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Atypical language representation in children with intractable temporal lobe epilepsy
Epilepsy & Behavior 58 (2016) 91–96
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Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Atypical language representation in children with intractable temporal lobe epilepsy Alice Maulisova a,b, Brandon Korman c,⁎, Gustavo Rey d, Byron Bernal e, Michael Duchowny c,d, Marketa Niederlova a, Pavel Krsek f,b, Vilem Novak g,h a
Charles University, Faculty of Arts, Department of Psychology, Prague, Czech Republic Motol University Hospital, Prague, Czech Republic Brain Institute, Nicklaus Children's Hospital, Miami, FL, United States d Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, United States e Department of Radiology, Nicklaus Children's Hospital, Miami, FL, United States f Charles University, 2nd Faculty of Medicine, Prague, Czech Republic g University of Ostrava, Faculty of Medicine, Ostrava, Czech Republic h Faculty Hospital Ostrava, Ostrava, Czech Republic b c
a r t i c l e
i n f o
Article history: Received 5 October 2015 Revised 4 March 2016 Accepted 5 March 2016 Available online xxxx Keywords: Temporal lobe epilepsy Histopathology FCD Hippocampal sclerosis Cognition Handedness Status epilepticus
a b s t r a c t This study evaluated language organization in children with intractable epilepsy caused by temporal lobe focal cortical dysplasia (FCD) alone or dual pathology (temporal lobe FCD and hippocampal sclerosis, HS). We analyzed clinical, neurological, fMRI, neuropsychological, and histopathologic data in 46 pediatric patients with temporal lobe lesions who underwent excisional epilepsy surgery. The frequency of atypical language representation was similar in both groups, but children with dual pathology were more likely to be left-handed. Atypical receptive language cortex correlated with lower intellectual capacity, verbal abstract conceptualization, receptive language abilities, verbal working memory, and a history of status epilepticus but did not correlate with higher seizure frequency or early seizure onset. Histopathologic substrate had only a minor influence on neuropsychological status. Greater verbal comprehension deficits were noted in children with atypical receptive language representation, a risk factor for cognitive morbidity. © 2016 Elsevier Inc. All rights reserved.
1. Introduction The evaluation of patients undergoing epilepsy surgery has enhanced our understanding of the normal and abnormal organization of cortical networks, particularly language centers. Although the left hemisphere is dominant for propositional aspects of language (i.e., semantics and syntax) in most healthy individuals, atypical representation occurs most often after early-acquired lesions [1,2]. Atypical (right-sided or bilateral) language representation is also more frequent in patients with focal epilepsy than in healthy individuals [3]. Language competence is dependent upon multiple brain regions working together [4]. Although abnormal epileptiform activity disrupts the neurological framework of cognitive networks, function can still be Abbreviations: FCD, focal cortical dysplasia; FET, Fisher's Exact Test; fMRI, functional magnetic resonance imaging; HS, hippocampal sclerosis; IVMF, immediate visual memory for faces; SE, status epilepticus; TL, temporal lobe; TLE, temporal lobe epilepsy; MWW, Mann–Whitney–Wilcoxon Test. ⁎ Corresponding author at: Nicklaus Children's Hospital, Brain Institute, 3100 SW 62nd Avenue, Miami, FL 33155, United States. Tel.: +1 786 624 2469; fax: +1 305 663 6857. E-mail address: [email protected] (B. Korman).
http://dx.doi.org/10.1016/j.yebeh.2016.03.006 1525-5050/© 2016 Elsevier Inc. All rights reserved.
maintained through innate reorganization of connectivity. This process is influenced by many factors including the age of brain injury, its localization, and the epileptic activity itself [3]. Patients with language reorganization often exhibit significant language deficits that are postulated to involve transcallosal inhibition [5]. This mechanism may also explain the language improvement observed in some children after dominant hemispherectomy [6]. In accordance with classical neurological concepts, patients with temporal foci transfer receptive language whereas patients with frontal foci transfer expressive language [1]. However, left temporal pathology is more often associated with atypical language representation than left frontal pathology [2]. Two common structural pathologies in children with temporal lobe epilepsy (TLE) are hippocampal sclerosis (HS) and focal cortical dysplasia (FCD) [7]. These structural lesions, the underlying epileptogenic processes, and the resultant aberrant electrographic activity may all influence temporal function and promote network reorganization [8], but their interrelationships are poorly understood. Several studies confirm the utility of functional magnetic resonance imaging (fMRI) for noninvasive language mapping [1,2,9]. However, the utility of fMRI is limited without histological confirmation of lesion
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pathology and documentation of both receptive and expressive language networks. By studying children undergoing excisional surgery for epilepsy, we evaluated language organization in children with intractable temporal lobe epilepsy caused by different types of lesions within the temporal lobe. More specifically, we compared children with FCD, a prenatally acquired cortical abnormality to children with both FCD and HS, a known postnatal lesion. We hypothesized that patients with dual pathology (FCD + HS) (“two hits”) would have a higher probability of atypical language representation cortex compared with subjects with FCD alone (“one hit”). We also hypothesized that reorganization of language cortex occurs more frequently in children with dominant temporal lobe lesions and that earlier seizure onset more significantly impacts language competence. The role of seizure burden for language competence was also examined. 2. Material and methods
conditions, for a total of 105 time points. During the control condition, each participant was instructed to “think of a blue sky”. This visualization task served as an orthogonal contrast to the language tasks, while providing the subject with an appropriate nonverbal focus of attention. For the receptive task, the subject listened to a unique story prerecorded in the laboratory with a female voice. Following testing, subjects were asked questions about the story to ascertain that they were attending to the task. The expressive language paradigm consisted of mental word generation, either semantic fluency or verb generation. Fluency categories included animals, fruits, and vegetables. For verb generation, the subject heard a noun and was instructed to mentally generate multiple verbs related to that noun. Because of varying cognitive levels within this population, we chose from a small number of different paradigms (active vs. passive and of varying complexity) to match the required effort level to patient skills. While some children could only perform passive paradigms (e.g., listening to a story), others were capable of performing expressive language tasks.
