Etiological Classification of Stroke in Patients with Chagas Disease Using TOAST, Causative Classification System TOAST, and ASCOD Phenotyping

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Etiological Classification of Stroke in Patients with Chagas Disease Using TOAST, Causative Classification System TOAST, and ASCOD Phenotyping Rodrigo de Paiva Bezerra, MD, MsC, Maramélia Araújo de Miranda Alves, MD, Msc, Adriana Bastos Conforto, MD, PhD, Daniela Laranja Gomes Rodrigues, MD, and Gisele Sampaio Silva, MD, MPH PhD

Background: Cardioembolism is considered a major pathophysiological mechanism in patients with ischemic stroke (IS) and Chagas disease (CD). However, a previous study reported that other stroke subtypes are present in more than 40% of CD patients according to the TOAST classification. Therefore, the aim of our study was to evaluate the etiologic classification of stroke in patients with CD using the Causative Classification System (CCS), the ASCOD, and the TOAST classifications in a prospective cohort of patients. Methods: Patients evaluated in our outpatient clinic from 2012 to 2015 with IS and CD were included and underwent full investigation for stroke etiology. TOAST, CCS TOAST, and the ASCOD classifications were compared. Findings: We Included 32 patients (18 men; mean age 62.7 +/−10.1 years). A total of 93.8% had at least 1 vascular risk factor; the most frequent was hypertension (87.5%). According to TOAST, we defined 87.5% as having cardioembolic stroke, being 9.4% as large-artery atherosclerotic (LAA) and 3.1% as undetermined cause. Using the CCS TOAST, 62.5% were classified as cardioaortic embolism evident and 15.6% as possible, 6.3% as small artery occlusion evident and 3.1% as probable, and 12.5% as LAA evident. When ASCOD phenotyping was applied, atherosclerosis was present in 50.1% of patients (A1 = 6.3%, A3 = 43.8%), cardiac pathology in 84.4% (C1 = 62.5%, C2 = 15.6%, C3 = 6.3%), and small-vessel disease in 66% (S1 = 9.4%, S2 = 3.1%, S3 = 3.1%). Findings: In conclusion, the use of the CCS and the ASCOD phenotyping in patients with CD confirmed a high frequency of cardioembolic IS but also showed that other etiologies are prevalent, such as large-artery atherosclerosis and small-vessel occlusion. Key Words: Ischemic—stroke—Chagas—embolism. © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Introduction From the Department of Neurology and Neurosurgery, Universidade Federal de São Paulo, São Paulo, Brazil. Received February 21, 2017; revision received July 4, 2017; accepted July 10, 2017. Address corresponding to Rodrigo de Paiva Bezerra, MD, MsC, Neurology Department, UNIFESP - Federal University of São Paulo, Rua Pedro de Toledo 650, Vila Clementino, 04039-002 São Paulo, Brazil. E-mail: [email protected]. 1052-3057/$ - see front matter © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2017.07.007

Ischemic stroke (IS) is a common complication of Chagas disease (CD) chronic cardiomyopathy (CCC) with a lifetime risk of 15%-64.5%.1 Despite a significant decrease in cases of CD, there is still a large population of adults coming from endemic areas that are at risk of chronic disease.2 The World Health Organization estimated 6-7 million infected individuals worldwide in 2015.3 Cardioembolism is considered a major pathophysiological mechanism in patients with IS and CCC, mainly related to the presence of apical aneurysms, heart failure,

