Acute brain MRI DWI patterns and stroke recurrence after mild-moderate stroke

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1 J Neurol (2010) 257: DOI /s ORIGINAL COMMUNICATION Acute brain MRI DWI patterns and stroke recurrence after mild-moderate stroke Jaume Roquer A. Rodríguez-Campello E. Cuadrado-Godia R. M. Vivanco-Hidalgo J. Jiménez-Conde X. Perich A. Ois Received: 20 April 2009 / Revised: 3 December 2009 / Accepted: 21 December 2009 / Published online: 3 January 2010 Ó Springer-Verlag 2010 Abstract Brain ischemic lesions identified by diffusionweighted imaging (DWI) have been shown to predict high risk of early future ischemic events in patients with transient ischemic attacks and minor stroke. The aim of this study is to analyze different brain MRI DWI patterns in patients with mild-moderate stroke to define acute patterns related with a higher risk of stroke recurrence in long-term follow-up (from 6 to 36 months). Retrospective review of case series from a prospective stroke record including 253 patients with mild-moderate stroke (NIHSS from 1 to 7) and acute MRI DWI lesions. MRI DWI lesions were analyzed to determine clinically relevant lesions, based on the number, location, age and affected arterial territories. We defined three patterns: (1) multiple versus single lesions; (2) single deep versus single cortical lesions; and (3) single lesions versus multiple lesions affecting different arterial territories and/or of different age. The impact of these patterns on recurrence was analyzed by Cox regression analysis. 38 patients (15.0%) suffered a recurrence. Univariate analysis showed the risk of recurrence for each pattern. Pattern 1: patients with multiple lesions had greater risk of recurrence than those with single lesions (28.2 vs. J. Roquer A. Rodríguez-Campello E. Cuadrado-Godia R. M. Vivanco-Hidalgo J. Jiménez-Conde A. Ois NeuroMar Research Group, Stroke Unit, Department of Neurology, Hospital del Mar-IMIM, Barcelona, Spain X. Perich Radiodiagnostic Department, CRC-Mar, Barcelona, Spain J. Roquer (&) Servei de Neurologia, Hospital del Mar, Passeig Maritim 25-29, Barcelona, Spain jroquer@hospitaldelmar.cat 9.9%; OR: 3.75 (95% CI: ), p \ ). Pattern 2: patients with single cortical lesions had higher risk than those with deep lesions (14.3 vs. 6.7% OR: 2.33 (95% CI: ), p \ 0.089). Pattern 3: patients with multiple DWI in different territories or different age had the highest recurrence rate (30.6%), OR: 4.01 (95% CI: ), p \ 0.001, compared to patients with single lesions. Cox regression analysis adjusted by possible confounders, showed that for pattern 1 the OR for recurrence was 2.49 (95% CI: ), p = 0.008; for pattern 2, OR:1.99 (95% CI: ), p = 0.17; for pattern 3, OR: 2.85 (95% CI: ), p = Brain MRI DWI patterns assessed in the acute phase of mild-moderate stroke are useful to identify those patients at high risk of recurrence. Keywords Acute stroke Brain ischemic lesions Diffusion-weighted image Introduction Brain ischemic lesions identified by diffusion-weighted imaging (DWI) have been shown to predict high risk of early future ischemic events in patients with transient ischemic attacks (TIA) and minor stroke [4, 11, 12, 14]. Recently, it has been shown that having multiple DWI lesions of varying ages suggests very active early recurrence over time and portends a higher early risk of future ischemic events [15]. However, the recurrence indicator in the reported study was the presence of new brain DWI lesions, independent of clinical relevance. Other factors, such as the detection of severe symptomatic extra or intracranial arterial disease (SSAD), improve the identification of patients with a higher risk of 90-day recurrence after an initial minor stroke or TIA [10].

