Journal of Stroke 2019;21(2):184-189 https://doi.org/10.5853/jos.2018.03601 Original Article Long-Term Stroke Recurrence after Transient Ischemic Attack: Implications of Etiology Angel Ois,a,b,c,d Elisa Cuadrado-Godia,a,b,c,d Eva Giralt-Steinhauer,a,b,c,d Jordi Jimenez-Conde,a,b,c,d Carolina Soriano-Tarraga,a,b,c,d Ana Rodríguez-Campello,a,b,c,d Carla Avellaneda,a,b,c,d Diego Cascales,a Isabel Fernandez-Perez,a Jaume Roquera,b,c,d a Department of Neurology, Hospital del Mar, Barcelona, Spain b Neurovascular Research Group, IMIM (Institut Hospital del Mar d’Investigacions Mèdiques), Barcelona, Spain c Autonomous University of Barcelona, Barcelona, Spain d Department of Experimental and Health Sciences, University Pompeu Fabra, Barcelona, Spain Background and Purpose To analyze long-term stroke recurrence (SR) characteristics after transient Correspondence: Eva Giralt-Steinhauer Department of Neurology, Hospital del ischemic attack (TIA) according to initial etiological classification. Mar, Passeig Marítim 25-29, Barcelona Methods A prospective cohort of 706 TIA patients was followed up in a single tertiary stroke center. 08003, Spain Tel: +34-932483235 Endpoint was SR. Etiologic subgroup was determined according to the evidence-based causative Fax: +34-932483615 classification system. Location of TIA and SR was recorded as right, left, or posterior territory. E-mail: egiralt@imim.es Disability stroke recurrence (DSR) was defined as modified Rankin Scale (mRS) score >1 or a one- Received: December 24, 2018 point increase in those with previous mRS >1 at 3-month follow-up. Revised: January 23, 2019 Results During a follow-up of 3,493 patient-years (mean follow-up of 58.9±35.9 months), total SR Accepted: February 18, 2019 was 125 (17.7%), corresponding to 3.6 recurrences per 100 patient-years. The etiology subgroups with a higher risk of SR were the unclassified (more than one cause) and large-artery atherosclerosis (LAA) categories. Of the SR cases, 88 (70.4%) had the same etiology as the index TIA; again, LAA etiology was the most frequent (83.9%). Notably, cardioaortic embolism was the most frequent cause (62.5%) of SR in the subgroup of 24 patients with undetermined TIA. Overall, SR occurred in the same territory in 74 of 125 patients (59.2%), with significant differences between etiological TIA subgroups (P=0.015). Eighty-two of 125 (65.6%) with SR had DSR, without differences between etiologies (P=0.453). Conclusions SR occurred mainly with the same etiology and location as initial TIA, although undetermined TIA was associated with a high proportion of cardioaortic embolism SR. More than half of the recurrences caused some disability, regardless of etiology. Keywords Stroke; Recurrence; Ischemic attack, transient Introduction after TIA.2-7 It is usually assumed that the etiologic cause of TIA and early recurrence are the same, but in prolonged follow-up Assessing the early risk of stroke recurrence (SR) after transient this may not be the case. Consequently, the relationship of SR ischemic attack (TIA) has been the goal of many studies.1 How- etiology to the initial TIA has not been described. We hypothe- ever, few reports have analyzed data related to long-term SR sized that the etiology of TIA can be related to the cause, loca- Copyright © 2019 Korean Stroke Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 184 http://j-stroke.org pISSN: 2287-6391 • eISSN: 2287-6405 Vol. 21 / No. 2 / May 2019 tion, and prognosis of long-term SR. Our objective was to de- termined causes, unclassified strokes (more than one apparent scribe the long-term SR characteristics (etiology, location, and mechanism), and other (infrequent) causes.13 We applied the outcome) after a TIA and relate them to the etiological data SAD classification when patients with no evidence of athero- recorded at the time of TIA diagnosis. thrombotic or CE cause reported classical lacunar syndrome (pure motor, pure sensitive, and sensitive-motor syndrome in- Methods volving at least two of three specific body parts [face, arm, and leg] and ataxic hemiparesis or dysarthria-clumsy hand syn- A prospective observational registry was designed, including all drome).14 