2.1. Participants We analyzed the clinical, neurological, neuropsychological, and histopathologic data of 46 children and young adults aged 5.5 to 22 yrs (mean = 13.3 yrs, SD = 4.0) with a confirmed diagnosis of temporal lobe epilepsy based on seizure semiology, electroclinical features, and confirmed MRI lesions. All subjects underwent excisional epilepsy surgery at Miami Children's Hospital. Combined MRI and histopathologic criteria (see below) revealed temporal lobe FCD in 17 patients and dual pathology (FCD + HS) in 29 patients. Presurgically, all children underwent comprehensive neuropsychological testing. Functional magnetic resonance imaging using receptive paradigms was available in 29 children; 26 patients underwent fMRI using expressive language paradigms. Subject selection was not influenced by gender, race, ethnic background, or handedness. Since neuropsychological testing was performed in English, all subjects were native English speakers or bilinguals whose primary language was English. We excluded subjects with severe intellectual or developmental impairment who could not be examined with standard psychometric instruments and subjects with incomplete datasets. 2.2. Clinical, MRI, and fMRI evaluation 2.2.1. Clinical evaluation A complete neurological workup was performed for each patient during his/her epilepsy surgery evaluation. Historical data were collected via parent report and medical records including age at seizure onset, duration of epilepsy, frequency of seizures, and prior status epilepticus. 2.2.2. Structural MRI All preoperative MRIs were performed on a 1.5-Tesla scanner using a standard epilepsy protocol. The following MRI features were evaluated: laterality of structural lesion (right or left hemisphere) and extent of lesion as defined by the number of affected lobes (confined to one lobe or multilobar). The diagnosis of hippocampal sclerosis (HS) was based on both histopathologic data and MRI evidence of hippocampal atrophy, signal intensity change, and abnormal internal architecture. 2.2.3. fMRI imaging All studies were performed immediately prior to the structural MRI, utilizing a quadrature birdcage head coil. Activation maps were obtained with a single shot echo-planar imaging sequence sensitive to the blood oxygenation level-dependent response (TR, 2000 ms; TE, 60 ms; flip angle 90°). Fourteen 5-mm axial slices were obtained per case. A 240-mm field of view was divided into a 64 × 64 matrix. All paradigms used a block design with 15 time points per epoch, with each time point representing one volume acquisition. Every sequence began with a control epoch, followed by three alternating cycles of activity and control
2.2.4. Analysis of fMRI findings Areas of activation were qualitatively evaluated for localization, extent, and dispersion by three raters (BB, GR, BK) while blinded for subject's neuropsychological performance, pathology, and lesion location. Each paradigm's results were evaluated by ranking the activation into four independent categories based on models of adaptive variant activation maps by Berl [10]. Expected cluster activations predominantly within the left hemisphere were marked as typical receptive or expressive language organization. Consistent with large-scale studies utilizing the intracarotid amobarbital procedure [11,12], atypical language organization was categorized as: (a) reorganization into atypical language areas within the left hemisphere, (b) bilateral representation with greater activation on the right, and (c) complete transfer of language to the right hemisphere. Based on published data and our experience with healthy subjects, expected areas of activation when listening to a story were Brodmann's 21, 22, 40, 41, 42, and 37, with activity predominantly in the left hemisphere. For the expressive language paradigms, expected activations included areas 44, 45, and 8 and the posterior aspect of area 9 (inferior bank of the middle frontal gyrus). 2.2.5. Neuropsychological evaluation All study subjects judged to be medically stable (i.e., not evaluated during a significant increase of baseline seizure frequency) underwent presurgical neuropsychological evaluation prior to epilepsy surgery. If a seizure occurred during testing, measures with questionable validity were repeated after sufficient rest and complete recovery from the postictal state. Domains examined included intellectual functioning, language skills, memory, visual–motor construction, and executive functions (for more detailed information, see Table 2). For general intellectual functioning, different versions of the Wechsler Intelligence Scales were administered (e.g., WPPSI-III, WISC-II, WISC-IV, WASI, or WAISIII), with the specific test chosen dependent upon the subject age, the latest version available at testing, and clinical presentation. The high Full Scale IQ (FSIQ) intercorrelations allow for valid comparison between these measures (Table 2). The Peabody Picture Vocabulary Test (PPVT-III or -IV) was used to gauge receptive language ability. Verbal memory was assessed using a measure of word list learning and delayed retention from the Wide Range Assessment of Memory and Learning (WRAML and WRAML-2). The memory for faces (MF) subtest from the Developmental Neuropsychological Assessment (NEPSY-II) was used to evaluate nonverbal memory. Categorical (animals) and phonemic verbal fluency (NEPSYII) were used as measures of executive functioning, with age-based norms used to transform raw scores to standard scores. The Beery– Buktenica Developmental Test of Visual–Motor Integration served as a metric of visuospatial constructional capacity. We used the most current
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version available, as norms for the fourth and fifth editions have a 0.99 correlation. Trail Making Tests (A & B) were used to evaluate visual attention and task switching. Dominant hand was determined via parent statement of handedness and observation of the child’s writing behaviors. 2.2.6. Neuropathologic analysis and classification Brain tissue analysis was performed at the Department of Pathology, Miami Children's Hospital, Miami, Florida for patients seen from 1999 to 2003 and at the Department of Pathology and Laboratory Medicine (Neuropathology), David Geffen School of Medicine at the University of California, Los Angeles, California for subjects operated after 2003. Histopathologic classification of cortical malformations was based on the ILAE classification scheme [13]. Presence of HS was evaluated using ILAE criteria [14]. In several cases, hippocampal specimens were fragmented and insufficient for histopathologic analysis, and MRI criteria alone were used to diagnose HS. 2.2.7. Statistical analysis Although the data were normally distributed, we used nonparametric methods (Mann–Whitney–Wilcoxon Test (MWW) for quantitative variables and the Fisher's Exact Test (FET) for qualitative variables) to avoid errors due to the small number of subjects in each subgroup being compared. Spearman correlation coefficients were calculated to quantify association between continuous variables. Statistical analyses were conducted using IBM SPSS (Statistical Package for the Social Sciences), version 15. Western IRB approval was obtained as an exempt, archival study. 3. Results 3.1. Whole group analysis Demographic and clinical data are summarized in Table 1. No significant differences were found between histopathologic groups for age at testing, gender, duration of seizures, age at seizure onset, or side of lesion. The dual pathology group differed significantly from the group with FCD for handedness: seven of 29 patients with dual pathology were lefthanders in contrast to no left-handed subjects among 17 patients with FCD; i.e., all left-handers had dual pathology (FET, p = 0.036). Among all subjects, right-handers demonstrated significantly later age at seizure onset than left-handers (MWW, p = 0.046). Left-handers also had significantly lower verbal abstract reasoning scores than their righthanded counterparts (MWW, p = 0.026). (Table 3) We found no other significant group differences for any other clinical or neuropsychological variables based on histopathology or handedness. Among the 14 children with FCD, three evidenced atypical receptive language representation, and two had atypical expressive language representation. One subject with frontal lobe FCD had atypical expressive language representation without reorganizing receptive language cortex. Two of the 20 patients with dual pathology had atypical receptive
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Table 2 FSIQ correlations (r) between various Wechsler intelligence tests.
WPPSI-III WASI WISC-III WISC-IV WAIS-IV
WISC-III
WISC-IV
.89 .87
.89 .86 .89 .91
WAIS-III
WASI-II
WPPSI-IV .86
.92 .88 .89 .94
.91 .91 .92
.84
Note: Corrected r obtained by using Fisher's z transformation.
language representation, and one evidenced atypical expressive representation (combined with reorganization of receptive language cortex). Patients with a history of status epilepticus (SE) were statistically more likely to have atypical receptive language representation (FET, p = 0.048). (Tables 4) In the subgroup with SE, receptive language reorganization was noted in 42.9% (3/7) of cases compared with that in only 7.4% (2/27) of patients without SE. However, the incidence of atypical expressive language activation did not vary with SE history (FET, p = 0.564), occurring in 14.3% (1/7) cases with SE and 8.7% (2/23) in the subgroup without SE. Our data also suggested a relationship between SE and underlying pathology: Only 11.8% (2/17) of patients with SE were in the group with FCD compared with 31% (9/29) in the group with dual pathology. However, these results were not statistically significant (FET, p = 0.172). Seizure frequency showed no relationship to language laterality as only one child with daily seizures showed atypical receptive language representation and another evidenced atypical expressive language representation. In the subgroup of patients with low seizure frequency (monthly or less, NMonthlySeizures = 9), two children had atypical receptive language representation, and one had expressive language representation. This difference was also not statistically significant for either receptive (FET, p = 0.596) or expressive language (FET, p = 0.571). There was also little difference (FET, p = 0.616) in receptive language organization in relation to age of seizure onset. Atypical networks were identified in 13.3% (2/15) of children with seizure onset prior to age five and 15.8% (3/19) of children with later seizure onset. None of the 14 patients with right-sided lesions who underwent fMRI studies of receptive language organization showed atypical receptive language sites compared with five of the 20 children with left-sided lesions and atypical receptive representation. Despite this impressive trend, the difference did not reach statistical significance (FET, p = 0.063). Similarly, none of the 12 patients with right-sided lesions and expressive language fMRI investigations evidenced atypical expressive language representation, compared with 3 of 18 children with leftsided lesions who had atypical expressive language representation. Again, this difference was not statistically significant (FET, p = 0.255). All study subjects had primary temporal epileptogenic zones, with six considered as having “temporal plus” epilepsy requiring larger (multilobar) excisions including the frontal lobe. Five had FCD without HS, with the remaining one having dual pathology; the latter subject was excluded from additional analyses because of left handedness.
Table 1 Demographic data of the whole group of children with temporal epilepsy (N = 46) and subgroups with FCD (NFCD = 17) and dual pathology (FCD combined with HS, NDUAL = 29).
Age at seizure onset Mean (SD) (yrs) Duration of epilepsy Mean (SD) (yrs) Male/female Daily seizures History of status epilepticus Handedness: right/left
All patients with TLE NTOT = 46
Isolated FCD NFCD = 17
Dual pathology (FCD + HS) NDUAL = 29
5.8(4.5)
7.3(4.1)
5.0(4.6)
7.5(4.4)
6.2(3.7)
8.2(4.7)
30/16 15 11 39/7
13/4 9 2 17/0
17/12 6 9 22/7
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Table 3 Significant differences between left-handers and right-handers.
