Cortical superficial siderosis in the general population: The Framingham Heart and Rotterdam studies

Objective We aimed to characterize cortical superficial siderosis, its determinants and sequel, in community-dwelling older adults. Methods The sample consisted of Framingham ( n = 1724; 2000–2009) and Rotterdam ( n = 4325; 2005–2013) study participants who underwent brain MRI. In pooled individual-level analysis, we compared baseline characteristics in patients with cortical superficial siderosis to two reference groups: (i) persons without hemorrhagic MRI markers of cerebral amyloid angiopathy (no cortical superficial siderosis and no microbleeds) and (ii) those with presumed cerebral amyloid angiopathy based on the presence of strictly lobar microbleeds but without cortical superficial siderosis. Results Among a total of 6049 participants, 4846 did not have any microbleeds or cortical superficial siderosis (80%), 401 had deep/mixed microbleeds (6.6%), 776 had strictly lobar microbleeds without cortical superficial siderosis (12.8%) and 26 had cortical superficial siderosis with/without microbleeds (0.43%). In comparison to participants without microbleeds or cortical superficial siderosis and to those with strictly lobar microbleeds but without cortical superficial siderosis, participants with cortical superficial siderosis were older (OR 1.09 per year, 95% CI 1.05, 1.14; p < 0.001 and 1.04, 95% CI 1.00, 1.09; p = 0.058, respectively), had overrepresentation of the APOE ɛ4 allele (5.19, 2.04, 13.25; p = 0.001 and 3.47, 1.35, 8.92; p = 0.01), and greater prevalence of intracerebral hemorrhage (72.57, 9.12, 577.49; p < 0.001 and 81.49, 3.40, >999.99; p = 0.006). During a mean follow-up of 5.6 years, 42.4% participants with cortical superficial siderosis had a stroke (five intracerebral hemorrhage, two ischemic strokes and four undetermined strokes), 19.2% had transient neurological deficits and 3.8% developed incident dementia. Conclusion Our study adds supporting evidence to the association between cortical superficial siderosis and cerebral amyloid angiopathy within the general population. Community-dwelling persons with cortical superficial siderosis may be at high risk for intracerebral hemorrhage and future neurological events.

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The Characteristics of Superficial Siderosis and Convexity Subarachnoid Hemorrhage and Clinical Relevance in Suspected Cerebral Amyloid Angiopathy

Cerebrovascular Diseases ◽

10.1159/000381223 ◽

2015 ◽

Vol 39 (5-6) ◽

pp. 278-286 ◽

Cited By ~ 27

Author(s):

Jun Ni ◽

Eitan Auriel ◽

Jenelle Jindal ◽

Alison Ayres ◽

Kristin M. Schwab ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Intracerebral Hemorrhage ◽

Cerebral Amyloid Angiopathy ◽

Epileptiform Activity ◽

Brain Mri ◽

Superficial Siderosis ◽

Amyloid Angiopathy ◽

Cerebral Bleeding ◽

Cerebral Amyloid

Background and Aims: Systematic studies of superficial siderosis (SS) and convexity subarachnoid hemorrhage (cSAH) in patients with suspected cerebral amyloid angiopathy (CAA) without lobar intracerebral hemorrhage (ICH) are lacking. We sought to determine the potential anatomic correlation between SS/cSAH and transient focal neurological episodes (TFNE) and whether SS/cSAH is predictor of future cerebral hemorrhagic events in these patients. Methods: We enrolled 90 consecutive patients with suspected CAA (due to the presence of strictly lobar microbleeds (CMBs) and/or SS/cSAH) but without the history of symptomatic lobar ICH who underwent brain MRI including T2*-weighted, diffusion-weighted imaging and fluid-attenuated inversion recovery sequences from an ongoing single center CAA cohort from 1998 to 2012. Evaluation of SS, cSAH and CMBs was performed. Medical records and follow-up information were obtained from prospective databases and medical charts. TFNE was defined according to published criteria and electroencephalogram reports were reviewed. Results: Forty-one patients (46%) presented with SS and/or cSAH. The prevalence of TFNE was significantly higher in those with SS/cSAH (61 vs. 10%; p < 0.001) and anatomically correlated with the location of cSAH, but not SS. The majority of TFNE in patients with SS/cSAH presented with spreading sensory symptoms. Intermittent focal slowing on electroencephalogram was present in the same area as SS/cSAH in 6 patients, but no epileptiform activity was found in any patients. Among those with available clinical follow-up (76/90 patients, 84%), ten patients with SS/cSAH (29%, median time from the scan for all patients with SS/cSAH: 21 months) had a symptomatic cerebral bleeding event on follow up (average time to events: 34 months) compared with only 1 event (2.4%, 25 months from the scan) in patients without SS/cSAH (time to event: 25 months) (p = 0.001). The location of hemorrhages on follow-up scan was not in the same location of previously noted SS/cSAH in 9 of 10 patients. Follow-up imaging was obtained in 9 of 17 patients with cSAH and showed evidence of SS in the same location as initial cSAH in all these 9 cases. Conclusions: SS/cSAH is common in patients with suspected CAA without lobar intracerebral hemorrhage and may have a significantly higher risk of future cerebral bleeding events, regardless of the severity of the baseline CMB burden. The findings further highlight a precise anatomical correlation between TFNE and cSAH, but not SS. Distinct from transient ischemic attack or seizure, the majority of TFNE caused by SS/cSAH appear to present with spreading sensory symptoms.

