Prevalence of superficial siderosis in patients with cerebral amyloid angiopathy.
ABSTRACT: Cerebral amyloid angiopathy (CAA) typically presents with lobar intracerebral macrohemorrhages (ICH) or microbleeds (MBs). Several case reports also found superficial siderosis (SS) in patients with CAA. We aimed to assess the value of SS for the in vivo diagnosis of CAA, and tested whether the inclusion of SS as a criterion alters the sensitivity and specificity of the Boston criteria for CAA-related hemorrhage.We retrospectively analyzed the T2*-weighted MRIs of 38 patients with histopathologically proven CAA and of 22 control patients with histopathologically proven non-CAA ICHs regarding the presence of ICHs, MBs, and SS. We compared the sensitivity and specificity of the classic Boston criteria to that of modified criteria, which included SS as a criterion.ICHs were present in 71% of the patients with CAA, and in all control patients. MBs were found in 47.4% of patients with CAA and in 22.7% of controls. SS was detected in 60.5% of patients with CAA, but in none of the controls. The classic criteria had a sensitivity of 89.5% for CAA-related hemorrhage, while inclusion of SS increased their sensitivity to 94.7% (not significant). On the contrary, the specificity of the Boston criteria was 81.2% both for the classic and for the modified criteria.Superficial siderosis (SS) occurs with high prevalence in cerebral amyloid angiopathy (CAA) and is rare in non-CAA forms of intracerebral hemorrhages. Thus, we propose that inclusion of SS in the Boston criteria might enhance their sensitivity for CAA-related hemorrhage without loss of specificity.
Project description:Despite its clinical relevance, cerebral amyloid angiopathy (CAA) is underdiagnosed worldwide. This retrospective study aimed to assess the incidence, etiology, predictors, and outcome of intracerebral hemorrhages (ICHs) in this region, with special focus on possible underlying CAA. Database screening of acute cares with intracranial hemorrhage diagnosis within 01/07/2014-01/07/2018 were conducted analyzing medical records and imaging. Spontaneous ICHs were classified as deep (basal ganglionic/thalamic/brainstem) and lobar/cerebellar (i.e., CAA-compatible) ICHs. Probable/definite CAA was established using the modified Boston criteria in a subgroup with 'complete' radiological/neuropathological work-up. The ability of several factors to discriminate between deep and lobar/cerebellar ICHs, between probable/definite CAA and non-probable CAA cases, and to predict 1-month case fatality was assessed. Of the 213 ICHs identified, 121 were in deep and 92 in lobar/cerebellar localization. Sub-analysis of 47 lobar/cerebellar ICHs with 'complete' work-up identified 16 probable/definite CAA patients, yielding an estimated 14.7% prevalence of CAA-related ICHs. Chronic hypertension was the most prevalent risk factor for all types of ICHs (including CAA-related), with hypertensive excess and younger age being independent predictors of deep whereas antiplatelet use of lobar/cerebellar localization. The 1-month case fatality was 33.8%, driven predominantly by age and INR?>?1.4. Probable/definite CAA diagnosis was independently predicted by age, prior intracranial hemorrhage, and antiplatelet use. First in this region and among the few in the literature, this study reports a remarkable prevalence of CAA-related ICHs, emphasizing the need for an increased awareness of CAA and its therapeutic implications, especially regarding antiplatelets among the elderly.
Project description:OBJECTIVE: To investigate whether cortical superficial siderosis (cSS) on MRI, especially if disseminated (involving more than 3 sulci), increases the risk of future symptomatic lobar intracerebral hemorrhage (ICH) in cerebral amyloid angiopathy (CAA). METHODS: European multicenter cohort study of 118 patients with CAA (104 with baseline symptomatic lobar ICH) diagnosed according to the Boston criteria. We obtained baseline clinical, MRI, and follow-up data on symptomatic lobar ICH. Using Kaplan-Meier and Cox regression analyses, we investigated cSS and ICH risk, adjusting for known confounders. RESULTS: During a median follow-up time of 24 months (interquartile range 9-44 months), 23 of 118 patients (19.5%, 95% confidence interval [CI]: 12.8%-27.8%) experienced symptomatic lobar ICH. Any cSS and disseminated cSS were predictors of time until first or recurrent ICH (log-rank test: p = 0.0045 and p = 0.0009, respectively). ICH risk at 4 years was 25% (95% CI: 7.6%-28.3%) for patients without siderosis; 28.9% (95% CI: 7.7%-76.7%) for patients with focal siderosis; and 74% (95% CI: 44.1%-95.7%) for patients with disseminated cSS (log-rank test: p = 0.0031). In Cox regression models, any cSS and disseminated cSS were both independently associated with increased lobar ICH risk, after adjusting for ? 2 microbleeds and age (hazard ratio: 2.53; 95% CI: 1.05-6.15; p = 0.040 and hazard ratio: 3.16; 95% CI: 1.35-7.43; p = 0.008, respectively). These results remained consistent in sensitivity analyses including only patients with symptomatic lobar ICH at baseline. CONCLUSIONS: Our findings indicate that cSS, particularly if disseminated, is associated with an increased risk of symptomatic lobar ICH in CAA. cSS may help stratify future bleeding risk in CAA, with implications for prognosis and treatment.
