Ischemic stroke of unclear aetiology: a case-by-case analysis and call for a multi-professional predictive, preventive and personalised approach

Abstract

Due to the reactive medical approach applied to disease management, stroke has reached an epidemic scale worldwide. In 2019, the global stroke prevalence was 101.5 million people, wherefrom 77.2 million (about 76%) suffered from ischemic stroke; 20.7 and 8.4 million suffered from intracerebral and subarachnoid haemorrhage, respectively. Globally in the year 2019 — 3.3, 2.9 and 0.4 million individuals died of ischemic stroke, intracerebral and subarachnoid haemorrhage, respectively. During the last three decades, the absolute number of cases increased substantially. The current prevalence of stroke is 110 million patients worldwide with more than 60% below the age of 70 years. Prognoses by the World Stroke Organisation are pessimistic: globally, it is predicted that 1 in 4 adults over the age of 25 will suffer stroke in their lifetime. Although age is the best known contributing factor, over 16% of all strokes occur in teenagers and young adults aged 15–49 years and the incidence trend in this population is increasing. The corresponding socio-economic burden of stroke, which is the leading cause of disability, is enormous. Global costs of stroke are estimated at 721 billion US dollars, which is 0.66% of the global GDP.Clinically manifested strokes are only the “tip of the iceberg”: it is estimated that the total number of stroke patients is about 14 times greater than the currently applied reactive medical approach is capable to identify and manage. Specifically, lacunar stroke (LS), which is characteristic for silent brain infarction, represents up to 30% of all ischemic strokes. Silent LS, which is diagnosed mainly by routine health check-up and autopsy in individuals without stroke history, has a reported prevalence of silent brain infarction up to 55% in the investigated populations. To this end, silent brain infarction is an independent predictor of ischemic stroke. Further, small vessel disease and silent lacunar brain infarction are considered strong contributors to cognitive impairments, dementia, depression and suicide, amongst others in the general population. In sub-populations such as diabetes mellitus type 2, proliferative diabetic retinopathy is an independent predictor of ischemic stroke.According to various statistical sources, cryptogenic strokes account for 15 to 40% of the entire stroke incidence. The question to consider here is, whether a cryptogenic stroke is fully referable to unidentifiable aetiology or rather to underestimated risks. Considering the latter, translational research might be of great clinical utility to realise innovative predictive and preventive approaches, potentially benefiting high risk individuals and society at large.In this position paper, the consortium has combined multi-professional expertise to provide clear statements towards the paradigm change from reactive to predictive, preventive and personalised medicine in stroke management, the crucial elements of which are: Consolidation of multi-disciplinary expertise including family medicine, predictive and in-depth diagnostics followed by the targeted primary and secondary (e.g. treated cancer) prevention of silent brain infarction Application of the health risk assessment focused on sub-optimal health conditions to effectively prevent health-to-disease transition Application of AI in medicine, machine learning and treatment algorithms tailored to robust biomarker patterns Application of innovative screening programmes which adequately consider the needs of young populations

Diabetic retinopathy as the leading cause of blindness and early predictor of cascading complications—risks and mitigation

“…blindness [8]. Moreover, it has to be noted that PDR is considered an independent predictor of other severe diabetic complications such as ischemic stroke [9][10][11]. Contextually, a "domino effect" is characteristic for the cascading DM complications with a key role of DR as the early indicator of impaired molecular and visual signaling (Fig.…”

“…There is evidence that diabetes is an important risk factor for stroke; people with diabetes have a 2 to 4 times higher stroke incidence than those without the disease. Diabetes-related microvascular complications are widely acknowledged as a risk factor for the macrovascular sequelae of stroke [9]. Moreover, it has to be noted that according to the metaanalysis of 19 studies involving 45,495 patients, people with diabetes who have DR have an elevated stroke risk-a relationship that was significant for patients with T2D but inconclusive for patients with T1D [10].…”

“…Further, small vessel disease and neuroretinal changes create a vicious cycle fostering the development of proliferative diabetic retinopathy (PDR) with characteristic attributes including excessive mitochondrial and retinal cell death, chronic inflammation, neovascularisation, and impaired visual field leading to blindness [ 8 ]. Moreover, it has to be noted that PDR is considered an independent predictor of other severe diabetic complications such as ischemic stroke [ 9 – 11 ]. Contextually, a “domino effect” is characteristic for the cascading DM complications with a key role of DR as the early indicator of impaired molecular and visual signaling (Fig.…”

“…Contextually, a “domino effect” is characteristic for the cascading DM complications with a key role of DR as the early indicator of impaired molecular and visual signaling (Fig. 1 ) [ 9 ].

Fig.

…”

“…A stroke is the second leading cause of death among the world’s population, particularly in low- and middle-income countries [ 9 ]. In previous studies, stroke risk was typically associated with CVD; however, as further clinical studies and statistical reviews have been done, CVD no longer seems to be an appropriate explanation and predictor of stroke development [ 51 ].…”