Intracerebral Hemorrhage and Small Vessel Disease
Spontaneous intracerebral hemorrhage (ICH) is a severe and life-threatening condition with significant morbidity and mortality. Globally, ICH affects approximately 2 million people annually, with more than one-third of patients dying within the first month of onset. Among survivors, 40% remain disabled. Despite its devastating impact, there is a lack of evidence-based therapies for ICH. Cerebral small vessel disease (CSVD) is a pathological disorder that affects perforating arterioles, capillaries, and possibly venules in the brain parenchyma or subarachnoid space. CSVD can be classified into hypertensive arteriopathy (HA), caused by long-term hypertension and vascular risk factors, and cerebral amyloid angiopathy (CAA), characterized by amyloid-beta (Ab) deposition in cortical and leptomeningeal small-to-medium-sized arteries, arterioles, and capillaries. While CSVD may be clinically silent in its chronic phase, it is associated with a wide range of clinical manifestations, including stroke, mood disorders, and cognitive impairment. The coexistence and location of CSVD may provide clues to the etiology of ICH.
Imaging Markers of Cerebral Small Vessel Disease
Magnetic resonance imaging (MRI) is increasingly used in patients with ICH, and MRI-based CSVD markers have been defined. In 2013, the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE) criteria were published to standardize the reporting of brain MRI markers of SVD. Lesions on conventional MRI include enlarged perivascular spaces (EPVS), white matter hyperintensities (WMH), and lacunes of presumed vascular origin. Advanced MRI techniques such as T2*-gradient recall echo (GRE) and susceptibility-weighted imaging (SWI) can detect additional imaging markers, including cerebral microbleeds (CMBs), cortical superficial siderosis (cSS), and acute convexity subarachnoid hemorrhage (cSAH), which are not visible on conventional T1- and T2-weighted sequences.
Cerebral Microbleeds and Intracerebral Hemorrhage
CMBs are small, round to ovoid hypointense lesions, typically 2–5 mm in diameter, visible on T2*-GRE and SWI. Lobar microbleeds are commonly associated with CAA, while deep CMBs are often linked to hypertension. In the cerebellum, superficial gray matter and vermis CMBs are independently associated with CAA-related ICH, whereas cerebellar white matter CMBs are more likely hypertensive and may coexist with supratentorial deep CMBs. Mixed-location hemorrhages are frequent in clinical settings, and the underlying type of SVD may vary. The lobar/total CMB ratio and the presence of cSS can help differentiate the underlying SVD in ICH patients. A higher lobar/total CMB ratio is significantly correlated with lobar ICH and cSS, suggesting it may be a novel biomarker for underlying CAA. This is particularly important as it may help identify more CAA patients for inclusion in future clinical trials.
CMBs are associated with an increased risk of stroke. A meta-analysis involving 15,693 participants from multiple stroke cohorts and stroke-free populations demonstrated that CMBs increase the risk of ICH by 3.82-fold, compared to a 2-fold increased risk of ischemic stroke. CMBs have also been used in clinical trials to evaluate future bleeding risk in populations receiving antithrombotic therapy. Studies such as the Clinical Relevance of Microbleeds in Stroke-2 (CROMIS-2) and the Hemorrhage Predicted by Resonance in Patients Receiving Oral Anticoagulants (HERO) have shown that CMBs are independent predictors of ICH in patients prescribed oral anticoagulants. Alternative treatments may be considered for such patients. A subgroup analysis of the REstart or STop Antithrombotics Randomised Trial (RESTART) suggested that restarting antiplatelet therapy in ICH patients with CMBs might be safe.
Cortical Superficial Siderosis and Intracerebral Hemorrhage
cSS is defined as a characteristic gyriform hypointense signal pattern on T2*-GRE or SWI, reflecting hemosiderin deposited on the outermost surface of the cortex or subarachnoid space. As a novel key hemorrhagic feature of CAA, cSS has been included in the modified Boston Criteria for in vivo diagnosis of CAA, increasing the sensitivity of the criteria. cSS strongly predicts both first and recurrent lobar ICH. The risk of recurrence increases with the burden of cSS. A recent meta-analysis of six studies showed that the annual ICH incidence was higher in patients with cSS (11.1%) compared to those without (3.9%), and the risk increased with the extent of cSS (9.1% for focal cSS vs. 12.5% for disseminated cSS). Multifocality of cSS was associated with a higher annual ICH recurrence rate and was the only independent predictor of future ICH recurrence among other MRI SVD markers. Severe cSS progression over time was independently associated with an increased future ICH risk.