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and arrhythmias. However, other mechanisms of IS could potentially be involved in patients with CD. For example, CD is known to affect the microvascular function in the heart through microvascular spasm, reduced myocardium blood flow, increased platelet aggregation, inflammation, and myocardial fibrosis.5,6 Therefore, it is possible that small vessels in the brain will be involved in the pathophysiology of stroke in patients with CD.7 Actually an inflammatory imbalance (strong inflammatory response dominated by Th1 patterns) seems to be associated with an increased stroke risk in patients with chronic CD.8 Additionally, patients with CCC often present with other cardiovascular risk factors that may overlap with the cardiomyopathy and be related to the etiology of IS.9 In order to better characterize the etiology of stroke in patients with CD, a previous study using the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification system10 showed that subtypes of stroke other than cardioembolism (large artery, small-vessel disease, and undetermined cause) are present in more than 40% of patients with CD, with a high frequency of stroke of undetermined etiology.11 The TOAST system, however, identifies a single mechanism for IS, ignoring the possible interactions that can occur between 2 or more mechanisms. Indeed, IS can often be the final result of multiple abnormalities, and treatment decisions require a more comprehensive assessment, such as that provided by the Causative Classification System (CCS).12 This system is an automated version of Stop-Stroke Study TOAST Classification (SSS-TOAST) TOAST, which was shown to have a high reliability and the ability to identify the etiology of IS.13 The CCS can be accessed using a web-based questionnaire system (http://ccs.martinos.org or http://ccs.mgh.harvard.edu). The CCS allows for a fast analysis with great confidence, with a potential utility of improving the accuracy of the etiologic classification of IS in multicenter studies or databases where the classification of IS subtype is essential. A multicenter evaluation corroborated and ensured the accuracy of communication between different researchers and institutions.14 A previous retrospective study evaluated the etiology of stroke in patients with IS and CD using the TOAST and SSS/ CCS TOAST classification criteria and found that SSS/ CCS TOAST was superior to the classic TOAST criteria in identifying a cardioembolic etiology.15 However, retrospective TOAST subtyping based solely on medical records review has only moderate interrater reliability.16 The ASCOD phenotyping (A: atherosclerosis; S: smallvessel disease; C: cardiac pathology; O: other causes; D dissection) is another very useful classification for patients with IS.17 In contrast to other classifications that lump IS in rigid groups, ASCOD grades all conditions present, describes the overlap between the diseases, and weights the potentially causal relationship between the condition detected and the IS.

Therefore, the aim of our study was to evaluate the etiologic classification of stroke in patients with CD using the CCS, ASCOD, and TOAST classifications in a prospective cohort of patients.

Methods All patients consecutively evaluated in the outpatient stroke clinic of the Federal University of São Paulo from June 2012 to March 2015 with the clinical diagnosis of IS and a positive Chagas serology (on both immunofluorescent antibody assay and enzyme-linked immunosorbent assay tests) were included in this prospective study. Data were collected on vascular risk factors, location of brain lesion, electrocardiography (ECG), and transthoracic echocardiography findings. All patients underwent a diagnostic protocol for stroke, including head computerized tomography (CT) and either carotid Doppler, CT angiography, or magnetic resonance angiography (MRA). Some patients underwent brain magnetic resonance imaging (MRI) and Holter monitoring at the discretion of the treating physician. All neuroimaging data were reviewed using the Synapse Picture Archiving and Communication System. Patients were classified according to the location of their IS according to the Oxfordshire classification.18 Stroke severity was measured using the National Institutes of Health Scale score19 and functional outcome, with the modified Rankin Scale20 at the time of the outpatient visit. The diagnosis of IS was obtained through clinical history, neurological examination, and neuroimaging (CT or MRI). The etiologic classification using the TOAST criteria was carried out using data from the clinical interview and exams available through electronic medical records. The etiologic classification using the CCS algorithm and the ASCOD phenotyping were performed by a different neurologist. For the CCS, a web-based system was used: https:// ccs.mgh.harvard.edu/ccs_title.php. The investigator underwent the web-based training on how to perform the CCS and completed a certification module available at the CCS website. The ASCOD classification categorized 5 predefined phenotypes: atherosclerosis (A), small-vessel disease (S), cardiac pathology (C), other causes (O), and dissection (D). Each of the five phenotypes was graded according to following categories: 1 when the disease was a potential cause of the index stroke, 2 when causality was uncertain, 3 when the disease was present but was unlikely a direct cause, 0 when the disease was absent, and 9 when the workup was insufficient to rule out the disease. The study received institutional review board approval. All participants gave written informed consent.

