Hippocampal volume in childhood complex partial seizures

Hippocampal volume in childhood complex partial seizures

Epilepsy Research 72 (2006) 57–66 Hippocampal volume in childhood complex partial seizures Melita Daley a,∗ , Derek Ott a , Rebecca Blanton a , Prabh...

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Epilepsy Research 72 (2006) 57–66

Hippocampal volume in childhood complex partial seizures Melita Daley a,∗ , Derek Ott a , Rebecca Blanton a , Prabha Siddarth a , Jennifer Levitt a , Elizabeth Mormino a , Cornelius Hojatkashani a , Raquel Tenorio a , Suresh Gurbani b , W. Donald Shields c , Raman Sankar c , Arthur Toga d , Rochelle Caplan a a

UCLA Department of Psychiatry, Psychiatry and Biobehavioral Sciences, UCLA, Semel Institute, Rm. 48-253B, 760 Westwood Plaza, Los Angeles, CA 90095-1759, United States b Department of Pediatrics, University of California at Irvine, CA, United States c UCLA Departments of Neurology and Pediatrics, CA, United States d UCLA Department of Neurology, CA, United States Received 8 March 2006; received in revised form 25 May 2006; accepted 7 July 2006 Available online 22 August 2006

Abstract Purpose: This study compared hippocampal volume in children with cryptogenic epilepsy, all of whom had complex partial seizures (CPS), and age and gender matched normal children controlling for between group differences in IQ and demographic variables (e.g., age, gender, ethnicity, socioeconomic status). It also examined the relationship between hippocampal volumes and seizure variables in the patients. Methods: Using quantitative magnetic resonance imaging (MRI), we compared the hippocampal volumes of 19 medically treated children with CPS, aged 6–14 years, to 21 age and gender matched normal children. Results: The children with CPS had significantly smaller total hippocampal volumes than the normal children. This finding was accounted for primarily by significantly smaller anterior hippocampal volumes. Within the CPS group, smaller total and posterior hippocampus volumes were significantly associated with longer duration of illness. Anterior hippocampal volumes, however, were unrelated to seizure variables. Conclusions: These findings imply impaired development of the hippocampus, particularly the anterior hippocampus, and a differential effect of the underlying illness and on-going seizures on hippocampal development in medically controlled pediatric CPS. © 2006 Elsevier B.V. All rights reserved. Keywords: Complex partial seizure disorder; Childhood; Magnetic resonance imaging; Hippocampus; Seizure variables



Corresponding author. Tel.: +1 310 794 4007. E-mail address: [email protected] (M. Daley).

0920-1211/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.eplepsyres.2006.07.006

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1. Introduction Adults with temporal lobe epilepsy (TLE) and partial epilepsy (Martinez et al., 1994; Baulac et al., 1998) have hippocampal volume reduction ipsilateral, and in some cases also contralateral to the epileptic focus (Jack et al., 1992; Cendes et al., 1993; Hoshida et al., 1995; Quigg et al., 1997; DeCarli et al., 1998; Kalviainen et al., 1998; Bernasconi et al., 1999; Tasch et al., 1999; Marsh et al., 2001; Lambert et al., 2003; Bonilha et al., 2004). Although consistently associated with lateralization of the seizure focus, in these patients hippocampal volume loss has been inconsistently related to longer duration of illness (Kalviainen et al., 1998; Tasch et al., 1999; Theodore et al., 1999; Salmenpera et al., 2001; Briellmann et al., 2002; Fuerst et al., 2003), earlier age of onset (Salmenpera et al., 2001; Hermann et al., 2002; Seidenberg et al., 2005), and distribution of epileptic discharges at anterior temporal electrodes (Diehl et al., 2002). Among the few childhood epilepsy morphometric studies with positive findings, Lawson et al. (2002) reported hippocampal volume reduction and hippocampal asymmetry (Lawson et al., 2000a,b) in a large sample of medically controlled children with intractable partial and generalized epilepsy syndromes compared to normal age matched control subjects before, but not after controlling for total brain volumes. In addition, Scott et al. (2001) found smaller hippocampi, prolonged T2 relaxation time ipsilateral to the seizure focus, as well as more side-to-side asymmetry of T2 relaxation time and hippocampal volume in 16 children with TLE who were surgical candidates and had a history of prolonged febrile convulsion compared to both patients without such a history and normal children. Cormack et al. (2005) recently demonstrated reduced gray matter density in the hippocampus ipsilateral to the seizure focus in 31 TLE children compared to 22 age matched normal children using voxel-based morphometry. Varho et al. (2005) found reduced hippocampal volume ipsilateral to the seizure focus and a trend for hippocampal volume contralateral to the focus in 11 children with medically controlled focal epilepsy and infrequent seizures, most of whom had secondarily generalized tonic clonic seizures. Hippocampal asymmetry has not been a consistent finding in these studies (Lawson et al., 1998; Cormack et al., 2005).