Table 5 Descriptive statistics for neuropsychological performance for all subjects (N = 46). SS =
Left-handed subjects
Right-handed subjects
Significance
Seizure onset earlier Lower verbal abstract reasoning
Seizure onset later Higher verbal abstract reasoning
p = 0.046 p = 0.026
Comparative analyses with and without extratemporal lesions clearly demonstrate that extratemporal lesions did not bias our results. 3.2. Analysis after exclusion of left-handers Analyses after excluding seven left-handed patients were conducted in order to focus exclusively on the cohort of 39 right-handed subjects. Because we could not definitively ascertain whether left handedness was familial or acquired, we excluded left-handed subjects from further analyses. We identified right-sided pathology in 48.7% of right-handed subjects (19/39) compared with that in 51.2% (20/39) of children with left-hemispheric lesions. Five of the seven left-handers had known left-sided lesions. 3.2.1. The impact of lesion type on neuropsychological profile Descriptive statistics for neuropsychological performance are provided in Table 5. Patients with FCD had higher scores compared with patients with dual pathology only for immediate visual memory for faces (MWW: p = 0.034; temporal only p = 0.048). There were no other statistically significant differences between groups across neuropsychological domains. 3.2.2. The impact of lesion extent on receptive language representation Although unilobar temporal lesions corresponded more strongly with atypical language organization than multilobar lesions, the difference was not statistically significant (FET, p = 0.447). None of the five patients with multilobar lesions had atypical receptive representation, and one had atypical expressive language representation; five of 20 right-handed patients with a unilobar temporal lesion presented with atypical receptive language representation. 3.2.3. Relation of atypical receptive language representation to other variables Patients with atypical representation of receptive language centers were significantly more likely to have left hemisphere lesions (FET, p = 0.034; temporal only p = 0.046), a higher incidence of status epilepticus (FET, p = 0.024; temporal only p = 0.018), and lower general intellectual capacity (MWW, p = 0.002; temporal only p = 0.002), especially for verbal abstract reasoning (similarities: MWW, p = 0.004; temporal only p = 0.001) and verbal working memory (digit span: MWW, p = 0.012; temporal only p = 0.010). Receptive vocabulary competence (PPVT: MWW, p = 0.003; temporal only p = 0.003) was also significantly lower. Other neurocognitive variables showed no differences between patients with typical and atypical receptive language representations. 3.2.4. Relation of atypical expressive language representation to other variables We identified only three subjects with atypical expressive language representation. All had left temporal lesions, with one having additional left frontal involvement. They showed similar differences between neuropsychological variables as those with atypical receptive Table 4 Language representation in patients with and without status epilepticus. History of SE
No history of SE
Significance
Higher frequency of atypical language representation
Lower frequency of atypical language representation
p = 0.048
Standard Score, ss = scaled score. Measures
Min. value
Max. value
Mean
SD
FSIQ VIQ PIQ Vocabulary (ss) Similarities (ss) Block design (ss) PPVT (SS) Beery VMI (SS) Digit span (ss) Word List Learning Total (ss) Word List Delayed Recall (ss) Faces Immediate Recog (ss) Faces Delayed Recog (ss) Trails A (SS) Trails B (SS) FAS (SS) Animals (SS)
56 59 55 2 1 1 40 47 1 1 2 1 2 17 20 22 40
116 126 130 13 13 18 117 115 15 14 12 15 15 121 125 123 131
84.24 83.36 89.38 6.33 6.98 8.50 85.65 83.34 7.45 7.09 7.00 9.43 8.83 83.80 75.49 76.72 86.46
14.936 15.315 16.924 2.847 3.252 3.409 17.040 14.933 3.295 2.754 3.045 3.319 3.524 26.738 29.147 20.707 20.571
representation. These differences included general intellectual capacity (FSIQ: MWW, p = 0.041; temporal only p = 0.049) and receptive vocabulary competence (PPVT: MWW, p = 0.049; temporal only p = 0.031). 4. Discussion This report includes a complex analysis of language cortex representation in a series of children with intractable temporal lobe epilepsy caused by either FCD or dual pathology (FCD + HS). Most importantly, we found that the two histopathologic groups did not differ in the incidence of atypical language cortex representation, suggesting that language organization is neither substrate-specific nor influenced by the occurrence of a “single” or “double” hit. Our findings suggest that language organization is primarily influenced by the anatomic proximity of the epileptic focus to eloquent language centers in the dominant hemisphere. In other words, the ontological timing of lesion acquisition (prenatal vs. some combination of pre- and postnatal factors) is not the critical determinant of either language organization or linguistic competence. These results support the previous observations of Korman et al. [8], demonstrating that the histological composition of the substrate and the timing of its acquisition are not critical in the determination of cortical language representation. They are also consistent with the higher incidence of atypical language networks in adults with left HS compared with those in patients with epileptogenic lesions more remote from receptive language cortex [15,16]. Children with dual pathology did however differ significantly from children with FCD in their handedness; notably, we found that all left-handers evidenced dual pathology. This finding suggests that the association of pre- and postnatal pathologies results in greater functional reorganization of nonlanguage neural networks, including those regulating motor dominance. It is also possible that the over-representation of lefthanders with dual pathology results from epileptiform activity. The finding that left-handers had significantly earlier seizure onset supports this hypothesis and suggests that the epileptic process itself might influence motor reorganization. Reorganized motor function must involve modulation of the frontal lobes. Chlebus et al. [17] surmised that epileptiform activity guides motor cortex development in patients with temporal lobe epilepsy. It was further suggested that regions with earlier consolidation and maturation trajectories, such as temporal cortex, may have a profound and far-reaching effect on distant connected regions within a distributed network [16]. Distant regions would be more likely to follow the “reorganization” of the pathologically involved temporal cortex. Nonetheless, we did not find a significant association between handedness and side of the lesion (two left-handers had right-sided lesions).
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While the factors relating localization of the epileptogenic substrate with handedness were not readily revealed through this data set, further exploration is warranted to search for additional mediating factors. Atypical handedness is known to be associated with an increased likelihood of atypical language representation in patients [18,19] as well as healthy volunteers [20,21]. Histopathologic groups differed in one important neuropsychological domain: patients with dual pathology showed significantly poorer immediate visual memory for faces (IVMF). While facial recognition is not a language skill, it has important implications for social development. This ability is a function of associative pathways and has also been localized to the fusiform face area (FFA) within the fusiform gyrus of the temporal lobe [22]. In a recent study [23] comparing children with TLE and controls, the subgroup with TLE exhibited inferior recognition of facial identity, direction of eye gaze, and emotional facial expressions. There was no relationship between the type of deficit and age of seizure onset, duration of epilepsy, or size of the affected cerebral hemisphere. Pathological substrates of the TLE were not taken into account. Our data extend these observations by suggesting a linkage between the type of pathological substrate of epilepsy (FCD or dual pathology) and level of IVMF. The percentage of patients in our sample with atypical receptive language localization (20%) is also consistent with studies revealing a greater occurrence of atypical language in patients with focal epilepsy (20–30%), using visual rating of fMRI data [24–26] and studies based on other processing of fMRI data [27]. Berl et al. [28] found a 25.5% incidence of atypical receptive language localizations in patients with focal epilepsy compared with 2.5% in healthy volunteers. Patients with atypical localization of receptive language centers had lower general intellectual capacity (in the context of diminished verbal abstract reasoning, verbal working memory, and receptive language competence) compared with subjects with classical receptive language representation. Furthermore, these subjects more frequently evidenced left hemisphere brain lesions. Our results are thus in accordance with the accepted view