2 948 J Neurol (2010) 257: The aim of our study is to evaluate various brain MRI DWI patterns assessed in the acute phase of mild-moderate stroke to determine their independent relationship with new clinical cerebrovascular events during long-term follow-up. Methods Patients were included in this study as part of an ongoing prospective single-center study of subjects with stroke admitted to hospital (BASICMAR register). From June 2005 to June 2008, 788 consecutive patients with acute ischemic stroke (IS) were admitted with a diagnosis of stroke based on the World Health Organization definition [2]. We included in this study those patients who fulfilled the following criteria: (1) Admission to hospital from 1 to 24 h after stroke; (2) Clinical and neurological assessment performed by a stroke-trained neurologist; (3) MRI performed from 1 to 72 h after stroke; (4) Presence of at least one acute brain DWI lesion; (5) Previous good functional status (modified Rankin scale 0 or 1); (6) Mild-moderate stroke (NIHSS [5] from 1 to 7) diagnosis at discharge; (7) Follow-up data at least 6 months after acute stroke; and (8) Signed informed consent. The research was approved by the local institutional ethics committee. A total of 253 patients fulfilled the study inclusion criteria. All included patients fulfilled the BASICMAR protocol [9] (BASICMAR is a stroke register designed as a tool, to study epidemiological data of stroke in a hospitalbased population, of a single centre in Barcelona, that attends a population of approximately 300,000 in-habitants) for demographic data and the presence (at admission, thorough physician diagnosis, or as demonstrated by medical treatment) of the following vascular risk factors: arterial hypertension (evidence of at least two blood pressure measurements [140/90 mmhg recorded on different days before stroke onset); diabetes (fasting serum glucose level C7.0 mmol/l); hyperlipidemia (serum cholesterol levels [220 mg/dl or triglyceride levels [200 mg/dl); atrial fibrillation (AF), confirmed by an electrocardiogram performed during admission or previously; previous history of angina pectoris or myocardial infarction; peripheral arterial disease (intermittent claudication or a resting anklebrachial index \0.90 in any leg); previous TIA during the 2 weeks before stroke index, and current smoking. Stroke severity was assessed by the NIHSS performed at admission. Patients were classified according to the TOAST (Trial of Org in Acute Stroke Treatment) criteria [1]. All patients had a complete medical exploration, blood test, chest radiography, ECG, and head scan (CT) at admission. Patients were admitted to our stroke unit during at least the first 24 h after stroke, where we performed a monitoring of neurological status, a continuous cardiac monitoring, and a strict control of blood pressure, temperature, and serum glucose levels. Intra- and extracranial Doppler studies of the supra-aortic arteries (Multi-Dop-Portable Doppler System-DWL) were performed in all patients by a trained neurologist in ultrasonographic techniques. SSAD was defined by the detection of ipsilateral carotid stenosis C70% or symptomatic intracranial stenosis C50%, following previous described criteria [10]. Treatment was decided in each case by a neurologist experienced in neurovascular diseases following international consensus. In all cases we started antiplatelet therapy in the acute phase with the exception of those patients with cardioembolic strokes, and in some selected patients with severe arterial disease (patients already pretreated with antiplatelet, crescendo TIA, or progressive stroke after antiplatelet treatment) in whom anticoagulation was initiated. MRI study: imaging was performed from 1 to 72 h after stroke using a 1.5 T scanner (Signa Echo Speed, General Electric), equipped with high-performance gradients (33 mt and slow rate of 120 T/m/s) MRI sequences such as DWI, apparent diffusion coefficient (ADC), and fluidattenuated inversion recovery (FLAIR) provide useful information on the time course