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Research paper
Acute convexity subarachnoid haemorrhage and cortical superficial siderosis in probable cerebral amyloid angiopathy without lobar haemorrhage
  1. Andreas Charidimou1,
  2. Grégoire Boulouis1,
  3. Panagiotis Fotiadis1,
  4. Li Xiong1,
  5. Alison M Ayres1,
  6. Kristin M Schwab1,
  7. Mahmut Edip Gurol2,3,
  8. Jonathan Rosand2,3,
  9. Steve M Greenberg1,
  10. Anand Viswanathan1
  1. 1 Hemorrhagic Stroke Research Program, Department of Neurology, Massachusetts General Hospital Stroke Research Center, Harvard Medical School, Boston, Massachusetts, USA
  2. 2 Department of MIND Informatics, Université Paris-Descartes, Centre Hospitalier Sainte Anne, Paris, Ile de France, France
  3. 3 Division of Neurocritical Care and Emergency Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA
  1. Correspondence to Dr Andreas Charidimou, Department of Neurology, Massachusetts General Hospital Stroke Research Center, Harvard Medical School, Boston, MA 02114, USA; andreas.charidimou.09{at}ucl.ac.uk

Abstract

Introduction Acute non-traumatic convexity subarachnoid haemorrhage (cSAH) is increasingly recognised in cerebral amyloid angiopathy (CAA). We investigated: (a) the overlap between acute cSAH and cortical superficial siderosis—a new CAA haemorrhagic imaging signature and (b) whether acute cSAH presents with particular clinical symptoms in patients with probable CAA without lobar intracerebral haemorrhage.

Methods MRI scans of 130 consecutive patients meeting modified Boston criteria for probable CAA were analysed for cortical superficial siderosis (focal, ≤3 sulci; disseminated, ≥4 sulci), and key small vessel disease markers. We compared clinical, imaging and cortical superficial siderosis topographical mapping data between subjects with versus without acute cSAH, using multivariable logistic regression.

Results We included 33 patients with probable CAA presenting with acute cSAH and 97 without cSAH at presentation. Patients with acute cSAH were more commonly presenting with transient focal neurological episodes (76% vs 34%; p<0.0001) compared with patients with CAA without cSAH. Patients with acute cSAH were also more often clinically presenting with transient focal neurological episodes compared with cortical superficial siderosis-positive, but cSAH-negative subjects with CAA (76% vs 30%; p<0.0001). Cortical superficial siderosis prevalence (but no other CAA severity markers) was higher among patients with cSAH versus those without, especially disseminated cortical superficial siderosis (49% vs 19%; p<0.0001). In multivariable logistic regression, cortical superficial siderosis burden (OR 5.53; 95% CI 2.82 to 10.8, p<0.0001) and transient focal neurological episodes (OR 11.7; 95% CI 2.70 to 50.6, p=0.001) were independently associated with acute cSAH.

Conclusions This probable CAA cohort provides additional evidence for distinct disease phenotypes, determined by the presence of cSAH and cortical superficial siderosis.

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Introduction

Sporadic cerebral amyloid angiopathy (CAA) is a small vessel disease of the brain characterised by progressive amyloid-β deposition in the small cortical and leptomeningeal arterioles.1 2 CAA is a frequent neuropathological finding in older people, an important cause of symptomatic lobar intracerebral haemorrhage (ICH) and a contributor to cognitive impairment.1–3 The clinical spectrum of CAA, however, seems to be more variable. It includes major lobar ICH, and diverse syndromes such as transient focal neurological episodes (TFNEs) and rapidly progressive or chronic cognitive impairment.1 4