Seizure-related variables, such as age of onset and duration of illness do not appear to be related to hippocampal morphometry in a mixed group of children with intractable and medically controlled epilepsy (Lawson et al., 2000a,b). However, cross-sectional and prospective child studies demonstrate that complex febrile but not simple febrile convulsions (Lawson et al., 2000a,b) are associated with hippocampal abnormalities including significant decrease in hippocampal volume (Kuks et al., 1993; Szabo et al., 1999; Lawson et al., 2000a,b; Scott et al., 2001) and hippocampal asymmetry (Grunewald et al., 2001). Among the studies that examined the relationship between hippocampal volume and cognition, Cormack et al. (2005) found no relationship with IQ scores. However, adults with childhood onset TLE exhibit significantly smaller hippocampal volumes, as well as significantly poorer performance on measures of IQ than patients with late onset and normal subjects (Hermann et al., 2002). Evidence for intellectual deficits in children with epilepsy (Nolan et al., 2003; Caplan et al., 2004) underscores the need to study the relationship between cognition and hippocampal volumes in these children. From the developmental perspective, an age-related increase in hippocampal volume in normal children (Sowell and Jernigan, 1998; Giedd et al., 1999; Pfluger et al., 1999), more prominent earlier in girls (Pfluger et al., 1999) and later in adolescent boys (Suzuki et al., 2005), might be related to better cognitive and academic skills, as well as acquisition of knowledge (Yurgelun-Todd et al., 2003). Together with evidence from animal studies that early onset seizures impair normal postnatal fascia dentata development and lead to alterations in granule cell number and axon circuitry (Mathern et al., 2002a,b), these findings emphasize the importance of considering how age, gender, and cognition are related to hippocampal morphometry in childhood epilepsy. The study presented in this paper compared hippocampal volume in children with cryptogenic epilepsy who had complex partial seizures (CPS) with varying degrees of seizure control to age and gender matched normal children controlling for between group differences in IQ and demographic variables (e.g., age, gender, ethnicity, socioeconomic status). We hypothesized that the children with CPS would have significantly smaller hippocampi and greater

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hippocampal asymmetry than the normal children. We explored if smaller hippocampal volumes reflect reduction in anterior, posterior, or both anterior and posterior hippocampal volumes. Within the CPS group, we posited smaller hippocampal volumes ipsilateral to the focus and investigated if localization of the EEG focus would also be associated with hippocampal volumes. In addition, we predicted that the CPS patients with earlier onset, longer duration, more frequent seizures, as well as a history of prolonged seizures and febrile convulsions would have smaller hippocampi and more hippocampal asymmetry than those with later onset, shorter duration, lower seizure frequency, and no history of prolonged seizures or febrile convulsions. The association of temporal lobe epilepsy with hippocampal sclerosis, history of febrile seizures, and status epilepticus (Keller et al., 2002; Theodore et al., 2003) might reflect underlying perinatal abnormalities involving the hippocampus rather than the consequence of seizures. Therefore, in addition to prolonged seizures and febrile seizures, we also investigated the association of hippocampal volumes with perinatal abnormalities (e.g., pregnancy, delivery). Finally, from the developmental perspective, we predicted age, gender, and cognitive effects with significantly larger hippocampi in older compared to younger children, girls compared to boys, and an association of hippocampal volumes with IQ in girls but not boys.

2. Methods 2.1. Subjects The study included 19 children with cryptogenic epilepsy, all of whom had CPS, and 21 children without epilepsy, aged 6–16 years. Table 1 describes the demographic and cognitive features of the study subjects. There was a trend for more CPS children to come from lower socioeconomic status families than the normal group based on the Hollingshead 2 factor index (Hollingshead, 1973), derived from parent occupational and educational status. A score of I–III was classified as high while a score of IV–V was classified as low SES. The CPS group also had significantly lower mean IQ scores than the normal subjects.

