Epilepsy & Behavior 44 (2015) 17–22
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Neuropsychological functioning in children with temporal lobe epilepsy and hippocampal atrophy without mesial temporal sclerosis: A distinct clinical entity? Charlotte S.M. Schmidt a,b,c, Maryse Lassonde a,b, Louise Gagnon a, Catherine H. Sauerwein a,b, Lionel Carmant a, Philippe Major a, Natacha Paquette a,b, Franco Lepore a,b, Anne Gallagher a,b,⁎ a b c
Centre de Recherche du CHU Sainte-Justine, 3175 Chemin de la Côte-Sainte-Catherine, Montréal, QC H3T 1C5, Canada Centre de Recherche en Neuropsychologie et Cognition (CERNEC), Département de Psychologie, Université de Montréal, 90 Avenue Vincent-d'Indy, Montréal, QC H2V 2S9, Canada Department of Neuropsychology, Maastricht University, Universiteitssingel 40, 6229 Maastricht, The Netherlands
a r t i c l e
i n f o
Article history: Received 4 November 2014 Revised 17 December 2014 Accepted 18 December 2014 Available online 16 January 2015 Keywords: Pediatric epilepsy Intelligence Memory Attention Executive functions Hippocampus Neuropsychological assessment Cognition
a b s t r a c t Unilateral hippocampal atrophy (HA) is considered as a precursor of mesial temporal sclerosis (MTS) in some patients with temporal lobe epilepsy. However, in other cases, it has been suggested that HA without MTS may constitute a distinct epileptic entity. Hippocampal atrophy without MTS was deﬁned as HA without T2-weighted hyperintensity, loss of internal architecture, or associated lesion seen on the MRI data. To date, no study has focused on the cognitive pattern of children with epilepsy with HA without MTS. The objectives of the present study were to characterize the cognitive proﬁle of these children and to investigate the presence (or the absence) of material-speciﬁc memory deﬁcits in these young patients, as found in patients with MTS. Toward this end, 16 young patients with epilepsy with either left or right HA without MTS completed a set of neuropsychological tests, assessing overall intelligence, verbal memory and nonverbal memory, and some aspects of attention and executive functions. Results showed normal intellectual functioning without speciﬁc memory deﬁcits in these patients. Furthermore, comparison between patients with left HA and patients with right HA failed to reveal a material-speciﬁc lateralized memory pattern. Instead, attention and executive functions were found to be impaired in most patients. These results suggest that HA may constitute a distinct epileptic entity, and this information may help health-care providers initiate appropriate and timely interventions. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Mesial temporal sclerosis (MTS) is one of the most common neuropathological substrates of temporal lobe epilepsy (TLE) . Mesial temporal sclerosis can be suspected on MRI when hippocampal atrophy is associated with loss of internal architecture and T2-weighted signal hyperintensity . Most patients with unilateral MTS have intractable epilepsy  and poor neuropsychological prognosis [4–11]. In adult patients with MTS, most studies investigated memory function deﬁcits [5,8,12,13], which further seem to be of a material-speciﬁc nature . The notion of material-speciﬁc impairment proposes that the left and right temporal lobes process different types of material and that lateralized MTS leads to different memory proﬁles. Notably, left mesial temporal epilepsy and right mesial temporal epilepsy lead to verbal memory impairment and nonverbal memory impairment, respectively . Pediatric studies have also shown memory dysfunctions in children with epilepsy with unilateral MTS [15–18]. However, compared with ⁎ Corresponding author at: Centre de Recherche du CHU Sainte-Justine, 3175, Chemin de la Côte-Sainte-Catherine, H3T 1C5 Montreal, QC, Canada. E-mail address: [email protected]
http://dx.doi.org/10.1016/j.yebeh.2014.12.023 1525-5050/© 2014 Elsevier Inc. All rights reserved.