of the stroke evolution. We estimated the age of the lesions by studying their characteristics on these MR sequences, following the methodology previously described [8]. MRI interpretations were done jointly by two investigators (AO and XP) blinded to the clinical data, with a third investigator s opinion in cases of disagreement. For each patient, the three MR sequences (DWI, ADC, and FLAIR) were examined. All included patients had at least one acute brain DWI lesion of vascular origin. Acute ischemic lesions were grouped according to the following radiological data: number of DWI lesions (single/multiple, with multiple acute ischemic lesions defined as multiple non-contiguous hyperintense lesions on DWI); location (cortical/deep); lesion age (same/different, estimated from DWI and ADC sequence data; lesions on MRI at ADC remain low for about 1 week, are pseudonormal for another week, and then become supranormal); and affected arterial territories (single/multiple). Using these data, we defined three MRI DWI patterns: (1) multiple versus single DWI lesions; (2) single deep versus single cortical DWI lesions; and (3) single lesions versus multiple DWI lesions affecting different arterial territories and/or of different age (Fig. 1). The primary end-point of the study was clinical stroke recurrence at least 72 h after stroke and during a follow-up from 6 to 36 months (mean of 18.5 months): 27 patients were followed 36 months, 26 patients 30 months, 67 patients 24 months, 14 patients 18 months, 72 patients 12 months, and 47 patients from 6 to 11 months. Followup data were obtained by direct patient visit or by telephone interview if patients failed to attend the visit. All but

3 J Neurol (2010) 257: a b c d Pattern 1 Pattern 2 e f g(*) h i Pattern 3 Fig. 1 Examples of the three different DWI patterns analyzed. DWI pattern 1: Multiple (a) versus single lesions (b). DWI pattern 2: Single deep (c) versus single cortical lesions (d). DWI pattern 3: Single lesion (e) versus multiple lesions of different age (f and g) and/or affecting different arterial territories (h and i). (*) G image corresponds to an ADC sequence. Arrow shows a lesion of different age (it is hyperintense in DWI and pseudo normal in ADC, whereas the other hyperintense DWI lesions are low in ADC) three patients with stroke recurrence were attended in our hospital from onset (clinical data was provided for 1 patient by the attending hospital; 2 patients were sent to our hospital from other centers). Statistical analysis The t test was used to evaluate differences in continuous variables and the chi-square test for those in proportions. First, a univariate analysis analyzed the patients demographic profile, risk factors, and clinical differences with respect to stroke recurrence. To estimate odds ratios (OR) and the resulting 95% confidence intervals (CI) of MRI DWI patterns and stroke recurrence, variables that reached p B 0.10 in the univariate analysis were included in a Cox regression model. The variables were cross tabulated to assess for multicollinearity, and TOAST subtype variable was removed from the model because colinearity between large artery disease and SSAD. Ethics The study information was collected from the BASICMAR protocol, which fulfilled the local ethical guidelines. All patients included in the protocol signed an informed consent. Results A total of 253 patients, 152 men and 101 women, mean age of 70.2 years (SD 11.8), were included in the study; 38 (15.0%) patients suffered a recurrence during a mean follow-up of 18.5 months (6 36 months). Timing of recurrences is as follows: 12 cases in the 1st month, 7 cases in the 2nd month, 7 cases in the 3rd month, 5 cases in the 4th month, 2 cases in the 5th month, 1 case in the 6th month, 2 cases from the 7th to the 12th months, and 2 from the 13th to the 36th months. Demographic data, vascular risk factors, stroke characteristics, and classification (presence or absence of recurrences) are shown in Table 1. Among the 78 patients with severe symptomatic stenosis, 24 were treated by endarterectomy (22) or stenting (2). The remaining 54 cases were not treated due to the following reasons: 20 cases were posterior territory stenosis, 12 were MCA intracranial stenosis, 11 were extracranial complete occlusions, 9 were very older patients or patients with severe concomitant illness, and finally 2 patients refused surgical treatment. A total of 182 patients (71.9%) had a single DWI lesion; 77 (42.3%) of these were cortical and 105 were deep. Of the 71 patients (28.1%) with multiple DWI lesions, the lesions were the same age in 47 (66.2%) cases and had