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Table 1 Demographic features of study groups CPS

Normal

N Age (years)a

19 9.9 (2.17)

21 11.5 (2.59)

Gender Male Female

32% 68%

48% 52%

Socioeconomic statusb High (I–III) Low (IV–V)

37% 63%

70% 30%

Ethnicity Caucasian Non-Caucasian

68% 32%

71% 29%

Full Scale IQc

96 (16.45)

119 (14. 10)

a b c

t(38) = 2.08, p = 0.04. X2 (1) = 2.88, p < 0.09. t(38) = 4.94, p < 0.0001.

To be included in the study, the patients had to have a diagnosis of cryptogenic epilepsy with CPS, as defined by the International Classification of Epilepsy (Commission, 1989) and at least one seizure during the year prior to the child’s participation in the study. As described in this classification, children with a clinical history of CPS with or without EEG evidence for focal epileptic activity were included in the study sample. None of the children in the study had an underlying lesion. We recruited 47% CPS from tertiary centers (e.g., UCLA Pediatric Neurology services, Children’s Hospital of Los Angeles) and 53% from the community (e.g., Kaiser Sunset, Kaiser-Orange County, private pediatric neurologists, Los Angeles and San Diego branches of the Epilepsy Foundation of America). The primary pediatric neurologist at each site reviewed the clinical history, EEG records, and diagnosis of potential CPS subjects and referred them for the study. We excluded patients with a mixed seizure disorder, an underlying neurological disorder, a metabolic disorder, a hearing disorder, and past epilepsy surgery. One UCLA pediatric neurology investigator (W.D.S.) reviewed the history, EEG records performed at about the time of the child’s diagnosis, and diagnosis of each epileptic subject from the different recruitment sites. If he did not concur with the diagnosis or EEG findings, the child was not included in the study.

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Table 2 Seizure-related variables in CPS group

2.3. MRI procedures CPS

Seizure frequency ≤1 year−1 2–10 year−1 >10 year−1

32% 42% 26%

Age of onset (S.D.) Duration (S.D.)

5.9 (2.67) 4.0 (2.56)

AEDs None Monotherapy Polytherapy

5% 84% 11%

Prolonged seizures Febrile seizures

53% 26%

Table 2 presents information on seizure frequency during the past year, current AEDs, age of onset of seizures, duration of illness, as well as the number of febrile convulsions and number of prolonged seizures (i.e., >5 min) from the parent’s and the child’s medical records. With the exception of one CPS child who was left handed, all the other patients in the study were right handed. Of the 19 CPS patients, 2 had non-lateralized EEG findings, 8 had a left focus, 3 a right focus, and 4 bilateral foci. EEGs were unavailable for two CPS patients. Regarding focal EEG findings, one child had no focal findings, six patients had interictal spikes in the temporal lobe, four in the frontal and temporal lobe, and six in other areas. Four CPS patients had secondary generalization and five had background slowing. We recruited the non-epileptic control subjects from four public and two private schools in the Los Angeles community after screening for neurological, psychiatric, language, and hearing disorders through a telephone conversation with a parent. We excluded from the study non-epileptic children manifesting symptoms of these disorders in the past. 2.2. Procedures This study was conducted in accordance with the policies of the Human Subjects Protection Committees of the University of California, Los Angeles. Informed assents and consents were obtained from all subjects and their parents, respectively.

2.3.1. Magnetic resonance imaging (MRI) acquisition All subjects completed MRI scanning on a 1.5 T GE Signa magnetic resonance imaging scanner (GE Medical Systems, Milwaukee, WI). The imaging acquisition protocol used to obtain high resolution three-dimensional (3D) T-1 weighted spoiled grass (SPGR) sequences included: a sagittal plane acquisition with slice thickness of 1.2 mm, repetition time of 14.6, echo time of 3.3, flip angle of 35, acquisition matrix of 256 × 192, FOV 24, and two excitations. 2.3.2. Image preprocessing Each scan was processed with a series of steps to assess volumes of tissue types. Initially, potential fluctuations in signal resulting from magnetic field inhomogeneities were addressed by applying a radiofrequency correction (Sled and Pike, 1998). Next an automated brain extraction program (BET) was used to create a brain mask that separates brain tissue from non-brain tissue (skull and meninges) (Shattuck et al., 2001). This mask was manually modified to assure accurate separation of tissues. The automated tissue classification method of Shattuck et al. (2001) was then used to segment the scans by tissue types to create gray matter, white matter, and cerebrospinal fluid masks. The total intracranial volume was then automatically computed by summing the volumes of these masks including cerebellar tissue. 2.3.3. Hippocampal volumes For hippocampal volume analysis, the data were aligned into the Talairach co-ordinate system using the anterior commissure as the center of origin, and then reformatted into an oblique coronal plane to assure that the images were oriented in space with the long axis of the anterior hippocampus perpendicular to the coronal plane (Bartzokis et al., 1993). These reformatting methods, described briefly here, are detailed in Bartzokis et al. (1998). While viewing the image data in all three planes, the most anterior section containing the anterior commissure was marked in the coronal plane, and then located in the axial plane. Using these landmarks, the images were then rotated so that the interhemispheric fissure was perpendicular to a horizontal line at 0◦ . Next, the sagittal image containing the most lateral slice