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Cortical superficial siderosis and intracerebral hemorrhage risk in cerebral amyloid angiopathy

Neurology ◽

10.1212/01.wnl.0000435298.80023.7a ◽

2013 ◽

Vol 81 (19) ◽

pp. 1666-1673 ◽

Cited By ~ 87

Author(s):

A. Charidimou ◽

A. P. Peeters ◽

R. Jager ◽

Z. Fox ◽

Y. Vandermeeren ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Cerebral Amyloid Angiopathy ◽

Superficial Siderosis ◽

Amyloid Angiopathy ◽

Hemorrhage Risk ◽

Cerebral Amyloid ◽

Cortical Superficial Siderosis

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Stopping “transient ischemic attacks” by antiplatelet withdrawal

Neurological Research and Practice ◽

10.1186/s42466-021-00117-0 ◽

2021 ◽

Vol 3 (1) ◽

Author(s):

Lina Palaiodimou ◽

Aikaterini Theodorou ◽

Stefanos Lachanis ◽

George P. Paraskevas ◽

Matilda Papathanasiou ◽

...

Keyword(s):

Differential Diagnosis ◽

Cerebral Amyloid Angiopathy ◽

Brain Mri ◽

Superficial Siderosis ◽

Amyloid Angiopathy ◽

Perivascular Spaces ◽

The Past ◽

Cerebral Amyloid ◽

Ischemic Attack ◽

Cortical Superficial Siderosis

Abstract Introduction Transient ischemic attack (TIA) is considered to be an important risk factor for the development of ischemic stroke and requires complete etiopathogenic evaluation and prompt initiation of secondary prevention treatment. In addition, an accurate differential diagnosis should be performed in order to exclude other disorders mimicking TIA. Methods In this case report, we describe the clinical and neuroimaging evaluation and the differential diagnosis of a patient with suspected crescendo TIAs. Results A 79-year-old man presented with recurrent episodes of right-sided numbness over the past 7 months, despite different single and dual antiplatelet therapies that were sequentially prescribed for suspected TIAs. Brain MRI revealed cortical superficial siderosis, symmetrical periventricular leukoencephalopathy and enlarged perivascular spaces. Cerebral amyloid angiopathy was considered in the differential diagnosis of the patient. Antiplatelet withdrawal was recommended and led to complete remission of the patient’s transient focal neurological episodes (TFNE) that were initially misdiagnosed as TIAs. Discussion Cortical superficial siderosis has been implicated as a key neuroimaging feature of cerebral amyloid angiopathy, a diagnosis which can be supported by the additional radiological findings of symmetrical white matter hyperintensities and enlarged perivascular spaces. Antiplatelet treatment in patients with cortical superficial siderosis may increase the frequency and severity of TFNE, while it increases exponentially the risk of intracerebral hemorrhage. The present case highlights that recognition of cortical superficial siderosis is crucial in the management of patients presenting with transient focal neurological symptoms that can be misdiagnosed as recurrent TIAs.

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P4-196: Clinical Impacts of Cortical Superficial Siderosis in Patients With Clinically Diagnosed Cerebral Amyloid Angiopathy

Alzheimer s & Dementia ◽

10.1016/j.jalz.2016.06.2288 ◽

2016 ◽

Vol 12 ◽

pp. P1099-P1099

Author(s):

Young Kyoung Jang ◽

Hee Jin Kim ◽

Yeo Jin Kim ◽

Jin San Lee ◽

Juyoun Lee ◽

...

Keyword(s):

Cerebral Amyloid Angiopathy ◽

Superficial Siderosis ◽

Amyloid Angiopathy ◽

Cerebral Amyloid ◽

Cortical Superficial Siderosis

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Abstract 36: The Boston Criteria V2.0 for Cerebral Amyloid Angiopathy: Updated Criteria and Multicenter MRI-Neuropathology Validation

Stroke ◽

10.1161/str.52.suppl_1.36 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Andreas Charidimou ◽

Gregoire Boulouis ◽

Matthew Frosch ◽

Jean-Claude Baron ◽

Marco Pasi ◽

...

