The Edinburgh CT and genetic diagnostic criteria for lobar intracerebral haemorrhage associated with cerebral amyloid angiopathy: model development and diagnostic test accuracy study

Abstract

Background: Identification of lobar spontaneous intracerebral haemorrhage associated with cerebral amyloid angiopathy (CAA) is important because it is associated with a higher risk of recurrent intracerebral haemorrhage than arteriolosclerosis-associated intracerebral haemorrhage. We aimed to develop a prediction model for the identification of CAA-associated lobar intracerebral haemorrhage using CT features and genotype.

Methods: We identified adults with first-ever intracerebral haemorrhage diagnosed by CT, who died and underwent research autopsy as part of the Lothian IntraCerebral Haemorrhage, Pathology, Imaging and Neurological Outcome (LINCHPIN) study, a prospective, population-based, inception cohort. We determined APOE genotype and radiologists rated CT imaging appearances. Radiologists were not aware of clinical, genetic, and histopathological features. A neuropathologist rated brain tissue for small vessel diseases, including CAA, and was masked to clinical, radiographic, and genetic features. We used CT and APOE genotype data in a logistic regression model, which we internally validated using bootstrapping, to predict the risk of CAA-associated lobar intracerebral haemorrhage, derive diagnostic criteria, and estimate diagnostic accuracy.

Findings: Among 110 adults (median age 83 years [IQR 76-87], 49 [45%] men) included in the LINCHPIN study between June 1, 2010 and Feb 10, 2016, intracerebral haemorrhage was lobar in 62 (56%) participants, deep in 41 (37%), and infratentorial in seven (6%). Of the 62 participants with lobar intracerebral haemorrhage, 36 (58%) were associated with moderate or severe CAA compared with 26 (42%) that were associated with absent or mild CAA, and were independently associated with subarachnoid haemorrhage (32 [89%] of 36 vs 11 [42%] of 26; p=0·014), intracerebral haemorrhage with finger-like projections (14 [39%] of 36 vs 0; p=0·043), and APOE ɛ4 possession (18 [50%] of 36 vs 2 [8%] of 26; p=0·0020). A prediction model for CAA-associated lobar intracerebral haemorrhage using these three variables had excellent discrimination (c statistic 0·92, 95% CI 0·86-0·98), confirmed by internal validation. For the rule-out criteria, neither subarachnoid haemorrhage nor APOE ɛ4 possession had 100% sensitivity (95% CI 88-100). For the rule-in criteria, subarachnoid haemorrhage and either APOE ɛ4 possession or finger-like projections had 96% specificity (95% CI 78-100).

Interpretation: The CT and APOE genotype prediction model for CAA-associated lobar intracerebral haemorrhage shows excellent discrimination in this cohort, but requires external validation. The Edinburgh rule-in and rule-out diagnostic criteria might inform prognostic and therapeutic decisions that depend on identification of CAA-associated lobar intracerebral haemorrhage.

Funding: UK Medical Research Council, The Stroke Association, and The Wellcome Trust.

Figure 1

Pathological severity of CAA and other small vessel disease according to intracerebral haemorrhage location CAA=cerebral amyloid angiopathy.

Figure 2

Discrimination and calibration measures of prediction model performance (A) Receiver operating characteristic curve for predicted probability of moderate or severe CAA. The AUC is equivalent to the c statistic. The shaded area represents the 95% CI of the AUC based on 2000 bootstrap replicates. The dotted line indicates a non-informative AUC of 0·50 for comparison. (B) Calibration plot of predicted probability versus observed frequency of moderate or severe CAA. Grey line indicates perfect calibration, the model's calibration is shown by the dotted line. Triangles represent the six different moderate or severe CAA risk groups produced by the prediction model. Vertical lines represent the frequency and distribution of model predicted probabilities. CAA=cerebral amyloid angiopathy. AUC=area under the curve.

Figure 3

Categorisation of probability of lobar intracerebral haemorrhage associated with moderate or severe cerebral amyloid angiopathy according to the three predictor variables, with example CT images CAA=cerebral amyloid angiopathy. Adapted from Salman and Rodrigues (Creative Commons 4.0).