that some neuropsychological functions are compromised in patients with transferred language functions, indicating that some degree of hemispheric specialization is already in place when cortical networks undergo reorganization [5,6,29]. With expressive language function represented in the dominant frontal lobe, it is not surprising that reorganization of expressive language was infrequent (three cases) in our series of patients with TLE. Since only one of these three patients had FCD within the left frontal lobe, our results suggest the potential for temporal lobe epileptic activity to affect distant language sites via functional networks, in accordance with observations of Brazdil et al. [9]. Our results do not support the hypothesis that earlier seizure onset increases the probability of language reorganization. This finding is unexpected as it is generally accepted that age at brain injury strongly influences language reorganization [3]. However, prior studies have also refuted such a connection between atypical language representation and age of seizure onset [2,8]. Seizure frequency itself carried no predictive value for language reorganization. On the other hand, patients with atypical language representation did have a higher incidence of status epilepticus. Furthermore, history of SE was considerably more frequent in patients with dual pathology, consistent with the generally accepted association of SE and the development of HS [30]. Status epilepticus is believed to not only structurally damage the hippocampus but to also cause more extensive network disruption, reorganization, and atypical language representation [3]. It is likely, therefore, that SE simultaneously caused the hippocampal damage and promoted early language network reorganization. The hippocampus represents higher-order associative cortex integrated in different cognitive systems via multiple reciprocal connections [15]. A difficulty in studying children with intractable epilepsy has been their high incidence of cognitive impairment. We therefore selected fMRI paradigms that are simple, yet robust, and associated with a
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large degree of standardization across subjects. By choosing well validated block design fMRI paradigms similar to other pediatric centers performing language mapping, we maintained a high degree of confidence in the validity of our results, rather than having unreliable artifacts produced by “cognitive or emotional noise” (i.e., effort, frustration, anxiety). While it is tempting to employ taskless resting-state (rs) fMRI techniques in children with a limited ability to cooperate, more research is needed before rs-fMRI is considered clinically viable for mapping language networks in young children [31]. Acknowledgments This study was supported by GAUK 1162/13, Faculty of Arts, Charles University, Prague, Czech Republic and MH CZ–DRO, University Hospital Motol, Prague, Czech Republic 00064203. Disclosure The authors report no conflicts of interest. References [1] Springer JA, Binder JR, Hammeke TA, Swanson SJ, Frost JA, Bellgowan PS, et al. Language dominance in neurologically normal and epilepsy subjects: a functional MRI study. Brain 1999;122(Pt 11):2033–46. [2] Liegeois F, Connelly A, Cross JH, Boyd SG, Gadian DG, Vargha-Khadem F, et al. Language reorganization in children with early-onset lesions of the left hemisphere: an fMRI study. Brain 2004;127:1229–36. [3] Janszky J, Jokeit H, Heinemann D, Schulz R, Woermann FG, Ebner A. Epileptic activity influences the speech organization in medial temporal lobe epilepsy. Brain 2003; 126:2043–51. [4] Goldmann Gross R, Golby A, Schachter SC, Holmesm GL, Kasteleijn-Nolst Trenité D. Atypical language organization in epilepsy. In: Schachter SC, Holmes GL, Kasteleijn-Nolst Trenité D, editors. Behavioral aspects of epilepsy: principles and practice. New York: Demos; 2008. p. 165–8. [5] Duchowny M, Jayakar P, Harvey AS, Resnick T, Alvarez L, Dean P, et al. Language cortex representation: effects of developmental vs. acquired pathology. Ann Neurol 1996;40:31–8. [6] Moosa AN, Jehi L, Marashly A, Cosmo G, Lachhwani D, Wyllie E, et al. Long-term functional outcomes and their predictors after hemispherectomy in 115 children. Epilepsia 2013;54(10):1771–9. [7] Harvey AS, Cross JH, Shinnar S, Mathern GW. ILAE Pediatric Epilepsy Surgery Survey Taskforce. Defining the spectrum of international practice in pediatric epilepsy surgery patients. Epilepsia 2008;49(1):146–55. [8] Korman B, Bernal B, Duchowny M, Jayakar P, Altman N, Garaycoa G, et al. Atypical propositional language organization in prenatal and early-acquired temporal lobe lesions. J Child Neurol 2010;25(8):985–93. [9] Brazdil M, Chlebus P, Mikl M, Pazourkova P, Krupa P, Rektor I. Reorganization of language-related neuronal networks in patients with left temporal lobe epilepsy — an fMRI study. Eur J Neurol 2005;12:268–75. [10] Berl MM, Vaidya CJ, Gaillard WD. Functional imaging of developmental and adaptive changes inneurocognition. NeuroImage 2006;30(3):679–91. [11] Kurthen M, Helmstaedter C, Linke DB, Hufnagel A, Elger CE, Schramm J. Quantitative and qualitative evaluation of patterns of cerebral language dominance. An amobarbital study. Brain Lang 1994;46:536–64. [12] Loring DW, Meador KJ, Lee GP, Murro AM, Smith JR, Flanigin HF, et al. Cerebral language lateralization: evidence from intracarotid amobarbital testing. Neuropsychologia 1990; 28:831–8. [13] Blümcke I, Coras R, Miyata H, Ozkara C. Defining clinico-neuropathological subtypes of mesial temporal lobe epilepsy with hippocampal sclerosis. Brain Pathol 2012; 22(3):402–11. [14] Blumcke I, Cross JH, Spreafico R. The international consensus classification for hippocampal sclerosis: an important step towards accurate prognosis. Lancet Neurol 2013;12(9):844–6. [15] Weber B, Wellmer J, Reuber M, Mormann F, Weis S, Urbach H, et al. Left hippocampal pathology is associated with atypical language lateralization in patients with focal epilepsy. Brain 2006;129:346–51. [16] Duke ES, Tesfaye M, Berl MM, Walker JE, Ritzl EK, Fasano RE, et al. The effect of seizure focus on regional language processing areas. Epilepsia 2012;53(6):1044–50. [17] Chlebus P, Brazdil M, Hlustik P, Mikl M, Pazourkova M, Krupa P. Handedness shift as a consequence of motor cortex reorganization after early functional impairment in left temporal lobe epilepsy: an fMRI case report. Neurocase 2004;10(4):326–9. [18] Gaillard WD, Berl MM, Moore EN, Ritzl EK, Rosenberger LR, Weinstein SL. Atypical language in lesional and nonlesional complex partial epilepsy. Neurology 2007;69: 1761–71. [19] Rasmussen T, Milner B. The role of early left-brain injury in determining lateralization of cerebral speech functions. Ann N Y Acad Sci 1977;299:355–69. [20] Pujol J, Deus J, Losilla JM, Capdevila A. Cerebral lateralization of language in normal left-handed people studied by functional MRI. Neurology 1999;52:1038–43.
96
A. Maulisova et al. / Epilepsy & Behavior 58 (2016) 91–96
[21] Szaflarski JP, Binder JR, Possing ET, McKiernan KA, Ward BD, Hammeke TA. Language lateralization in left-handed and ambidextrous people: fMRI data. Neurology 2002; 59:238–44. [22] Kanwisher N, Yovel G. The fusiform face area: a cortical region specialized for the perception of faces. Philos Trans R Soc Lond B Biol Sci 2006;361(1476):2109–28. [23] Laurent A, Arzimanoglou A, Panagiotakaki E, Sfaello I, Kahane P, Ryvlin P, et al. Visual and auditory sociocognitive perception in unilateral temporal lobe epilepsy in children and adolescents: a prospective controlled study. Epileptic Disord 2014;16(4): 456–70. [24] Fernandez G, de Greiff A, von Oertzen J, Reuber M, Lun S, Klaver P, et al. Language mapping in less than 15 minutes: real-time functional MRI during routine clinical investigation. NeuroImage 2001;14:585–94. [25] Gaillard WD, Balsamo L, Xu B, Grandin CB, Braniecki SH, Papero PH. Language dominance in partial epilepsy patients identified with an fMRI reading task. Neurology 2002;59:256–65. [26] Gaillard WD, Balsamo L, Xu B, McKinney C, Papero PH, Weinstein S, et al. fMRI language task panel improves determination of language dominance. Neurology 2004;63:1403–8.
[27] Wang J, You X, Wu W, Guillen MR, Cabrerizo M, Sullivan J, et al. Classification of MRI patterns—a study of the language network segregation in pediatric localization related epilepsy. Hum Brain Mapp 2014;35(4):1446–60. [28] Berl MM, Zimmaro LA, Khan OI, Dustin I, Ritzl E, Duke ES, et al. Characterization of atypical language activation patterns in focal epilepsy. Ann Neurol 2014;75(1): 33–42. [29] You X, Adjouadi M, Guillen MR, Ayala M, Barreto A, Rishe N, et al. Subpatterns of language network reorganization in pediatric localization related epilepsy: a multisite study. Hum Brain Mapp 2011;32(5):784–99. [30] Mathern GW, Babb TL, Pretorius JK, Melendez M, Lévesque MF. The pathophysiologic relationships between lesion pathology, intracranial ictal EEG onsets, and hippocampal neuron losses in temporal lobe epilepsy. Epilepsy Res 1995;21(2):133–47. [31] Lee MH, Smyser CD, Simony JS. Resting-state fMRI: a review of methods and clinical applications. AJNR Am J Neuroradiol 2013;34(10):1866–72.
