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AJNR Am J Neuroradiol. Author manuscript; available in PMC 2017 June 01. Published in final edited form as: AJNR Am J Neuroradiol. 2016 December ; 37(12): 2356–2362. doi:10.3174/ajnr.A4919.
Quantitative evaluation of medial temporal lobe morphology in children with febrile status epilepticus: Results of the FEBSTAT study
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Andrew C. McClelland, MD PhD, Department of Radiology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY William A. Gomes, MD PhD, Department of Radiology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY Shlomo Shinnar, MD PhD, Department of Neurology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY Department of Pediatrics, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY Department of Epidemiology and Population Health, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY
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Dale C Hesdorffer, PhD, GH Sergievsky Center, Epidemiology, Columbia University, New York, NY Emilia Bagiella, PhD, Department of Health Evidence and Policy, Mount Sinai School of Medicine, New York, New York
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Address all correspondence to: William A Gomes MD PhD, Division of Neuroradiology, Department of Radiology, Montefiore Medical Center, 111 East 210th St, Bronx, NY 10467, Tel: 718-920-4030, Fax: 718-798-7983, [email protected]. FEBSTAT Study Team: Montefiore and Jacobi Medical Centers, Bronx, NY: Shlomo Shinnar MD PhD (PI), Jacqueline Bello MD, William Gomes MD PhD, James Hannigan RT, Sharyn Katz R-EEGT, FASET, David Masur PhD, Solomon L. Moshé MD. Ruth Shinnar RN MSN, Erica Weiss PhD. Ann & Robert Lurie Children’s Hospital, Chicago, IL: Douglas Nordli MD (site PI), John Curran MD, Leon G Epstein MD, Andrew Kim MD, Diana Miazga, Julie Rinaldi PhD. Columbia University, New York, NY: Dale Hesdorffer PhD (site PI), Stephen Chan MD, Binyi Liu MS, Yokasta Tineo BA. Duke University Medical Center, Durham, NC: Darrell Lewis MD (site PI), Melanie Bonner PhD, Karen Cornett BS, MT, William Gallentine DO, James MacFall PhD, James Provenzale MD, Allen Song PhD, James Voyvodic PhD, Yuan Xu BS Eastern Virginia Medical School, Norfolk, VA: L. Matthew Frank MD (site PI), Joanne Andy RT, Terrie Conklin RN, Susan Grasso MD, Connie S. Powers R-EEG T, David Kushner MD, Susan Landers RT, Virginia Van de Water PhD. International Epilepsy Consortium/Department of Biostatistics, Virginia Commonwealth University, Richmond Virginia: Shumei Sun PhD (site PI), John M Pellock MD, Brian J Bush MSMIT, Lori L Davis BA, Xiaoyan Deng MS, Christiane Rogers, Cynthia Shier Sabo MS Mount Sinai Medical Center, NY NY: Emilia Bagiella PhD Virginia Commonwealth University, Richmond, VA: John M Pellock MD (site PI), Tanya Brazemore R-EEGT, James Culbert PhD, Kathryn O’Hara RN, Syndi Seinfeld DO, Jean Snow RT-R Additional Collaborators: Joan Conry MD Childrens National Medical Center, Safety Monitor; Tracy Glauser MD Cincinnati Childrens Medical Center, Genomics; Jeffrey L Noebels MD PhD, Baylor College of Medicine, Genetics Prior presentation of this work in abstract form: Andrew McClelland, Shinnar, S., Bello, J., Chan, S. and Gomes, W. Quantitative evaluation of medial temporal lobe morphology following febrile status epilepticus in children. American Society of Neuroradiology Annual Meeting. April 25–30, 2015. Chicago, Il.
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Darrell V Lewis, MD, Department of Pediatrics (Neurology), Duke University Medical Center, Durham, NC Jacqueline A Bello, MD, Department of Radiology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY Stephen Chan, MD, GH Sergievsky Center, Radiology, Columbia University, New York, NY James MacFall, PhD, Department of Radiology, Duke University Medical Center, Durham, NC Min Chen, GH Sergievsky Center, Epidemiology, Columbia University, New York, NY
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John M Pellock, MD, Department of Neurology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA Douglas R Nordli Jr, MD, Department of Neurology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL L. Mathew Frank, MD, Department of Neurology, Children’s Hospital of The King’s Daughters and Eastern Virginia Medical School, Norfolk, VA
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Solomon Moshe, MD, Department of Neurology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY Department of Pediatrics, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY Department of Neuroscience, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY Ruth C Shinnar, RN MSN, and Department of Neurology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY Shumei Sun, PhD Department of Biostatistics, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA
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for the FEBSTAT Study Team
Abstract Purpose—The pathogenesis of febrile status epilepticus is poorly understood, but prior studies suggest an association with temporal lobe abnormalities including hippocampal malrotation. We employ a quantitative morphometric method to assess the association between temporal lobe morphology and febrile status epilepticus.
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Methods—Brain MR imaging was obtained in children presenting with febrile status epilepticus and control subjects as part of the FEBSTAT study. Medial temporal lobe morphologic parameters were measured manually, including distance of the hippocampus from midline, hippocampal height:width ratio, hippocampal angle, collateral sulcus angle, and width of the temporal horn. Results—Temporal lobe morphologic parameters are correlated with presence of visual hippocampal malrotation; the strongest association is with left temporal horn width (p < 0.001, Adjusted OR 10.59). Multiple morphologic parameters correlate with febrile status epilepticus, encompassing both right and left sides. This association is statistically strongest in the right temporal lobe, whereas hippocampal malrotation is almost exclusively left-sided in this cohort. The association between temporal lobe measurements and febrile status epilepticus persists when the analysis is restricted to cases with visually normal imaging without hippocampal malrotation or other visually apparent abnormality.