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of the anterior hippocampus was marked with a line dropped perpendicular to the anterior third of the left hippocampus. This angle was then used to obtain the oblique coronal sections used for volumetric analysis of the anterior and posterior hippocampi. Manual tracings of the anterior and posterior hippocampus, as outlined in Fig. 1(a and b), respectively, were used to calculate volumes of these regions of interest. These methods have been described in detail previously (Bartzokis et al., 1998; Levitt et al., 2001) and will be summarized briefly here. The T1-weighted SPGR scan produced excellent contrast of gray and white matter, resulting in clear resolution of the fimbria and alveus. The alveus delineated the superior boundary of the hippocampus, the white matter of the parahippocampal gyrus delineated the inferior border of the hippocampus, and the inferior temporal horn of the lateral ventricle its lateral boundary. Drawing of the posterior hippocampus began at the first slice where the crus of the fornix could be delineated and traced through the level where all four colliculi were present. The level at which the alveus was first well visualized marked the anterior boundary of the anterior hippocampus, and the first slice where the crus cerebri connected to the pons marked the last slice of this region of interest. 2.3.4. Reliability of measurements The drawings were performed by one rater (DO) and checked by a second rater (RB), both without knowledge of the children’s diagnosis. A consensus drawing was then determined by agreement of the two raters about the boundaries of the regions of interest. Ten re-drawings of the medial temporal lobe regions in this study population showed intra-rater reliability >0.9 and an inter-rater reliability of 0.9. 2.3.5. Cognition The Wechsler Intelligence Scale for Children-III (Wechsler, 1991) administered to the children generated Full Scale, Verbal, and Performance IQ scores.

Fig. 1. (a and b) Manual tracings of anterior and posterior hippocampi. Manual tracings outlining (a) anterior hippocampi show superior anterior left hippocampus (yellow line) and superior anterior right hippocampus (red line) and (b) posterior hippocampi show superior posterior left hippocampus (blue line), inferior posterior left hippocampus (red line), superior posterior right hippocampus (purple line), and inferior posterior right hippocampus (pale blue line). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of the article.)

2.3.6. Data analysis We compared total hippocampal volumes and hippocampal asymmetries (left–right anterior and posterior hippocampal volumes) between the CPS and normal groups using ANOVAs. To compare anterior and posterior hippocampal volumes in the CPS and nor-

mal groups, we performed repeated measures analyses of covariance with group (CPS, normal) as the intersubject and hemisphere (left, right) as the intra-subject classification variable for anterior and posterior hippocampi, separately. Total brain volume, demographic (i.e., age, gender, socioeconomic status, ethnicity), and

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Table 3 Mean total brain (TBV) and hippocampal volumes by group Volumes (S.D.)

(cm3 )

Total brain volume Total hippocampus (cm3 ) Anterior Left Right Posterior Left Right

CPS

Normal

1363.12(102.92) 3.10 (0.10)

1452.67 (139.15) 3.96 (0.87)a

0.48 (0.23) 0.24 (0.12) 0.24 (0.13)

0.99 (0.37)b 0.48 (0.22) 0.51 (0.21)

2.62 (0.99) 1.26 (0.53) 1.36 (0.46)

(0.69)c

2.97 1.50 (0.38) 1.47 (0.33)

TBV, age, gender, socioeconomic status, ethnicity, and IQ in model. a F 1,33 = 6.30, p < 0.01. b F 1,33 = 8.79, p < 0.005. c F 1,33 = 3.41, p < 0.07.

cognitive variables (Full Scale IQ) were used as covariates in all these analyses. In investigating the association of hippocampal volumes with seizure and cognitive variables within the CPS group, similar repeated measures analyses of covariance were computed within the CPS group. Demographic, seizure, perinatal, and IQ scores were used as predictors, and total brain volume was controlled for in all the analyses. The standard checks of collinearity and potential interactions among the covariates and dependent measures were performed. All tests were two-tailed and an alpha level of 0.05 was adopted for all inferences.