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Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Atypical language representation in children with intractable temporal lobe epilepsy Alice Maulisova a,b, Brandon Korman c,⁎, Gustavo Rey d, Byron Bernal e, Michael Duchowny c,d, Marketa Niederlova a, Pavel Krsek f,b, Vilem Novak g,h a
Charles University, Faculty of Arts, Department of Psychology, Prague, Czech Republic Motol University Hospital, Prague, Czech Republic Brain Institute, Nicklaus Children's Hospital, Miami, FL, United States d Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, United States e Department of Radiology, Nicklaus Children's Hospital, Miami, FL, United States f Charles University, 2nd Faculty of Medicine, Prague, Czech Republic g University of Ostrava, Faculty of Medicine, Ostrava, Czech Republic h Faculty Hospital Ostrava, Ostrava, Czech Republic b c
a r t i c l e
i n f o
Article history: Received 5 October 2015 Revised 4 March 2016 Accepted 5 March 2016 Available online xxxx Keywords: Temporal lobe epilepsy Histopathology FCD Hippocampal sclerosis Cognition Handedness Status epilepticus
a b s t r a c t This study evaluated language organization in children with intractable epilepsy caused by temporal lobe focal cortical dysplasia (FCD) alone or dual pathology (temporal lobe FCD and hippocampal sclerosis, HS). We analyzed clinical, neurological, fMRI, neuropsychological, and histopathologic data in 46 pediatric patients with temporal lobe lesions who underwent excisional epilepsy surgery. The frequency of atypical language representation was similar in both groups, but children with dual pathology were more likely to be left-handed. Atypical receptive language cortex correlated with lower intellectual capacity, verbal abstract conceptualization, receptive language abilities, verbal working memory, and a history of status epilepticus but did not correlate with higher seizure frequency or early seizure onset. Histopathologic substrate had only a minor influence on neuropsychological status. Greater verbal comprehension deficits were noted in children with atypical receptive language representation, a risk factor for cognitive morbidity. © 2016 Elsevier Inc. All rights reserved.
1. Introduction The evaluation of patients undergoing epilepsy surgery has enhanced our understanding of the normal and abnormal organization of cortical networks, particularly language centers. Although the left hemisphere is dominant for propositional aspects of language (i.e., semantics and syntax) in most healthy individuals, atypical representation occurs most often after early-acquired lesions [1,2]. Atypical (right-sided or bilateral) language representation is also more frequent in patients with focal epilepsy than in healthy individuals [3]. Language competence is dependent upon multiple brain regions working together [4]. Although abnormal epileptiform activity disrupts the neurological framework of cognitive networks, function can still be Abbreviations: FCD, focal cortical dysplasia; FET, Fisher's Exact Test; fMRI, functional magnetic resonance imaging; HS, hippocampal sclerosis; IVMF, immediate visual memory for faces; SE, status epilepticus; TL, temporal lobe; TLE, temporal lobe epilepsy; MWW, Mann–Whitney–Wilcoxon Test. ⁎ Corresponding author at: Nicklaus Children's Hospital, Brain Institute, 3100 SW 62nd Avenue, Miami, FL 33155, United States. Tel.: +1 786 624 2469; fax: +1 305 663 6857. E-mail address: [email protected] (B. Korman).
http://dx.doi.org/10.1016/j.yebeh.2016.03.006 1525-5050/© 2016 Elsevier Inc. All rights reserved.
maintained through innate reorganization of connectivity. This process is influenced by many factors including the age of brain injury, its localization, and the epileptic activity itself [3]. Patients with language reorganization often exhibit significant language deficits that are postulated to involve transcallosal inhibition [5]. This mechanism may also explain the language improvement observed in some children after dominant hemispherectomy [6]. In accordance with classical neurological concepts, patients with temporal foci transfer receptive language whereas patients with frontal foci transfer expressive language [1]. However, left temporal pathology is more often associated with atypical language representation than left frontal pathology [2]. Two common structural pathologies in children with temporal lobe epilepsy (TLE) are hippocampal sclerosis (HS) and focal cortical dysplasia (FCD) [7]. These structural lesions, the underlying epileptogenic processes, and the resultant aberrant electrographic activity may all influence temporal function and promote network reorganization [8], but their interrelationships are poorly understood. Several studies confirm the utility of functional magnetic resonance imaging (fMRI) for noninvasive language mapping [1,2,9]. However, the utility of fMRI is limited without histological confirmation of lesion
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pathology and documentation of both receptive and expressive language networks. By studying children undergoing excisional surgery for epilepsy, we evaluated language organization in children with intractable temporal lobe epilepsy caused by different types of lesions within the temporal lobe. More specifically, we compared children with FCD, a prenatally acquired cortical abnormality to children with both FCD and HS, a known postnatal lesion. We hypothesized that patients with dual pathology (FCD + HS) (“two hits”) would have a higher probability of atypical language representation cortex compared with subjects with FCD alone (“one hit”). We also hypothesized that reorganization of language cortex occurs more frequently in children with dominant temporal lobe lesions and that earlier seizure onset more significantly impacts language competence. The role of seizure burden for language competence was also examined. 2. Material and methods
conditions, for a total of 105 time points. During the control condition, each participant was instructed to “think of a blue sky”. This visualization task served as an orthogonal contrast to the language tasks, while providing the subject with an appropriate nonverbal focus of attention. For the receptive task, the subject listened to a unique story prerecorded in the laboratory with a female voice. Following testing, subjects were asked questions about the story to ascertain that they were attending to the task. The expressive language paradigm consisted of mental word generation, either semantic fluency or verb generation. Fluency categories included animals, fruits, and vegetables. For verb generation, the subject heard a noun and was instructed to mentally generate multiple verbs related to that noun. Because of varying cognitive levels within this population, we chose from a small number of different paradigms (active vs. passive and of varying complexity) to match the required effort level to patient skills. While some children could only perform passive paradigms (e.g., listening to a story), others were capable of performing expressive language tasks.