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Conclusions—Several component morphological features of hippocampal malrotation are independently associated with febrile status epilepticus, even when complete hippocampal malrotation is absent. Unexpectedly, this association predominantly involves the right temporal lobe. These findings suggest that a spectrum of bilateral temporal lobe anomalies are associated with febrile status epilepticus in children. Hippocampal malrotation may represent a visually apparent subset of this spectrum. Keywords febrile status epilepticus; febrile seizures; imaging; hippocampal malformation
Introduction Author Manuscript
Prolonged febrile seizures are associated with subsequent development of epilepsy whereas brief febrile seizures are not1. The factors that predispose to prolonged febrile seizures are therefore of profound interest but are not well understood. The FEBSTAT study (Consequences of Prolonged Febrile Seizures in Childhood) is a prospective multi-center trial studying children who present with febrile status epilepticus (FSE), defined as febrile seizures lasting longer than 30 minutes, in comparison to a control group consisting of children presenting with brief, simple febrile seizures2. Initial evaluation of subjects in the FEBSTAT study identified several risk factors for FSE including the morphological anomaly hippocampal malrotation (HIMAL)3, 4. While these findings suggest a relationship between medial temporal lobe anatomical variation and FSE, the precise nature and extent of this relationship is not clear.
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Medial temporal lobe structural anatomy is the result of a complex developmental process in which the medial temporal lobe cortex infolds and rotates around the hippocampal gyrus5, 6. Qualitative descriptions of abnormal hippocampal morphology have been reported in a number of pathologic conditions, including temporal lobe epilepsy, both as an isolated finding7 and in association with other developmental abnormalities8. HIMAL is a specific anomaly of hippocampal development which has also been described by other terms including incomplete hippocampal inversion7. Published criteria for HIMAL vary slightly between reports but include an abnormally rounded, “globular” configuration of the
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hippocampus on coronal images, blurring of internal hippocampal architecture, abnormally medial location of the hippocampus, vertical orientation of the collateral sulcus, and enlargement of the temporal horn of the lateral ventricle (apparently reflecting medial displacement of the hippocampus). Visual interpretation of scans obtained in FEBSTAT revealed an increased incidence of HIMAL in subjects presenting with FSE, relative to control subjects, establishing HIMAL as a risk factor for FSE9. However, the specific morphologic features of HIMAL that are most associated with prolonged febrile seizures remain undefined. In addition, a substantial majority of scans in children with febrile seizures from the FEBSTAT study demonstrate no abnormality on visual interpretation. It is unclear what role variation in medial temporal lobe morphology may play in these visually normal subjects.
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The goal of this study was to elucidate the relationship between medial temporal lobe morphology and prolonged febrile seizures by performing a quantitative analysis of medial temporal lobe morphology in subjects from the FEBSTAT study. We address three primary questions: 1) Does the visual interpretation of HIMAL by experienced interpreters reflect quantitative variation in underlying temporal lobe morphology? 2) Of the individual morphological features of HIMAL, which are most strongly associated with FSE? 3) In subjects without HIMAL or other overt abnormality, does subtle variation in temporal lobe morphology predict FSE?
Materials and Methods Subject Groups and Imaging
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Cohort selection, patient recruitment, and imaging procedures for the FEBSTAT study have been described in detail previously2, 9, 10. All procedures were approved the Institutional Review Board for the Protection of Human Subjects at all participating institutions. Written informed consent was obtained from the parents of all subjects. FSE was defined as a provoked seizure where the sole acute provocation was fever (temperature >38.4°C, 101.0°F) without prior history of afebrile seizures and without evidence of an acute CNS infection or insult11. The 226 FSE subjects in this study were enrolled from three prospective studies as described previously12: 191 from the FESBSTAT cohort9, 23 from the Duke FEBSTAT pilot study13, and 12 from the Columbia first FS study14. A control group consisting of 96 children who presented with a simple febrile seizure (SFS) and who underwent baseline MRI imaging similar to those with FSE were also obtained from the Columbia study14. SFS are febrile seizures lasting fewer than 10 minutes without focal features and without recurrence during the febrile illness.15
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In FSE cases, 67% of scans were performed within three days of presentation and 88% were done within 7 days9. Seizure classification was performed by review of source documents by a central phenomenology core blind to EEG and MRI findings2. MRI sequences have been described in detail previously9, 10 and included coronal oblique T2-weighted fast spin echo sequences. All scans were performed at 1.5T. Visual analysis of MRIs was performed by two experienced American Board of Radiology-certified radiologists (J.A.B and S.C.) with Certificate of Advanced Qualification in Neuroradiology. MRI readers were informed about
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the subject age at the time of examination but were blinded to all other clinical parameters. HIMAL was scored as negative for HIMAL, left HIMAL, bilateral HIMAL, or equivocal. Hippocampal T2 signal was scored from 0 to 4 with 0=normal, 1=equivocal, 2=mildly abnormal T2 signal on ≥1 slices, 3=moderately abnormal, and 4=markedly abnormal throughout the hippocampus. All studies were read independently but discordant reads were discussed for consensus. For the purposes of this study, visually normal cases were those in which HIMAL was scored as negative for HIMAL and T2 signal was scored as 0. The results of the initial qualitative analysis from the baseline MRI scans have been reported previously9. Quantitative Image Analysis
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Quantitative evaluation of bilateral medial temporal lobe morphology was performed by manual measurement of pre-determined structures of interest on a T2-weighted coronal oblique image at the level of the cerebral aqueduct. All measurements were performed blind to all clinical data except patient age. The measurement strategy is illustrated in Figure 1. The subject’s midline was defined as a line through the cerebral aqueduct. Unless otherwise specified, measurements were performed parallel to the horizontal axis of the patient, defined as a line orthogonal to the subject’s mid-sagittal plane. Hippocampal shape was evaluated by calculating the ratio of hippocampal height to width. The medial aspect of the hippocampus was defined as point at the most medial extent of the hippocampal body as a distinct from the subiculum. The width of the hippocampus was defined by extending the longest line possible from the medial aspect of the hippocampus laterally to the border of the hippocampus and the temporal horn CSF. The hippocampal height was defined as the greatest extent of the hippocampal body orthogonal to the line defining the hippocampal width.
