A 62-year-old previously healthy man presents to the emergency department with a fever, cough and persistent headache following a fall. A head CT scan, is negative for bleed. Incidentally, mild to moderate white-matter-disease (WMD) and an old lacune (anterior internal capsule) are noted. The patient and his wife credibly deny any prior stroke symptoms. The patient is ultimately diagnosed with pneumonia, told his CT scan shows “nothing to worry about” and sent home with antibiotics.
Had the prior infarct occurred in more articulate portions of the brain, or been larger, and thus been accompanied by clinically-evident stroke, he would have received a diagnostic work-up including head and neck vessel imaging, cardiac rhythm monitoring, echocardiography and blood tests (lipids, diabetes). Additionally, secondary stroke prevention could have been initiated, including a statin, an antiplatelet agent, and blood pressure control, if indicated. Yet in routine practice, covert cerebrovascular disease (CCD), including both focal covert brain infarction (CBI) and WMD, are generally regarded as incidental findings of unclear or minor significance amongst non-neurologists.
The burden of incidentally-discovered CCD
CCD is a remarkably common, age-related phenomenon affecting more than 30% of 70-year-olds using screening MRI in population-based research cohorts.1 Yet translating findings from population-based screening studies to clinical care is not straightforward, since CCD findings only come to clinical attention when they are incidentally-discovered on neuroimaging, typically CT, obtained for other clinical indications. Furthermore, CCD includes disparate pathologies: cortical infarcts generally have atherothromboembolic sources and well-established evidence-based secondary prevention for their symptomatic counterparts, whereas the far more common WMD and lacunes are features of intrinsic small vessel disease (SVD), for which evidence-based therapies are less established.2
The study of these covert lesions has been impeded by the absence of disease coding until recently (ICD-11 introduced codes for CCD), and these findings generally do not appear in patients’ medical history or problem list. Using natural language processing (NLP) algorithms capable of reading neuroimaging reports, we recently confirmed that an enormous burden of CCD in patients over 50 years is uncovered during routine clinical care: about 5% of neuroimaging reports in patients free of stroke, dementia or cognitive decline note incidentally-discovered CBI and about 30% note WMD.3 Additionally, electronic health record transparency might leverage adequate care by highlighting CCD to health-savvy patients and bringing it to medical attention.
With about 25 brain imaging exams being performed per 1000 inhabitants per year in developed countries, there are millions of neuroimages of older adults residing in the picture archiving and communication systems across US hospitals. Such broad use of imaging, combined with efficient extraction tools, may permit routinely-obtained imaging to be leveraged for prevention of neurological morbidity in an approach called “opportunistic screening.” This might facilitate research to form an evidence base for future treatments for stroke and dementia prevention in this neglected population and, subsequently, for case finding for its clinical application.
The prognostic significance of CCD
In research cohorts of community-dwelling adults examined by MRI, both WMD (hazard ratio, 2.5; 95%CI, 1.9–3.1) and CBI (HR, 2.4; 95%CI, 1.9–3.0) were associated with higher risk of incident stroke.1 In parallel, in clinically-acquired imaging, the adjusted hazard ratio for future stroke was approximately two-fold as compared to patients without vascular lesions and slightly higher with focal CBI as compared to WMD.3 The annualized incidence of future stroke was about 3% for patients with incidentally discovered CBI; 2% for those with incidentally discovered WMD, compared to less than 1% in those without any CCD.