CAA is also associated with brain MRI markers of small vessel disease including multiple strictly lobar cerebral microbleeds (the hallmark of the Boston criteria for CAA diagnosis),5 6 white matter hyperintensities and enlarged perivascular spaces (EPVS) in the centrum semiovale.1 7 The radiologic spectrum of CAA-related brain injury extends beyond these lesions to include cortical superficial siderosis (cSS) and acute convexity subarachnoid haemorrrhage (cSAH)—among cardinal haemorrhagic signatures of the disease.8 cSS quite characteristically affects the cerebral convexities, and its imaging manifestation reflects blood-breakdown residues, including haemosiderin, that line the outermost surface of the cortex or lie in the subarachnoid space. cSS has recently gained enormous interest since it is important as both a diagnostic marker of CAA9 and a predictor of future ICH10 and might provide insights into CAA pathophysiology and different disease phenotypes.8 11 Acute cSAH is increasingly recognised in CAA and appears not to represent aneurysmal or traumatic bleeding like other forms of SAH.8 11 Both the previous case series and case-control studies on the topic had patients with CAA presenting with acute cSAH with or without a history of previous lobar ICH,12 and hence, by definition, patients had different disease severity and diagnostic certainty. Also, the spectrum of clinical-imaging markers of patients with CAA presenting with cSAH compared with other symptomatic CAA cases presenting without lobar ICH in the appropriate clinical context, remain somewhat limited12 13 and further studies are needed. Thus, many questions of clinical relevance remain unanswered in the field, and CAA presentations with acute cSAH are not clearly appreciated as a disease phenotype. In most instances, it is hypothesised that acute cSAH in the context of CAA reflects episodes of leaking from brittle amyloid-loaded leptomeningeal or very superficial cortical small vessels,14 resulting in cSS at the chronic stage.8 14 15

To test this hypothesis of the inter-relation between cSS and acute cSAH8 and gain further insights into different CAA subtypes, we performed a systematic analysis of patients with symptomatic CAA presenting without any lobar ICH at a tertiary centre stroke clinic. We specifically aimed to investigate the overlap between acute cSAH with cSS, as well as similarity of other risk factors (such as APOE ε2). In addition, we investigated if cSAH in the acute phase presents with particular clinical symptoms that differ from the patients with symptomatic CAA without ICH that present without acute cSAH at baseline.

Patients and methods

Case selection and study population

We analysed prospectively collected data from consecutive patients meeting modified Boston criteria for probable CAA in the absence of ICH (symptomatic or asymptomatic) seen at Massachusetts General Hospital Stroke service (including stroke unit and outpatient clinics) between 1994 and 2015. Detailed inclusion criteria included: 1) diagnosis of probable CAA by modified Boston criteria; 2) clinical presentation other than haemorrhagic stroke and 3) available MR images (including T2*-weighted/susceptibility weighted imaging (SWI), diffusion-weighted imaging, T2-weighted and fluid attenuated inversion recovery (FLAIR) sequences). Patients with history of ICH at baseline or inflammatory CAA were excluded. Patients without acute, chronic (symptomatic or asymptomatic) or previous history of ICH but with strictly deep cerebral microbleeds (CMBs), mixed (deep and lobar) and exclusively cerebellar CMBs, or single strictly lobar CMBs were not considered in this cohort. A flow chart of patient selection is provided in figure 1.

Figure 1

Flow-chart of patient selection. CAA, cerebral amyloid angiopathy; CMB, cerebral microbleeds; ICH, intracerebral haemorrhage; MGH, Massachusetts General Hospital.

Clinical and APOE data

Full medical history, including demographic and clinical information and data on medication, was obtained at presentation through in-person interview with patient or surrogate using standardised data collection forms. Baseline neurological examination was performed as part of standard of care and symptoms recorded prospectively.

APOE genotype was determined in a subset of patients who provided blood samples and consented to genetic testing as previously described,16–18 and without knowledge of clinical or neuroimaging data.

Detailed symptoms of the baseline clinical presentations were collected blinded to imaging findings using prespecified forms. Presentations were reviewed independently by two investigators and were classified based on all available clinical information but blinded to small vessel disease markers on MRI as: TFNEs (episodes of positive or negative neurological symptoms lasting for minutes with subsequent complete resolution, without a cause other than CAA after adequate evaluation, including angiography studies and carotid imaging, as previously suggested),19 20 cognitive complaints (eg, mainly memory impairment, acute worsening of known cognitive impairment and mental status changes) or other non-focal neurological symptoms (including dizziness, confusion and gait impairment). Cases of disagreement were resolved by consensus.