studies in adults, pediatric data could only partially conﬁrm the notion of material-speciﬁc deﬁcits in children with epilepsy with MTS [6,7,19, 20]. An association between left MTS and verbal memory problems has frequently been observed [18,21–23], but there are no consistent ﬁndings for right MTS and nonverbal memory deﬁcits [9,14,24]. For instance, Gargaro and colleagues  found the typical memory proﬁle (e.g., left MTS and verbal memory problems and right MTS and nonverbal memory problems) in only 25% of their pediatric cohort. The remaining children had atypical memory proﬁles, which included i) no memory impairments, ii) both verbal and nonverbal memory deﬁcits, or iii) memory deﬁcits that are typically found contralateral to the epileptic focus . In contrast with MTS, unilateral hippocampal atrophy (HA) is a decrease in size or diminishing amount of tissue in the hippocampus without loss of internal architecture. It is still unclear whether epileptic seizures cause HA or whether HA causes epileptic seizures [3,25]. In some cases, hippocampal atrophy has been found to be a precursor of MTS , whereas, in other cases, HA does not evolve toward MTS. In a prior study , we were interested in clinical characteristics and evolution of 16 children with epilepsy with isolated HA. We found a distinct clinical presentation of unilateral HA compared with unilateral MTS,
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including an association with a positive family history of epilepsy, a lower incidence of febrile seizures, and a better seizure prognosis. These results suggest that unilateral HA might represent a distinct epileptic entity and that HA is not necessarily a precursor of MTS in children with epilepsy. To our knowledge, the cognitive proﬁle of children with unilateral HA without MTS has not been speciﬁed. Therefore, the aim of the present study was to establish a comprehensive cognitive proﬁle of children with epilepsy with unilateral HA without MTS, focusing not only on memory functions but also on other cognitive domains, including attention and executive functions. In addition, the presence of material-speciﬁc memory deﬁcits (verbal versus nonverbal) in these young patients was investigated by comparing results of patients with left HA with those of patients with right HA. 2. Methods 2.1. Participants Sixteen children with epilepsy with left or right HA without MTS were recruited from the Comprehensive Epilepsy Clinic of the University of Montreal Hospital Center Sainte-Justine. Inclusion criteria included the following: 1) a diagnosis of childhood-onset epilepsy; 2) the presence of unilateral HA without MTS on MRI, deﬁned by a pediatric neuroradiologist as HA without T2-weighted hippocampal hyperintensity, loss of internal architecture, or associated lesion; 3) ﬂuency in French or English; and 4) between 6 years (minimal age for using standardized neuropsychological tests) and 19 years (maximal age of patients that have been followed at the clinic since childhoodonset epilepsy) of age. Patients who had undergone neurosurgery, had a tumor or a space-occupying lesion, or no clear lateralization of HA were excluded. The study was approved by the Sainte-Justine Hospital Ethics Committee, and informed written consent was obtained from all participants or their parents before they underwent a neuropsychological assessment. 2.2. Neuropsychological assessment The neuropsychological evaluation was performed by a qualiﬁed neuropsychologist who was blind to the hemispheric lateralization of HA. Testing was carried out in the morning for optimizing vigilance and attentional resources and lasted approximately 3 1/2 h including rest periods. The assessment included several standardized cognitive measures. An estimate of intellectual functioning was obtained using an ageappropriate intelligence scale: the Wechsler Intelligence Scale for Children, fourth edition (WISC-IV), for children under 16 years of age  and the Wechsler Adult Intelligence Scale, third edition (WAISIII), for participants 16 years of age and older . Memory functions were assessed by means of the Children Memory Scale (CMS) for patients below 16 years of age  and the Wechsler Memory Scale (WMS) for children 16 years of age and older . In addition, the Rey–Osterrieth Complex Figure (ROCF; ) was administered to assess immediate visual memory and delayed visual memory as well as executive functions such as organizational skills and planning ability. Finally, the California Verbal Learning Tests, both the child version (CVLT-C) for children under 16 years of age  and the adult version (CVLT) for patients 16 years of age and older , were used to investigate different aspects of verbal memory such as learning strategies, short- and longdelay free recall, recognition memory, and susceptibility to interference (e.g., List B). 2.3. Data analyses The following results obtained from the WISC-IV or the WAIS-III were included for analysis: Full-Scale Intellectual Quotient (IQ), Verbal
