Translational Immunodiagnostics in Suspected Stroke (TrImS): A Two-centre, Pragmatic, Prospective, Observational Study

Introduction

Stroke is a leading cause of overall mortality, morbidity and disability worldwide. In 2010 it was the second leading cause of death whilst in 2019 it ranked third overall for disability adjusted life years (DALYs) and second for those aged 50 years and over. Acute ischaemic stroke (AIS) is a leading cause of mortality and morbidity in the USA affecting over 800 000 adults each year. In Hong Kong it is the fourth leading cause of death. It is frequently preceded by a transient ischaemic attack (TIA) which is a harbinger for future cerebral ischaemic events with a 20% risk of stroke within 90 days.

Stroke is associated with ischaemic, inflammatory, haemorrhagic and atherosclerotic processes linked to disruption of the blood brain barrier and increased blood borne proteins and nucleic acids. It is estimated that 'the average duration of non-lacunar stroke evolution is 10 hours (range 6 to 18 hours), and the average number of neurones in the human forebrain is 22 billion. In patients experiencing a typical large vessel AIS, 120 million neurones, 830 billion synapses and 714 km (447 miles) of myelinated fibres are lost each hour. In each minute, 1.9 million neurones, 14 billion synapses, and 12 km (7.5 miles) of myelinated fibres are destroyed. Compared with the normal rate of neurone loss in brain aging, the ischaemic brain ages 3.6 years each hour without treatment'. There is also evidence of such injury in the circulation within minutes to hours of major trauma including head injury.

The timely diagnosis of stroke and its aetiological classification into stroke-types is important as early appropriate intervention results in vastly improved outcomes. Firstly, determining the cause of the stroke affects which treatment is immediately prescribed. For example, early thrombolysis is indicated for AIS but contraindicated for haemorrhagic stroke (HS). A diagnosis of AIS within 4.5 hours of stroke onset followed by timely thrombolytic intervention improves stroke outcome. Anticoagulant and antiplatelet therapy is indicated for cardioembolic stroke or TIA but contraindicated for atherogenic strokes. In the case of the latter, antiplatelets are recommended. Large vessel occlusion is better treated by surgery than conservatively. Delays in diagnosis and early intervention count as avoidable DALYs, morbidity, healthcare expenditure and early mortality.

In the developed world, stroke is suspected and detected by clinical history and examination and confirmed diagnostically by cerebrovascular imaging either by CT and/or MRI. Whilst neuroimaging presents the current best standard for stroke identification and classification it is far from optimal. Neuroimaging provides only gross estimates of neurovascular damage, fails to identify the cause (cryptogenic stroke) in a significant 5 - 15% cases, and provides little information on cellular and molecular pathophysiology. This in turn delays early treatment and limits the search for potential agents for stroke prevention and recovery. Further, the absence of an objective method for determining stroke onset, for example in patients who wake with a suspected stroke, results in 80% of patients with AIS not receiving thrombolysis. Therefore, there is a need to understand the dynamic pathophysiology of stroke at an early stage.