Charcot–Bouchard aneurysms revisited: clinicopathologic correlations

Modern Pathology https://doi.org/10.1038/s41379-021-00847-1 ARTICLE Charcot–Bouchard aneurysms revisited: clinicopathologic correlations Shino Magaki 1 Zesheng Chen1 Mohammad Haeri1,4 Christopher K. Williams1 Negar Khanlou1 William H. Yong1,5 Harry V. Vinters1,2,3 ● ● ● ● ● ● 1234567890();,: 1234567890();,: Received: 5 April 2021 / Revised: 20 May 2021 / Accepted: 20 May 2021 © The Author(s) 2021. This article is published with open access Abstract Intracerebral hemorrhage (ICH) is a significant cause of morbidity and mortality worldwide. Hypertension and cerebral amyloid angiopathy (CAA) are the most common causes of primary ICH, but the mechanism of hemorrhage in both conditions is unclear. Although fibrinoid necrosis and Charcot–Bouchard aneurysms (CBAs) have been postulated to underlie vessel rupture in ICH, the role and significance of CBAs in ICH has been controversial. First described as the source of bleeding in hypertensive hemorrhage, they are also one of the CAA-associated microangiopathies along with fibrinoid necrosis, fibrosis and “lumen within a lumen appearance.” We describe clinicopathologic findings of CBAs found in 12 patients out of over 2700 routine autopsies at a tertiary academic medical center. CBAs were rare and predominantly seen in elderly individuals, many of whom had multiple systemic and cerebrovascular comorbidities including hypertension, myocardial and cerebral infarcts, and CAA. Only one of the 12 subjects with CBAs had a large ICH, and the etiology underlying the hemorrhage was likely multifactorial. Two CBAs in the basal ganglia demonstrated associated microhemorrhages, while three demonstrated infarcts in the vicinity. CBAs may not be a significant cause of ICH but are a manifestation of severe cerebral small vessel disease including both hypertensive arteriopathy and CAA. Introduction Intracerebral hemorrhage (ICH) accounts for ~10–15% of strokes in the West and 20–30% of strokes in Asia, with two million cases per year worldwide [1]. It is the stroke type * Shino Magaki 1 Section of Neuropathology, Department of Pathology and Laboratory Medicine, Ronald Reagan UCLA Medical Center and David Geffen School of Medicine, Los Angeles, CA, USA 2 Department of Neurology, Ronald Reagan UCLA Medical Center and David Geffen School of Medicine, Los Angeles, CA, USA 3 Brain Research Institute, Ronald Reagan UCLA Medical Center and David Geffen School of Medicine, Los Angeles, CA, USA 4 Present address: Department of Pathology and Laboratory Medicine and Alzheimer Disease Research Center, University of Kansas Medical Center, Kansas City, KS, USA 5 Present address: Department of Pathology and Laboratory Medicine, University of California—Irvine School of Medicine, Irvine, CA, USA associated with the highest mortality, with 1 month survival of 40% and significant morbidity with functional independence rate of around 10–40% [2, 3]. Although the incidence of ischemic strokes has decreased in recent decades, the incidence of ICH has remained stable [4]. In primary ICH, hypertension is thought to be the underlying cause in 65% of cases, followed by cerebral amyloid angiopathy (CAA). Secondary ICH is caused by various etiologies such as coagulopathy, berry/saccular aneurysms, vascular malformations, and tumors [3]. The most common location for ICH is the deep gray matter including basal ganglia and thalamus followed by the cerebral hemispheres, cerebellum and brainstem, predominantly the pons [1, 5]. Hypertensive hemorrhage frequently involves deep gray matter but can occur anywhere in the brain [6, 7]. CAA, characterized by the deposition of amyloid β (Aβ) preferentially in the walls of small- to medium-sized arteries and arterioles within the cortex and leptomeninges and less commonly in capillaries and veins, is associated solely with lobar hemorrhage due to the location of the involved vessels and has a higher risk for recurrence and poststroke dementia [6–8]. CAA is seen in S. Magaki et al. the majority of patients with Alzheimer disease and in 20–40% of the nondemented elderly, with increasing prevalence with age in nondemented individuals [8–10]. Elevated blood pressure is associated with ICH recurrence regardless of location [4], and lowering blood pressure can decrease risk from hemorrhage in both hypertension and CAA-associated ICH [11]. Despite the well-known risk factors, the pathogenesis of ICH is unclear, and the site of bleeding has rarely been demonstrated histologically due to the difficulty in examining tissue destroyed by hemorrhage as well as secondary bleeding caused by the disruption of surrounding arteries [12, 13]. In hypertension, the cause of hemorrhage is thought to be elevated blood pressureinduced degenerative changes in the penetrating arterioles leading to rupture [14]. However, the precise nature of the degenerative changes is uncertain, although it has been attributed to fibrinoid necrosis, with deposition of plasma proteins including fibrin in the arteriolar wall with accompanying degeneration of smooth muscle cells, and Charcot–Bouchard aneurysms (CBAs) [5, 12, 15–17]. CBAs, also known as miliary aneurysms or microaneurysms, are small aneurysms that arise from arterioles usually less than 300 µm in diameter [18]. They were first described by Charcot and Bouchard in 1868 as a cause of hypertensive hemorrhage when they rupture [18, 19]. Since their description over 100 years ago, there has been controversy as to their very existence, prevalence and significance as a cause of ICH [15, 16]. Microaneurysms are also seen in CAA as one of the CAA-associated microangiopathies, which also include fibrinoid necrosis and “double barrel” or “lumen within a lumen” appearance, most often in severe CAA [10, 20]. The pathogenesis of hemorrhage in CAA is also not entirely clear but is thought to result from replacement of the smooth muscle cells of the media by amyloid with resultant weakening of the vessel walls and consequent rupture [10, 21, 22]. Fibrinoid necrosis and microaneurysms have also been associated with ICH in sporadic and familial CAA [10, 23–25]. Recent studies on microaneurysms are sparse and although previous studies have examined CBAs in the setting of hypertension or CAA generally separately, later studies, especially those investigating CAA, have shown that such a distinction may be artifactual [16, 26, 27]. Hypertension and CAA commonly co-exist [26, 28], and it has recently been proposed that hypertensive arteriopathy and CAA may be on a spectrum of age-related small vessel diseases (SVDs) with common underlying mechanisms including blood–brain barrier (BBB) dysfunction and impaired perivascular Aβ clearance [29, 30]. In this study, we describe the clinicopathologic features of microaneurysms encountered during routine brain autopsy in the setting of hypertension and/or CAA. Materials and methods We searched the database of autopsies including brain or brain only autopsies, performed at UCLA Medi (...truncated)