Comprehension Index (VCI) or Verbal IQ, Perceptual Reasoning Index (PRI) or Nonverbal IQ, Working Memory Index (WMI), and Processing Speed Index (PSI). For the CMS or the WMS, the following results were used: nonverbal memory (nonverbal memory = immediate nonverbal memory index + delayed nonverbal memory index / 2), verbal memory (verbal memory = immediate verbal memory + delayed verbal memory / 2), global memory quotient (MQ), and attention/ concentration index (AC). Furthermore, copy, immediate, and delayed recall standard scores from the ROCF were compiled and used for group comparison. Standard scores of the total score for trials one to ﬁve (learning trials) and trial one and trial ﬁve separately were evaluated from the CVLT-C or the CVLT to determine differences between groups for immediate attention. The scores of List B (interference list) and List A (immediate recall) were analyzed to evaluate the effect of interference. Moreover, List A short-delayed free recall and List A long-delayed free recall were included for additional short- and longterm verbal memory functions. The scores from all participants were compared with normative data in order to obtain a neuropsychological proﬁle of young patients with unilateral HA without MTS. Moreover, cognitive results from patients with left HA were compared with those from patients with right HA in order to investigate for material-speciﬁc lateralization patterns. 2.4. Statistical analyses The statistical analyses were performed using Statistic Package for the Social Sciences Version 20.0 (SPSS, IBM Corp., Armonk, NY). In order to characterize the global cognitive proﬁle of children with unilateral HA (N = 15) with respect to normative data, a one-sample t-test using a test value of 100 ± 15, (which corresponds to the normative mean and standard deviation) was performed on overall IQ, verbal IQ, nonverbal IQ, MQ, verbal memory, nonverbal memory, WMI, AC index, and PSI. All t-tests were two-tailed. In order to lower the risk of type 1 error when computing multiple comparisons, the alpha level of signiﬁcance was adjusted to p b 0.01. Finally, between-groups analysis (left HA versus right HA) consisted of a one-way analysis of variance (ANOVA), with the side of HA as an independent variable and with a signiﬁcance level of p ≤ 0.05. 3. Results All datasets were normally distributed, except for the WMI of the group with left HA as shown using the Kolmogorov–Smirnov test (p = 0.04). In addition to parametric tests, nonparametric equivalents tests (Wilcoxon signed-rank test and Kruskal–Wallis test) were, thus, performed and provided similar results. In the interests of clarity, only parametric test results are presented here . 3.1. Demographic and clinical characteristics of patients with epilepsy with unilateral HA Demographic and clinical data are provided in Table 1. From the initial 16 children, data from one patient with left HA were excluded after the neuropsychological assessment because of missing data and a suspected ﬂoor effect, which precluded a valid interpretation of the results. Data from the 15 remaining patients (8 girls) with a mean age (± standard deviation (SD)) of 13.1 ± 3.7 years (range: 9–19 years) were used for analyses. Ten patients had left HA (mean age ± SD of 12.6 ± 3.8 years, range: 9–19 years, 6 girls), and ﬁve had right HA (mean age ± SD of 14 ± 3.7 years, range: 9–17 years, 2 girls). Demographic characteristics of this sample showed no signiﬁcant differences between groups (left HA versus right HA) with respect to gender, age at testing, age at onset of epilepsy, duration of the epilepsy, and presence or absence of anticonvulsant medication at testing and medically refractory epilepsy (see Table 2 for details).
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Table 1 Demographic and clinical data. Patient
Age at testing (yrs;mo)
Age at onset of epilepsy (yrs;mo)
Epilepsy duration (yrs;mo)
AED at testing
Medically refractory epilepsya
1 2 3 4 5 6
F F M M F F
L L R R L L
19;0 9;1 16;4 17;1 19;8 11;3
9;0 6;3 3;4 10;5 4;7 5;0
7;11 1;4 1;4 3;5 1;0 6;3
Bilateral frontotemporal spikes Left temporal spikes Normal Normal N/A 3-Hz spike and wave
Yes Yes No No Yes Yes
No No No No No Yes
7b 8 9 10 11 12 13 14 16 18
F F M F M F F M M M
Partial Partial Partial Partial Partial Generalized (absences) Partial Partial Partial Partial Partial Partial Partial Partial Partial Partial
L L L R L R L L R L
13;0 13;10 9;6 11;11 12;5 17;0 14;6 9;10 9;1 10;4
6;0 10;0 2;7 6;0 6;0 10;11 6;0 4;0 4;5 3;0
2;0 0;7 0;5 2;2 7;11 2;0 4;0 4;0 4;6 7;0
Normal Left temporal spikes Normal Normal Left frontocentrotemporal Right temporal slowing Normal Left hemispheric spikes Right frontotemporal spikes and slowing Left temporal spikes
Yes No No No No Yes Yes Yes Yes Yes
No No No No No No No No No Yes
Note. yrs;mo = years; months, AED = antiepileptic drug, HA = side of hippocampal atrophy. a No treatment or combination of treatments brought complete control of seizures at the time of testing. b Excluded patient.