Statistical Analysis Means and standard deviations or medians and interquartile intervals were used to describe patients’ char-

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acteristics. The t-test for independent samples or the Mann– Whitney test was used to compare continuous variables (patients with cardioembolic IS versus patients with other etiologies). Categorical variables were compared using the chi-square or Fisher’s exact tests. We considered statistically significant P values less than .05. All analyses were performed using the SPSS 17, Inc. (Chicago, IL).

Results During the study period, 32 patients (18 men; mean age 62.7 +/−10.1 years) with a diagnosis of IS and CD were evaluated in our outpatient clinic. Thirty-one patients were Brazilian and 1 was Bolivian. Most patients were originally from the northeast region of the country (59.5%), followed by the southeast (34.4%; Fig 1). Patients were mostly white (34.4%) or mixed race (34.4%). They had a low educational level (median years of schooling was 3.50 [interquartile range 0-4.0]), with 34% of them being completely illiterate. The median monthly familiar income was US$ 258.19 (interquartile range 258.19526.38). A total of 84% of patients recalled contact with the CD vector (Table 1). Most patients (93.8%) had at least 1 defined vascular risk factor, with the most frequent being hypertension (87.5%) followed by hyperlipidemia (59.4%) and smoking (43.7%). A history of stroke or Transient Ischemic Attack (TIA) before the incident event was identified in 56.2% of our patients. Heart failure was present in 65.6%, alcohol consumption in 43.7%, diabetes in 21.9%, and coronary artery disease in 15.6% (Table 1). CCC was present in 62.5% of our patients, indeterminate CD in 31.25%, and chronic CD mixed form (affecting the heart and digestive system) in 6.25%. Table 2 de-

Figure 1. State of origin of the patients evaluated. Abbreviations: AL, Alagoas; BA, Bahia; MG: Minas Gerais; PA, Paraná; PB, Paraíba; PE, Pernambuco; SP, São Paulo. One patient was from Bolívia.

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Table 1. Patient characteristics (N = 32) Characteristic Age (years) Males Race White Mixed race Black Contact with the vector Mean years of schooling (years) Mean monthly familiar income (US$) Previous stroke or TIA Heart failure Diabetes Coronary artery disease mRs 0-2

62.7 + /−10.1 56.2% 34.4% 34.4% 28.1% 84.4% 3.34 ± 3.34 392 ± 301 56.2% 65.6% 21.9% 15.6% 43.7%

Abbreviations: mRs, modified Rankin scale; TIA, Transient Ischemic Attack.

scribes the ECG, Holter monitoring, and echocardiographic findings of our patients. Three patients evaluated with a 24-hour Holter who had a normal sinus rhythm on ECG were found to have atrial fibrillation (AF). The mean left ventricle ejection fraction was 49.84 ± 16.10%. A total of 6.25% of the patients had an intracavitary thrombus, and

Table 2.

Electrocardiographic and echocardiographic findings ECG (N = 28)

Sinus rhythm Pacemaker Atrial fibrillation RBBB LBBB Holter 24 h (N = 18) Sinus rhythm Sinus with ectopic atrial beats Permanent AF Paroxysmal AF Atrial flutter Pacemaker RBBB LBBB AV blocks Echocardiogram (N = 32) Mean LV ejection fraction Left atrium size (mm) Wall motion abnormalities Intracavitary thrombus Apical aneurysm

60.8% 21.4% 17.8% 32.1% 21.9% 66.8% 5.5% 11.2% 5.5% 5.5% 5.5% 66.7% 50% 16.7% 49.8 ± 16.1% 43.5 ± 5.7 59.4% 6.25% 9.4%

Abbreviations: AF, atrial fibrillation; AV, Atrioventricular; ECG, electrocardiography; LBBB, left bundle branch block; LV, left ventricle; RBBB, right bundle branch block.