2.1. Participants We analyzed the clinical, neurological, neuropsychological, and histopathologic data of 46 children and young adults aged 5.5 to 22 yrs (mean = 13.3 yrs, SD = 4.0) with a confirmed diagnosis of temporal lobe epilepsy based on seizure semiology, electroclinical features, and confirmed MRI lesions. All subjects underwent excisional epilepsy surgery at Miami Children's Hospital. Combined MRI and histopathologic criteria (see below) revealed temporal lobe FCD in 17 patients and dual pathology (FCD + HS) in 29 patients. Presurgically, all children underwent comprehensive neuropsychological testing. Functional magnetic resonance imaging using receptive paradigms was available in 29 children; 26 patients underwent fMRI using expressive language paradigms. Subject selection was not influenced by gender, race, ethnic background, or handedness. Since neuropsychological testing was performed in English, all subjects were native English speakers or bilinguals whose primary language was English. We excluded subjects with severe intellectual or developmental impairment who could not be examined with standard psychometric instruments and subjects with incomplete datasets. 2.2. Clinical, MRI, and fMRI evaluation 2.2.1. Clinical evaluation A complete neurological workup was performed for each patient during his/her epilepsy surgery evaluation. Historical data were collected via parent report and medical records including age at seizure onset, duration of epilepsy, frequency of seizures, and prior status epilepticus. 2.2.2. Structural MRI All preoperative MRIs were performed on a 1.5-Tesla scanner using a standard epilepsy protocol. The following MRI features were evaluated: laterality of structural lesion (right or left hemisphere) and extent of lesion as defined by the number of affected lobes (confined to one lobe or multilobar). The diagnosis of hippocampal sclerosis (HS) was based on both histopathologic data and MRI evidence of hippocampal atrophy, signal intensity change, and abnormal internal architecture. 2.2.3. fMRI imaging All studies were performed immediately prior to the structural MRI, utilizing a quadrature birdcage head coil. Activation maps were obtained with a single shot echo-planar imaging sequence sensitive to the blood oxygenation level-dependent response (TR, 2000 ms; TE, 60 ms; flip angle 90°). Fourteen 5-mm axial slices were obtained per case. A 240-mm field of view was divided into a 64 × 64 matrix. All paradigms used a block design with 15 time points per epoch, with each time point representing one volume acquisition. Every sequence began with a control epoch, followed by three alternating cycles of activity and control
2.2.4. Analysis of fMRI findings Areas of activation were qualitatively evaluated for localization, extent, and dispersion by three raters (BB, GR, BK) while blinded for subject's neuropsychological performance, pathology, and lesion location. Each paradigm's results were evaluated by ranking the activation into four independent categories based on models of adaptive variant activation maps by Berl [10]. Expected cluster activations predominantly within the left hemisphere were marked as typical receptive or expressive language organization. Consistent with large-scale studies utilizing the intracarotid amobarbital procedure [11,12], atypical language organization was categorized as: (a) reorganization into atypical language areas within the left hemisphere, (b) bilateral representation with greater activation on the right, and (c) complete transfer of language to the right hemisphere. Based on published data and our experience with healthy subjects, expected areas of activation when listening to a story were Brodmann's 21, 22, 40, 41, 42, and 37, with activity predominantly in the left hemisphere. For the expressive language paradigms, expected activations included areas 44, 45, and 8 and the posterior aspect of area 9 (inferior bank of the middle frontal gyrus). 2.2.5. Neuropsychological evaluation All study subjects judged to be medically stable (i.e., not evaluated during a significant increase of baseline seizure frequency) underwent presurgical neuropsychological evaluation prior to epilepsy surgery. If a seizure occurred during testing, measures with questionable validity were repeated after sufficient rest and complete recovery from the postictal state. Domains examined included intellectual functioning, language skills, memory, visual–motor construction, and executive functions (for more detailed information, see Table 2). For general intellectual functioning, different versions of the Wechsler Intelligence Scales were administered (e.g., WPPSI-III, WISC-II, WISC-IV, WASI, or WAISIII), with the specific test chosen dependent upon the subject age, the latest version available at testing, and clinical presentation. The high Full Scale IQ (FSIQ) intercorrelations allow for valid comparison between these measures (Table 2). The Peabody Picture Vocabulary Test (PPVT-III or -IV) was used to gauge receptive language ability. Verbal memory was assessed using a measure of word list learning and delayed retention from the Wide Range Assessment of Memory and Learning (WRAML and WRAML-2). The memory for faces (MF) subtest from the Developmental Neuropsychological Assessment (NEPSY-II) was used to evaluate nonverbal memory. Categorical (animals) and phonemic verbal fluency (NEPSYII) were used as measures of executive functioning, with age-based norms used to transform raw scores to standard scores. The Beery– Buktenica Developmental Test of Visual–Motor Integration served as a metric of visuospatial constructional capacity. We used the most current
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version available, as norms for the fourth and fifth editions have a 0.99 correlation. Trail Making Tests (A & B) were used to evaluate visual attention and task switching. Dominant hand was determined via parent statement of handedness and observation of the child’s writing behaviors. 2.2.6. Neuropathologic analysis and classification Brain tissue analysis was performed at the Department of Pathology, Miami Children's Hospital, Miami, Florida for patients seen from 1999 to 2003 and at the Department of Pathology and Laboratory Medicine (Neuropathology), David Geffen School of Medicine at the University of California, Los Angeles, California for subjects operated after 2003. Histopathologic classification of cortical malformations was based on the ILAE classification scheme [13]. Presence of HS was evaluated using ILAE criteria [14]. In several cases, hippocampal specimens were fragmented and insufficient for histopathologic analysis, and MRI criteria alone were used to diagnose HS. 2.2.7. Statistical analysis Although the data were normally distributed, we used nonparametric methods (Mann–Whitney–Wilcoxon Test (MWW) for quantitative variables and the Fisher's Exact Test (FET) for qualitative variables) to avoid errors due to the small number of subjects in each subgroup being compared. Spearman correlation coefficients were calculated to quantify association between continuous variables. Statistical analyses were conducted using IBM SPSS (Statistical Package for the Social Sciences), version 15. Western IRB approval was obtained as an exempt, archival study. 3. Results 3.1. Whole group analysis Demographic and clinical data are summarized in Table 1. No significant differences were found between histopathologic groups for age at testing, gender, duration of seizures, age at seizure onset, or side of lesion. The dual pathology group differed significantly from the group with FCD for handedness: seven of 29 patients with dual pathology were lefthanders in contrast to no left-handed subjects among 17 patients with FCD; i.e., all left-handers had dual pathology (FET, p = 0.036). Among all subjects, right-handers demonstrated significantly later age at seizure onset than left-handers (MWW, p = 0.046). Left-handers also had significantly lower verbal abstract reasoning scores than their righthanded counterparts (MWW, p = 0.026). (Table 3) We found no other significant group differences for any other clinical or neuropsychological variables based on histopathology or handedness. Among the 14 children with FCD, three evidenced atypical receptive language representation, and two had atypical expressive language representation. One subject with frontal lobe FCD had atypical expressive language representation without reorganizing receptive language cortex. Two of the 20 patients with dual pathology had atypical receptive
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Table 2 FSIQ correlations (r) between various Wechsler intelligence tests.
WPPSI-III WASI WISC-III WISC-IV WAIS-IV
WISC-III
WISC-IV
.89 .87
.89 .86 .89 .91
WAIS-III
WASI-II
WPPSI-IV .86
.92 .88 .89 .94
.91 .91 .92
.84
Note: Corrected r obtained by using Fisher's z transformation.
language representation, and one evidenced atypical expressive representation (combined with reorganization of receptive language cortex). Patients with a history of status epilepticus (SE) were statistically more likely to have atypical receptive language representation (FET, p = 0.048). (Tables 4) In the subgroup with SE, receptive language reorganization was noted in 42.9% (3/7) of cases compared with that in only 7.4% (2/27) of patients without SE. However, the incidence of atypical expressive language activation did not vary with SE history (FET, p = 0.564), occurring in 14.3% (1/7) cases with SE and 8.7% (2/23) in the subgroup without SE. Our data also suggested a relationship between SE and underlying pathology: Only 11.8% (2/17) of patients with SE were in the group with FCD compared with 31% (9/29) in the group with dual pathology. However, these results were not statistically significant (FET, p = 0.172). Seizure frequency showed no relationship to language laterality as only one child with daily seizures showed atypical receptive language representation and another evidenced atypical expressive language representation. In the subgroup of patients with low seizure frequency (monthly or less, NMonthlySeizures = 9), two children had atypical receptive language representation, and one had expressive language representation. This difference was also not statistically significant for either receptive (FET, p = 0.596) or expressive language (FET, p = 0.571). There was also little difference (FET, p = 0.616) in receptive language organization in relation to age of seizure onset. Atypical networks were identified in 13.3% (2/15) of children with seizure onset prior to age five and 15.8% (3/19) of children with later seizure onset. None of the 14 patients with right-sided lesions who underwent fMRI studies of receptive language organization showed atypical receptive language sites compared with five of the 20 children with left-sided lesions and atypical receptive representation. Despite this impressive trend, the difference did not reach statistical significance (FET, p = 0.063). Similarly, none of the 12 patients with right-sided lesions and expressive language fMRI investigations evidenced atypical expressive language representation, compared with 3 of 18 children with leftsided lesions who had atypical expressive language representation. Again, this difference was not statistically significant (FET, p = 0.255). All study subjects had primary temporal epileptogenic zones, with six considered as having “temporal plus” epilepsy requiring larger (multilobar) excisions including the frontal lobe. Five had FCD without HS, with the remaining one having dual pathology; the latter subject was excluded from additional analyses because of left handedness.
Table 1 Demographic data of the whole group of children with temporal epilepsy (N = 46) and subgroups with FCD (NFCD = 17) and dual pathology (FCD combined with HS, NDUAL = 29).
Age at seizure onset Mean (SD) (yrs) Duration of epilepsy Mean (SD) (yrs) Male/female Daily seizures History of status epilepticus Handedness: right/left
All patients with TLE NTOT = 46
Isolated FCD NFCD = 17
Dual pathology (FCD + HS) NDUAL = 29
5.8(4.5)
7.3(4.1)
5.0(4.6)
7.5(4.4)
6.2(3.7)
8.2(4.7)
30/16 15 11 39/7
13/4 9 2 17/0
17/12 6 9 22/7
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Table 3 Significant differences between left-handers and right-handers.