3.2. Neuropsychological proﬁle of patients with epilepsy with unilateral HA Neuropsychological data, as well as mean scores and standard deviations (SD), are presented in Table 3. Individual neuropsychological data for each patient are presented in Supplementary Table S1. Compared with normative data, patients showed normal intellectual and memory functioning (see Fig. 1, black square). However, one-sample t-tests revealed that patients had signiﬁcantly lower scores on WMI (t(14) = −3.16, p = 0.007; 95% conﬁdence interval of the difference (CI) = −25.19 to −4.81) compared with normative data and that patients tended to have signiﬁcantly lower scores on AC index (t(14) = − 2.62, p = 0.02; 95% CI = − 25.84 to − 2.56) and PSI (t(14) = −2.42, p = 0.03; 95% CI = −20.01 to −1.19) compared with normative data. In addition, patients had signiﬁcantly lower scores for the ROCF copy (t(14) = −3.27, p = 0.006; 95 %CI = −23.00 to − 4.8) and List B of the CVLT (t(14) = 3.01, p = 0.009; 95% CI = 3.16 to 18.84) compared with normative data.
3.3. Patients with left HA versus right HA Statistical results for the group comparisons are presented in Table 4. Overall, the cognitive proﬁle of the group with right HA was superior to that of the group with left HA (see Fig. 1), except for intellectual functioning and processing speed index, which were comparable. The one-way ANOVA revealed signiﬁcant differences between the two groups for MQ (F(1,13) = 11.45, p = 0.005), verbal memory (F(1,13) = 6.78, p = 0.022), nonverbal memory (F(1,13) = 6.33,
Table 2 Demographic and clinical data of each patient group. Characteristics
Number of patients Sex (male/female) Age at testing, yr (mean(SD)) Age at onset of epilepsy, yr (mean(SD)) Epilepsy duration, yr (mean(SD)) AED at testing (yes/no) Medically refractory epilepsy (yes/no)
10 4/6 13(4) 6(3) 4(3) 9/1 2/8
5 3/2 14(4) 7(3) 2(1) 2/3 0/5
p-Value (t-test) 0.500 n.s. 0.489 n.s. 0.468 n.s. 0.370 n.s. 0.113 n.s. 0.371 n.s.
Note. AED = antiepileptic drug, yr = years, SD = standard deviation, n.s. = not signiﬁcant.
p = 0.026), WMI (F(1,13) = 8.49, p = 0.012), and AC index (F(1,13) = 6.06, p = 0.029) (Fig. 1). There was no signiﬁcant difference between the two groups on scores of the ROCF and the CVLT (all p N 0.05, for all subcomponents). 4. Discussion The current study was designed to specify the cognitive proﬁle of children with epilepsy and young adults with unilateral HA without MTS and to explore the nature of memory impairments in these children. Overall, the results showed normal intellectual functioning in our cohort. More importantly, no speciﬁc memory impairments were observed. Surprisingly, in patients with right HA, memory functions were even superior to intellectual functions in all domains. Taken together, these ﬁndings suggest that patients with epilepsy with unilateral HA have relatively favorable cognitive outcome without speciﬁc memory dysfunction. This proﬁle differs from the neuropsychological proﬁle of children with unilateral MTS, in whom memory dysfunctions have consistently been reported [15–18]. The absence of memory impairments may be explained by the speciﬁc nature of the hippocampal abnormality found in our participants. In contrast with patients with MTS, the hippocampus of patients with HA may be normally functioning or, at least, partially functioning , thus explaining the normal memory performance measured in this study. Furthermore, detailed analyses of our neuropsychological results revealed no signiﬁcant differences between verbal memory and nonverbal memory in our patients, regardless of the laterality of HA. Although this subject is still a matter of debate, our results are in accordance with most previous studies in pediatric populations, which failed to detect a speciﬁc lateralized memory pattern in patients with unilateral HA compared with patients with MTS [14,15,23]. On the other hand, this absence of material-speciﬁc patterns in children may be attributable to greater cerebral plasticity and brain adaptation [37,38]. In this context, Helmstaedter and Elger  examined age-related regression of verbal learning and memory in patients with chronic TLE. Their results indicate that although chronic epilepsy may interfere with normal development of cognitive functions, laterality differences were only present in adolescent (age above 16 years) and adult patients, not in children. This may suggest that the maturing brain is able to compensate more effectively for one dysfunctional temporal lobe compared with the mature brain [38,39]. It may also explain the absence of
