Transient Focal Neurological Events in Cerebral Amyloid Angiopathy and the Long-term Risk of Intracerebral Hemorrhage and Death: A Systematic Review and Meta-analysis

Abstract

Importance: Transient focal neurological episodes (TFNEs) are a frequently overlooked presentation of cerebral amyloid angiopathy (CAA), a condition with prognostic implications that are still not well described.

Objective: To perform a systematic review and meta-analysis to examine the factors associated with incident lobar intracerebral hemorrhage (ICH) and death in patients with CAA presenting with TFNEs.

Data sources: A systematic review and individual participant meta-analysis including (1) a hospital-based cohort and (2) the results obtained from a systematic search performed in MEDLINE and Embase completed in December 2019.

Study selection: Included studies were observational reports of TFNEs. Patient-level clinical, imaging, and prognostic data were required for inclusion. For aggregate data studies, patient-level data were requested. Disagreements were resolved by consensus.

Data extraction and synthesis: Data were extracted following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines by 4 independent reviewers. The quality of reports was determined based on the modified Pearson Case Report Quality Scale.

Main outcomes and measures: The clinical characteristics of TFNEs, neuroimaging features, and use of antithrombotics during follow-up were considered exposures. The predefined main outcomes were lobar ICH and risk of death during follow-up.

Results: Forty-two studies and 222 CAA-associated TFNE cases were included from the initial 1612 records produced by the systematic search; 26 additional patients (11 men [42.3%]; mean [SD] age, 77 [8] years) were provided by the hospital-based cohort. A total of 108 TFNEs (43.5%) consisted of motor symptoms. Convexity subarachnoid hemorrhage and cortical superficial siderosis were detected in 193 individuals (77.8%) and 156 individuals (62.9%) in the systematic search and hospital-based cohort, respectively. Follow-up duration could be obtained in 185 patients (median duration, 1 year [IQR, 0.8-2.5 years]). During follow-up, symptomatic lobar ICH occurred in 76 patients (39.4%). Motor symptoms (odds ratio, 2.08 [95% CI, 1.16-3.70]) at baseline and antithrombotic use during follow-up (odds ratio, 3.61 [95% CI, 1.67-7.84]) were associated with an increase in risk of lobar ICH. A total of 31 patients (16.5%) died during follow-up; lobar ICH during follow-up and cortical superficial siderosis were the main risk factors for death (odds ratio, 3.01 [95% CI, 1.36-6.69]; odds ratio, 3.20 [95% CI, 1.16-8.91], respectively).

Conclusions and relevance: Patients presenting with CAA-associated TFNEs are at high risk of lobar ICH and death. Motor TFNEs and use of antithrombotics after a TFNE, in many cases because of misdiagnosis, are risk factors for ICH, and therefore accurate diagnosis and distinguishing this condition from transient ischemic attacks is critical.

Figure 1.. Neuroimaging Findings in Patients With Transient Focal Neurological Episodes

Example images from the hospital-based cohort. A-B, Patient 16. Multiple cortical and subcortical microbleeds, right frontoparietal cortical superficial siderosis, and right frontal chronic lobar intracerebral hemorrhage (arrowhead) (A). Predominantly posterior periventricular white matter hyperintensities (arrowhead) and subcortical white matter hyperintensities (arrowhead) (B). C-E, Patient 10. Focal convexity subarachnoid hemorrhage (arrowhead) (C). Frontoparietal focal cortical superficial siderosis (arrowhead) (D). Forty-five days after image C, parietal acute lobar intracerebral hemorrhage and more extensive surrounding cortical superficial siderosis than in image D (E). CT indicates computed tomography; FLAIR, fluid-attenuated inversion recovery; GRE, gradient echo sequences; MRI, magnetic resonance imaging; SWI, susceptibility-weighted imaging.

Figure 2.. Risk of Lobar Intracerebral Hemorrhage (ICH) After a Cerebral Amyloid Angiopathy–Associated Transient Focal Neurological Episode (TFNE)

A, Bivariate analysis of risk of lobar ICH. B, Binary logistic regression of risk of lobar ICH. C, The proportion of antithrombotics use stratified by convexity subarachnoid hemorrhage (CSAH) in neuroimaging shows a significantly higher use of antithrombotics when no CSAH was detected, which suggests a confounding association in the analysis of the correlation between CSAH and lobar ICH. D-F, Survival curves and log-rank analysis for ICH occurrence when stratifying by motor TFNEs, CSAH, and antithrombotics use. MS indicates motor symptoms.

Figure 3.. Risk of Death After an Associated Transient Focal Neurological Episode (TFNE)

A, Bivariate analysis of risk of death. B, Distribution of acute ischemic stroke (AIS) on magnetic resonance imaging (MRI) stratified by cortical superficial siderosis (CSS) presence. C, Binary logistic regression of risk of death. D-F, Survival curves and log-rank analysis for death during follow-up when stratifying by CSS, AIS, and lobar intracerebral hemorrhage (ICH), respectively. OR indicates odds ratio.