Standard protocol approvals, registrations and patient consents

This study was performed in accordance with the guidelines and with approval of the institutional review boards at our institution.

Neuroimaging data acquisition and analysis

Images were obtained using a 1.5 Tesla MR scanner and included whole brain T2-weighted, T2*-weighted gradient-recalled echo (T2*-GRE; echo time (TE) 750/50 ms, 5 mm slice thickness, 1 mm interslice gap) and FLAIR (TR/TE 10 000/140 ms, inversion time 2200 ms, 1 number of excitations, 5 mm slice thickness, 1 mm interslice gap). For a subset of patients (n=24), the paramagnetic MRI sequences included SWI (TR/TE 27/20 ms, 1.5 mm slice thickness). All MR images were reviewed blinded to clinical and genetic data by two trained observers, according to the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE).21 MRIs were in general performed 1–3 days after the onset of symptoms in patients presenting with TFNEs.

CMBs presence and number were evaluated on axial T2*-GRE or SWI images using current consensus criteria7 and categorised according to previously validated Microbleed Anatomical Rating Scale.22 For purposes of statistical analyses, the number of lobar CMBs was categorised using cut-points as defined previously (0, 1, 2–4 or ≥5).17

cSS and acute cSAH were defined and assessed in line with recent consensus recommendations.8 cSS was defined as curvilinear hypointensities following the cortical surface, distinct from the vessels, and was assessed on axial blood-sensitive sequences according to a validated scale: absent, focal (restricted to ≤3 sulci) or disseminated (affecting four or more sulci).9 23 cSS was also rated for multifocality (ie, taking into account cSS presence at spatially separate foci in each hemisphere) using a protocol developed in our group as: (a) 0–none; (b) 1–1 sulcus or up to 3 immediately adjacent sulci with cSS or (c) 2–2 or more non-adjacent sulci or >3 adjacent sulci with cSS. Based on the total score (ie, adding the right and left hemisphere scores, 0–4): 0—no cSS, 1—unifocal cSS, while ≥2—multifocal cSS. This method showed excellent inter-rater reliability (k=0.87). Acute cSAH was defined as linear hypointensity in the subarachnoid space affecting one or more cortical sulci on T2*-GRE/SWI sequences with corresponding hyperintensity in the subarachnoid space on T1-weighted or FLAIR images.7 23 The inter-rater reliability for acute cSAH definition was excellent (k=0.93 between two raters). All cSS and acute cSAH rating were jointly performed by two experienced raters.

EPVS were assessed on axial T2-weighted MR images, in the basal ganglia and centrum semiovale (CSO), using a validated 4-point visual rating scale (0=no PVS, 1=<10 PVS, 2=11–20 PVS, 3=21–40 PVS and 4=>40 PVS).24–26 We prespecified a dichotomised classification of EPVS degree as high (score >2) or low (score ≤2) in line with previous studies.26–28

White matter hyperintensities volumes were calculated on axial FLAIR sequences with a previously described semi-automated planimetric method using MRICron software.29 Periventricular and deep WMH were also classified using the 0–3 Fazekas scale.30 The anteroposterior ratio of WMH lesions’ distribution was computed using a validated approach.31 As previously shown using this method, a lower score reflects more posteriorly distributed WMH lesions.31

Global atrophy was rated on axial brain T1-weighted imaging according to a previously validated 0–3 scale,32 where 3 represents severe atrophy. We dichotomised patients into those with no or mild atrophy (0–1) and those with moderate-to-severe atrophy (2–3). Lacunes were defined according to the STRIVE criteria,21 as round or ovoid fluid-filled cavities, between 3 and 15 mm in diameter.

cSS topographical mapping

cSS outlines were obtained from blood-sensitive sequences (T2*-GRE or SWI) using a semi-automated sequential approach in MRICron33 from lesions first jointly characterised as cSS. This method involved a first manual outline followed by a threshold filtering higher values of the dynamic range (Figure 2). Visual checks were performed to control for accuracy of the outlines of each affected area.