Table 5 Descriptive statistics for neuropsychological performance for all subjects (N = 46). SS =
Left-handed subjects
Right-handed subjects
Significance
Seizure onset earlier Lower verbal abstract reasoning
Seizure onset later Higher verbal abstract reasoning
p = 0.046 p = 0.026
Comparative analyses with and without extratemporal lesions clearly demonstrate that extratemporal lesions did not bias our results. 3.2. Analysis after exclusion of left-handers Analyses after excluding seven left-handed patients were conducted in order to focus exclusively on the cohort of 39 right-handed subjects. Because we could not definitively ascertain whether left handedness was familial or acquired, we excluded left-handed subjects from further analyses. We identified right-sided pathology in 48.7% of right-handed subjects (19/39) compared with that in 51.2% (20/39) of children with left-hemispheric lesions. Five of the seven left-handers had known left-sided lesions. 3.2.1. The impact of lesion type on neuropsychological profile Descriptive statistics for neuropsychological performance are provided in Table 5. Patients with FCD had higher scores compared with patients with dual pathology only for immediate visual memory for faces (MWW: p = 0.034; temporal only p = 0.048). There were no other statistically significant differences between groups across neuropsychological domains. 3.2.2. The impact of lesion extent on receptive language representation Although unilobar temporal lesions corresponded more strongly with atypical language organization than multilobar lesions, the difference was not statistically significant (FET, p = 0.447). None of the five patients with multilobar lesions had atypical receptive representation, and one had atypical expressive language representation; five of 20 right-handed patients with a unilobar temporal lesion presented with atypical receptive language representation. 3.2.3. Relation of atypical receptive language representation to other variables Patients with atypical representation of receptive language centers were significantly more likely to have left hemisphere lesions (FET, p = 0.034; temporal only p = 0.046), a higher incidence of status epilepticus (FET, p = 0.024; temporal only p = 0.018), and lower general intellectual capacity (MWW, p = 0.002; temporal only p = 0.002), especially for verbal abstract reasoning (similarities: MWW, p = 0.004; temporal only p = 0.001) and verbal working memory (digit span: MWW, p = 0.012; temporal only p = 0.010). Receptive vocabulary competence (PPVT: MWW, p = 0.003; temporal only p = 0.003) was also significantly lower. Other neurocognitive variables showed no differences between patients with typical and atypical receptive language representations. 3.2.4. Relation of atypical expressive language representation to other variables We identified only three subjects with atypical expressive language representation. All had left temporal lesions, with one having additional left frontal involvement. They showed similar differences between neuropsychological variables as those with atypical receptive Table 4 Language representation in patients with and without status epilepticus. History of SE
No history of SE
Significance
Higher frequency of atypical language representation
Lower frequency of atypical language representation
p = 0.048
Standard Score, ss = scaled score. Measures
Min. value
Max. value
Mean
SD
FSIQ VIQ PIQ Vocabulary (ss) Similarities (ss) Block design (ss) PPVT (SS) Beery VMI (SS) Digit span (ss) Word List Learning Total (ss) Word List Delayed Recall (ss) Faces Immediate Recog (ss) Faces Delayed Recog (ss) Trails A (SS) Trails B (SS) FAS (SS) Animals (SS)
56 59 55 2 1 1 40 47 1 1 2 1 2 17 20 22 40
116 126 130 13 13 18 117 115 15 14 12 15 15 121 125 123 131
84.24 83.36 89.38 6.33 6.98 8.50 85.65 83.34 7.45 7.09 7.00 9.43 8.83 83.80 75.49 76.72 86.46
14.936 15.315 16.924 2.847 3.252 3.409 17.040 14.933 3.295 2.754 3.045 3.319 3.524 26.738 29.147 20.707 20.571
representation. These differences included general intellectual capacity (FSIQ: MWW, p = 0.041; temporal only p = 0.049) and receptive vocabulary competence (PPVT: MWW, p = 0.049; temporal only p = 0.031). 4. Discussion This report includes a complex analysis of language cortex representation in a series of children with intractable temporal lobe epilepsy caused by either FCD or dual pathology (FCD + HS). Most importantly, we found that the two histopathologic groups did not differ in the incidence of atypical language cortex representation, suggesting that language organization is neither substrate-specific nor influenced by the occurrence of a “single” or “double” hit. Our findings suggest that language organization is primarily influenced by the anatomic proximity of the epileptic focus to eloquent language centers in the dominant hemisphere. In other words, the ontological timing of lesion acquisition (prenatal vs. some combination of pre- and postnatal factors) is not the critical determinant of either language organization or linguistic competence. These results support the previous observations of Korman et al. [8], demonstrating that the histological composition of the substrate and the timing of its acquisition are not critical in the determination of cortical language representation. They are also consistent with the higher incidence of atypical language networks in adults with left HS compared with those in patients with epileptogenic lesions more remote from receptive language cortex [15,16]. Children with dual pathology did however differ significantly from children with FCD in their handedness; notably, we found that all left-handers evidenced dual pathology. This finding suggests that the association of pre- and postnatal pathologies results in greater functional reorganization of nonlanguage neural networks, including those regulating motor dominance. It is also possible that the over-representation of lefthanders with dual pathology results from epileptiform activity. The finding that left-handers had significantly earlier seizure onset supports this hypothesis and suggests that the epileptic process itself might influence motor reorganization. Reorganized motor function must involve modulation of the frontal lobes. Chlebus et al. [17] surmised that epileptiform activity guides motor cortex development in patients with temporal lobe epilepsy. It was further suggested that regions with earlier consolidation and maturation trajectories, such as temporal cortex, may have a profound and far-reaching effect on distant connected regions within a distributed network [16]. Distant regions would be more likely to follow the “reorganization” of the pathologically involved temporal cortex. Nonetheless, we did not find a significant association between handedness and side of the lesion (two left-handers had right-sided lesions).
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While the factors relating localization of the epileptogenic substrate with handedness were not readily revealed through this data set, further exploration is warranted to search for additional mediating factors. Atypical handedness is known to be associated with an increased likelihood of atypical language representation in patients [18,19] as well as healthy volunteers [20,21]. Histopathologic groups differed in one important neuropsychological domain: patients with dual pathology showed significantly poorer immediate visual memory for faces (IVMF). While facial recognition is not a language skill, it has important implications for social development. This ability is a function of associative pathways and has also been localized to the fusiform face area (FFA) within the fusiform gyrus of the temporal lobe [22]. In a recent study [23] comparing children with TLE and controls, the subgroup with TLE exhibited inferior recognition of facial identity, direction of eye gaze, and emotional facial expressions. There was no relationship between the type of deficit and age of seizure onset, duration of epilepsy, or size of the affected cerebral hemisphere. Pathological substrates of the TLE were not taken into account. Our data extend these observations by suggesting a linkage between the type of pathological substrate of epilepsy (FCD or dual pathology) and level of IVMF. The percentage of patients in our sample with atypical receptive language localization (20%) is also consistent with studies revealing a greater occurrence of atypical language in patients with focal epilepsy (20–30%), using visual rating of fMRI data [24–26] and studies based on other processing of fMRI data [27]. Berl et al. [28] found a 25.5% incidence of atypical receptive language localizations in patients with focal epilepsy compared with 2.5% in healthy volunteers. Patients with atypical localization of receptive language centers had lower general intellectual capacity (in the context of diminished verbal abstract reasoning, verbal working memory, and receptive language competence) compared with subjects with classical receptive language representation. Furthermore, these subjects more frequently evidenced left hemisphere brain lesions. Our results are thus in accordance with the accepted