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9.4% had an apical aneurysm. Wall motion abnormalities were seen in 59.4% of the patients (Table 2). Thirty-one patients were evaluated with neck vessel imaging using either carotid ultrasound, CT angiography, MRA, or digital angiography. Patients who underwent CT angiography or MRA also had intracranial vessel imaging. Significant large-vessel stenosis was seen in 12.9% of the patients using either method. One patient (3.1%) had a carotid stenosis, and 3 patients (9.4%) had an intracranial large-vessel stenosis, all in the corresponding stroke topography. Two patients evaluated with digital angiography were found to have asymptomatic intracranial aneurysms, one 10-mm wide in the right internal carotid artery and the other 8-mm wide at the top of the basilar artery. The most frequent clinical topography was a partial anterior circulation infarct (46.8%), followed by total anterior circulation, posterior circulation (18.8% each), and lacunar syndromes (15.6%). According to the TOAST criteria, stroke etiology was cardioembolism in 87.5% of patients, large-artery atherosclerosis in 9.4%, and stroke of undetermined cause in 3.1%. Among patients classified as having cardioembolic stroke, 85.7% were defined as probable and 14.7% as possible. Using the SSS TOAST classification (CCS TOAST algorithm), 62.5% of the patients were classified as evident and 15.6% as possible cardioaortic embolism, 6.3% were classified as evident and 3.1% as probable small-artery occlusion, and 12.5% as large-artery atherosclerotic (LAA) evident. When ASCOD phenotyping was applied, A was present in 50.1% of patients (A1 = 6.3%, A3 = 43.8%), C in 84.4% (C1 = 62.5%, C2 = 15.6%, C3 = 6.3%), and S in 15.6% (S1 = 9.4%, S2 = 3.1%, S3 = 3.1%). Dissections and other etiologies were not present in any of our patients. On the basis of grades 1 and 2, 6.3% of patients had multiple underlying diseases, and 40.6% when all 3 grades (A, S and C: 3 patients, A and C: 9 patients, S and C: 1 patient) were considered. The main overlap was found between A and C (Table 3). At the time of the clinical evaluation (median 20 [6.565.5] months from the index stroke), most patients had a modified Rankin Scale of 3 or more (56.3%). Most patients were treated with oral anticoagulation with warfarin (75%), while the remaining patients received antiplatelet therapy.

Discussion A not negligible prevalence of noncardioembolic stroke was detected in patients with CD using the TOAST classification, the automated CCS, and the ASCOD phenotyping. One of the great advantages of the CCS algorithm is allowing the concurrent classification defined in patients with 2 high-risk sources (eg, patients with AF and carotid stenosis), while the TOAST would classify

Table 3. TOAST, CCS TOAST, and ASCOD classifications (frequency of subtypes) TOAST (N = 32)

%

Large-artery atherosclerosis Cardioembolism Undetermined CCS TOAST (N = 32) Large-artery atherosclerosis Cardioembolism evident Cardioembolism possible Small-vessel occlusion evident Small-vessel occlusion probable ASCOD phenotyping (N = 32) A (atherosclerosis)

9.4 87.5 3.1 % 12.5 62.5 15.6 6.3 3.1

S (small vessel) C (cardiac sources) O (other causes) D (dissections)

0: 46.9%; 1: 6.3%; 2: 0%; 3: 43.8%; 9: 3.1% 0: 84.4%; 1: 9.4%, 2: 3.1%; 3: 3.1%; 9: 0% 0: 15.6%; 1: 62.5%, 2: 15.6%; 3: 6.3%; 9: 0% 0: 100% 0: 100%

Abbreviations: CCS, Causative Classification System; TOAST, Trial of ORG 10172 in Acute Stroke Treatment.

