Andreas Charidimou

Sporadic cerebral amyloid angiopathy revisited: recent insights into pathophysiology and clinical spectrum

Sporadic cerebral amyloid angiopathy (CAA) is a common age related cerebral small vessel disease, characterised by progressive deposition of amyloid-β (Aβ) in the wall of small to medium sized arteries, arterioles and capillaries of the cerebral cortex and overlying leptomeninges. Previously considered to be a rare neurological curiosity, CAA is now recognised as an important cause of spontaneous intracerebral haemorrhage and cognitive impairment in the elderly, two fundamental challenges in the field of cerebrovascular disease. Our understanding of the pathophysiology and clinical manifestations of CAA continues to evolve rapidly, with the use of transgenic mouse models and advanced structural and/or molecular neuroimaging techniques. Yet, despite remarkable recent interest, CAA remains under-recognised by neurologists and stroke physicians. In this review, a fresh look at key developments in understanding the complex pathophysiology, important clinical and radiological features, diagnostic approaches and prospects for rational therapies for this enigmatic small vessel disorder is provided.

Spectrum of transient focal neurological episodes in cerebral amyloid angiopathy: multicentre magnetic resonance imaging cohort study and meta-analysis.

Background and Purpose— Transient focal neurological episodes (TFNE) are recognized in cerebral amyloid angiopathy (CAA) and may herald a high risk of intracerebral hemorrhage (ICH). We aimed to determine their prevalence, clinical neuroimaging spectrum, and future ICH risk. Methods— This was a multicenter retrospective cohort study of 172 CAA patients. Clinical, imaging, and follow-up data were collected. We classified TFNE into: predominantly positive symptoms (“aura-like” spreading paraesthesias/positive visual phenomena or limb jerking) and predominantly negative symptoms (“transient ischemic attack–like” sudden-onset limb weakness, dysphasia, or visual loss). We pooled our results with all published cases identified in a systematic review. Results— In our multicenter cohort, 25 patients (14.5%; 95% confidence interval, 9.6%–20.7%) had TFNE. Positive and negative symptoms were equally common (52% vs 48%, respectively). The commonest neuroimaging features were leukoaraiosis (84%), lobar ICH (76%), multiple lobar cerebral microbleeds (58%), and superficial cortical siderosis/convexity subarachnoid hemorrhage (54%). The CAA patients with TFNE more often had superficial cortical siderosis/convexity subarachnoid hemorrhage (but not other magnetic resonance imaging features) compared with those without TFNE (50% vs 19%; P=0.001). Over a median period of 14 months, 50% of TFNE patients had symptomatic lobar ICH. The meta-analysis showed a risk of symptomatic ICH after TFNE of 24.5% (95% confidence interval, 15.8%–36.9%) at 8 weeks, related neither to clinical features nor to previous symptomatic ICH. Conclusions— TFNE are common in CAA, include both positive and negative neurological symptoms, and may be caused by superficial cortical siderosis/convexity subarachnoid hemorrhage. TFNE predict a high early risk of symptomatic ICH (which may be amenable to prevention). Blood-sensitive magnetic resonance imaging sequences are important in the investigation of such episodes.

Cortical superficial siderosis: detection and clinical significance in cerebral amyloid angiopathy and related conditions

Cortical superficial siderosis describes a distinct pattern of blood-breakdown product deposition limited to cortical sulci over the convexities of the cerebral hemispheres, sparing the brainstem, cerebellum and spinal cord. Although cortical superficial siderosis has many possible causes, it is emerging as a key feature of cerebral amyloid angiopathy, a common and important age-related cerebral small vessel disorder leading to intracerebral haemorrhage and dementia. In cerebral amyloid angiopathy cohorts, cortical superficial siderosis is associated with characteristic clinical symptoms, including transient focal neurological episodes; preliminary data also suggest an association with a high risk of future intracerebral haemorrhage, with potential implications for antithrombotic treatment decisions. Thus, cortical superficial siderosis is of relevance to neurologists working in neurovascular, memory and epilepsy clinics, and neurovascular emergency services, emphasizing the need for appropriate blood-sensitive magnetic resonance sequences to be routinely acquired in these clinical settings. In this review we focus on recent developments in neuroimaging and detection, aetiology, prevalence, pathophysiology and clinical significance of cortical superficial siderosis, with a particular emphasis on cerebral amyloid angiopathy. We also highlight important areas for future investigation and propose standards for evaluating cortical superficial siderosis in research studies.

Cortical superficial siderosis and intracerebral hemorrhage risk in cerebral amyloid angiopathy.

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.

White matter perivascular spaces An MRI marker in pathology-proven cerebral amyloid angiopathy?