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Medial/lateral location of the hippocampus was evaluated at both the medial aspect of the hippocampus by the distance of the hippocampus from midline and at the lateral aspect of the hippocampus by the width of the temporal horn of the lateral ventricle. The distance of the hippocampus from midline was determined by measuring the distance from the subject’s midline to the medial aspect of the hippocampus. To account for differences in brain size, this distance of the hippocampus from midline was normalized to the distance of the uncus from midline, defined on the same image as the distance from midline to the most medial aspect of the temporal lobe. The width of the temporal horn of the lateral ventricle was defined as the distance from the most lateral aspect of the hippocampus to the most lateral aspect of the lateral CSF space. If a thin curvilinear CSF space extended from the lateral aspect of the temporal horn around the collateral eminence (see Figure 1, left side), this region was not included in the temporal horn width. Hippocampal rotation was evaluated by determining the angles of the hippocampus and the collateral sulcus. The angle of the hippocampus was defined as the angle of the line defining the hippocampal width as described above relative to the subject’s horizontal axis. The collateral sulcus angle was determined with a single line drawn through the middle of the collateral sulcus relative to the subject’s midline.
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HIMAL is reportedly associated with blurring of internal hippocampal architecture. However, internal hippocampal architecture is not reliably demonstrated at 1.5T in young children, the magnet strength utilized in the vast majority of the FEBSTAT cohort at initial presentation. This component of HIMAL therefore could not be assessed in this study.
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Scans in which accurate and comparable measurements could not be made due to imaging factors such as artifact, patient rotation, or slice selection were not included in this analysis. Of the 226 FSE subjects and 96 SFS subjects described above, 33 FSE subjects and 4 SFS subjects were excluded due to imaging features for a final analysis of 193 FSE subjects and 92 SFS subjects. In the majority of cases, all measurements were made from a single image. In several cases, one or both of the collateral sulci could not be identified on the chosen image. If the collateral sulcus could be identified on an adjacent slice, this measurement was included. If not, a collateral sulcus measurement was not included for that subject. Left collateral sulcus measurement was not obtained for 17 subjects, and right collateral sulcus measurement was not obtained for 8 subjects. In addition, right sided measurements were not included for a single case in which a choroidal fissure cyst distorted right medial temporal lobe anatomy. Statistical Analysis
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All analyses was performed in SAS 9.4, and P values ≤ 0.05 were considered statistically significant. Descriptive statistics for all MRI measurements were generated (Table 1). Univariate statistical comparisons were performed between the MRI measures and both HIMAL (present vs absent) and seizure duration (SFS vs FSE). Multivariate statistical analysis of the MRI data was then performed. Cutoff measurements were determined by conducting univariate logistic regression for each of the MRI measurements separately, with a binary outcome variable. This analysis was performed separately using as the outcome variable either the consensus determination of HIMAL (present versus absent) or subject seizure duration (FSE vs SFS). The optimal cutoff point was obtained for each of the measurements by selecting the one resulting in the maximum sum of sensitivity and specificity (Youden’s index)16 for the outcome variable (Table 4). From this, a dummy variable was created for each of the MRI measurements, based on the corresponding cutoffs. Values at or below the cutoff were the reference for each measurement. Univariate logistic analysis was repeated with the newly created dummy variables. Multivariate logistic regression analyses were then fit with all five MRI dummy variables. This was done separately for each side (left and right) for the seizure duration outcome variable. A similar analysis was conducted with seizure duration (FSE versus SFS) as the outcome variable.
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Results Relationship of medial temporal lobe morphology to visual HIMAL Descriptive statistics for the five bilateral measurements are detailed in Table 1. To determine whether our quantitative evaluation of medial temporal lobe morphology captured the subjective differences present in cases identified as HIMAL, we first evaluate the relationship between medial temporal lobe morphology and visual HIMAL. Because HIMAL was almost exclusively identified on the left side, we analyzed the relationship
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between left sided measurements and cases read as either left sided HIMAL or bilateral HIMAL. The cutoff for left sided measurements that maximize Youden’s index for distinguishing between cases with and without left-sided HIMAL are detailed in Table 2. Univariate logistic regression analysis using these cutoff values revealed significant associations between each of the five left sided measurements and the presence of left sided HIMAL (Table 2). In the final multivariate model, HIMAL was associated with an increased left lateral ventricle width (>0.5283 cm; p=0.0009), and a “rounder” hippocampus (hippocampal height:width ratio > 0.7502 cm; p=0.0332). A negative relationship was seen between HIMAL and the distance of the hippocampus from midline, with a value of this distance normalized to the distance of the uncus from midline > 1.4236 (p=0.0094). Although HIMAL was associated with a more vertical angle of the left hippocampus (> 178.4 degrees; p=0.0059) and a more vertical orientation of the collateral sulcus (> 56.26 degrees; p=0.0184) in the univariate logistic regression analysis, these relationships were not significant in the multivariate logistic regression analysis. Relationship of medial temporal lobe morphology to seizure duration
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We next evaluated the relationship between medial temporal lobe morphology and seizure duration, using a multivariate model approach similar to that employed for comparison of MRI measurements to HIMAL. The cutoffs for temporal lobe measurements to maximize Youden’s index for distinguishing between FSE and SFS are detailed in Table 3. In both univariate and multivariate logistic regression analysis, we find a significant relationship between increased width of the left lateral ventricle and FSE (Table 3). In the multivariate analysis, left lateral ventricle width > 0.169 cm is associated with FSE (p=0.0038). We also observe a relationship between multiple right sided measurements and FSE (Table 3). In the multivariate logistic regression model, FSE was associated with width of the right lateral ventricle > 0.202 cm (p 1.523 (p 0.660 (p 71.35 degrees (p 185.5 degrees (p 0.169 cm (p=0.0078) and normalized distance of the left hippocampus from midline > 1.51 (p=0.0315). FSE was associated with right lateral
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ventricle width > 0.202 cm (p 1.52 (p=0.0245), right hippocampal height:width > 0.6999 (p=0.0494), and right hippocampal angle > 185.5 degrees (p 0.53 cm predicts HIMAL with sensitivity 84.2%, specificity 86.1%, adjusted odds ratio 10.6). Decreased distance of the hippocampus from midline and increased hippocampal height:width ratio (i.e., a rounder hippocampus) are also strong predictors. These features of temporal lobe anatomy are easily measured on coronal MR images, and may provide a basis for improved consistency in the visual identification of HIMAL between interpreters. Angles of the hippocampus and collateral sulcus, in contrast, are not significant predictors of HIMAL in our multivariate model. While these features may be associated with HIMAL, lack of predictive value in our model suggests that variance of these features in the normal population may be sufficiently high to render them less helpful in the identification of HIMAL.