Figure 2

Cortical superficial siderosis (cSS) topographical mapping pipeline and methodology.

For each subject, a surface map was constructed corresponding to the projection of each cSS site on the cortical mantle. All individual surface maps were then registered to a common space, and an average surface heat map was generated (Figure 2). The software suite FreeSurfer (https://surfer.nmr.mgh.harvard.edu, V.5.3.0) was used for the aforementioned analyses.34–36

Statistics

Categorical variables were analysed using Pearson’s χ2 test or Fisher’s exact test, and continuous variables by the two-sample t-test (for normal distributions), and Wilcoxon rank-sum test (for non-normal distributions). We compared demographic, clinical, imaging and APOE data of patients with CAA with versus without acute cSAH. A multivariable logistic regression analysis model was used to look for independent associations with acute cSAH, including clinical presentation and other CAA MRI signatures and correcting for potential confounders identified in the univariable analysis or based on potential biological significance. As sensitivity analyses, we further adjusted these models for different blood-sensitive MRI sequences (eg, T2*-GRE vs SWI). In a post hoc analysis, we assessed the relationship between cSS (presence or burden) and other markers of CAA and APOE genotype. APOE genotype was analysed using two categorical variables indicating presence of any ε2 or ε4 alleles. Significance level was set at 0.05. All tests of significance were two-tailed. Stata software (V.13, StataCorp) was used. The manuscript was prepare with reference to the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) guidelines.37

Results

Our final sample included 130 consecutive patients with probable CAA presenting to our centre without any ICH (Figure 1). Review of all available clinical data of these cases yielded the following predominant baseline presentations: TFNEs (58/130; 45%), cognitive complains including non-focal neurological symptoms (72/130; 55%). Seven patients (5%) presented with a combination of these symptom clusters. MRI was performed within 1–3 days of symptoms onset in all patients. None of the included cases had a history of acute or previous history of head trauma. A total of 24/130 (19%) had SWI sequences available, while the rest of the patient cohort had T2*-GRE. Patients who underwent SWI versus T2*-GRE were not different in demographic, clinical or neuroimaging characteristics (data not shown).

Fifty-three per cent of patients with TFNEs experienced sensory symptoms, typically consisting of (‘aura-like’, ‘migraine-like’ or ‘seizure-like’) stereotyped positive spreading paraesthesias lasting a few minutes to 1 hour. Transient visual symptoms (positive or negative phenomena) were seen in 16% of patients with TFNEs, while transient focal weakness and episodes of language impairment in 22% and 21%, respectively. Patients with cognitive complaints had subacute memory impairment over months-years with a combination of symptoms, prompting referral to our stroke service and brain MRI scan (CDR median: 1). A clinical diagnosis of dementia before the baseline presentation was made in 57% (95% CI 41% to 71%) patients with cognitive complaints. Only 8% (95% CI 3% to 19%) of patients presenting with TFNEs were diagnosed with dementia.

Table 1 presents the clinical and imaging characteristics of the whole cohort and the comparisons between patients with CAA with versus without acute cSAH. No differences were found in demographic characteristics and vascular risk factors (table 1). TFNEs were common among patients with cSAH (76% vs 34%; p<0.0001). In these cases, all TFNEs could be anatomically correlated with the location of acute cSAH. In cases presenting with TFNEs but without acute cSAH on baseline MRI, patient’s transient symptoms were in general anatomically correlated with areas of cSS. Patients with acute cSAH were also more often clinically presenting with TFNEs compared with subjects with cSS-positive but cSAH-negative CAA (76% vs 30%; p<0.0001).