Objective: We investigated whether severe, MRI-visible perivascular spaces (PVS) in the cerebral hemisphere white matter (centrum semiovale) are more common in patients with pathology-proven cerebral amyloid angiopathy (CAA) than in those with pathology-proven non–CAA-related intracerebral hemorrhage (ICH). Methods: Using a validated 4-point scale on axial T2-weighted MRI, we compared PVS in patients with pathology-proven CAA to PVS in those with spontaneous ICH but no histopathologic evidence of CAA. In a preliminary analysis restricted to patients with T2*-weighted gradient-recalled echo MRI, we also investigated whether including severe centrum semiovale PVS increases the sensitivity of existing diagnostic criteria for probable CAA. Results: Fourteen patients with CAA and 10 patients with non–CAA-related ICH were included. Eight of the patients with CAA were admitted for symptomatic, spontaneous lobar ICH, 1 because of ischemic stroke, 1 with transient focal neurologic episodes, and 4 due to cognitive decline. Severe (>20) centrum semiovale PVS were more frequent in patients with CAA compared to controls (12/14 [85.7%; 95% confidence interval (CI): 57.2%–98.2%] vs 0/10 [1-sided 95% CI: 0%–30.8%], p < 0.0005); this was robust to adjustment for age. The original Boston criteria for probable CAA showed a sensitivity of 76.9% (95% CI: 46.2%–95%), which increased to 92.3% (95% CI: 64%–99.8%), without loss of specificity, after including severe centrum semiovale PVS. Conclusions: Severe centrum semiovale PVS on MRI may be a promising new neuroimaging marker for the in vivo diagnosis of CAA. However, our findings are preliminary and require confirmation and external validation in larger cohorts of pathology-proven CAA.

Volume and functional outcome of intracerebral hemorrhage according to oral anticoagulant type.

Objective: To compare intracerebral hemorrhage (ICH) volume and clinical outcome of non–vitamin K oral anticoagulants (NOAC)–associated ICH to warfarin-associated ICH. Methods: In this multicenter cross-sectional observational study of patients with anticoagulant-associated ICH, consecutive patients with NOAC-ICH were compared to those with warfarin-ICH selected from a population of 344 patients with anticoagulant-associated ICH. ICH volume was measured by an observer blinded to clinical details. Outcome measures were ICH volume and clinical outcome adjusted for confounding factors. Results: We compared 11 patients with NOAC-ICH to 52 patients with warfarin-ICH. The median ICH volume was 2.4 mL (interquartile range [IQR] 0.3–5.4 mL) for NOAC-ICH vs 8.9 mL (IQR 4.0–21.3 mL) for warfarin-ICH (p = 0.0028). In univariate linear regression, use of warfarin (difference in cube root volume 1.61; 95% confidence interval [CI] 0.69 to 2.53) and lobar ICH location (compared with nonlobar ICH; difference in cube root volume 1.52; 95% CI 2.20 to 0.85) were associated with larger ICH volumes. In multivariable linear regression adjusting for confounding factors (sex, hypertension, previous ischemic stroke, white matter disease burden, and premorbid modified Rankin Scale score [mRS]), warfarin use remained independently associated with larger ICH (cube root) volumes (coefficient 0.64; 95% CI 0.24 to 1.25; p = 0.042). Ordered logistic regression showed an increased odds of a worse clinical outcome (as measured by discharge mRS) in warfarin-ICH compared with NOAC-ICH: odds ratio 4.46 (95% CI 1.10 to 18.14; p = 0.037). Conclusions: In this small prospective observational study, patients with NOAC-associated ICH had smaller ICH volumes and better clinical outcomes compared with warfarin-associated ICH.

Cerebral microbleeds and postthrombolysis intracerebral hemorrhage risk Updated meta-analysis