Project description:BACKGROUND:The key imaging features of cerebral amyloid angiopathy (CAA) are lobar, cortical, or cortico-subcortical microbleeds, macrohaemorrhages and cortical superficial siderosis (cSS). In contrast, hypertensive angiopathy is characterized by (micro) haemorrhages in the basal ganglia, thalami, periventricular white matter or the brain stem. Another distinct form of haemorrhagic microangiopathy is mixed cerebral microbleeds (mixed CMB) with features of both CAA and hypertensive angiopathy. The distinction between the two entities (CAA and mixed CMB) is clinically relevant because the risk of haemorrhage and stroke should be well balanced if oral anticoagulation is indicated in CAA patients. We aimed to comprehensively compare these two entities. METHODS:Patients with probable CAA according to the modified Boston criteria and mixed CMB without macrohaemorrhage were retrospectively identified from our database. Comprehensive comparison regarding clinical and radiological parameters was performed between the two cohorts. RESULTS:Patients with CAA were older (78?±?8 vs. 74?±?9 years, p?=?0.036) and had a higher prevalence of cSS (19% vs. 4%, p?=?0.027) but a lower prevalence of lacunes (73% vs. 50%, p?=?0.018) and deep lacunes (23% vs. 51%, p?=?0.0003) compared to patients with mixed CMB. Logistic regression revealed an association between the presence of deep lacunes and mixed CMB. The other collected parameters did not reveal a significant difference between the two groups. CONCLUSIONS:CAA and mixed CMB demonstrate radiological differences in the absence of macrohaemorrhages. However, more clinically available biomarkers are needed to elucidate the contribution of CAA and hypertensive angiopathy in mixed CMB patients.
Project description:Restricted lobar cerebral microbleeds (CMBs) and cortical superficial siderosis (CSS) are the characteristic markers of cerebral amyloid angiopathy (CAA). However, their effects on clinical features has not been evaluated well. The purpose of this study is to investigate the clinical implication of these markers in clinical-radiologically diagnosed CAA. A total of 372 patients with possible or probable CAA who met the modified Boston criteria were recruited in a memory clinic setting. Cortical thickness was measured using surface based methods. Presence of restricted multiple lobar CMBs were independently associated with cortical thinning across the entire cortical regions while presence of CSS was independently associated with cortical thinning primarily in the bilateral frontal region. Presence of restricted multiple lobar CMBs was associated with impairment in all cognitive domains such as attention, language, visuospatial, memory and frontal executive functions while presence of CSS was associated with attention and frontal dysfunction. The relationships of restricted multiple lobar CMBs or CSS with cognitive impairment were partially mediated by thinning in the corresponding cortical regions. Our findings suggested that restricted multiple lobar CMBs and CSS affect distinctive clinical features, providing new insights into potential mechanisms in CAA.
Project description:Atraumatic convexal subarachnoid hemorrhage (cSAH) in elderly patients is a rare entity that has been associated with cerebral amyloid angiopathy (CAA) and intracerebral hematomas (ICH). To characterize this entity and to study these associations, 22 patients over 60 with cSAH were included in a multicenter ambispective cohort study. Clinical data, magnetic resonance imaging (MRI) studies, APOE genotyping, and cerebrospinal fluid (CSF) biomarkers were evaluated. Results were compared with data from healthy controls (HC), non-cSAH CAA patients (CAAo), and Alzheimer disease patients. Convexal subarachnoid hemorrhage presented with transient sensory or motor symptoms. At follow-up (median 30.7 months), 5 patients had died, 6 survivors showed functional disability (modified Rankins Scale (mRS)>2), and 12 cognitive impairment. Four patients had prior ICH and six had an ICH during follow-up. CSF-Aß40 and Aß42 levels were lower in cSAH and CAAo compared with HC. Convexal subarachnoid hemorrhage presented an APOE-?2 overrepresentation and CAAo had an APOE-?4 overrepresentation. On MRI, all patients fulfilled CAA-modified Boston criteria and 9 showed cortical ischemia in the surrounding cortex or the vicinity of superficial siderosis. The neuropathologic study, available in one patient, showed severe CAA and advanced Alzheimer-type pathology. Convexal subarachnoid hemorrhage in the elderly is associated with cognitive impairment and lobar ICH occurrence. Our findings support the existence of an underlying CAA pathology.