103 (15) 102 (15) 104 (16) 107 (14) 102 (18) 109 (21) 102 (14) 93 (8) 106 (15) 102 (17) 107 (21) 100 (14) 103 (18) 110 (11) 100 (20) 92 (14) 88 (5) 94 (16) 92 (17) 89 (5) 94 (21) 89 (17) 93 (17) 88 (18)
86 (16) 80 (20) 89 (15)
List B Del Imm T5 T1 T1–5
List A Copy
86 (21) 102 (18) 78 (18) 85 (18) 101 (17) 77 (14) 101 (22) 122 (15) 90 (18) 101 (23) 119 (20) 92 (20) 101 (21) 118 (13) 92 (20) 93 (15) 98 (12) 90 (16) 99 (13) 100 (8) 98 (15)
Overall Nonverbal Verbal Nonverbal
93 (14) 96 (9) 91 (16) All patients Right HA Left HA
CVLT ROCF PSI AC WMI Memory IQ
Table 3 Neuropsychological data for all patients, patient group with right HA, and patient group with left HA (standardized scores; mean = 100, SD = 15).
Note. Cells contain means; standard deviations are shown in parentheses. HA = hippocampal atrophy; IQ = intelligence quotient; WMI = working memory index; AC = attention/concentration index; PSI = processing speed index; ROCF = Rey– Osterrieth Complex Figure; CVLT = California Verbal Learning Task; T1–5 = total of trials one to ﬁve of the CVLT; T1 = total of trial one; T5 = total of trial ﬁve; Imm = immediate recall; Del = delayed recall.
C.S.M. Schmidt et al. / Epilepsy & Behavior 44 (2015) 17–22 111 (14) 114 (17) 110 (13)
material-speciﬁc patterns we found in our group, since most of our participants were 16 years old or younger. The hypothesis regarding brain plasticity has been studied by Gleissner and colleagues . These authors compared the cognitive outcome in children and adults 3 and 12 months posttemporal lobe surgery. They found that children recovered more quickly and more completely compared with adults. In fact, the children were able to reach their preoperative level one year postsurgery, while most adults were still obtaining lower neuropsychological results compared with their presurgical assessment. In addition, greater improvements of attentional abilities and a better postsurgical seizure outcome were observed in children compared with adult patients, which points once more to a greater plasticity and compensational capacity of the developing brain . This compensatory mechanism may also operate in our patients with epilepsy with unilateral HA, thereby providing an explanation for the absence of memory deﬁcits in this pediatric cohort. In addition to memory, other cognitive functions have been assessed in the present study. The combined results of all participants revealed impairments in working memory and in organizational skills and planning ability as evidenced by low WMI index and low performance on the copy of the ROCF compared with delayed recall, respectively. Weaknesses in immediate and selective attention were also shown with low AC index and PSI (statistical tendency). These ﬁndings point to impairment of attention and executive functions in children with epilepsy and adolescents with unilateral (left or right) HA without MTS. These speciﬁc difﬁculties have also been reported in recent studies including children with TLE [17,41,42]. Several hypotheses can be offered to explain the impairments in attention and executive functions in patients with HA. Although the medial temporal lobe, including the hippocampus, is known to be essential for memory and learning , previous studies have shown that damage to the hippocampus results not only in learning and memory deﬁcits but also in impairments of attention and executive functions, such as working memory [44,45]. The temporal lobe is known to have rich connections to the prefrontal cortex, which, together with other subcortical structures such as the hippocampus, the caudate nucleus, and the thalamus, have been implicated in working memory, executive function, and attention regulation [5,13,41,46]. In addition, connectivity through numerous pathways of the temporal lobes with the frontal lobes facilitates propagation of seizure activity, which might further explain why executive and attention impairments are found in children with temporal lobe epilepsy and unilateral HA [5,41,42,47,48]. In fact, HA has been associated with extratemporal epileptic discharges, which may explain the presence of extratemporal functional