Table 1

Clinical, imaging and genetic characteristics for patients with CAA presenting with versus without acute cSAH.

The prevalence of cSS was significantly higher among patients with cSAH compared to patients with CAA without acute cSAH, especially disseminated (48% vs 19%; p<0.0001) and multifocal cSS (55% vs 21%; p<0.0001) (table 1 and figure 3). There was no difference in the two groups in the prevalence or burden of all the other small vessel disease imaging markers: WMH (volume, Fazekas or posterior distribution), CSO-EPVS, atrophy and lacunes (table 1). There was a trend for patients with acute cSAH to have lower lobar CMBs counts (table 1). Patients with acute cSAH had higher frequency of APOE ε2 allele, but this was not statistically significant (35% vs 24%).

Figure 3

Representative patients with and without convexity subarachnoid haemorrhage. 1.5 Tesla axial brain MRI sequences (A) fluid attenuated inversion recovery (left) sequence and susceptibility weighted imaging (SWI) (right) axial sections in an elderly patient evaluated for rapidly progressing right-sided tingling resolved in 15 min after onset. No relevant medical history. Imaging demonstrates acute subarachnoid blood in the central sulcus (white arrowheads) and bilateral disseminated foci of cortical superficial siderosis (white rectangles). (B) SWI axial sequence in an elderly patient with repeated stereotyped episodes of dizziness and left-sided hand tingling. Imaging demonstrates chronic focal cortical superficial siderosis affecting the right central sulcus (white rectangle) as well as strictly lobar cerebral microbleeds (black arrowheads).

In multivariable logistic regression, cSS burden (OR 5.53; 95% CI 2.82 to 10.8, p<0.0001) and TFNEs (OR 11.7; 95% CI 2.70 to 50.6, p=0.001) were independent correlates of acute cSAH (table 2). Models remained consisted and of similar effect size in sensitivity analyses further adjusting for SWI versus T2*-GRE sequences. Figure 4 presents the overall cSS topographical heat maps in patients with and without acute cSAH, demonstrating more extensive cSS involvement in multiple brain regions in the patient group with probable CAA presenting with acute cSAH.

Figure 4

Averaged surface heat maps showcasing the whole brain distribution and frequency of cortical superficial siderosis sites in the two patient study groups: (A) patients with probable cerebral amyloid angiopathy (CAA) without acute convexity subarachnoid haemorrhage (cSAH) (ie, cSAH-negative group, top panel) and (B) patients with probable CAA presenting with acute cSAH (cSAH-positive group, lower panel). The areas in the circle include the precentral and central sulcus for illustration purposes. Compared with patients without acute cSAH (top panel), the patient group with acute cSAH in the lower panel demonstrates more extensive involvement by cortical superficial siderosis (cSS)—more brain areas are affected with higher degree of cSS per region. This is especially evident in the precentral and central sulcus (circled areas), in which multiple cSS sites are covering the whole sulci. These eloquent areas are particular symptomatogenic and the occurrence of cSS (or cSAH in the acute stage) might underpin transient focal neurological episodes often seen in patients with CAA (‘amyloid spells’). The colour scale bar indicates the degree of cSS involvement in different brain areas in our cohort.

Table 2

Multivariable logistic regression analysis for acute cSAH presence.

cSS and APOE in the whole CAA group

cSS (presence and burden) was not associated with any of the other markers of CAA, including WMH, lobar CMBs, CSO-PVS and atrophy (all p>0.2). Among subjects with available genetic testing (n=62), APOE ε2 (but not ε4) allele was over-represented in cases with cSS (40% vs 16%; p=0.032), especially disseminated cSS (56% vs 17% vs 16% in those with disseminated vs focal vs no cSS, p=0.006 across the three groups). These results remained consistent and of similar effect size in a sensitivity multivariable logistic regression analysis adjusting for age and sex (OR 2.75; 95% CI 1.33 to 5.68; p=0.006 for the association between cSS burden and APOE ε2). There was no association between cSS (burden or presence) and APOE ε4. There was no association between CMBs counts and APOE genotype (p>0.2).