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The findings of this study suggest that subtle anatomical differences in temporal lobe morphology, not appreciable on visual inspection, are associated with, and may predispose to, prolonged febrile seizures. This suggestion is in keeping with a large body of prior evidence correlating subtle anatomical abnormalities found on automated, quantitative brain MRI analysis to various types of epilepsy23. Application of automated analysis techniques to young children, including the FEBSTAT cohort, is complicated by rapid brain growth and progressive myelination during this period. Nevertheless, we anticipate that application of similar automated or semi-automated techniques may further define the nature and extent of anatomical abnormalities associated with prolonged febrile seizures.
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The anatomical differences described in this article could, in theory, reflect either anomalous development of the temporal lobes or secondary degeneration resulting from pathological processes. We consider an anomaly of primary development the more likely explanation because subjects in the FEBSTAT cohort were previously healthy children who were scanned shortly after their first febrile seizure. Most of the measurements included in this study (e.g., distance of hippocampus from midline) are unlikely to change significantly in the acute post-ictal setting. The ratio of hippocampal height to width is an exception since it could, in theory, be affected by hippocampal edema. This is unlikely to be a significant confounding factor, however, since the relationship of increased hippocampal height:width ratio to FSE is unchanged after exclusion of cases with overt evidence of hippocampal edema (increased T2-weighted signal).
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Two limitations of the current study must be recognized. First, our results demonstrate an association between morphological variation in the medial temporal lobes and the duration of febrile seizures, in particular with FSE. While patients presenting with FSE are at increased risk of later epilepsy, further observation of the FEBSTAT cohort will be required to determine which subjects develop epilepsy and, accordingly, whether the medial temporal lobe anatomical anomalies considered here are risk factors for epilepsy.
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A second limitation of the current work is the use of only a single coronal image for our temporal lobe measurements. This was necessary given the time-intensive nature of manual measurements and the large size of the FEBSTAT cohort. Nevertheless, evaluation of the temporal lobe at a single anteroposterior location may result in underestimation of the incidence of anatomical anomalies of limited spatial extent. This limitation could be addressed through the use of automated whole-brain analysis techniques, as discussed above.
Conclusions In summary, we find that the morphological component features of HIMAL are independent predictors of FSE, even in the absence of HIMAL or other overt temporal lobe abnormalities. We conclude that a broader spectrum of subtly anomalous temporal lobe development exists that may confer increased risk for prolonged febrile seizures and resulting hippocampal injury. Those cases with HIMAL may represent a subset of this spectrum that is particularly amenable to visual identification. Further studies on other aspects of brain development in these children are planned.
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Acknowledgments Supported by NINDS grant 2R37 NS43209 (P.I. S. Shinnar, M.D., Ph.D) and NICHD grant 36867 (PI: D.C. Hesdorffer PhD).
Abbreviations HIMAL
hippocampal malrotation
FSE
febrile status epilepticus
SFS
simple febrile seizure
FEBSTAT
Consequences of Prolonged Febrile Seizures in Childhood
EEG
electroencephalography
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Figure 1.
Medial Temporal Lobe Morphological Measurements. Linear and angular measurements, shown in red, were obtained in relation to reference lines, shown in yellow. Measurements were obtained bilaterally; right side measurements are omitted here for clarity. Note presence of HIMAL in this subject. A, B: Distances of hippocampal formation and uncus from midline. C: Angle of hippocampal formation. D, E: Height and width of hippocampal formation. F: Width of temporal horn. G: Angle of collateral sulcus.
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Table 1
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Descriptive summary of the MRI measurements Measurement
N
Mean
Std Dev
Collateral Sulcus Angle
268
61.9534
12.3098
Lateral Ventricle Width
285
0.3604
0.2053
Hipp Angle
285
174.4526
12.5996
Hipp Heigth:Width
285
0.7129
0.1106
Hipp Distance from midline
285
1.5141
0.217
Collateral Sulcus Angle
277
68.9564
9.6766
Lateral Ventricle Width
284
0.257
0.158
Hipp Angle
284
184.1936
9.0709
Hipp Heigth:Width
284
0.6862
0.0919
Hipp Distance from midline
284
1.5267
0.2166
Left side
Right side
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Author Manuscript 0.8947
1.42
Hipp Distance from midline
0.8421
178.37
Hipp Angle 0.6842
0.8421
0.53
0.75
0.5789
56.26
Collateral Sulcus Angle
Lateral Ventricle Width
Hipp Heigth:Width
Sensitivity
Cut-off
Measurement
0.6988
0.7181
0.4595
0.861
0.7355
Specificity
0.05 (0.01, 0.23)
5.52 (2.02, 15.07)
0.22 (0.06, 0.78)
33.04 (9.16, 119.11)
0.26 (0.10, 0.68)
Unadjusted OR (95% CI)
AJNR Am J Neuroradiol. Author manuscript; available in PMC 2017 June 01. Published in final edited form as: AJNR Am J Neuroradiol. 2016 December ; 37(12): 2356–2362. doi:10.3174/ajnr.A4919.