Objective: We performed a systematic review and meta-analysis to assess whether the presence of cerebral microbleeds (CMBs) on pretreatment MRI scans of patients with acute ischemic stroke treated with thrombolysis is associated with an increased risk of symptomatic intracerebral hemorrhage (ICH). Methods: We searched PubMed for relevant studies and calculated pooled odds ratios (ORs) for symptomatic ICH, using the Mantel–Haenszel fixed-effects method, among individuals with vs without CMBs on pretreatment MRI scans. To minimize potential bias, sensitivity analysis was performed including studies providing data on patients treated only with IV thrombolysis. Results: Ten eligible studies including 2,028 patients were pooled in meta-analysis. The overall prevalence of CMBs was 23.3%. Among patients with CMBs, 40 of 472 (8.5%; 95% confidence interval [CI]: 6.1%–11.4%) experienced a symptomatic ICH after thrombolysis compared with 61 of 1,556 patients (3.9%; 95% CI: 3%–5%) without CMBs. The pooled OR of ICH across all studies was 2.26 (95% CI: 1.46–3.49; p p Conclusions: Our meta-analysis of the available published data demonstrates an increased risk of symptomatic ICH after thrombolysis for acute ischemic stroke in patients with CMBs. However, we cannot fully exclude bias or confounding, so our results should be considered hypothesis-generating. Detecting CMBs should not prevent thrombolytic treatment based on present evidence. Further analyses, taking into account CMB number and location, as well as measures of functional outcome, are needed.Objective: We performed a systematic review and meta-analysis to assess whether the presence of cerebral microbleeds (CMBs) on pretreatment MRI scans of patients with acute ischemic stroke treated with thrombolysis is associated with an increased risk of symptomatic intracerebral hemorrhage (ICH). Methods: We searched PubMed for relevant studies and calculated pooled odds ratios (ORs) for symptomatic ICH, using the Mantel–Haenszel fixed-effects method, among individuals with vs without CMBs on pretreatment MRI scans. To minimize potential bias, sensitivity analysis was performed including studies providing data on patients treated only with IV thrombolysis. Results: Ten eligible studies including 2,028 patients were pooled in meta-analysis. The overall prevalence of CMBs was 23.3%. Among patients with CMBs, 40 of 472 (8.5%; 95% confidence interval [CI]: 6.1%–11.4%) experienced a symptomatic ICH after thrombolysis compared with 61 of 1,556 patients (3.9%; 95% CI: 3%–5%) without CMBs. The pooled OR of ICH across all studies was 2.26 (95% CI: 1.46–3.49; p < 0.0001). Eight studies, including 1,704 patients (n = 401 with CMBs), provided data on patients treated with IV thrombolysis only; OR for the presence of CMBs and the development of symptomatic ICH was 2.87 (95% CI: 1.76–4.69; p < 0.0001). Conclusions: Our meta-analysis of the available published data demonstrates an increased risk of symptomatic ICH after thrombolysis for acute ischemic stroke in patients with CMBs. However, we cannot fully exclude bias or confounding, so our results should be considered hypothesis-generating. Detecting CMBs should not prevent thrombolytic treatment based on present evidence. Further analyses, taking into account CMB number and location, as well as measures of functional outcome, are needed.

Cerebral amyloid angiopathy with and without hemorrhage Evidence for different disease phenotypes

Objective: To gain insight into different cerebral amyloid angiopathy (CAA) phenotypes and mechanisms, we investigated cortical superficial siderosis (CSS), a new imaging marker of the disease, and its relation with APOE genotype in patients with pathologically proven CAA, who presented with and without intracerebral hemorrhage (ICH). Methods: MRI scans of 105 patients with CAA pathologic confirmation and MRI were analyzed for CSS (focal, ≤3 sulci; disseminates, ≥4 sulci) and other imaging markers. We compared pathologic, imaging, and APOE genotype data between subjects with vs without ICH, and investigated associations between CSS and APOE genotype. Results: Our cohort consisted of 54 patients with CAA with symptomatic lobar ICH and 51 without ICH. APOE genotype was available in 53 patients. More than 90% of pathology samples in both groups had neuritic plaques, whereas neurofibrillary tangles were more commonly present in the patients without ICH (87% vs 42%, p < 0.0001). There was a trend for patients with CAA with ICH to more commonly have APOE ε2 (48.7% vs 21.4%, p = 0.075), whereas patients without ICH were more likely to be APOE ε4 carriers (85.7% vs 53.9%, p = 0.035). Disseminated CSS was considerably commoner in patients with ICH (33.3% vs 5.9%, p < 0.0001). In logistic regression, disseminated CSS was associated with APOE ε2 (but not APOE ε4) (odds ratio 5.83; 95% confidence interval 1.49–22.82, p = 0.011). Conclusions: This neuropathologically defined CAA cohort suggests that CSS and APOE ε2 are related to the hemorrhagic expression of the disease; APOE ε4 is enriched in nonhemorrhagic CAA. Our study emphasizes the concept of different CAA phenotypes, suggesting divergent pathophysiologic mechanisms.