Project description:OBJECTIVE:In order to explore the mechanisms of cortical superficial siderosis (cSS) multifocality and its clinical implications for recurrent intracerebral hemorrhage (ICH) risk in patients with cerebral amyloid angiopathy (CAA), we used a new rating method that we developed specifically to evaluate cSS extent at spatially separated foci. METHODS:Consecutive patients with CAA-related ICH according to Boston criteria from a single-center prospective cohort were analyzed. The new score that assesses cSS multifocality (total range 0-4) showed excellent interrater reliability (k = 0.87). The association of cSS with markers of CAA and acute ICH was investigated. Patients were followed prospectively for recurrent symptomatic ICH. RESULTS:The cohort included 313 patients with CAA. Multifocal cSS prevalence was 21.1%. APOE ?2 allele prevalence was higher in patients with multifocal cSS. In probable/definite CAA, cSS multifocality was independently associated with neuroimaging markers of CAA severity, including lobar microbleeds, but not with acute ICH features, which conversely, were determinants of cSS in possible CAA. During a median follow-up of 2.6 years (interquartile range 0.9-5.1 years), the annual ICH recurrence rates per cSS scores (0-4) were 5%, 6.5%, 13.5%, 16.2%, and 26.9%, respectively. cSS multifocality (presence and spread) was the only independent predictor of increased symptomatic ICH risk (hazard ratio 3.19; 95% confidence interval 1.77-5.75; p < 0.0001). CONCLUSIONS:The multifocality of cSS correlates with disease severity in probable CAA; therefore cSS is likely to be caused by discrete hemorrhagic foci. The new cSS scoring system might be valuable for clinicians in determining annual risk of ICH recurrence.
Project description:Cerebral amyloid angiopathy (CAA) is a common age-related small vessel disease (SVD). Patients without intracerebral hemorrhage (ICH) typically present with transient focal neurologic episodes (TFNEs) or cognitive symptoms. We sought to determine if SVD lesion burden differed between patients with CAA first presenting with TFNEs vs cognitive symptoms.A total of 647 patients presenting either to a stroke department (n = 205) or an outpatient memory clinic (n = 442) were screened for eligibility. Patients meeting modified Boston criteria for probable CAA were included and markers of SVD were quantified, including cerebral microbleeds (CMBs), perivascular spaces, cortical superficial siderosis (cSS), and white matter hyperintensities (WMHs). Patients were classified according to presentation symptoms (TFNEs vs cognitive). Total CAA-SVD burden was assessed using a validated summary score. Individual neuroimaging markers and total SVD burden were compared between groups using univariable and multivariable models.There were 261 patients with probable CAA included. After adjustment for confounders, patients first seen for TFNEs (n = 97) demonstrated a higher prevalence of cSS (p < 0.0001), higher WMH volumes (p = 0.03), and a trend toward higher CMB counts (p = 0.09). The total SVD summary score was higher in patients seen for TFNEs (adjusted odds ratio per additional score point 1.46, 95% confidence interval 1.16-1.84, p = 0.013).Patients with probable CAA without ICH first evaluated for TFNEs bear a higher burden of structural MRI SVD-related damage compared to those first seen for cognitive symptoms. This study sheds light on neuroimaging profile differences across clinical phenotypes of patients with CAA without ICH.