Patients with no evidence of atherothrombotic or CE consecutive patients with first-ever TIA evaluated in our stroke cause who reported cortical symptoms were assigned the “un- unit within the first 24 hours of symptoms onset from January determined” classification. All patients (in both TIA and SR 2005 to June 2016 (n=706). Hospital del Mar is a tertiary events, except when the responsible physician considered a stroke center with an on-call neurologist and a stroke unit, as short time had elapsed between the two) were assessed in the well as capabilities for systemic thrombolysis and neurovascu- same way by a vascular-trained neurologist following our lar interventions. In its catchment area, which comprises the group’s previously described therapeutic and diagnostic work- 330,000 inhabitants of three of the 10 city districts of Barcelo- up.11,12 Briefly, this includes a complete neurological and physi- na, it is the only hospital that can provide urgent etiological cal exploration, blood test, 12-lead electrocardiography, brain studies in patients with TIA.8 According to World Health Orga- computed tomography (CT), and neurovascular imaging (mag- nization criteria, TIA was defined as rapidly developing clinical netic resonance imaging, CT and/or ultrasound that includes symptoms and/or signs of focal loss of cerebral function with the study of supra-aortic trunks and intracranial territory). Af- reversal symptoms within 24 hours (classical criteria9) with no ter hospital admission, all patients had continuous electrocar- apparent cause other than of vascular origin.10 All patients with diography monitoring in the stroke unit for at least 24 hours. alternative non-vascular explanation of symptoms (TIA mimics, When no etiologic cause was determined, echocardiography n=16), those not evaluated in the stroke unit (n=9), and those (transthoracic and/or transesophageal) was performed. Contin- with incomplete data or who declined study inclusion (n=7) uous Holter monitoring (24 hours or 7 to 20 days) or implant- were excluded. Follow-up consisted of a visit with a neurolo- able cardiac device also was performed after hospital dis- gist at 3 months post-TIA and, at the physician’s discretion, a charge, but this information was not used to determine initial clinic appointment and/or telephone contact every 3 to 6 etiology. As part of our work routine, the clinical data associat- months thereafter until study conclusion (December 2017); ed with the TIA are thoroughly explored with patients, rela- 227 patients were censored due to losses to follow-up (n=34, tives, or witnesses. Acute infarction (n=129) was detected by 4.8%) and non-neurological death (n=168, 23.8%). We re- CT, performed in all 706 patients (although images for 27 pa- viewed all patient events, deaths, electronic medical records, tients were not available for analysis), and/or by magnetic res- and hospital admissions records, and consulted the primary onance studies (available for 357 patients [50.6%]). Based on care physician before considering patients lost to follow-up. these data, the location of the symptoms was categorized as This methodology has been detailed in a previous study.11 right, left, or posterior (typical symptoms of vertebrobasilar ar- teries;15 e.g., diplopia, ataxia, isolated vision loss in campime- Data collection and work-up try). Due to the lack of information about isolated dysarthria A structured questionnaire was used to record age, sex, and localization, the present study did not consider this as a TIA. vascular risk factors, defined according to previously reported Following recommendations of appropriate guidelines, 537 pa- criteria: hypertension, diabetes mellitus, hyperlipidemia, cur- tients were treated with antiplatelet (single or double) plus rent smoking habit, and atrial fibrillation.11,12 We also recorded statins, except those that received anticoagulation therapy: the following data: previous TIA, defined as a TIA in the 7 days 163 patients with major CE source, two with other infrequent preceding the index TIA, ABCD21 score and multiple TIA defined causes, and two with multiple TIA despite antiplatelet therapy. as new TIA within 72 