissue of Sprague-Dawley rats at 3 days after the induction of unilateral photothrombotic stroke in the sensorimotor cortex. Forepaw function was tested up to 28 days after stroke. Cellular changes in peri-infarct tissue at 28 days were assessed using immunohistochemistry. Rats treated with the stem cells showed faster recovery compared with vehicle-treated animals in a test of forelimb placing in response to vibrissae stimulation and in first attempt success in a skilled forelimb reaching test. Total success in the skilled reaching test and forepaw use during exploration in a Perspex cylinder were not significantly different between the 2 groups. At 28 days after stroke, rats treated with the stem cells showed decreased immunolabeling for glial fibrillary acidic protein in tissue up to 1 mm from the infarct, suggesting decreased reactive astrogliosis. Synaptophysin, a marker of synapses, and collagen IV, a marker of capillaries, were not significantly altered at this time by the stem-cell treatment. These results indicate that dental pulp stem cells can accelerate recovery without modifying initial infarct formation. Decreases in reactive astrogliosis in peri-infarct tissue could have contributed to the change by promoting adaptive responses in neighboring neurons.

Correction: Two-year efficacy of varenicline tartrate and counselling for inpatient smoking cessation (STOP study): A randomized controlled clinical trial.

[This corrects the article DOI: 10.1371/journal.pone.0231095.].

Implanted adult human dental pulp stem cells induce endogenous axon guidance.

The human central nervous system has limited capacity for regeneration. Stem cell-based therapies may overcome this through cellular mechanisms of neural replacement and/or through molecular mechanisms, whereby secreted factors induce change in the host tissue. To investigate these mechanisms, we used a readily accessible human cell population, dental pulp progenitor/stem cells (DPSCs) that can differentiate into functionally active neurons given the appropriate environmental cues. We hypothesized that implanted DPSCs secrete factors that coordinate axon guidance within a receptive host nervous system. An avian embryonic model system was adapted to investigate axon guidance in vivo after transplantation of adult human DPSCs. Chemoattraction of avian trigeminal ganglion axons toward implanted DPSCs was mediated via the chemokine, CXCL12, also known as stromal cell-derived factor-1, and its receptor, CXCR4. These findings provide the first direct evidence that DPSCs may induce neuroplasticity within a receptive host nervous system.

Transient ischaemic attacks - assessment and management.

BACKGROUND: Transient ischaemic attacks (TIAs) can be challenging to diagnose, but early assessment and effective management can reduce the subsequent risk of stroke. OBJECTIVE: This article reviews the assessment and management of TIAs for general practitioners. DISCUSSION: Transient ischaemic attacks can be a trap for the unwary, with difficulty in making a diagnosis and varied assessment and management pathways. There is a significant risk of subsequent stroke. Early assessment and initiation of treatment, which can take place in the general practice setting, could lower the risk of stroke. Liaising with regional stroke care centres is required to establish an optimal pathway of care.