Project description:Background: Cortical superficial siderosis (cSS) represents a key neuroimaging marker of cerebral amyloid angiopathy (CAA) that is associated with intracranial hemorrhages and cognitive impairment. Nevertheless, the association between cSS and core cerebrospinal fluid (CSF) biomarkers for dementia remain unclear. Methods: One hundred and one patients with probable (79%, 80/101) or possible (21%, 21/101) CAA according to the modified Boston criteria and mild cognitive impairment according to Petersen criteria were prospectively included between 2011 and 2016. CSF analyses of ß-amyloid 42, ß-amyloid 40, total tau and phosphorylated tau were performed using sandwich-type enzyme-linked immunosorbent-assay. All patients received MRI and Mini-Mental-State Examination (MMSE). Logistic regression analysis was used to adjust for possible confounders. Results: cSS was present in 61% (62/101). Of those, 53% (33/62) had disseminated cSS and 47% (29/62) focal cSS. ß-amyloid 42 was lower in patients with cSS than in patients without cSS (OR 0.2; 95% CI 0.08-0.6; p = 0.0052) and lower in patients with disseminated cSS than in those with focal cSS (OR 0.02; 95% CI 0.003-0.2; p = 0.00057). Presence of cSS had no association with regard to ß-amyloid 40, total tau and phosphorylated tau. Conclusions: Our results demonstrate that the presence and extent of cSS are associated with reduced CSF ß-amyloid 42 levels. Further studies are needed to investigate the underlying mechanisms of this association.
Project description:To identify predictors of early lobar intracerebral hemorrhage (ICH) recurrence, defined as a new ICH within 6 months of the index event, in patients with cerebral amyloid angiopathy (CAA).Participants were consecutive survivors (age ?55 years) of spontaneous symptomatic probable or possible CAA-related lobar ICH according to the Boston criteria, drawn from an ongoing single-center cohort study. Neuroimaging markers ascertained in CT or MRI included focal (?3 sulci) or disseminated (>3 sulci) cortical superficial siderosis (cSS), acute convexity subarachnoid hemorrhage (cSAH), cerebral microbleeds, white matter hyperintensities burden and location, and baseline ICH volume. Participants were followed prospectively for recurrent symptomatic ICH. Cox proportional hazards models were used to identify predictors of early recurrent ICH adjusting for potential confounders.A total of 292 patients were enrolled. Twenty-one patients (7%) had early recurrent ICH. Of these, 24% had disseminated cSS on MRI and 19% had cSAH on CT scan. In univariable analysis, the presence of disseminated cSS, cSAH, and history of previous ICH were predictors of early recurrent ICH (p < 0.05 for all comparisons). After adjusting for age and history of previous ICH, disseminated cSS on MRI and cSAH on CT were independent predictors of early recurrent ICH (hazard ratio [HR] 3.92, 95% confidence interval [CI] 1.38-11.17, p = 0.011, and HR 3.48, 95% CI 1.13-10.73, p = 0.030, respectively).Disseminated cSS on MRI and cSAH on CT are independent imaging markers of increased risk for early recurrent ICH. These markers may provide additional insights into the mechanisms of ICH recurrence in patients with CAA.
Project description:The relationship between recurrent intracerebral hemorrhage (ICH) and total burden of cerebral small vessel disease (CSVD) is not completely investigated. We aimed to study whether recurrent intracerebral hemorrhage (ICH) had higher CSVD score than first-ever ICH. Lacunes, white matter hyperintensities (WMH), cerebral microbleeds (CMBs), enlarged perivascular spaces (EPVS), cortical superficial siderosis (cSS) and CSVD score were rated on brain magnetic resonance imaging (MRI) in primary ICH patients. Recurrent ICHs were confirmed by reviewing the medical records and MRI scans. Mixed hematomas were defined as follows: deep + lobar, deep + cerebellar, or deep + lobar + cerebellar. Of the 184 patients with primary ICH enrolled (mean age, 61.0 years; 75.5% men), recurrent ICH was present in 45 (24.5%) patients; 26.1% (48/184) had ≥2 hematomas, 93.8% (45/48) of which exhibited recurrent ICH. Mixed hematomas were identified in 8.7% (16/184) of patients and bilateral hematomas in 17.9% (33/184). All mixed hematomas and bilateral hematomas were from cases of recurrent ICH. Patients with mixed etiology-ICH were more likely to have recurrent ICH than patients with cerebral amyloid angiopathy (CAA) or hypertensive angiopathy (HA)-related ICH (36.8% vs17.8%, p=0.008). Multivariate ordinal regression analysis showed that the presence of recurrent ICH (p=0.001), ≥2 hematomas (p=0.002), mixed hematomas (p<0.00001), and bilateral hematomas (p=0.002) were separately significantly associated with a high CSVD score. Recurrent ICH occurs mostly among patients with mixed etiology-ICH and is associated with a higher CSVD burden than first-ever ICH, which needs to be verified by future larger studies.