By Santosh Murthy, MD
Assistant Professor of Neurology, Weill Cornell Medical College
SYNOPSIS: In this large, observational population study using databases from the UK Biobank and the All of Us research program, spontaneous subdural hemorrhage occurred more often in patients with cerebral amyloid angiopathy compared to a matched control group.
SOURCE: Rivier CA, Kamel H, Sheth KN, et al. Cerebral amyloid angiopathy and risk of isolated nontraumatic subdural hemorrhage. JAMA Neurol 2023; Dec 26:e234918. doi:10.1001/jamaneurol.2023.4918. [Online ahead of print].
Subdural hemorrhage (SDH), a condition that mostly occurs among elderly individuals, is a common cause of brain injury leading to cognitive decline and dementia. In the past decade, hospitalizations for SDH have increased by about 40%, with a corresponding associated increase in the cost of care. The widely performed treatment intervention for SDH is surgical hematoma evacuation, which is associated with recurrence rates as high as 20%. Notably, patients can continue to have a poor functional status with a high associated cost of care. The purported pathophysiology of cerebral atrophy is believed to cause stretching and rupture of cerebral bridging veins, which then causes SDH. However, the presence of bleeding leptomeningeal arteries during surgical evacuation of SDH questions this prevailing paradigm.
In this context, this study by Rivier and colleagues, published in JAMA Neurology, evaluated the association between cerebral amyloid angiopathy (CAA), a brain vasculopathy caused by amyloid protein deposition, and incident SDH. The authors performed a cohort study leveraging data from two ongoing population studies, the United Kingdom (UK) Biobank, with 487,223 participants, and the All of Us research program in the United States, with 158,008 participants. The exposure was a new diagnosis of CAA, which was identified using International Classification of Diseases, Tenth Revision, diagnosis codes, while the outcome was SDH, without concurrent sequelae of traumatic brain injury.
In the UK Biobank (discovery cohort), a total of 126 participants had a diagnosis of CAA and 649 participants were diagnosed with an SDH. There were three cases of SDH in the participants with CAA and 646 cases in those without CAA (2.4% vs. 0.1%). Over a median follow-up time of 20.8 years, the incidence per 10,000 person-years of SDH was 8.9 (95% confidence interval [CI], 8.0-9.9) among participants with CAA, and 0.7 (95% CI, 0.6-0.7) in those without CAA.
In adjusted Cox regression analyses, a diagnosis of CAA was associated with an eight-fold increased risk of incident SDH compared to participants without CAA. Similarly, in the All of Us cohort, a new diagnosis of SDH occurred in two (3.8%) patients with CAA compared to 318 (0.2%) patients without CAA, translating to a nearly five-fold increased risk of SDH with CAA in adjusted time-to-event analyses.
COMMENTARY
The hemorrhagic manifestations of CAA include intracerebral hemorrhage (ICH), cerebral microbleeds, and cortical subarachnoid hemorrhage. Although SDH has been described in CAA, it usually is in the context of concurrent ICH. In this context, the present study sheds light on a novel association between CAA and isolated SDH, i.e., in the absence of an accompanying ICH. Caution does need to be exercised in drawing conclusions about causality, given that brain atrophy, cognitive decline, and falls can occur in CAA, and may separately influence the occurrence of SDH. Nevertheless, these findings could have important implications.
First, tests to diagnose underlying CAA, such as brain magnetic resonance imaging scans, are not routinely performed in SDH patients. Additional routine imaging studies may uncover more cases of CAA after SDH. Second, these findings eventually could lead to an isolated SDH included in the spectrum of CAA, which currently is not the case. Third, there may be a role of arterial mechanisms involved in causing SDH, since CAA can involve the meninges and leptomeningeal vessels. This may further support the exploration of artery-specific interventions, such as middle meningeal artery embolization, currently being investigated in several clinical trials in patients with a chronic SDH. Lastly, CAA may explain the rapid cognitive decline and brain atrophy seen in a substantial proportion of patients with SDH and improve our understanding of neurodegeneration in the elderly population.