deﬁcits, such as attention and executive impairments [20,27,42]. Regardless of the underlying mechanisms accounting for impairments in attention and executive function, these deﬁcits may have signiﬁcant clinical implications and should be investigated as part of the clinical management of patients with epilepsy with HA. Comparisons between groups (left HA versus right HA) did not reveal any differences in global intellectual functioning as reported in previous studies [7,40]. However, patients with right HA were superior to children with left HA with regard to memory, attention, and executive functions. This pattern of results is similar to that reported for patients with MTS [7,40,49]. Studies that investigated preoperative and postoperative cognitive functions in left or right hippocampal resection also indicate that patients with right resection tend to have a better outcome compared with those with left hippocampal resection [7,23,50]. To explain this discrepancy, it has been suggested that there is larger functional plasticity in the right temporal lobe than in the left temporal lobe . This notion has gained support from studies comparing preoperative and postoperative cognitive functioning of children with either left or right temporal lobe resection, which have shown greater deterioration of cognitive functions after left resection than after right resection . Finally, another factor that may explain the superior
C.S.M. Schmidt et al. / Epilepsy & Behavior 44 (2015) 17–22
Fig. 1. Between-groups comparisons for speciﬁc cognitive functioning. The black square indicates the mean performance of all patients combined; the blue X indicates the mean performance of patients with left HA, and the red circle indicates the mean performance of patients with right HA for each cognitive domain. The straight horizontal dotted line indicates the mean of standardized scores; and the gray shaded area indicates the normal range based on normative data (range from ±1 SD to the mean 100 ± 15). IQ = intelligence quotient, MQ = memory quotient, WMI = working memory index, AC = attention/concentration index, PSI = processing speed index.
results of the group with right HA is our small sample size (10 patients with left HA versus 5 patients with right HA). The small sample size constitutes, indeed, the main limitation of this study. Therefore, results have to be interpreted with caution, and generalization of our data is limited. Furthermore, the small sample size did not allow exploration of the effect of demographic variables (e.g., age and sex) or epilepsy-related factors (e.g., age at onset, seizure frequency, and number of medication) on cognitive functioning that have been shown to inﬂuence neuropsychological data [48,51]. Nevertheless, no group differences were found regarding these factors. 5. Conclusion To our knowledge, this study is the ﬁrst to specify the cognitive proﬁle of children with epilepsy with HA without MTS. All patients showed favorable global intellectual outcome and no memory deﬁcits or material-speciﬁc memory impairments but exhibited deﬁcits in attention, working memory, and executive functions. This neuropsychological proﬁle contrasts with that reported for children with MTS, who tend to have poor cognitive outcome including memory dysfunction [4–8]. Although generalization of our data is limited because of the small sample size, it is possible to speculate that HA may be a distinct clinical entity. Furthermore, our study points to the importance of performing a global cognitive assessment that includes the investigation of attention and executive functions, since deﬁcits in these Table 4 Statistical group comparisons: left HA versus right HA. Cognitive function
p-Value (t-test, p ≤ 0.05)
Overall IQ Verbal IQ Nonverbal IQ MQ Verbal memory Nonverbal memory WMI AC PSI
90 (16) 91 (16) 98 (15) 90 (18) 92 (20) 92 (20) 77 (14) 78 (18) 88 (18)
98 (12) 96 (9) 100 (8) 122 (15) 118 (13) 119 (20) 101 (17) 102 (18) 93 (17)
0.323 n.s. 0.503 n.s. 0.812 n.s. 0.005a 0.022a 0.026a 0.012a 0.029a 0.624 n.s.
Note. Cells contain means; standard deviations are shown in parentheses. n.s. = not signiﬁcant; IQ = intelligence quotient; MQ = memory index; WMI = working memory index; AC = attention/concentration index; PSI = processing speed index. a Signiﬁcant difference.
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