hours of admission for index TIA. Based Carotid surgery (n=40) or arterial stenting (n=8, three out of on all available data at hospital discharge (clinical data and internal carotid artery) was performed within 20 days from TIA explorations), we assigned one etiology subgroup for each TIA onset in all patients with clinical criteria except one patient following an evidence-based causative classification system who refused treatment. A strict control of all vascular risk fac- (CSS) for ischemic stroke: large-artery atherosclerosis (LAA), tors, appropriate diet, and physical exercise was recommended small-artery disease (SAD), cardioaortic embolism (CE), unde- in all patients. https://doi.org/10.5853/jos.2018.03601 http://j-stroke.org 185 Ois et al. Stroke Recurrence Etiology after TIA Endpoint Table 1. Baseline characteristics The primary study endpoint was SR, defined as a new neuro- Variable Total (n=706) logical event with symptoms duration ≥24 hours and acute ra- Age (yr) 71.4±13.9 diological lesion (ischemic or hemorrhagic) attributable to Male sex 372 (52.7) symptoms. Secondary outcomes were: disability stroke recur- Hypertension 509 (72.1) rence (DSR), defined as modified Rankin Scale (mRS)16 score >1 Diabetes mellitus 194 (27.5) or a one-point increase in those with previous MRS >1 at Hyperlipidemia 353 (50) 3-month follow-up and localization of SR same/different terri- Current smoking 68 (9.6) tory categorized as right, left, or posterior. Atrial fibrillation 163 (23.1) Previous TIA 139 (19.7) Ethics Multiple TIA* 62 (8.8) The local ethics committee approved the register. We obtained ABCD 2 risk† written informed consent from all participants or a designated Low 203 (28.8) representative, as appropriate. Moderate 384 (54.4) High 119 (16.9) Statistical analysis Values are presented as mean±standard deviation or number (%). Descriptive data are presented as mean±SD and as a number TIA, transient ischemic attack. *Multiple TIA: new TIA within 72 hours of admission for TIA index; †ABCD2 and percentage for categorical variables. Time-data are ex- score, stratified as 0–3 (low risk), 4–5 moderate, >5 high. pressed in months. All comparative analysis are time-depended and were obtained by Kaplan-Meier log rank test. Statistical analyses were performed with the SPSS version 23.0 for Win- SR patients, without significant differences (P=0.453) between dows (IBM Co., Armonk, NY, USA). Statistical analysis was re- etiological categories. Excluding patients lost to follow-up, 57 viewed by Eva Giralt-Steinhauer, Specialization in Statistics patients (46%) with SR died, compared with 136 patients Applied to Health Sciences (Universitat Autònoma de Barcelo- (24.8%) without SR (P<0.001) (Table 3). Regarding localization, na). 74 patients (59.2%) had a SR within the same territory as the index TIA, with significant differences between etiological SR Results subgroups (higher rates in LAA; P=0.010). Temporal description of SR characteristic is detailed in Figure 1. SR onset was signifi- The study sample was 706 patients, with a mean age of cantly later in those patients with SR etiology different from 71.4±13.9 years. Mean follow-up was 58.9±35.9 months (range, the index TIA (35±35.3 months vs. 12.1±22.3 months, P<0.001) 0 to 148; 3,493 patient-years). Demographics and vascular risk but earlier in those with the same affected territory (12±25.8 factors are shown in Table 1. The largest etiological subgroup of months vs. 28.8±29.8. months, P<0.001). index TIA was SAD (29.1%), followed by undetermined cause (26.9%) and CE (21.4%). There were 125 patients with SR Discussion (17.7%; 3.6 recurrences per 100 patient-years) and seven pa- tients (1%) had more than one SR during follow-up. The sub- Few studies have shown the long-term risk of SR after TIA and groups with a higher risk of SR were unclassified etiology results differ depending on study design (population, national (11/24) and LAA (31/126); undetermined and other less frequent registers, hospital registers) and specific objectives.2-7 The SR causes showed lower SR risk. Regarding the SR etiology, 88 of risk in our study was in the low range reported by previous 125 patients (70.4%) had