Discussion

The major findings from this study show that patients with symptomatic CAA without ICH presenting at a tertiary stroke service with acute cSAH are more likely to have cSS (particularly disseminated) and a trend for less lobar CMBs counts compared with patients with CAA without acute cSAH. The prevalence and burden of other small vessel disease markers are comparable between the two groups. While CMBs burden is associated with WMH, cSS demonstrated no associations with any other CAA markers in the whole group. In addition, there was an overall higher representation of the APOE ε2 in patients with cSS.

cSS and acute cSAH has been recently identified as key imaging signatures of CAA.8 15 38 Although the clinical-imaging features of CAA-related lobar ICH are well established, little is known about the specific patterns of symptomatic CAA presenting without major ICH,4 39 especially CAA-related cSAH. Our results provide new insights into the clinical and imaging spectrum of sporadic CAA, pointing to potentially different disease phenotypes according to acute cSAH presence.40 The most distinctive neuroimaging feature between the two groups was the much higher prevalence of disseminated and multifocal cSS in patients with CAA with acute cSAH. In line with a recent study,15 the reported prevalence of cSS in this group is much higher compared with histopathology-confirmed CAA-ICH9 and the reported prevalence in a previous imaging study of CAA-ICH.23 The high prevalence of cSS among patients with CAA-related acute cSAH and the high prevalence of TFNE in patients with CAA with either cSAH or cSS suggest a link between cSAH and cSS.8 41 Of note, patients with versus without acute cSAH had a very similar profile of putative neuroimaging biomarkers of CAA severity, including lobar CMBs, WMH and CSO-PVS. It is hence possible that factors other than overall CAA pathological severity might be driving a more superficial haemorrhagic subtype of the disease, such as more predominant leptomeningeal pathology (with a trend for sparing cortical arteries) or specific associations with superficial vessel fragility partly driven by the APOE ε2 allele. Further neuropathological studies are needed to directly test this hypothesis.

Although the pathophysiological basis underlying acute cSAH and cSS in CAA remain poorly understood, the prevailing view is that fragile leptomeningeal or very superficial cortical vessels severely affected by amyloid deposition might lead to blood-leaking episodes into the subarachnoid space and thus cSAH in some patients.39 40 These mechanisms could be linked with the neuropathological observation of more severe leptomeningeal CAA compared with cortical parenchymal in some cases.42 Depending on the location, if acute cSAH occurs in eloquent areas, such as the precentral or central sulci, they will trigger TFNEs.41 43 In other locations, these episodes might be clinically silent and the breakdown of blood products will ultimately lead to cSS in the chronic stage,11 a process which needs the mobilisation of macrophages and inflammatory pathways.44 Hence, it is possible that patients presenting with acute cSAH have had multiple previous episodes of asymptomatic cSAH, but only when such an episode happens in an eloquent brain area they come to medical attention and get an MRI. This hypothesis might explain our observations in the cSS topographical mapping analysis. In this analysis, we observed more involvement by cSS in multiple brain regions in patients with probable CAA presenting with acute cSAH compared with patients without, likely representing multiple bleeding episodes in the subarachnoid space. This was particularly evident in the precentral and central sulcus, symptomatogenic eloquent areas often responsible for TFNEs in patients with CAA. Appropriate imaging can potentially reveal different time points of the same pathophysiological processes, providing information about the timing, as well as pattern, of cSAH/cSS bleeding events (ie, dissemination in time and space). This hypothesis is also supported by a number of small imaging studies showing evolution of acute cSAH into cSS in follow-up scans.11 15 38 Large systematic studies assessing the evolution from acute cSAH through cSS need to be performed.