4 950 J Neurol (2010) 257: Table 1 Demographic, clinical data and stroke subtypes in relation to the presence of recurrences during the follow-up Total cases (n = 253) Recurrence (n = 38) No recurrence (n = 215) p value (OR 95% CI) Mean age (SD, years) 70.1 (11.9) 69.6 (12.5) 70.2 (11.7) 0.75 Men (%) 152 (61.3) 19 (12.5) 133 (87.5) ( ) Women (%) 101 (38.7) 19 (18.8) 82 (81.2) Arterial hypertension (%) 174 (68.8) 24 (63.2) 150 (69.8) ( ) Diabetes mellitus (%) 82 (32.4) 12 (31.6) 70 (32.6) ( ) Atrial fibrillation (%) 43 (17.0) 5 (13.2) 38 (17.7) ( ) Ischemic heart disease (%) 28 (11.1) 6 (15.8) 22 (10.2) ( ) Peripheral arterial disease (%) 40 (15.8) 6 (15.8) 34 (15.8) ( ) Previous TIA 31 (12.3) 9 (23.7) 23 (10.2) 0.02* 2.72 ( ) Hyperlipidemia (%) 128 (50.6) 15 (39.5) 113 (52.6) ( ) NIHSS (median, q1 q3) 3 (2 5) 3 (2 5) 3 (2 5) 0.69 SSAD 78 (30.8) 20 (52.6) 58 (27.0) 0.002* 3.01 ( ) Glycemia (SD) (mmol/l) (57.8) (66.1) (56.0) 0.10* TOAST subtype Large arterial (%) 72 (28.5) 20 (27.7) 52 (72.3) Lacunar (%) 75 (29.6) 4 (5.3) 71 (94.7) Cardioembolism (%) 56 (22.1) 6 (10.7) 50 (89.3) Undetermined (%) 50 (19.8) 8 (16.0) 42 (84.0) OR odds ratio for recurrence, SSAD severe symptomatic extra or intracranial arterial disease * Variables included in the multivariate analysis. TOAST subtype was not included due to colinearity with SSAD different ages in 24 cases. In 52 (73.2%) cases the multiple DWI lesions were located in the same arterial territory, and in 19 cases were in different arterial territories. In 35 (49.3%) patients, the multiple lesions had the same age and were in the same arterial territory and in 36 (50.7%) the lesions differed in age and/or affected different vascular territories. The distribution of DWI lesions in atherothrombotic patients was as follows: a total of 41 patients (53.2%) had a single lesion (22 cortical and 19 deep), whereas multiple lesions were seen in 36 cases (46.8%), in 20 of them were in a unique arterial territory and had the same age (55.6%) and in 16 cases the DWI lesions were in different arterial territories or had different age. The distribution of single lesions was slightly different that those seen in cardioembolic strokes (single lesions were more frequent in cortical distribution in atherothrombotic stroke than in cardioembolic ones), and lacunar strokes (all lesions were deep). Table 2 summarizes the MRI DWI data and its relationship with recurrences. Table 3 summarizes the relationship between the three MRI DWI patterns and recurrences. The results of Cox regression analysis for each DWI pattern adjusted by confounders (previous TIA, glycemia at admission and SSAD) were: For pattern 1: DWI-pattern: OR 2.49 (95% CI: ), p = 0.008; SSAD: OR 2.02 (95% CI: ), p = 0.040; Previous TIA: OR 1.56 (95% CI: ), p = 0.268; Glycemia at admission: OR (95% CI: ), p = For pattern 2: DWI pattern: OR 1.99 (95% CI: ), p = 0.173; SSAD: OR 2.31 (95% CI: ), p = Previous TIA: OR 1.67 (95% CI: ), p = 0.432; Glycemia at admission: OR (95% CI: ), p = 0.622; For pattern 3: DWI pattern: OR 2.85 (95% CI: ), p = 0.008; SSAD: OR 2.02 (95% CI: ), p = 0.069; Previous TIA: OR 1.88 (95% CI: ), p = 0.19; Glycemia at admission: OR (95% CI: ), p = Figure 2 graphically represents the adjusted survival curves for each MRI DWI pattern. Discussion We know that patients with TIA [11, 14] or minor stroke [4] associated with acute MRI DWI lesions have a greater rate of early recurrent TIA and stroke than patients with normal DWI results. It also has been reported that patients with TIA [3, 7, 16] or minor stroke [3] with multiple DWI lesions are at higher risk of early recurrence. Moreover, a recent study emphasized the importance of DWI lesions of varying age based on ADC values [15] as a marker of early stroke recurrences, although the study used only radiological criteria to identify recurrences. On the other hand, the predictive value of DWI lesions for late recurrences is unknown because the longest reported follow-up was just