Quantitative evaluation of medial temporal lobe morphology in children with febrile status epilepticus: Results of the FEBSTAT study
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Andrew C. McClelland, MD PhD, Department of Radiology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY William A. Gomes, MD PhD, Department of Radiology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY Shlomo Shinnar, MD PhD, Department of Neurology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY Department of Pediatrics, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY Department of Epidemiology and Population Health, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY
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Dale C Hesdorffer, PhD, GH Sergievsky Center, Epidemiology, Columbia University, New York, NY Emilia Bagiella, PhD, Department of Health Evidence and Policy, Mount Sinai School of Medicine, New York, New York
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Address all correspondence to: William A Gomes MD PhD, Division of Neuroradiology, Department of Radiology, Montefiore Medical Center, 111 East 210th St, Bronx, NY 10467, Tel: 718-920-4030, Fax: 718-798-7983, [email protected]. FEBSTAT Study Team: Montefiore and Jacobi Medical Centers, Bronx, NY: Shlomo Shinnar MD PhD (PI), Jacqueline Bello MD, William Gomes MD PhD, James Hannigan RT, Sharyn Katz R-EEGT, FASET, David Masur PhD, Solomon L. Moshé MD. Ruth Shinnar RN MSN, Erica Weiss PhD. Ann & Robert Lurie Children’s Hospital, Chicago, IL: Douglas Nordli MD (site PI), John Curran MD, Leon G Epstein MD, Andrew Kim MD, Diana Miazga, Julie Rinaldi PhD. Columbia University, New York, NY: Dale Hesdorffer PhD (site PI), Stephen Chan MD, Binyi Liu MS, Yokasta Tineo BA. Duke University Medical Center, Durham, NC: Darrell Lewis MD (site PI), Melanie Bonner PhD, Karen Cornett BS, MT, William Gallentine DO, James MacFall PhD, James Provenzale MD, Allen Song PhD, James Voyvodic PhD, Yuan Xu BS Eastern Virginia Medical School, Norfolk, VA: L. Matthew Frank MD (site PI), Joanne Andy RT, Terrie Conklin RN, Susan Grasso MD, Connie S. Powers R-EEG T, David Kushner MD, Susan Landers RT, Virginia Van de Water PhD. International Epilepsy Consortium/Department of Biostatistics, Virginia Commonwealth University, Richmond Virginia: Shumei Sun PhD (site PI), John M Pellock MD, Brian J Bush MSMIT, Lori L Davis BA, Xiaoyan Deng MS, Christiane Rogers, Cynthia Shier Sabo MS Mount Sinai Medical Center, NY NY: Emilia Bagiella PhD Virginia Commonwealth University, Richmond, VA: John M Pellock MD (site PI), Tanya Brazemore R-EEGT, James Culbert PhD, Kathryn O’Hara RN, Syndi Seinfeld DO, Jean Snow RT-R Additional Collaborators: Joan Conry MD Childrens National Medical Center, Safety Monitor; Tracy Glauser MD Cincinnati Childrens Medical Center, Genomics; Jeffrey L Noebels MD PhD, Baylor College of Medicine, Genetics Prior presentation of this work in abstract form: Andrew McClelland, Shinnar, S., Bello, J., Chan, S. and Gomes, W. Quantitative evaluation of medial temporal lobe morphology following febrile status epilepticus in children. American Society of Neuroradiology Annual Meeting. April 25–30, 2015. Chicago, Il.
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Darrell V Lewis, MD, Department of Pediatrics (Neurology), Duke University Medical Center, Durham, NC Jacqueline A Bello, MD, Department of Radiology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY Stephen Chan, MD, GH Sergievsky Center, Radiology, Columbia University, New York, NY James MacFall, PhD, Department of Radiology, Duke University Medical Center, Durham, NC Min Chen, GH Sergievsky Center, Epidemiology, Columbia University, New York, NY
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John M Pellock, MD, Department of Neurology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA Douglas R Nordli Jr, MD, Department of Neurology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL L. Mathew Frank, MD, Department of Neurology, Children’s Hospital of The King’s Daughters and Eastern Virginia Medical School, Norfolk, VA
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Solomon Moshe, MD, Department of Neurology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY Department of Pediatrics, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY Department of Neuroscience, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY Ruth C Shinnar, RN MSN, and Department of Neurology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY Shumei Sun, PhD Department of Biostatistics, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA
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for the FEBSTAT Study Team
Abstract Purpose—The pathogenesis of febrile status epilepticus is poorly understood, but prior studies suggest an association with temporal lobe abnormalities including hippocampal malrotation. We employ a quantitative morphometric method to assess the association between temporal lobe morphology and febrile status epilepticus.
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Methods—Brain MR imaging was obtained in children presenting with febrile status epilepticus and control subjects as part of the FEBSTAT study. Medial temporal lobe morphologic parameters were measured manually, including distance of the hippocampus from midline, hippocampal height:width ratio, hippocampal angle, collateral sulcus angle, and width of the temporal horn. Results—Temporal lobe morphologic parameters are correlated with presence of visual hippocampal malrotation; the strongest association is with left temporal horn width (p < 0.001, Adjusted OR 10.59). Multiple morphologic parameters correlate with febrile status epilepticus, encompassing both right and left sides. This association is statistically strongest in the right temporal lobe, whereas hippocampal malrotation is almost exclusively left-sided in this cohort. The association between temporal lobe measurements and febrile status epilepticus persists when the analysis is restricted to cases with visually normal imaging without hippocampal malrotation or other visually apparent abnormality.