3. Results 3.1. Between group differences Table 3 presents mean hippocampal volumes of the CPS and normal groups. ANOVAs with demographic and IQ variables demonstrated significantly smaller total hippocampal volumes in the children with CPS compared to the normal children (F1,33 = 6.30, p < 0.01). We explored if these findings derived primarily from smaller anterior or posterior hippocampal volumes in the CPS group. The repeated measures analyses of covariance indicated that the CPS group had significantly smaller anterior hippocampal volumes (F1,33 = 8.79, p < 0.005) and a trend for reduced posterior hippocampal volumes (F1,33 = 3.41, p < 0.07)

compared to the normal children. There were no significant differences between the CPS and normal groups in hippocampal asymmetry (left-right volumes). 3.2. Association of hippocampal volumes with seizure, cognitive, demographic, and perinatal variables Of the seizure variables, smaller total (F1,16 = 5.52, p < 0.007) and posterior hippocampal volumes (F1,16 = 6.99, p < 0.01) were significantly associated with increased duration of illness. Other illness variables, including lateralization of epileptic activity, age of onset, seizure frequency, and number of AEDs, as well as perinatal variables were unrelated to hippocampal volumes. We also found no age, gender, and IQ effects within the CPS and normal groups separately.

4. Discussion Controlling for IQ and demographic variables (e.g., age, gender, ethnicity, socioeconomic status), this study found significantly smaller total hippocampal volumes in the CPS compared to the normal subjects. This finding was accounted for by significantly smaller anterior hippocampal volumes and a trend for smaller posterior hippocampal volumes. The association between total hippocampal volumes and longer duration of CPS derived from the significantly smaller posterior hippocampal volumes in the CPS patients with longer duration of illness. Anterior hippocampal volumes, however, were unrelated to illness variables. In both the CPS and normal groups there was no statistically significant association of hippocampal volumes with age, gender, IQ, and perinatal variables. Our findings are similar to those of Scott et al. (2001) but unlike those of Lawson et al. (2000a,b) who found no significant hippocampal volume differences after controlling for the presence of intellectual disability (Lawson et al., 2000a,b; Nolan et al., 2004). Differences between our study and these studies in the type of seizure disorder, the intractability of seizures, tertiary versus community recruitment, patient IQ, and gender distribution, the type of control group, as well as the manner in which volumes were determined underscore

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the importance of replicating our findings on larger samples of CPS patients. More specifically, subjects included in our study had at least one seizure within a year of the study in contrast to the other previous studies that evaluated hippocampal volumes in patients with intractable epilepsies (Lawson et al., 2000a,b; Scott et al., 2001). In addition, while we recruited the majority of our CPS patients from the community, the other studies recruited their patients from epilepsy surgery (Scott et al., 2001) or tertiary centers (Lawson et al., 2000a,b; Scott et al., 2001). In contrast to the average-low average IQ of the patients in our study, these other studies had patients with IQ scores 1.6 standard deviations below agestandardized scores (Lawson et al., 2000a,b), intellectual disability that was mild in 21% (IQ = 56–70) and moderate/severe in 18% (IQ < 55) (Lawson et al., 2000a,b) or did not control for the effect of IQ (Scott et al., 2001). Our sample also included relatively more girls, whereas Lawson et al. (2000a,b) had more boys, and Scott et al. (2001) similar numbers of boys and girls. In addition, all the children in Scott et al. (2001) and 17% of those in Lawson et al. (2000a,b) had TLE, whereas the children in our study had CPS, 33% with a temporal focus, and 20% with a fronto-temporal focus. Furthermore, 50% of the patients in Scott et al. (2001) and 8% in Lawson et al.’s studies (Lawson et al., 2000a,b) but none of those in our study had a history of complex febrile convulsions. Like Lawson et al. (2000a,b), we used a control group of normal children recruited from the community, but Scott et al.’s control group consisted of the siblings of children with neurological disorders. Finally, in addition to total hippocampal volumes, and as described in Levitt et al. (2001), we differentiated anterior from posterior hippocampal volumes unlike the other pediatric epilepsy studies. Therefore, replicating our findings on a larger sample using this same technique is important. Our finding of increased anterior hippocampal vulnerability in CPS is similar to what has been described in imaging, neuropathology, and animal studies. Lin et al.’s finding of anterior volume loss in the contralateral hippocampus of surgically treated TLE adults with postoperative seizures compared to those with post surgical seizure control implies increased vulnerability of

