Spontaneous intracerebral hemorrhage (ICH) is a serious life-threatening event with the highest morbidity and mortality. ICH is a global burden affecting approximately 2 million people annually. It is estimated that more than one-third of ICH patients die within the first month of onset, and 40% of survivors remain disabled. However, there is an absence of evidence-proved therapies for ICH.
Cerebral small vessel disease (CSVD) is a pathological disorder, which affects perforating arterioles, capillaries, and probable venules in the brain parenchyma or the subarachnoid space. The sporadic small vessel disease (SVD) is classified into hypertensive arteriopathy (HA) caused by long-term hypertension and vascular risk factors, and cerebral amyloid angiopathy (CAA) characteristic by the amyloid-β (Aβ) deposition in cortical and leptomeningeal small-to-medium-sized arteries, arterioles, and capillaries. While CSVD in the chronic phase can be clinically silent, a wide range of clinical manifestations is related to CSVD, such as stroke, mood disorders, and cognitive impairment. The coexistence and location of CSVD may give a clue to the etiology of ICH.
Imaging Markers of Cerebral Small Vessel Disease
Magnetic resonance imaging (MRI) is increasingly performed in patients with ICH, and MRI-based CSVD markers have been defined. In 2013, the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE) criteria was published for reporting brain MRI markers of SVD. Lesions on conventional MRI include enlarged perivascular space (EPVS), white matter hyperintensities (WMH), and lacunes of presumed vascular origin. T2∗-gradient recall echo (GRE) and susceptibility-weighted imaging (SWI) are novel techniques to detect imaging markers including cerebral microbleeds (CMBs), cortical superficial siderosis (cSS), and acute convexity subarachnoid hemorrhage (cSAH), which are invisible on conventional T1- and T2-weighted sequences.
Cerebral Microbleed and Intracerebral Hemorrhage
CMBs are small (2–5 mm in diameter), round to ovoid hypointense lesions on T2∗-GRE and SWI. Lobar microbleeds are commonly seen in patients with CAA and deep CMBs may occur as a result of hypertension. Similar to the supratentorial region, superficial cerebellar CMBs in gray matter and vermis are independently associated with CAA-ICH, while cerebellar white matter CMBs are more likely hypertensive, and patients may have coexisted supratentorial deep CMBs. Mixed-location hemorrhage is frequent in the clinical setting, whereas the underlying type of SVD may differ. Lobar/total CMB ratio and presence of cSS may help further differentiate the underlying SVD in ICH patients. The lobar/total CMB ratio was significantly correlated with lobar ICH and cSS, implicating that it may be a novel biomarker of underlying CAA. This is of great interest because it may help include more CAA patients in the future clinical trials.
CMBs are associated with an increased risk of stroke. A meta-analysis pooling 15,693 participants from multiple stroke cohorts and stroke-free populations demonstrated that CMBs increased the risk of ICH by 3.82-fold compared with a mere 2-fold increased risk of incident ischemic stroke.
CMBs have played a role in clinical trials to evaluate future bleeding risk in populations with antithrombotic therapy. In the Clinical Relevance of Microbleeds in Stroke-2 (CROMIS-2) and the Hemorrhage Predicted by Resonance in Patients Receiving Oral Anticoagulants (HERO), CMB is an independent predictor of ICH for patients prescribed oral anticoagulants.[6,7] Alternative treatment may be considered in such a group. A subgroup analysis of the REstart or STop Antithrombotics Randomised Trial (RESTART) suggested that restarting antiplatelet therapy in ICH patients with CMB might be safe.
Cortical Superficial Siderosis and Intracerebral Hemorrhage
cSS defined as a characteristic gyriform hypointense signal pattern on T2∗-GRE or SWI without corresponding lesions on conventional sequence such as fluid-attenuated inversion recovery (FLAIR) reflects hemosiderin deposited on the outermost surface of the cortex or the subarachnoid space. As a novel key hemorrhagic feature of CAA, cSS has been added into the modified Boston Criteria for in vivo diagnosis of CAA as neuroimaging evidence to increase the sensitivity.
cSS strongly predicts first and recurrent lobar ICH. Moreover, the risk of recurrence is parallel with the burden of cSS. A recent meta-analysis of six studies showed that annual ICH incidence was higher in patients with cSS than those without (11.1% vs. 3.9%), and was increasingly higher with the extent of cSS (9.1% for focal cSS vs. 12.5% for disseminated). cSS multifocality was associated with a higher annual ICH recurrence rate and was the only independent predictor of future ICH recurrence (hazard ratio [HR] 3.19; 95% confidence interval [CI] 1.77–5.75) from other MRI SVD markers. Severe cSS progression over time was independently associated with increased future ICH risk (HR 5.90; 95% CI 1.30–26.68).