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Conclusions—Several component morphological features of hippocampal malrotation are independently associated with febrile status epilepticus, even when complete hippocampal malrotation is absent. Unexpectedly, this association predominantly involves the right temporal lobe. These findings suggest that a spectrum of bilateral temporal lobe anomalies are associated with febrile status epilepticus in children. Hippocampal malrotation may represent a visually apparent subset of this spectrum. Keywords febrile status epilepticus; febrile seizures; imaging; hippocampal malformation
Introduction Author Manuscript
Prolonged febrile seizures are associated with subsequent development of epilepsy whereas brief febrile seizures are not1. The factors that predispose to prolonged febrile seizures are therefore of profound interest but are not well understood. The FEBSTAT study (Consequences of Prolonged Febrile Seizures in Childhood) is a prospective multi-center trial studying children who present with febrile status epilepticus (FSE), defined as febrile seizures lasting longer than 30 minutes, in comparison to a control group consisting of children presenting with brief, simple febrile seizures2. Initial evaluation of subjects in the FEBSTAT study identified several risk factors for FSE including the morphological anomaly hippocampal malrotation (HIMAL)3, 4. While these findings suggest a relationship between medial temporal lobe anatomical variation and FSE, the precise nature and extent of this relationship is not clear.
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Medial temporal lobe structural anatomy is the result of a complex developmental process in which the medial temporal lobe cortex infolds and rotates around the hippocampal gyrus5, 6. Qualitative descriptions of abnormal hippocampal morphology have been reported in a number of pathologic conditions, including temporal lobe epilepsy, both as an isolated finding7 and in association with other developmental abnormalities8. HIMAL is a specific anomaly of hippocampal development which has also been described by other terms including incomplete hippocampal inversion7. Published criteria for HIMAL vary slightly between reports but include an abnormally rounded, “globular” configuration of the
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hippocampus on coronal images, blurring of internal hippocampal architecture, abnormally medial location of the hippocampus, vertical orientation of the collateral sulcus, and enlargement of the temporal horn of the lateral ventricle (apparently reflecting medial displacement of the hippocampus). Visual interpretation of scans obtained in FEBSTAT revealed an increased incidence of HIMAL in subjects presenting with FSE, relative to control subjects, establishing HIMAL as a risk factor for FSE9. However, the specific morphologic features of HIMAL that are most associated with prolonged febrile seizures remain undefined. In addition, a substantial majority of scans in children with febrile seizures from the FEBSTAT study demonstrate no abnormality on visual interpretation. It is unclear what role variation in medial temporal lobe morphology may play in these visually normal subjects.
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The goal of this study was to elucidate the relationship between medial temporal lobe morphology and prolonged febrile seizures by performing a quantitative analysis of medial temporal lobe morphology in subjects from the FEBSTAT study. We address three primary questions: 1) Does the visual interpretation of HIMAL by experienced interpreters reflect quantitative variation in underlying temporal lobe morphology? 2) Of the individual morphological features of HIMAL, which are most strongly associated with FSE? 3) In subjects without HIMAL or other overt abnormality, does subtle variation in temporal lobe morphology predict FSE?
Materials and Methods Subject Groups and Imaging
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Cohort selection, patient recruitment, and imaging procedures for the FEBSTAT study have been described in detail previously2, 9, 10. All procedures were approved the Institutional Review Board for the Protection of Human Subjects at all participating institutions. Written informed consent was obtained from the parents of all subjects. FSE was defined as a provoked seizure where the sole acute provocation was fever (temperature >38.4°C, 101.0°F) without prior history of afebrile seizures and without evidence of an acute CNS infection or insult11. The 226 FSE subjects in this study were enrolled from three prospective studies as described previously12: 191 from the FESBSTAT cohort9, 23 from the Duke FEBSTAT pilot study13, and 12 from the Columbia first FS study14. A control group consisting of 96 children who presented with a simple febrile seizure (SFS) and who underwent baseline MRI imaging similar to those with FSE were also obtained from the Columbia study14. SFS are febrile seizures lasting fewer than 10 minutes without focal features and without recurrence during the febrile illness.15
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In FSE cases, 67% of scans were performed within three days of presentation and 88% were done within 7 days9. Seizure classification was performed by review of source documents by a central phenomenology core blind to EEG and MRI findings2. MRI sequences have been described in detail previously9, 10 and included coronal oblique T2-weighted fast spin echo sequences. All scans were performed at 1.5T. Visual analysis of MRIs was performed by two experienced American Board of Radiology-certified radiologists (J.A.B and S.C.) with Certificate of Advanced Qualification in Neuroradiology. MRI readers were informed about
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the subject age at the time of examination but were blinded to all other clinical parameters. HIMAL was scored as negative for HIMAL, left HIMAL, bilateral HIMAL, or equivocal. Hippocampal T2 signal was scored from 0 to 4 with 0=normal, 1=equivocal, 2=mildly abnormal T2 signal on ≥1 slices, 3=moderately abnormal, and 4=markedly abnormal throughout the hippocampus. All studies were read independently but discordant reads were discussed for consensus. For the purposes of this study, visually normal cases were those in which HIMAL was scored as negative for HIMAL and T2 signal was scored as 0. The results of the initial qualitative analysis from the baseline MRI scans have been reported previously9. Quantitative Image Analysis
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Quantitative evaluation of bilateral medial temporal lobe morphology was performed by manual measurement of pre-determined structures of interest on a T2-weighted coronal oblique image at the level of the cerebral aqueduct. All measurements were performed blind to all clinical data except patient age. The measurement strategy is illustrated in Figure 1. The subject’s midline was defined as a line through the cerebral aqueduct. Unless otherwise specified, measurements were performed parallel to the horizontal axis of the patient, defined as a line orthogonal to the subject’s mid-sagittal plane. Hippocampal shape was evaluated by calculating the ratio of hippocampal height to width. The medial aspect of the hippocampus was defined as point at the most medial extent of the hippocampal body as a distinct from the subiculum. The width of the hippocampus was defined by extending the longest line possible from the medial aspect of the hippocampus laterally to the border of the hippocampus and the temporal horn CSF. The hippocampal height was defined as the greatest extent of the hippocampal body orthogonal to the line defining the hippocampal width.