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the anterior hippocampus. Babb et al. (1984a,b) have shown that mesial temporal cell loss in the anterior hippocampus is linked to focal spike activity in the anterior hippocampal formation, while reduced cell densities in both anterior and posterior hippocampus is related to widespread spiking throughout the hippocampal formation. A recent rat study demonstrated evolution of the anterior hippocampus into an epileptic focus following fluid percussion induced injury fronto-parietal seizures (D’Ambrosio et al., 2005). Similar to our study, several previous studies of longitudinal volume loss in adults with mesial TLE reported that the anterior hippocampus was preferentially affected (Woermann et al., 1998; Cook et al., 1992), while Quigg et al. (1997) showed diffuse hippocampal volume loss. In addition, as found in adults with TLE (Kalviainen et al., 1998; Tasch et al., 1999; Theodore et al., 1999; Salmenpera et al., 2001; Briellmann et al., 2002; Fuerst et al., 2003), increased duration of CPS was significantly related to reduction in total hippocampal volumes. The association of posterior, not anterior hippocampal volumes with increased duration of illness variable might shed some light on the on-going debate whether hippocampal structural abnormalities cause or result from seizures (see review in Lado et al., 2002). Thus, smaller anterior hippocampal volumes might reflect the underlying neuropathology causing CPS, as suggested by several researchers (Dam, 1980; Babb and Brown, 1987; Cook et al., 1992; O’Connor et al., 1996; Van Paesschen et al., 1997; Bernasconi et al., 2003) and emphasize the importance of considering the heterogeneity of the hippocampus. However, CPS might have a cumulative effect on the normal maturation of the posterior hippocampus. Evidence from animal models indicates that early onset seizures impair hippocampal development. Thus, early febrile seizures in very immature animals alter hippocampal connectivity even in the absence of cell loss or neurogenesis (Bender et al., 2003); prolonged seizures produce hippocampal and extrahippocampal injury (Sankar and Shin, 1998; Sankar et al., 2000a,b; Roch et al., 2002); and early onset seizures impair normal postnatal fascia dentata development leading to alterations in granule cell number and axon circuitry (Mathern et al., 2002a,b). The small sample size of the CPS subjects, the post hoc nature of the findings regarding the relationship between posterior not anterior hip-

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pocampal volumes with duration of illness, and the lack of evidence for a significant association between perinatal abnormalities and hippocampal volumes underscore the need for replication of our findings. Normal childhood studies indicate larger hippocampal volumes in healthy adolescent boys (Suzuki et al., 2005) but earlier prominent hippocampal maturation (Pfluger et al., 1999) and a positive correlation between hippocampal volume and cognitive ability in normal girls (Yurgelun-Todd et al., 2003). The younger mean age of the children in our study compared to the previously referenced normal developmental studies (Sowell and Jernigan, 1998; Giedd et al., 1999; Pfluger et al., 1999; Yurgelun-Todd et al., 2003; Suzuki et al., 2005) implies that our subjects might not yet have experienced puberty-related growth of the hippocampus. The lack of an association of hippocampal volumes with age, gender, and IQ in both the normal and CPS groups might reflect both the young mean age and relatively small number of boys in this study. The limitations of the present study include a relatively small sample size, multiple, yet hypothesis driven statistical comparisons, a greater proportion of girls than boys, possible parental memory bias for seizure-related information, few CPS subjects with right epileptic activity, and missing EEG data in 2 CPS subjects. Although the normal children in the study had high mean Full Scale IQ scores, we controlled for the IQ differences in all our analyses. In addition, the lack of a relationship with febrile convulsions might reflect the fact that none of our patients had a history of complex febrile convulsions. Furthermore, since we included children with seizures longer than five minutes in the prolonged seizure subgroup, their seizures might not be as prolonged as in other studies (Kuks et al., 1993; Szabo et al., 1999; Lawson et al., 2000a,b; Grunewald et al., 2001; Scott et al., 2001) and the associated impact on hippocampal volume, therefore, not as marked. With these limitations in mind, the findings demonstrate reduced total hippocampal volumes in medically treated children with CPS compared to normal children, primarily accounted for by significantly smaller anterior hippocampal volumes. In addition, they imply that anterior hippocampal volumes might reflect the underlying neuropathology of the illness, but smaller posterior hippocampal volumes might represent a cumulative effect of CPS. A more comprehensive

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