WMD was also associated with approximately a two-fold higher risk of incident dementia in community-dwelling adult research cohorts.1 In parallel, in clinically-acquired imaging identified through NLP, the annualized dementia incidence rates were 2% to 3% for patients with any form of CCD compared to just 0.5% for those without CCD.4 Fittingly, the adjusted hazard ratios of dementia progression were approximately two-fold higher for those with versus without CCD. WMD detection by CT was associated with several fold higher dementia progression rates as compared to WMD detected by MRI, presumably since detection on the less sensitive modality indicates more advanced disease.4
How experts believe CCD should be addressed versus how they are addressed
The American Heart Association/American Stroke Association scientific statement on the “Prevention of Stroke in Patients with Silent Cerebrovascular Disease”5 and the recent European Stroke Organization (ESO) guideline2 on covert SVD indicate that such findings should trigger assessment of common vascular risk factors to prevent manifest cardiovascular disease – based largely on extrapolated evidence from patients with stroke. The ESO guideline also states that lifestyle advice should be implemented and “lipid lowering with statins could be considered in patients with covert cerebral SVD, even when no other indication for statin treatment exists.” It also noted that incidental WMD and lacunes should not be a reason to prescribe antiplatelets or vascular dementia drugs, nor to aim routinely for stricter targets for glucose control in diabetics outside diabetes guidelines.2 While intense (systolic <120mmHg vs <140mmHg) blood pressure control led to reduced WMD progression in the SPRINT trial, participants were not selected based on CCD, the overall effect was small, did not translate to a reduction of probable dementia and caused minor adverse events. Thus, further trials with significantly longer follow-up specifically enrolling patients with more severe WMD are needed to test this promising approach in the target population.
In a recent survey addressing potentially embolic CBI phenotypes, several hundred neurological specialists indicated that all would assess vascular risk factors and a large majority recommended work-up including monitoring for atrial fibrillation and vascular imaging of the head and neck vessels as well as preventive treatments similar to secondary prevention of manifest ischemic stroke.6 However, CCD is typically encountered by generalist physicians, who appear to regard CCD as an incidental finding of unclear significance and there is scant evidence for change in management.
The urgent need for research on this common problem and what to do in the meantime
Regrettably, there is a lack of high-quality trials to support the evaluation and management of patients with incidentally-discovered CCD. Nevertheless, we believe this should not discourage diagnostic and therapeutic efforts. Encouraging regular exercise, smoking cessation, wholesome diet including reducing salt, other healthy lifestyle choices, and controlling blood pressure is associated with fewer adverse cardiovascular events in observational studies, with some evidence of benefit in randomized trials in at-risk elderly people not specifically selected by CCD (e.g., FINGER trial). Assessing and communicating objective vascular damage has been shown to lead to superior risk factor control in patients with coronary artery calcifications7, and a similar approach might also work for CCD.
The benefit-harm balance of intensive medical management for CCD is currently uncertain. Unless future randomized trials indicate otherwise, we recommend that healthcare professionals adopt an individualized approach to patients regarding assessment and treatment of incidentally discovered CCD in accordance with existing guidelines.2,5 At minimum, it is essential to inform patients about these findings to facilitate discussions and determine preferences for further diagnostic and therapeutic steps. Importantly, the large burden of CCD in older populations and the strong associations with important clinical outcomes of stroke and dementia strongly argue that research should be targeted at this common high-risk condition to prevent devastating major neurological morbidity in a population that is currently all but ignored.
Disclosures
Based on their belief that covert brain infarctions present an opportunity to prevent cerebrovascular morbidity and mortality, the authors established an outpatient clinic to provide counseling for patients with this condition. To further investigate the incidence of silent atrial fibrillation identified through implantable cardiac monitors and the effectiveness of a diagnostic stroke evaluation in patients with covert brain infarction, a multicenter study is being conducted by their group, supported by the Swiss National Science Foundation (Grant number 32003B_189077) and Swiss Heart Foundation. Dr Joanna Wardlaw received ESO GLs on SVD (part 1 covert SVD, part 2 lacunar ischaemic stroke in prep) as well as lead for the STRIVE initiative, the LACI trials, piloting an SVDs Clinic in my hospital with colleagues. Dr David Kent’s research related to this work was supported by two National Institutes of Health (NIH) grants (RF1 NS102233-05 and R01-NS102233), as well as his Alzheimer’s Drug Discovery Foundation (ADDF) grant (RC-202209-2024187).
Abbreviations:
- CBI
Focal covert brain infarction
- CCD
Covert cerebrovascular disease
- WMD
white matter disease
- SVD
small vessel disease
References
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