Association Between Hypodensities Detected by Computed Tomography and Hematoma Expansion in Patients With Intracerebral Hemorrhage

IMPORTANCE Hematoma expansion is a potentially modifiable predictor of poor outcome following an acute intracerebral hemorrhage (ICH). The ability to identify patients with ICH who are likeliest to experience hematoma expansion and therefore likeliest to benefit from expansion-targeted treatments remains an unmet need. Hypodensities within an ICH detected by noncontrast computed tomography (NCCT) have been suggested as a predictor of hematoma expansion. OBJECTIVE To determine whether hypodense regions, irrespective of their specific patterns, are associated with hematoma expansion in patients with ICH. DESIGN, SETTING, AND PARTICIPANTS We analyzed a large cohort of 784 patients with ICH (the development cohort; 55.6% female), examined NCCT findings for any hypodensity, and replicated our findings on a different cohort of patients (the replication cohort; 52.7% female). Baseline and follow-up NCCT data from consecutive patients with ICH presenting to a tertiary care hospital between 1994 and 2015 were retrospectively analyzed. Data analyses were performed between December 2015 and January 2016. MAIN OUTCOMES AND MEASURES Hypodensities were analyzed by 2 independent blinded raters. The association between hypodensities and hematoma expansion (>6 cm3 or 33% of baseline volume) was determined by multivariable logistic regression after controlling for other variables associated with hematoma expansion in univariate analyses with P ≤ .10. RESULTS A total of 1029 patients were included in the analysis. In the development and replication cohorts, 222 of 784 patients (28.3%) and 99 of 245 patients (40.4%; 321 of 1029 patients [31.2%]), respectively, had NCCT scans that demonstrated hypodensities at baseline (κ = 0.87 for interrater reliability). In univariate analyses, hypodensities were associated with hematoma expansion (86 of 163 patients with hematoma expansion had hypodensities [52.8%], whereas 136 of 621 patients without hematoma expansion had hypodensities [21.9%]; P < .001). The association between hypodensities and hematoma expansion remained significant (odds ratio, 3.42 [95% CI, 2.21-5.31]; P < .001) in a multivariable model; other independent predictors of hematoma expansion were a CT angiography spot sign, a shorter time to CT, warfarin use, and older age. The independent predictive value of hypodensities was again demonstrated in the replication cohort (odds ratio, 4.37 [95% CI, 2.05-9.62]; P < .001). CONCLUSION AND RELEVANCE Hypodensities within an acute ICH detected on an NCCT scan may predict hematoma expansion, independent of other clinical and imaging predictors. This novel marker may help clarify the mechanism of hematoma expansion and serve as a useful addition to clinical algorithms for determining the risk of and treatment stratification for hematoma expansion.

Validation of Clinicoradiological Criteria for the Diagnosis of Cerebral Amyloid Angiopathy-Related Inflammation.

IMPORTANCE Cerebral amyloid angiopathy-related inflammation (CAA-ri) is an important diagnosis to reach in clinical practice because many patients with the disease respond to immunosuppressive therapy. Reliable noninvasive diagnostic criteria for CAA-ri would allow some patients to avoid the risk of brain biopsy. OBJECTIVE To test the sensitivity and specificity of clinical and neuroimaging-based criteria for CAA-ri. DESIGN, SETTING, AND PARTICIPANTS We modified the previously proposed clinicoradiological criteria and retrospectively analyzed clinical medical records and magnetic resonance imaging fluid-attenuated inversion recovery and gradient-echo scans obtained from individuals with CAA-ri and noninflammatory CAA. At 2 referral centers between October 1, 1995, and May 31, 2013, and between January 1, 2009, and December 31, 2011, participants included 17 individuals with pathologically confirmed CAA-ri and 37 control group members with pathologically confirmed noninflammatory CAA. The control group was further divided into those with past lobar intracerebral hemorrhage (ICH) (n = 21) and those with cerebral microbleeds only and no history of ICH (n = 16). The dates of our analysis were September 1, 2012, to August 31, 2015. MAIN OUTCOMES AND MEASURES The sensitivity and specificity of prespecified criteria for probable CAA-ri (requiring asymmetric white matter hyperintensities extending to the subcortical white matter) and possible CAA-ri (not requiring the white matter hyperintensities to be asymmetric). RESULTS The 17 patients in the CAA-ri group were a mean (SD) of 68 (8) years and 8 (47%) were women. In the CAA-ri group, 14 of 17 (82%) met the criteria for both probable and possible CAA-ri. In the control group having noninflammatory CAA with lobar ICH, 1 of 21 (5%) met the criteria for possible CAA-ri, and none met the criteria for probable CAA-ri. In the control group having noninflammatory CAA with no ICH, 11 of 16 (69%) met the criteria for possible CAA-ri, and 1 of 16 (6%) met the criteria for probable CAA-ri. These findings yielded a sensitivity and specificity of 82% and 97%, respectively, for the probable criteria and a sensitivity and specificity of 82% and 68%, respectively, for the possible criteria. CONCLUSIONS AND RELEVANCE Our data suggest that a reliable diagnosis of CAA-ri can be reached from basic clinical and magnetic resonance imaging information alone, with good sensitivity and excellent specificity.