5 J Neurol (2010) 257: Table 2 DWI lesions in the acute stroke phase and its relationship with clinical recurrence DWI location and characteristics n (%) a Recurrences (%) Single lesion b 182 (71.9) 18 (9.9) Deep c 105 (41.5) 7 (6.7) Cortical c 77 (30.4) 11 (14.3) Multiple lesion b 71 (28.1) 20 (28.2) Same territory 52 (20.6) 15 (28.8) Different territory 19 (7.5) 5 (26.3) Same age 47 (18.6) 12 (25.5) Different age 24 (9.5) 8 (33.3) Same age/same territory 35 (13.8) 9 (25.7) Same age/different territory d 12 (4.7) 3 (25.0) Different age/same territory d 17 (6.7) 6 (35.2) Different age/different territory d 7 (2.8) 2 (28.6) a Percentages are calculated on the whole series (n = 253) b Subgroups used to analyze pattern 1 c Subgroups used to analyze pattern 2 d Subgroups used to analyze pattern 3 (against single lesion group) 90 days [6]. The detection of SSAD by dupplex and transcranial Doppler has been reported as other powerful predictor of early recurrences after TIA or minor stroke [10]. The main contributions of our study are three: first, careful description of the DWI lesions in a prospective series of mild-moderate acute ischemic stroke patients; second, the analysis of three distinct DWI patterns as related to clinical stroke recurrence; and third, the analysis of recurrences during a long (6 36 months) follow-up. Data on the distribution of DWI lesions and its relationship with clinical recurrences are shown in Table 2. Most patients (71.9%) had single DWI lesions, with a slightly greater proportion (57.7%) affecting deep areas. Among patients with multiple DWI lesions, 52 (73.2%) had scattered lesions placed in the same arterial territory and 47 (66.2%) had multiple lesions of the same age, based on ADC values. Among the four possible combinations of multiple DWI lesions, the most frequent was the presence of lesions of the same age in the same arterial territory (35 cases, 49.3%), followed by lesions of varying age affecting the same arterial territory (17 cases, 23.9%). The univariate study (Table 3) showed that recurrences were more frequent in patients with multiple DWI lesions. Among patients with single lesions, those with a cortical lesion had more recurrences than those with a deep lesion. Finally, recurrences were more frequent in patients with multiple lesions of varying age or affecting different arterial territories, as compared to patients with single lesions. To determine whether any of these three DWI patterns (single lesion, different age, and different location) had an independent effect on stroke recurrence, we performed a multivariate analysis, introducing in the model those variables related with stroke recurrence in the univariate analysis (Table 1). Results of the multivariate analysis confirms previous findings [3, 7, 14] that patients with multiple DWI lesions have an OR [ 2 of stroke recurrence compared to patients with single DWI lesions. Those patients with a single cortical DWI lesion presented a non-significant trend to greater recurrence than for patients with deep DWI lesions. In the univariate analysis, patients with single cortical lesions had higher risk than those with deep lesions (14.3 vs. 6.7% OR: 2.33, p \ 0.089). However when this variable is analyzed in a multivariable model, it lost its significance, probably due to a series size problem. The trend to greater risk can likely be explained by stroke etiology rather than by the lesion location: deep lesions usually are lacunar infarcts whereas cortical lesions are related with atherothrombotic or embolic