the same etiology as their index TIA, studies and consistent with recent data that show a lower risk with LAA the most frequent category, followed by unclassified of SR in patients who are treated urgently in stroke units and and CE. We found that 37 of 125 patients (29.6%) had a differ- in whom the etiological study is performed immediately.7,17 ent etiology in the SR, mainly in the initially undetermined sub- To our knowledge, this is the first study to analyze the rela- group, in which SR etiology was different in 16 of 24 (66.6%), tionship between the index TIA and long-term SR etiology. of whom 62.5% were CE. Nine patients (7.2%) had hemorrhagic These data provide relevant knowledge for clinical practice in- recurrence, mainly from SAD TIA subgroup (n=4, 44.4%). Other volving these patients. We observed that SR occurs more fre- SR etiologies that differed from the initial TIA etiology were quently in subgroups associated with significant atherosclero- much less frequent (Table 2). A DSR occurred in 82 (65.6%) of sis (LAA and unclassified [more than one major cause]). This 186 http://j-stroke.org https://doi.org/10.5853/jos.2018.03601 Vol. 21 / No. 2 / May 2019 Table 2. Etiological classification of stroke recurrence and relationship with index TIA etiological subgroups TIA etiology Variable SAD Undetermined CE LAA Unclassified Other Total population 199 (29.1) 190 (26.9) 151 (21.4) 126 (17.8) 24 (3.4) 16 (2.3) Stroke recurrence (% each subgroup) 30 (15.1) 24 (12.6) 27 (17.9) 31 (24.6) 11 (45.8) 2 (12.5) Same etiology 21 (70) 8 (33.3) 22 (81.5) 26 (83.9) 9 (81.8) 2 (100) Different etiology SAD - 1 (4.1) - - - - Undetermined 2 (6.6) - - - - - CE 3 (10) 15 (62.5) - - 2 (18.2) - LAA - - - - - - Unclassified - - 2 (7.4) 1 (3.2) - - Other less frequent - - - 2 (6.4) - - Hemorrhagic 4 (13.3) - 3 (11.1) 2 (6.4) - - Values are presented as number (%). TIA, transient ischemic attack; SAD, small-artery disease; CE, cardioaortic embolism; LAA, large-artery atherosclerosis. Table 3. Data about location (same/not same vascular territory) and prognosis (disabling/fatal) of stroke recurrence, related to index transient ischemic attack etiologies Stroke recurrence etiology Variable Total (n=125) SAD (n=30) Undetermined (n= 24) CE (n=27) LAA (n=31) Unclassified (n=11) Other (n=2) P Same location 74 (59.2) 19 (63.3) 9 (37.5) 12 (44.4) 25 (80.6) 8 (72.7) 1 (50) 0.015 Disabling/fatal 82 (65.6) 20 (66.7) 14 (58.3) 18 (66.7) 24 (77.4) 5 (45.5) 1 (50) 0.453 Values are presented as number (%). SAD, small-artery disease; CE, cardioaortic embolism; LAA, large-artery atherosclerosis. 1.0 1.0 1.0 Same etiology (P<0.001) Same territory (P=0.001) Disabling/fatal SR (P=0.812) No No No 0.8 Yes 0.8 Yes 0.8 Yes SR (cumulative survival) SR (cumulative survival) SR (cumulative survival) 0.6 0.6 0.6 0.4 0.4 0.4 0.2 0.2 0.2 0.0 0.0 0.0 0 20 40 60 80 100 120 A 0 20 40 60 80 100 120 B 0 20 40 60 80 100 120 C Follow-up (mo) Follow-up (mo) Follow-up (mo) Figure 1. Temporal description of characteristics of stroke recurrence (SR). (A) According to etiology. (B) According to vascular territory. (C) According to prognosis. relationship between etiological subgroup and the risk of re- and CE subgroups, likely due to the difficulty of resolving the currence has been previously described,12 being LAA the main underlying causes that increase the risk of SR (arterial athero- established predictor of subsequent early stroke.8,18 Our data sclerosis and/or structural heart disease). Nonetheless, we de- show that the majority of SR events have the same etiology as tected a difference in etiology between the index TIA and SR in the index TIA. The proportion is higher in the unclassified, LAA, almost 30% of patients, especially in those with later SR. In https://doi.org/10.5853/jos.2018.03601 http://j-stroke.org 187 Ois et al. Stroke Recurrence Etiology after TIA the undetermined TIA subgroup, most of the SR had CE etiolo- tation of our observation and to establish its usefulness. gy due to AF detection or development of other major CE Strengths of the study were that a long-term cohort of pa- causes over the years. These findings are relevant because pa- tients was directly