Keyword(s):

White Matter ◽

Intracerebral Hemorrhage ◽

Diagnostic Accuracy ◽

Cerebral Amyloid Angiopathy ◽

Brain Mri ◽

Amyloid Angiopathy ◽

Perivascular Spaces ◽

Validation Sample ◽

Temporal Validation ◽

Cerebral Amyloid

Introduction: The Boston criteria are used worldwide for in vivo diagnosis of cerebral amyloid angiopathy (CAA). Given substantial advances in CAA research, we aimed to update the Boston criteria and externally validate their diagnostic accuracy across the spectrum of CAA-related presentations and across international sites. Methods: As part of an International CAA Association multicenter study, we identified patients age 50 or older with potential CAA-related clinical presentations (spontaneous intracerebral hemorrhage, cognitive impairment, or transient focal neurological episodes), available brain MRI, and histopathologic assessment for the diagnosis of CAA. We derived Boston criteria v2.0 by selecting MRI features to optimize diagnostic specificity and sensitivity in a pre-specified derivation sample (Boston cases 1994 to 2012, n=159), then externally validated in pre-specified temporal (Boston cases 2012-2018, n=59) and geographical (non-Boston cases 2004-2018; n=123) validation samples and compared their diagnostic accuracy to the currently used modified Boston criteria. Results: Based on exploratory analyses in the derivation sample, we derived provisional criteria for probable CAA requiring presence of at least 2 strictly lobar hemorrhagic lesions (intracerebral hemorrhage, cerebral microbleed, or cortical superficial siderosis focus) or at least 1 strictly lobar hemorrhagic lesion and 1 white matter characteristic (severe degree of visible perivascular spaces in centrum semiovale or white matter hyperintensities multispot pattern). Sensitivity/specificity of the criteria were 74.8/84.6% in the derivation sample, 92.5/89.5% in the temporal validation sample, 80.2/81.5% in the geographic validation sample, and 74.5/95.0% in cases across all samples with autopsy as the diagnostic gold standard. The v2.0 criteria for probable CAA had superior accuracy to the currently modified Boston criteria (p<0.005) in the autopsied cases. Conclusion: The Boston criteria v.2.0 incorporate emerging MRI markers of CAA to enhance sensitivity without compromising their high specificity. Validation of the criteria across independent patient settings firmly supports their adoption into clinical practice and research.

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Cortical superficial siderosis and bleeding risk in cerebral amyloid angiopathy

Neurology ◽

10.1212/wnl.0000000000008590 ◽

2019 ◽

Vol 93 (24) ◽

pp. e2192-e2202 ◽

Cited By ~ 5

Author(s):

Andreas Charidimou ◽

Gregoire Boulouis ◽

Steven M. Greenberg ◽

Anand Viswanathan

Keyword(s):

Cerebral Amyloid Angiopathy ◽

Meta Analysis ◽

Bleeding Risk ◽

Superficial Siderosis ◽

Amyloid Angiopathy ◽

Class Iii ◽

Cerebral Amyloid ◽

T2 Mri ◽

Cortical Superficial Siderosis

ObjectiveTo assess the association of cortical superficial siderosis (cSS) presence and extent with future bleeding risk in cerebral amyloid angiopathy (CAA).MethodsThis was a meta-analysis of clinical cohorts of symptomatic patients with CAA who had T2*-MRI at baseline and clinical follow-up for future intracerebral hemorrhage (ICH). We pooled data in a 2-stage meta-analysis using random effects models. Covariate-adjusted hazard ratios (adjHR) from multivariable Cox proportional hazard models were used.ResultsWe included data from 6 eligible studies (n = 1,239). cSS pooled prevalence was 34% (95% confidence interval [CI] 26%–41%; I2 87.94%; p < 0.001): focal cSS prevalence was 14% (95% CI 12%–16%; I2 6.75%; p = 0.37), and disseminated cSS prevalence was 20% (95% CI 13%–26%; I2 90.39%; p < 0.001). During a mean follow-up of 3.1 years (range 1–4 years), 162/1,239 patients experienced a symptomatic ICH-pooled incidence rate 6.9% per year (95% CI 3.9%–9.8% per year; I2 83%; p < 0.001). ICH incidence rates per year according to cSS status were 3.9% (95% CI 1.7%–6.1%; I2 70%; p = 0.018) for patients without cSS, 11.1% (95% CI 7%–15.2%; I2 56.8%; p = 0.074) for cSS presence, 9.1% (95% CI 5.5%–12.8%; I2 0%; p = 0.994) for focal cSS, and 12.5% (95% CI 5.3%–19.7%; I2 73.2%; p = 0.011) for disseminated cSS. In adjusted pooled analysis, any cSS presence was independently associated with increased future ICH risk (adjHR 2.14; 95% CI 1.19–3.85; p < 0.0001). Focal cSS was linked with ICH risk (adjHR 2.11; 95% CI 1.31–2.41; p = 0.002), while disseminated cSS conferred the strongest bleeding risk (adjHR 4.28; 95% CI 2.91–6.30; p < 0.0001).ConclusionIn patients with CAA, cSS presence and extent are the most important MRI prognostic risk factors for future ICH, likely useful in treatment planning.Classification of evidenceThis study provides Class III evidence that in symptomatic CAA survivors with baseline T2*-MRI, cSS (particularly if disseminated, i.e., affecting >3 sulci) increases the risk of future ICH.