Our post hoc analysis in the whole cohort provide some evidence for the idea that cSS seems to be a stand-alone independent marker of the disease, indicating distinct pathophysiological mechanisms. APOE ε2 seems to be more strongly linked with cSS and bleeding, in line with a previous study on cSAH in CAA.13 This was a consistent finding in a separate cohort of CAA defined by clinicoradiographic criteria,45 as well as in a study of pathologically confirmed CAA.39 The APOE ε2 allele is known to be associated with CAA-related vasculopathic changes and lobar ICH,46 47 although any mechanistic links with cSS might be complex and need to be treated with caution.39

Notable strengths of our study include a large cohort of consecutive probable CAA cases without ICH (hence excluding the possibility of a ‘secondary’ mechanism of cSAH and cSS due to leakage of a lobar ICH into the subarachnoid space), with in-depth evaluation of MRIs by trained raters using validated scales. MR images were rated for a comprehensive range of imaging markers of small vessel disease that capture aspects of CAA severity, with volumetric assessment of total WMH burden and using cSS definitions and ratings according to recently suggested consensus standards.8 The detailed mapping of each individual cSS lesion allowed us to confirm the robustness of the findings. A number of previous papers have focused on acute cSAH related to CAA in the last few years.12 However, previous studies on the topic were relatively small case series, typically including all patients with possible and probable CAA presenting with and without a history of previous lobar ICH.12 Hence, previously reported cases were partly confounded by the different disease severity, duration, predominant phenotype (ICH vs non-ICH CAA) and diagnostic certainty for CAA. No studies, to the best of our knowledge, explored the whole spectrum of clinical-imaging markers of CAA in acute cSAH compared with other symptomatic CAA cases presenting without lobar ICH in the appropriate clinical context, a question of clinical relevance for accurately phenotyping the disease. Also previous studies have alluded to the potential relationship between cSAH and APOE ε2 genotype, and between cSAH and TFNEs,12 but these data are rather limited.13 Finally, the relationship from acute cSAH to cSS (ie, chronic) in a given patient has been proposed in previous reports and a recent consensus paper on the topic,8 but many aspects of this relationship have not been systematically explored at the group level and across different CAA subtypes without ICH at baseline.

We note the potential selection bias in our cohort due to our centre’s expertise in CAA and the requirement for MRI performed as part of routine clinical care. Another limitation is the lack of APOE data in a substantial proportion of patients included, limiting the statistical power for detecting an association with acure cSAH. An additional limitation is that it is impossible to score cSS without some unblinding to other imaging findings, although raters were blinded to MRI markers on the non-blood-sensitive sequences, including acute cSAH where possible and to all clinical data. Finally, the cross-sectional design of the current study did not allow us to assess potential causality of the reported associations and the clinical relevance of acute cSAH and cSS as risk factors for future symptomatic haemorrhage, key topics for further research.

Results from this cohort of patients with probable CAA without ICH provide additional evidence for distinct disease phenotypes, determined by the presence of acute cSAH. Our study emphasises the widening spectrum of CAA with presentations reflecting different neuroimaging and genetic features and suggests a crucial role for cSS. These findings require external validation in larger CAA cohorts. The natural history of patients presenting without ICH who have acute cSAH and/or cSS, and the risk of future ICH requires further investigation in prospective cohorts.

References

Footnotes

  • Contributors Statistical analysis was conducted by AC: study concept and design, data collection, imaging analysis, statistical analysis, write-up. GB: study concept and design, data collection, imaging analysis, critical revisions. PF: imaging analysis, write-up, critical revisions. LX: data collection, critical revisions. AMA: data collection and management. MJ: data collection and management. KMS: data collection and management. EMG: critical revisions. JR: data collection, critical revisions. SMG: funding, project design, critical revisions. AV: funding, project design, write-up, critical revisions.

  • Funding This work was supported by NIH grants R01!AG026484 (S.M. Greenberg). Gregoire Boulouis was supported by a J. William Fulbright Scholarship and a Monahan Foundation Biomedical Research Grant. Andreas Charidimou receives postdoctoral support from the Bodossaki Foundation. This study is not industry sponsored.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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