origin, etiologies with a greater recurrence rate. Finally, patients with multiple DWI lesions of varying age and/or affecting different arterial territories had a high recurrence risk (OR 2.85), and this is independent of the presence of SSAD. Interestingly, the DWI variable was the Table 3 Brain MRI DWI data and patterns, and relationship with clinical recurrence Total cases (n = 253) Recurrence (n = 38) No recurrence (n = 215) p value (OR 95% CI) Pattern 1 Multiple DWI lesions (%) 71 (28.1) 20 (28.2) 51 (71.8) ( ) Single DWI lesion (%) 182 (71.9) 18 (9.9) 164 (90.1) Pattern 2 Single cortical DWI lesion 77 (42.3) 11 (14.3) 66 (85.7) ( ) Single deep DWI lesion 105 (57.7) 7 (6.7) 98 (93.3) Pattern 3 Multiple different age and/or different territory a (30.6) 25 (69.3) ( ) a Compared with patients with single DWI lesion

6 952 J Neurol (2010) 257: of clopidogrel (300 mg) could reduce the incidence of recurrences in such patients. Survival curves (Fig. 2) show that after 6 months there were few differences with regard to DWI data, mainly because recurrences after 6 months were uncommon (only 4 of 38 recurrences happened after 6 months). Our study has some limitations. We excluded patients with early (\72 h) stroke recurrences because MRI studies were performed h after stroke in many cases, and also because the aim of the study was to identify high risk DWI patterns for stroke recurrence after hospital discharge. We included only patients with a mild-moderate stroke because the follow-up of patients with severe stroke is often difficult and also because clinical importance of recurrences is greater in mild stroke patients than in those patients with severe disability. In summary, MRI DWI patterns assessed in the acute stroke phase are useful to identify patients with mildmoderate stroke who are at high risk of recurrence mainly during the first 6 months after stroke. Acknowledgments This study was funded in part by the Ministry of Health, Instituto de Salud Carlos III (Red HERACLES RD06/0009). The authors have reported no con- Conflict of interest statement flicts of interest. References Fig. 2 Cox proportional hazards model: accumulative survival curves according to the three MRI DWI patterns, after controlling for confounders (previous TIA, glycemia at admission and SSAD). OR and p values are showed in Results most powerful predictor of stroke recurrence in two multivariate models. According to the EXPRESS study [13] results, early initiation of aspirin 300 mg and loading dose 1. Adams HP Jr, Bendixen BH, Kappelle LJ et al (1993) Trial of Org in acute stroke treatment. Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial. Stroke 24: Aho K, Harmsen P, Hatano S, Marquardsen J, Smirnov VE, Strasser T (1980) Cerebrovascular disease in the community: results of a WHO collaborative study. Bull World Health Org 58: Coutts SB, Hill MD, Simon JE, Sohn CH, Scott JN, Demchuk AM, for VISION Study Group (2005) Silent ischemia in minor stroke and TIA patients identified on MR imaging. Neurology 65: Coutts SB, Simon JE, Eliasziw M et al (2005) Triaging transient ischemic attack and minor stroke patients using acute magnetic resonance imaging. Ann Neurol 57: Goldstein LB, Samsa GP (1997) Reliability of the National Institutes of Health Stroke Scale: extension to non-neurologists in the context of a clinical trial. Stroke 28: Kang DW, Latour LL, Chalela JA, Dambrosia J, Warach S (2004) Early and late recurrence of ischemic lesion on MRI. Evidence of a prolonged stroke-prone state. Neurology 63: Kang DW, Latour LL, Chalela JA, Dambrosia JA, Warach S (2003) Early ischemic lesion recurrence within a week after acute ischemic stroke. Ann Neurol 54: Lansberg MG, Thijs VN, O Brien MW et al (2001) Evolution of apparent diffusion coefficient, diffusion-weighted, and T2-weighted signal intensity of acute stroke. Am J Neuroradiol 22: Ois A, Cuadrado-Godia E, Jiménez-Conde J et al (2007) Early arterial study in the prediction of mortality after acute ischemic stroke. Stroke 38:

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