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Clinical and radiological differences between patients with probable cerebral amyloid angiopathy and mixed cerebral microbleeds

Journal of Neurology ◽

10.1007/s00415-020-10038-8 ◽

2020 ◽

Vol 267 (12) ◽

pp. 3602-3608 ◽

Cited By ~ 1

Author(s):

Ulf R. Jensen-Kondering ◽

Caroline Weiler ◽

Patrick Langguth ◽

Naomi Larsen ◽

Charlotte Flüh ◽

...

Keyword(s):

Cerebral Amyloid Angiopathy ◽

Cerebral Microbleeds ◽

Superficial Siderosis ◽

Periventricular White Matter ◽

Amyloid Angiopathy ◽

Imaging Features ◽

Significant Difference ◽

Comprehensive Comparison ◽

Cerebral Amyloid ◽

Cortical Superficial Siderosis

Abstract 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.

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Cortical superficial siderosis progression in cerebral amyloid angiopathy

Neurology ◽

10.1212/wnl.0000000000009321 ◽

2020 ◽

Vol 94 (17) ◽

pp. e1853-e1865 ◽

Cited By ~ 3

Author(s):

Thanakit Pongpitakmetha ◽

Panagiotis Fotiadis ◽

Marco Pasi ◽

Gregoire Boulouis ◽

Li Xiong ◽

...

Keyword(s):

Logistic Regression ◽

Cerebral Amyloid Angiopathy ◽

Ordinal Scale ◽

Superficial Siderosis ◽

Amyloid Angiopathy ◽

Cox Regression Analysis ◽

Multivariable Logistic Regression ◽

Potential Biomarker ◽

Cerebral Amyloid ◽

Cortical Superficial Siderosis

ObjectiveTo investigate the prevalence, predictors, and clinical relevance of cortical superficial siderosis (cSS) progression in cerebral amyloid angiopathy (CAA).MethodsConsecutive patients with symptomatic CAA meeting Boston criteria in a prospective cohort underwent baseline and follow-up MRI within 1 year. cSS progression was evaluated on an ordinal scale and categorized into mild (score 1–2 = cSS extension within an already present cSS focus or appearance of 1 new cSS focus) and severe progression (score 3–4 = appearance of ≥2 new cSS foci). Binominal and ordinal multivariable logistic regression were used to determine cSS progression predictors. We investigated future lobar intracerebral hemorrhage (ICH) risk in survival analysis models.ResultsWe included 79 patients with CAA (mean age, 69.2 years), 56 (71%) with lobar ICH at baseline. cSS progression was detected in 23 (29%) patients: 15 (19%) patients had mild and 8 (10%) severe progression. In binominal multivariable logistic regression, ICH presence (odds ratio [OR], 7.54; 95% confidence interval [CI], 1.75–53.52; p = 0.016) and baseline cSS (OR, 10.41; 95% CI, 2.84–52.83; p = 0.001) were independent predictors of cSS progression. In similar models, presence of disseminated (but not focal) cSS at baseline (OR, 5.58; 95% CI, 1.81–19.41; p = 0.004) was an independent predictor of cSS progression. Results were similar in ordinal multivariable logistic regression models. In multivariable Cox regression analysis, severe cSS progression was independently associated with increased future ICH risk (HR, 5.90; 95% CI, 1.30–26.68; p = 0.021).ConclusionscSS evolution on MRI is common in patients with symptomatic CAA and might be a potential biomarker for assessing disease severity and future ICH risk. External validation of these findings is warranted.

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Cortical superficial siderosis multifocality in cerebral amyloid angiopathy

Neurology ◽

10.1212/wnl.0000000000004665 ◽

2017 ◽

Vol 89 (21) ◽

pp. 2128-2135 ◽

Cited By ~ 40

Author(s):

Andreas Charidimou ◽

Gregoire Boulouis ◽

Duangnapa Roongpiboonsopit ◽

Eitan Auriel ◽

Marco Pasi ◽

...

Keyword(s):

Cerebral Amyloid Angiopathy ◽

Interrater Reliability ◽

Superficial Siderosis ◽

Amyloid Angiopathy ◽

Recurrence Rates ◽

Rating Method ◽

Cerebral Amyloid ◽

Annual Risk ◽

Cortical Superficial Siderosis

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 ε2 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.

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