view that some neuropsychological functions are compromised in patients with transferred language functions, indicating that some degree of hemispheric specialization is already in place when cortical networks undergo reorganization [5,6,29]. With expressive language function represented in the dominant frontal lobe, it is not surprising that reorganization of expressive language was infrequent (three cases) in our series of patients with TLE. Since only one of these three patients had FCD within the left frontal lobe, our results suggest the potential for temporal lobe epileptic activity to affect distant language sites via functional networks, in accordance with observations of Brazdil et al. [9]. Our results do not support the hypothesis that earlier seizure onset increases the probability of language reorganization. This finding is unexpected as it is generally accepted that age at brain injury strongly influences language reorganization [3]. However, prior studies have also refuted such a connection between atypical language representation and age of seizure onset [2,8]. Seizure frequency itself carried no predictive value for language reorganization. On the other hand, patients with atypical language representation did have a higher incidence of status epilepticus. Furthermore, history of SE was considerably more frequent in patients with dual pathology, consistent with the generally accepted association of SE and the development of HS [30]. Status epilepticus is believed to not only structurally damage the hippocampus but to also cause more extensive network disruption, reorganization, and atypical language representation [3]. It is likely, therefore, that SE simultaneously caused the hippocampal damage and promoted early language network reorganization. The hippocampus represents higher-order associative cortex integrated in different cognitive systems via multiple reciprocal connections [15]. A difficulty in studying children with intractable epilepsy has been their high incidence of cognitive impairment. We therefore selected fMRI paradigms that are simple, yet robust, and associated with a
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large degree of standardization across subjects. By choosing well validated block design fMRI paradigms similar to other pediatric centers performing language mapping, we maintained a high degree of confidence in the validity of our results, rather than having unreliable artifacts produced by “cognitive or emotional noise” (i.e., effort, frustration, anxiety). While it is tempting to employ taskless resting-state (rs) fMRI techniques in children with a limited ability to cooperate, more research is needed before rs-fMRI is considered clinically viable for mapping language networks in young children [31]. Acknowledgments This study was supported by GAUK 1162/13, Faculty of Arts, Charles University, Prague, Czech Republic and MH CZ–DRO, University Hospital Motol, Prague, Czech Republic 00064203. Disclosure The authors report no conflicts of interest. References [1] Springer JA, Binder JR, Hammeke TA, Swanson SJ, Frost JA, Bellgowan PS, et al. Language dominance in neurologically normal and epilepsy subjects: a functional MRI study. Brain 1999;122(Pt 11):2033–46. [2] Liegeois F, Connelly A, Cross JH, Boyd SG, Gadian DG, Vargha-Khadem F, et al. Language reorganization in children with early-onset lesions of the left hemisphere: an fMRI study. Brain 2004;127:1229–36. [3] Janszky J, Jokeit H, Heinemann D, Schulz R, Woermann FG, Ebner A. Epileptic activity influences the speech organization in medial temporal lobe epilepsy. Brain 2003; 126:2043–51. [4] Goldmann Gross R, Golby A, Schachter SC, Holmesm GL, Kasteleijn-Nolst Trenité D. Atypical language organization in epilepsy. In: Schachter SC, Holmes GL, Kasteleijn-Nolst Trenité D, editors. Behavioral aspects of epilepsy: principles and practice. New York: Demos; 2008. p. 165–8. [5] Duchowny M, Jayakar P, Harvey AS, Resnick T, Alvarez L, Dean P, et al. Language cortex representation: effects of developmental vs. acquired pathology. Ann Neurol 1996;40:31–8. [6] Moosa AN, Jehi L, Marashly A, Cosmo G, Lachhwani D, Wyllie E, et al. Long-term functional outcomes and their predictors after hemispherectomy in 115 children. Epilepsia 2013;54(10):1771–9. [7] Harvey AS, Cross JH, Shinnar S, Mathern GW. ILAE Pediatric Epilepsy Surgery Survey Taskforce. Defining the spectrum of international practice in pediatric epilepsy surgery patients. Epilepsia 2008;49(1):146–55. [8] Korman B, Bernal B, Duchowny M, Jayakar P, Altman N, Garaycoa G, et al. Atypical propositional language organization in prenatal and early-acquired temporal lobe lesions. J Child Neurol 2010;25(8):985–93. [9] Brazdil M, Chlebus P, Mikl M, Pazourkova P, Krupa P, Rektor I. Reorganization of language-related neuronal networks in patients with left temporal lobe epilepsy — an fMRI study. Eur J Neurol 2005;12:268–75. [10] Berl MM, Vaidya CJ, Gaillard WD. Functional imaging of developmental and adaptive changes inneurocognition. NeuroImage 2006;30(3):679–91. [11] Kurthen M, Helmstaedter C, Linke DB, Hufnagel A, Elger CE, Schramm J. Quantitative and qualitative evaluation of patterns of cerebral language dominance. An amobarbital study. Brain Lang 1994;46:536–64. [12] Loring DW, Meador KJ, Lee GP, Murro AM, Smith JR, Flanigin HF, et al. Cerebral language lateralization: evidence from intracarotid amobarbital testing. Neuropsychologia 1990; 28:831–8. [13] Blümcke I, Coras R, Miyata H, Ozkara C. Defining clinico-neuropathological subtypes of mesial temporal lobe epilepsy with hippocampal sclerosis. Brain Pathol 2012; 22(3):402–11. [14] Blumcke I, Cross JH, Spreafico R. The international consensus classification for hippocampal sclerosis: an important step towards accurate prognosis. Lancet Neurol 2013;12(9):844–6. [15] Weber B, Wellmer J, Reuber M, Mormann F, Weis S, Urbach H, et al. Left hippocampal pathology is associated with atypical language lateralization in patients with focal epilepsy. Brain 2006;129:346–51. [16] Duke ES, Tesfaye M, Berl MM, Walker JE, Ritzl EK, Fasano RE, et al. The effect of seizure focus on regional language processing areas. Epilepsia 2012;53(6):1044–50. [17] Chlebus P, Brazdil M, Hlustik P, Mikl M, Pazourkova M, Krupa P. Handedness shift as a consequence of motor cortex reorganization after early functional impairment in left temporal lobe epilepsy: an fMRI case report. Neurocase 2004;10(4):326–9. [18] Gaillard WD, Berl MM, Moore EN, Ritzl EK, Rosenberger LR, Weinstein SL. Atypical language in lesional and nonlesional complex partial epilepsy. Neurology 2007;69: 1761–71. [19] Rasmussen T, Milner B. The role of early left-brain injury in determining lateralization of cerebral speech functions. Ann N Y Acad Sci 1977;299:355–69. [20] Pujol J, Deus J, Losilla JM, Capdevila A. Cerebral lateralization of language in normal left-handed people studied by functional MRI. Neurology 1999;52:1038–43.
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[21] Szaflarski JP, Binder JR, Possing ET, McKiernan KA, Ward BD, Hammeke TA. Language lateralization in left-handed and ambidextrous people: fMRI data. Neurology 2002; 59:238–44. [22] Kanwisher N, Yovel G. The fusiform face area: a cortical region specialized for the perception of faces. Philos Trans R Soc Lond B Biol Sci 2006;361(1476):2109–28. [23] Laurent A, Arzimanoglou A, Panagiotakaki E, Sfaello I, Kahane P, Ryvlin P, et al. Visual and auditory sociocognitive perception in unilateral temporal lobe epilepsy in children and adolescents: a prospective controlled study. Epileptic Disord 2014;16(4): 456–70. [24] Fernandez G, de Greiff A, von Oertzen J, Reuber M, Lun S, Klaver P, et al. Language mapping in less than 15 minutes: real-time functional MRI during routine clinical investigation. NeuroImage 2001;14:585–94. [25] Gaillard WD, Balsamo L, Xu B, Grandin CB, Braniecki SH, Papero PH. Language dominance in partial epilepsy patients identified with an fMRI reading task. Neurology 2002;59:256–65. [26] Gaillard WD, Balsamo L, Xu B, McKinney C, Papero PH, Weinstein S, et al. fMRI language task panel improves determination of language dominance. Neurology 2004;63:1403–8.
[27] Wang J, You X, Wu W, Guillen MR, Cabrerizo M, Sullivan J, et al. Classification of MRI patterns—a study of the language network segregation in pediatric localization related epilepsy. Hum Brain Mapp 2014;35(4):1446–60. [28] Berl MM, Zimmaro LA, Khan OI, Dustin I, Ritzl E, Duke ES, et al. Characterization of atypical language activation patterns in focal epilepsy. Ann Neurol 2014;75(1): 33–42. [29] You X, Adjouadi M, Guillen MR, Ayala M, Barreto A, Rishe N, et al. Subpatterns of language network reorganization in pediatric localization related epilepsy: a multisite study. Hum Brain Mapp 2011;32(5):784–99. [30] Mathern GW, Babb TL, Pretorius JK, Melendez M, Lévesque MF. The pathophysiologic relationships between lesion pathology, intracranial ictal EEG onsets, and hippocampal neuron losses in temporal lobe epilepsy. Epilepsy Res 1995;21(2):133–47. [31] Lee MH, Smyser CD, Simony JS. Resting-state fMRI: a review of methods and clinical applications. AJNR Am J Neuroradiol 2013;34(10):1866–72.