evaluated by neurologists experienced in tients with undetermined TIA are screened for CE sources19,20 vascular pathology and admitted to the stroke unit with cardi- and treated according to the current recommendations. Al- ac monitoring. The study had several limitations in addition to though a low rate of AF detection in TIAs has been reported,21 those already considered throughout the discussion. We as- our results suggest a subgroup of patients (cortical symptoms sessed a relatively small number of patients and the sample without a major cause) that could benefit more from prolonged was drawn from a hospital cohort; therefore, our results can- cardiac monitoring strategies. The second cause of diverse eti- not be extrapolated to other cohorts. Our cohort had a high ology in the SR was hemorrhagic stroke, which occurred more mean age with relatively high all-cause mortality. All patients frequently in patients with TIA of SAD etiology; these entities received the most appropriate secondary prevention treatments have similar pathophysiological mechanisms.22 The Secondary according to current guidelines but we did not have data on Prevention of Small Subcortical Strokes (SPS3) trial study, one adjustments over the years in response to new pathologies. Fi- of the main studies of patients with SAD, reported higher hem- nally, we used a clinical TIA definition and did not routinely orrhagic risk in these patients and emphasized that control of perform a magnetic resonance imaging study at hospital ad- hypertension is as important as antithrombotic treatment.23 mission, so we cannot analyze the existence of acute lesions The remaining etiological groups with hemorrhagic SR contain on diffusion-weighted imaging. These limitations do not invali- patients with higher risk for hemorrhagic strokes due to more date the conclusions of the study. aggressive antithrombotic treatments, such as CE and LAA eti- ologies. Other etiologies that differed between SR and index Conclusions TIA showed marginal percentages in our study. Our data showed that most events occurred in the same loca- Almost one in five patients had a long-term SR after a first TIA, tion as the initial TIA. This is expected in patients with etiologies and these events were mainly related to atherosclerotic and CE associated with significant atherosclerosis (LAA and unclassi- origins. In most cases, the recurrences had the same etiology fied), although not in patients with CE or SVD etiology. However, as the index TIA; the exception occurred in initial TIA of unde- the neurologist does not usually see the symptoms in patients termined etiology, with recurrences mostly classified as CE with TIA because these have been resolved upon arrival at the strokes. In our study, most patients had a DSR, highlighting the hospital; therefore, we could only categorize them on the affect- importance of secondary prevention. ed side or as vertebral basilar symptoms, with the limitations that this supposed for the interpretation of this finding. Disclosure Regarding stroke outcome, an important percentage of pa- tients had a DSR event and decreased survival. However, to The authors have no financial conflicts of interest. compare our results with similar studies, we must take into ac- count that we used a very restrictive DSR definition (mRS >1). Acknowledgments Our data highlight the importance of secondary prevention in these patients and the need of further analyzing the etiological Supported in part by Spain’s Ministry of Health (Ministerio de mechanisms at the time of SR and determining how they relate Sanidad y Consumo, Instituto de Salud Carlos III FEDER, to the initial etiology of the TIA. New therapeutic strategies, in- RD12/0042/0020 INVICTUS-PLUS). cluding new anticoagulants, treatment with double antiplate- Elaine M. Lilly, PhD, provided English language assistance. lets in the first months after TIA, or new treatments in refrac- tory hyperlipidemia, could reduce this risk in these patients References with SR of the same etiology. It was not unexpected that SR with different etiology from the index TIA occurred later, com- 1. 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