Convexity Subarachnoid Semorrhage and Intracerebral Hemorrhage
Acute cSAH is defined as linear hyperintense signal on FLAIR sequence with or without corresponding hypointense signal on T2∗-GRE or SWI in the subarachnoid space affecting at least one cortical sulci of the cerebral convexities. cSAH is a key marker of the acute focal bleeding event strongly associated with transient focal neurological episodes (TNFE) similar to transient ischemic attack (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 implicates a high risk of moderate-to-severe CAA with a specificity of 96%. It enables rapid etiological assessment for those who are unable to undergo MRI.
In a recent study of CAA-ICH survivors, the risk of recurrent ICH was seven-fold higher in cSAH present group when compared with those without. Another CT-based study validated that cSAH irrespective of spatial relationship from ICH was associated with cSS and higher recurrence risk. It is also implicated that APOE ε2 allele instead of ε4 allele contributes to cSAH/cSS because APOE ε2 allele may promote vasculopathic changes and vessel rupture, while APOE ε4 favors perivascular amyloid deposition and cortical microbleeds.
The exact underlying pathophysiology of cSAH and cSS is unclear. Cumulative evidence suggests that cSAH is the acute form of cSS. The prevailing view is that rupture of brittle leptomeningeal or superficial cortical vessels severely affected by Aβ deposition might lead to focal bleeding into the subarachnoid space. Corresponding with clinical findings, pathology-confirmed cSS was frequently observed with advanced CAA features such as concurrent concentric splitting of the leptomeningeal vessels but reduced CAA severity in cortical vessels. Furthermore, no association between cSS and CMBs was found, which may implicate different pathophysiological entities.
White Matter Hyperintensities and Intracerebral Hemorrhage
WMH characterized by hyperintensities on FLAIR sequence are very common in aging populations. Recent evidence suggests that posterior, peripheral punctuate WMH reflect CAA and deep, peri-basal ganglia (BG) WMH is evidence of HA. Extensive WMH doubled the risk of ischemic stroke and tripled the risk of ICH. Nonetheless, whether WMH severity correlates with larger hematoma volume and hematoma expansion is still controversial and requires further investigation in larger studies.
Lacune and Intracerebral Hemorrhage
Lacunes as covert brain infarct without acute neurological deficit and disability are round or ovoid, subcortical, fluid-filled cavities with a diameter of 3 to 15 mm, located in the lobar white matter, BG, thalamus, and infratentorial regions. In line with other MRI markers, the topographical distribution of lacunes may give a clue 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. Tsai et al found 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 doubled the risk of incident stroke, of which the risk of ICH was even higher, and were also associated with increased mortality (HR 1.64; 95% CI 1.40–1.91; P < 0.001).
Enlarged Perivascular Space and Intracerebral Hemorrhage
EPVS is commonly detected in elderly populations on T2-weighted sequences. EPVS in centrum semiovale (CSO-EPVS) is a marker of CAA, while a predominance of EPVS in BG (BG-EPVS) is generally caused by HA.
The severe burden of CSO-EPVS may be an early predictor of future hemorrhagic events. A study of CAA-ICH patients found that among multiple MRI markers high-degree CSO-EPVS along with cSS, rather than overall burden 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 as evidence of impaired cerebral glymphatic drainage and elevated arterial Aβ burden, promoting the formation of cSS and symptomatic ICH eventually.
Advanced MRI technology to investigate SVD markers has shed light on the impact of the lesions on future cerebral hemorrhagic events. These MRI markers may be useful to stratify the bleeding risk of CAA patients, a subgroup of whom present with ICH while others come to medical attention due to cognitive decline. However, there is still little therapeutic intervention to be offered in clinical practice. This fact should give motivation for those in the field to continue mechanistic and investigative studies to devise novel interventions for treatment.
This study was supported by grants from the National Key R&D Program of China (No. 2018YFC1312200, No. 2018YFC1312203), the National Nature Science Foundation of China (No. 82071337), the Chongqing Health and Family Planning Commission (No. 2017MSXM014), and the Chongqing High-end Young Investigator Project (No. 2019GDRC005).
Conflicts of interest
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