Convexity Subarachnoid Hemorrhage and Intracerebral Hemorrhage
Acute cSAH is defined as a linear hyperintense signal on FLAIR sequences, with or without corresponding hypointense signal on T2*-GRE or SWI, in the subarachnoid space affecting at least one cortical sulcus of the cerebral convexities. cSAH is a key marker of acute focal bleeding events and is strongly associated with transient focal neurological episodes (TNFE), similar to transient ischemic attacks (TIA). Unlike cSS, acute cSAH can also be observed on computed tomography (CT). According to the recently devised “Edinburgh CT and genetic diagnostic criteria” for CAA, the coexistence of cSAH on CT, finger-like projection, and apolipoprotein E (APOE) ε4 allele implicates a high risk of moderate-to-severe CAA with a specificity of 96%. This enables rapid etiological assessment for patients unable to undergo MRI.
In a recent study of CAA-ICH survivors, the risk of recurrent ICH was seven-fold higher in patients with cSAH compared to those without. Another CT-based study validated that cSAH, irrespective of its spatial relationship to ICH, was associated with cSS and a higher recurrence risk. The APOE ε2 allele, rather than the ε4 allele, appears to contribute to cSAH/cSS, as the ε2 allele may promote vasculopathic changes and vessel rupture, while the ε4 allele favors perivascular amyloid deposition and cortical microbleeds.
The exact pathophysiology of cSAH and cSS remains unclear. Cumulative evidence suggests that cSAH is the acute form of cSS. The prevailing view is that the rupture of brittle leptomeningeal or superficial cortical vessels severely affected by Ab deposition might lead to focal bleeding into the subarachnoid space. Pathology-confirmed cSS is frequently observed with advanced CAA features, such as concentric splitting of the leptomeningeal vessels, but reduced CAA severity in cortical vessels. No association between cSS and CMBs has been found, suggesting different pathophysiological entities.
White Matter Hyperintensities and Intracerebral Hemorrhage
WMH, characterized by hyperintensities on FLAIR sequences, are very common in aging populations. Recent evidence suggests that posterior, peripheral punctuate WMH reflect CAA, while deep, peri-basal ganglia (BG) WMH is evidence of HA. Extensive WMH doubles the risk of ischemic stroke and triples the risk of ICH. However, whether WMH severity correlates with larger hematoma volume and hematoma expansion remains controversial and requires further investigation in larger studies.
Lacunes and Intracerebral Hemorrhage
Lacunes are covert brain infarcts without acute neurological deficit or disability, appearing as round or ovoid, subcortical, fluid-filled cavities with a diameter of 3 to 15 mm. They are located in the lobar white matter, BG, thalamus, and infratentorial regions. The topographical distribution of lacunes may provide clues to the subtypes of SVD. In an ICH cohort, lobar lacunes were more commonly seen in CAA (20.4% vs. 5.7%), while deep lacunes were more frequent in hypertensive ICH (15.2% vs. 2.1%). This was confirmed by an Asian study, which found that lobar lacune number was independently associated with cerebral amyloid burden using Pittsburgh Compound B positron emission tomography. A large-scale meta-analysis concluded that lacunes double the risk of incident stroke, with an even higher risk of ICH, and are also associated with increased mortality.
Enlarged Perivascular Spaces and Intracerebral Hemorrhage
EPVS are commonly detected in elderly populations on T2-weighted sequences. EPVS in the centrum semiovale (CSO-EPVS) is a marker of CAA, while a predominance of EPVS in the BG (BG-EPVS) is generally caused by HA. A severe burden of CSO-EPVS may be an early predictor of future hemorrhagic events. A study of CAA-ICH patients found that high-degree CSO-EPVS, along with cSS, were independent predictors of ICH recurrence. The global burden of EPVS was consistently associated with a greater risk of incident ICH in a population-based study of 1678 participants. EPVS is speculated to be evidence of impaired cerebral glymphatic drainage and elevated arterial Ab burden, promoting the formation of cSS and symptomatic ICH.
Future Directions
Advanced MRI technology has shed light on the impact of SVD markers on future cerebral hemorrhagic events. These MRI markers may be useful in stratifying the bleeding risk of CAA patients, some of whom present with ICH while others come to medical attention due to cognitive decline. However, there is still a lack of therapeutic interventions available in clinical practice. This highlights the need for continued mechanistic and investigative studies to develop novel treatments for ICH and CSVD.
doi.org/10.1097/CM9.0000000000001620
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