patients with 2 possible etiologies as undetermined. For example, our patient classified as undetermined by the TOAST classification had an apical aneurysm and an intracranial arterial stenosis > 50% within the ischemic injury territory. The patient was classified as LAA evident by the CCS. The classification of the patient as undetermined might give a false idea of a low risk of recurrence. The ASCOD phenotyping, on the other hand, captured and weighted the overlap between diseases underlying IS in patients with CD. Present in 50.1% of cases, atherosclerotic disease was prevalent and considered potentially causal (A1) in 6.3% of patients. Small-vessel disease was present in 15.5% of cases and considered potentially causal (S1) in 9.4% of patients. The importance of a precise classification as LAA, A1, or S1 also includes the use of therapies such as high-power statins and possibly dual antiplatelet therapy within 3 months after the index event based on results of Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS)21 and Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE)22 trials. Another possible beneficial aspect of a more precise classification of etiology in patients with CD is avoiding unnecessary long-term anticoagulation. The 3 patients classified as IS of small-vessel etiology by the CCS TOAST were classified as possibly cardioembolic by the TOAST. The CCS is more inclusive in the neuroimaging characteristics, classifying lacunar lesions as less than 20 mm in diameter, while the TOAST includes only lesions with less than 15 mm. The CCS,

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unlike the TOAST classification, also takes into account a well-defined risk limit to separate high and low sources of cardioembolism as well as the clinical presentation.23 The prevalence of cardiovascular risk factors was high in our series, with 93.8% of the patients having at least 1 risk factor. Hypertension was the most common risk factor, similar to other series of IS and CD.24,25 The frequency of vascular risk factors, however, did not differ between patients with cardioembolic and those without cardioembolic stroke in our patients, suggesting that only the identification of risk factors is not sufficient to define the atherosclerotic etiology in patients with CD. This finding highlights the importance of a complete etiologic investigation. The retrospective study that evaluated stroke etiology in patients with IS and CD using the TOAST and SSS/CCS TOAST classification criteria also found fewer patients with an undetermined etiology using the SSS TOAST classification when compared with the TOAST. However, the frequency of undetermined stroke was higher in the retrospective series than in our study (34% versus 0%). This difference could be explained by a higher frequency of intracranial vessel evaluation in our study (54% versus 27%), as well as of Holter monitoring (58% versus 38%).15 We found a considerable frequency of arrhythmias with high embolic potential such as AF and atrial flutter using ECG and 24-hour Holter monitoring. In a cohort study that evaluated the ECG findings in patients with CCC, the main findings were heart rhythm changes (AF and atrial flutter), as well as the supraventricular and ventricular premature beats, right bundle branch block associated with left anterior fascicular block, and left bundle branch block.26 The proper treatment of patients with CD and such arrhythmias needs to be better assessed. For example, the use of the new oral anticoagulants in this group of patients could be an interesting alternative due to the safety profile of the new medications, in addition to fewer drug interactions. Another question that is still unclear is the role of prolonged monitoring of heart rate and rhythm in patients with CD. It is possible that a more prolonged monitoring might be able to detect further arrhythmias as in other patients with embolic strokes of undetermined causes. Proinflammatory and thrombotic states with uncontrolled inflammation caused by T. cruzi might also influence the mechanisms that lead to stroke in patients with chronic CD.8 Our study has some limitations. First, we have a small sample size, which limited our statistical power to evaluate the agreement between the classification systems studied. However, this is the first prospective series to use an etiological system and a phenotypic classification in the evaluation of these patients with stroke and CD, and generates hypotheses for further studies. Second, the patients were evaluated in the outpatient clinic setting, not in the acute phase. This might have caused the loss of some clinical information (recall bias). However, the

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ancillary tests used for etiologic classification were the ones of the acute phase available through an electronic medical record, which minimizes data loss, at least for complementary tests. Finally, not all patients were evaluated with MRI, which might have limited the identification of small-vessel lesions. In conclusion, the use of the CCS and the ASCOD phenotyping in patients with CD confirmed a high frequency of cardioembolic IS but also showed that other etiologies are prevalent, such as large-artery atherosclerosis and small-vessel occlusion. The use of classification systems with structured assessment based on evidence established in the literature as the CCS and ASCOD in patients with CD and IS seems to be important in targeting therapeutic interventions and avoiding unnecessary long-term anticoagulation.

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