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 infarctionApplication of the health risk assessment focused on sub-optimal health conditions to effectively prevent health-to-disease transitionApplication of AI in medicine, machine learning and treatment algorithms tailored to robust biomarker patternsApplication of innovative screening programmes which adequately consider the needs of young populations.

Keywords: Blood pressure; Blood–brain barrier breakdown; Body mass index; COVID-19; Cancer; Coagulation; Connective tissue impairments; Diabetes comorbidities; Endothelial dysfunction; Endothelin-1; Flammer Syndrome phenotype; Health policy; Health risk assessment; Health-to-disease transition; Hypoxia-reperfusion; Individualised protection; Ischemic stroke; Lacunar stroke; Mental health; Metastasis; Normal-tension glaucoma; Optic nerve degeneration; Paradigm change; Pre-pregnancy check-up; Predictive preventive personalised medicine (PPPM / 3PM); Primary care; Pro-inflammation; Retinal microvascular abnormalities; Screening; Secondary care; Silent brain infarct; Small vessel disease; Stress; Sub-optimal health; Systemic effects; Thromboembolism; Vascular stiffness; Vasospasm; Young populations.

Fig. 1

Schematic presentation of the health-to-disease transition in the stroke development and reciprocal cancer-stroke disease promotion; blood–brain barrier, BBB; and metalloproteinases, MMPs. Sub-optimal health conditions representing reversible damage are relevant for the cost-effective primary healthcare (blue frame) and are based on the individualised health risk assessment and targeted primary prevention. At this stage, subtle changes may include imbalanced stress, enhanced endothelin-1 blood plasma levels indicating pronounced vasoconstriction of peripheral vessels, increased stiffness of peripheral vessels co-diagnosed with connective tissues deficits/disease as demonstrated in pregnant women with the Flammer syndrome [–47, 51], enhanced homocysteine levels in blood plasma potentially leading to small vessel disease and associated SBI [52], blood pressure fluctuations with remarkable nocturnal lows [6] and low-grade inflammation [53, 54], all relevant to the manifestation of hypoxia-reperfusion and systemic ischemic lesions. These changes may result in irreversible damage leading to SBI, retinal microvascular changes, systemic inflammation, mitochondrial impairments, pre-cancerous lesions and pre-metastatic niches – altogether leading to the reciprocal cancer-stroke promotion in a “vicious cycle”. To this end, thromboembolic stroke is frequently observed in (treated) patients with cancer diagnoses. In turn, brain metastases are characteristic, e.g., for patients diagnosed with the triple-negative breast cancer and the Flammer syndrome phenotype demonstrating extensive vasoconstriction and systemic hypoxic-ischemic lesions including SBI [48, 55]. Extensive tissue remodelling plays a key role in both, neurodegeneration (stroke) and metastatic cancer performed by the core of metalloproteinases, which are excellent indicators and pathology-associated biomarkers [, –60]

Fig. 2

Brain-MRI performed in August 2022; Methodology: The examination was performed on the 3Tesla-MRI with weight-adjusted intravenous contrast medium administration (CMA, gadolinium). Sequences obtained: FLAIR, axial scan; DWI, ADC map, axial scan; SWI axial scan; axial FLAIR 3D scan; Time-of-Flight MR angiography; axial T2tse scan; 3D T1-weighted sequences after CMA with coronary and axial reconstructions. Results and conclusions: Although the cerebral vasculature is well-structured and intact without any detectable pathological changes (D), small vessels clearly show signs of micro-angiopathy; several lacunar microinfarction zones, white matter hyper-intensities and micro-haemorrhages (A, B, C) are evident; no any recent ischemic lesions have been recorded