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Medial/lateral location of the hippocampus was evaluated at both the medial aspect of the hippocampus by the distance of the hippocampus from midline and at the lateral aspect of the hippocampus by the width of the temporal horn of the lateral ventricle. The distance of the hippocampus from midline was determined by measuring the distance from the subject’s midline to the medial aspect of the hippocampus. To account for differences in brain size, this distance of the hippocampus from midline was normalized to the distance of the uncus from midline, defined on the same image as the distance from midline to the most medial aspect of the temporal lobe. The width of the temporal horn of the lateral ventricle was defined as the distance from the most lateral aspect of the hippocampus to the most lateral aspect of the lateral CSF space. If a thin curvilinear CSF space extended from the lateral aspect of the temporal horn around the collateral eminence (see Figure 1, left side), this region was not included in the temporal horn width. Hippocampal rotation was evaluated by determining the angles of the hippocampus and the collateral sulcus. The angle of the hippocampus was defined as the angle of the line defining the hippocampal width as described above relative to the subject’s horizontal axis. The collateral sulcus angle was determined with a single line drawn through the middle of the collateral sulcus relative to the subject’s midline.
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HIMAL is reportedly associated with blurring of internal hippocampal architecture. However, internal hippocampal architecture is not reliably demonstrated at 1.5T in young children, the magnet strength utilized in the vast majority of the FEBSTAT cohort at initial presentation. This component of HIMAL therefore could not be assessed in this study.
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Scans in which accurate and comparable measurements could not be made due to imaging factors such as artifact, patient rotation, or slice selection were not included in this analysis. Of the 226 FSE subjects and 96 SFS subjects described above, 33 FSE subjects and 4 SFS subjects were excluded due to imaging features for a final analysis of 193 FSE subjects and 92 SFS subjects. In the majority of cases, all measurements were made from a single image. In several cases, one or both of the collateral sulci could not be identified on the chosen image. If the collateral sulcus could be identified on an adjacent slice, this measurement was included. If not, a collateral sulcus measurement was not included for that subject. Left collateral sulcus measurement was not obtained for 17 subjects, and right collateral sulcus measurement was not obtained for 8 subjects. In addition, right sided measurements were not included for a single case in which a choroidal fissure cyst distorted right medial temporal lobe anatomy. Statistical Analysis
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All analyses was performed in SAS 9.4, and P values ≤ 0.05 were considered statistically significant. Descriptive statistics for all MRI measurements were generated (Table 1). Univariate statistical comparisons were performed between the MRI measures and both HIMAL (present vs absent) and seizure duration (SFS vs FSE). Multivariate statistical analysis of the MRI data was then performed. Cutoff measurements were determined by conducting univariate logistic regression for each of the MRI measurements separately, with a binary outcome variable. This analysis was performed separately using as the outcome variable either the consensus determination of HIMAL (present versus absent) or subject seizure duration (FSE vs SFS). The optimal cutoff point was obtained for each of the measurements by selecting the one resulting in the maximum sum of sensitivity and specificity (Youden’s index)16 for the outcome variable (Table 4). From this, a dummy variable was created for each of the MRI measurements, based on the corresponding cutoffs. Values at or below the cutoff were the reference for each measurement. Univariate logistic analysis was repeated with the newly created dummy variables. Multivariate logistic regression analyses were then fit with all five MRI dummy variables. This was done separately for each side (left and right) for the seizure duration outcome variable. A similar analysis was conducted with seizure duration (FSE versus SFS) as the outcome variable.
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Results Relationship of medial temporal lobe morphology to visual HIMAL Descriptive statistics for the five bilateral measurements are detailed in Table 1. To determine whether our quantitative evaluation of medial temporal lobe morphology captured the subjective differences present in cases identified as HIMAL, we first evaluate the relationship between medial temporal lobe morphology and visual HIMAL. Because HIMAL was almost exclusively identified on the left side, we analyzed the relationship
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between left sided measurements and cases read as either left sided HIMAL or bilateral HIMAL. The cutoff for left sided measurements that maximize Youden’s index for distinguishing between cases with and without left-sided HIMAL are detailed in Table 2. Univariate logistic regression analysis using these cutoff values revealed significant associations between each of the five left sided measurements and the presence of left sided HIMAL (Table 2). In the final multivariate model, HIMAL was associated with an increased left lateral ventricle width (>0.5283 cm; p=0.0009), and a “rounder” hippocampus (hippocampal height:width ratio > 0.7502 cm; p=0.0332). A negative relationship was seen between HIMAL and the distance of the hippocampus from midline, with a value of this distance normalized to the distance of the uncus from midline > 1.4236 (p=0.0094). Although HIMAL was associated with a more vertical angle of the left hippocampus (> 178.4 degrees; p=0.0059) and a more vertical orientation of the collateral sulcus (> 56.26 degrees; p=0.0184) in the univariate logistic regression analysis, these relationships were not significant in the multivariate logistic regression analysis. Relationship of medial temporal lobe morphology to seizure duration
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We next evaluated the relationship between medial temporal lobe morphology and seizure duration, using a multivariate model approach similar to that employed for comparison of MRI measurements to HIMAL. The cutoffs for temporal lobe measurements to maximize Youden’s index for distinguishing between FSE and SFS are detailed in Table 3. In both univariate and multivariate logistic regression analysis, we find a significant relationship between increased width of the left lateral ventricle and FSE (Table 3). In the multivariate analysis, left lateral ventricle width > 0.169 cm is associated with FSE (p=0.0038). We also observe a relationship between multiple right sided measurements and FSE (Table 3). In the multivariate logistic regression model, FSE was associated with width of the right lateral ventricle > 0.202 cm (p 1.523 (p 0.660 (p 71.35 degrees (p 185.5 degrees (p 0.169 cm (p=0.0078) and normalized distance of the left hippocampus from midline > 1.51 (p=0.0315). FSE was associated with right lateral
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ventricle width > 0.202 cm (p 1.52 (p=0.0245), right hippocampal height:width > 0.6999 (p=0.0494), and right hippocampal angle > 185.5 degrees (p 0.53 cm predicts HIMAL with sensitivity 84.2%, specificity 86.1%, adjusted odds ratio 10.6). Decreased distance of the hippocampus from midline and increased hippocampal height:width ratio (i.e., a rounder hippocampus) are also strong predictors. These features of temporal lobe anatomy are easily measured on coronal MR images, and may provide a basis for improved consistency in the visual identification of HIMAL between interpreters. Angles of the hippocampus and collateral sulcus, in contrast, are not significant predictors of HIMAL in our multivariate model. While these features may be associated with HIMAL, lack of predictive value in our model suggests that variance of these features in the normal population may be sufficiently high to render them less helpful in the identification of HIMAL.
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The findings of this study suggest that subtle anatomical differences in temporal lobe morphology, not appreciable on visual inspection, are associated with, and may predispose to, prolonged febrile seizures. This suggestion is in keeping with a large body of prior evidence correlating subtle anatomical abnormalities found on automated, quantitative brain MRI analysis to various types of epilepsy23. Application of automated analysis techniques to young children, including the FEBSTAT cohort, is complicated by rapid brain growth and progressive myelination during this period. Nevertheless, we anticipate that application of similar automated or semi-automated techniques may further define the nature and extent of anatomical abnormalities associated with prolonged febrile seizures.
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The anatomical differences described in this article could, in theory, reflect either anomalous development of the temporal lobes or secondary degeneration resulting from pathological processes. We consider an anomaly of primary development the more likely explanation because subjects in the FEBSTAT cohort were previously healthy children who were scanned shortly after their first febrile seizure. Most of the measurements included in this study (e.g., distance of hippocampus from midline) are unlikely to change significantly in the acute post-ictal setting. The ratio of hippocampal height to width is an exception since it could, in theory, be affected by hippocampal edema. This is unlikely to be a significant confounding factor, however, since the relationship of increased hippocampal height:width ratio to FSE is unchanged after exclusion of cases with overt evidence of hippocampal edema (increased T2-weighted signal).
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Two limitations of the current study must be recognized. First, our results demonstrate an association between morphological variation in the medial temporal lobes and the duration of febrile seizures, in particular with FSE. While patients presenting with FSE are at increased risk of later epilepsy, further observation of the FEBSTAT cohort will be required to determine which subjects develop epilepsy and, accordingly, whether the medial temporal lobe anatomical anomalies considered here are risk factors for epilepsy.
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A second limitation of the current work is the use of only a single coronal image for our temporal lobe measurements. This was necessary given the time-intensive nature of manual measurements and the large size of the FEBSTAT cohort. Nevertheless, evaluation of the temporal lobe at a single anteroposterior location may result in underestimation of the incidence of anatomical anomalies of limited spatial extent. This limitation could be addressed through the use of automated whole-brain analysis techniques, as discussed above.
Conclusions In summary, we find that the morphological component features of HIMAL are independent predictors of FSE, even in the absence of HIMAL or other overt temporal lobe abnormalities. We conclude that a broader spectrum of subtly anomalous temporal lobe development exists that may confer increased risk for prolonged febrile seizures and resulting hippocampal injury. Those cases with HIMAL may represent a subset of this spectrum that is particularly amenable to visual identification. Further studies on other aspects of brain development in these children are planned.
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Acknowledgments Supported by NINDS grant 2R37 NS43209 (P.I. S. Shinnar, M.D., Ph.D) and NICHD grant 36867 (PI: D.C. Hesdorffer PhD).
Abbreviations HIMAL
hippocampal malrotation
FSE
febrile status epilepticus
SFS
simple febrile seizure
FEBSTAT
Consequences of Prolonged Febrile Seizures in Childhood
EEG
electroencephalography
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References 1. Shinnar S. Febrile Seizures and Mesial Temporal Sclerosis. Epilepsy Curr. 2003; 3:115–118. [PubMed: 15309049] 2. Hesdorffer DC, Shinnar S, Lewis DV, et al. Design and phenomenology of the FEBSTAT study. Epilepsia. 2012; 53:1471–1480. [PubMed: 22742587] 3. Hesdorffer DC, Shinnar S, Lewis DV, et al. Risk factors for febrile status epilepticus: a case-control study. J Pediatr. 2013; 163:1147–1151 e1141. [PubMed: 23809042]
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Figure 1.
Medial Temporal Lobe Morphological Measurements. Linear and angular measurements, shown in red, were obtained in relation to reference lines, shown in yellow. Measurements were obtained bilaterally; right side measurements are omitted here for clarity. Note presence of HIMAL in this subject. A, B: Distances of hippocampal formation and uncus from midline. C: Angle of hippocampal formation. D, E: Height and width of hippocampal formation. F: Width of temporal horn. G: Angle of collateral sulcus.
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Table 1
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Descriptive summary of the MRI measurements Measurement
N
Mean
Std Dev
Collateral Sulcus Angle
268
61.9534
12.3098
Lateral Ventricle Width
285
0.3604
0.2053
Hipp Angle
285
174.4526
12.5996
Hipp Heigth:Width
285
0.7129
0.1106
Hipp Distance from midline
285
1.5141
0.217
Collateral Sulcus Angle
277
68.9564
9.6766
Lateral Ventricle Width
284
0.257
0.158
Hipp Angle
284
184.1936
9.0709
Hipp Heigth:Width
284
0.6862
0.0919
Hipp Distance from midline
284
1.5267
0.2166
Left side
Right side
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Author Manuscript 0.8947
1.42
Hipp Distance from midline
0.8421
178.37
Hipp Angle 0.6842
0.8421
0.53
0.75
0.5789
56.26
Collateral Sulcus Angle
Lateral Ventricle Width
Hipp Heigth:Width
Sensitivity
Cut-off
Measurement
0.6988
0.7181
0.4595
0.861
0.7355
Specificity
0.05 (0.01, 0.23)
5.52 (2.02, 15.07)
0.22 (0.06, 0.78)
33.04 (9.16, 119.11)
0.26 (0.10, 0.68)
Unadjusted OR (95% CI)
