- Email: [email protected]
Morphological variations of hippocampal formation in epilepsy: Image, clinical and electrophysiological data
Epilepsy & Behavior 26 (2013) 67–70
Contents lists available at SciVerse ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Morphological variations of hippocampal formation in epilepsy: Image, clinical and electrophysiological data Ana Paula Andrade Hamad a,⁎, Henrique Carrete Jr. b, Marino Muxfeldt Bianchin c, Taissa Ferrari-Marinho a, Katia Lin a, Elza Márcia Targas Yacubian a, Luiz Celso Pereira Vilanova a, Eliana Garzon a, Luís Otávio Caboclo a, Américo Ceiki Sakamoto a, c a
Departamento de Neurologia e Neurocirurgia, Hospital São Paulo, Universidade Federal de São Paulo, Rua Napoleão de Barros, 865, Vila Clementino, São Paulo/SP, Brazil Departamento de Diagnóstico por Imagem, Universidade Federal de São Paulo, Rua Napoleão de Barros, 800, Vila Clementino, São Paulo/SP, Brazil c Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Av. dos Bandeirantes, 3900, Monte Alegre, Ribeirão Preto/SP, Brazil b
a r t i c l e
i n f o
Article history: Received 4 October 2012 Revised 12 October 2012 Accepted 15 October 2012 Available online 7 December 2012 Keywords: Hippocampal formation Hippocampal sclerosis Malformation of cortical development Magnetic resonance imaging Morphological variations Epilepsy
a b s t r a c t Morphological variations of hippocampal formation (MVHF) are observed in patients with epilepsy but also in asymptomatic individuals. The precise role of these findings in epilepsy is not yet fully understood. This study analyzes the hippocampal formation (HF) morphology of asymptomatic individuals (n=30) and of patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis (MTLE-HS) (n=68), patients with malformations of cortical development (MCD) (n=34), or patients with pure morphological variations of hippocampal formation (pure MVHF) (n=12). Main clinical and electrophysiological data of patients with MVHF were also analyzed. Morphological variations of hippocampal formation are more frequently observed in patients with MCD than in patients with MTLE-HS or in asymptomatic individuals. Patients with pure morphological variations of hippocampal formation showed higher incidence of extratemporal seizure onset. Refractoriness seems to be more associated with other abnormalities, like HS or MCD, than with the HF variation itself. Thus, although morphological HF abnormalities might play a role in epileptogenicity, they seem to contribute less to refractoriness. © 2012 Elsevier Inc. All rights reserved.
1. Introduction Temporal lobe epilepsy (TLE) is the most frequent focal epileptic syndrome in adults [1], and hippocampal sclerosis (HS) its most common pathological substrate [2]. Mesial temporal lobe epilepsy associated with hippocampal sclerosis (MTLE-HS) is a well-defined syndrome with seizures originating in the hippocampal formation (HF) and, occasionally, in the amygdala [3]. Some authors have also reported that variations in shape, orientation, and position of the HF can be observed in patients with malformations of cortical development (MCD), corpus callosum agenesis, congenital hydrocephaly, chromosomal disorders, or MTLE-HS [4–6]. Lehéricy et Abbreviations: MVHF, morphological variations of hippocampal formation; HF, hippocampal formation; MTLE-HS, mesial temporal lobe epilepsy associated with hippocampal sclerosis; MCD, malformations of cortical development; PHFD, pure hippocampal formation dysmorphism; TLE, temporal lobe epilepsy; HS, hippocampal sclerosis; MRI, magnetic resonance imaging. ⁎ Corresponding author at: Departamento de Neurologia e Neurocirurgia, Rua Napoleão de Barros, 865, Vila Clementino, São Paulo/SP, Brazil. Fax: +55 11 3888 2220. E-mail addresses: [email protected] (A.P.A. Hamad), [email protected] (H. Carrete), [email protected] (M.M. Bianchin), [email protected] (T. Ferrari-Marinho), [email protected] (K. Lin), [email protected] (E.M.T. Yacubian), [email protected] (L.C.P. Vilanova), [email protected] (E. Garzon), [email protected] (L.O. Caboclo), [email protected] (A.C. Sakamoto). 1525-5050/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2012.10.028
al. previously suggested that HF abnormalities might be the consequence of cortical developmental disorders in some patients [7]. This hypothesis was later reconsidered by other authors who observed that MVHF could be seen in patients with MTLE-HS, MCD, or even in healthy subjects [8–14]. However, the impact of these structural variations on clinical and neurophysiological aspects has been poorly explored. The objective of the present study was to observe the HF morphology of healthy individuals, of patients with MTLE-HS, of patients with MCD, and of patients with morphological HF variation without any other structural signs (pure MVHF). We also analyzed clinical and neurophysiological findings in patients with MVHF in order to improve our understanding of epilepsy associated with this HF variation. 2. Methods 2.1. Patients We analyzed the neuroimaging findings of 114 consecutive patients with MTLE-HS (n = 68), MCD (n = 34), or pure MVHF (n = 12), focusing on HF morphology. Data were also seen in a voluntary group of 30 healthy controls. From the selected group of patients with MVHF, we also analyzed the neurophysiological and clinical findings and compared them to those of patients with MTLE-HS. Patients and controls were selected at the Epilepsy Outpatient Clinic
68
A.P.A. Hamad et al. / Epilepsy & Behavior 26 (2013) 67–70
Fig. 1. Variations of HF morphology among different groups. A) Bilateral abnormalities of the hippocampal formations with globular shape, verticalization, and position, in the presence of malformation of cortical development — lissencephaly. B) The right side is normal, but there is left-sided abnormal hippocampal formation: a rounded, medially displaced left side of the hippocampus, a vertical collateral sulcus and an enlarged-appearing temporal horn. C) Bilateral abnormalities of the hippocampal formations with globular shape and verticalization, in the presence of a right hippocampus sclerosis.
of Hospital São Paulo, Universidade Federal de São Paulo. The study was approved by the Ethics Committee of our institution.
avoid type I error due to the large number of comparisons, results were considered significant only if p b 0.01.
2.2. Neuroimaging data
3. Results
All patients were scanned using 1.5-T MRI equipment (Gyroscan; Philips Medical System, Eindhoven, The Netherlands or Magneton Sonata; Siemens, Erlangen, Germany). Acquisition protocol included FLAIR, sagittal T1 and axial T2 sequences as well as coronal T2, FLAIR and IR sequences with slices perpendicular to the longest axis of the hippocampus. Images were independently analyzed by two neuroradiologists with expertise in epilepsy neuroimaging. Patients were defined as having MVHF when they presented at least one of the criteria previously suggested by Baulac et al. [8] and also used by Bernasconi et al. [10] — round or pyramidal in shape, in vertical orientation or medial positioning with respect to the temporal horn (Fig. 1). Patients were classified in four groups according to the etiology and the presence of MVHF: 1) MTLE-HS plus MVHF; 2) MCD plus MVHF; 3) pure MVHF; and 4) MTLE-HS without MVHF. Patients with MCD without MVHF were excluded from further analyses.
Demographic and clinical data were obtained from hospital charts. Interictal and ictal EEG findings and seizure data were collected from video-EEG recordings, lasting from 12 to 120 h, with scalp plus sphenoidal electrodes.
Table 1 shows the demographic data of the patients. Patients with MCD were significantly younger (p b 0.0001) when compared to the other patients. Variations of HF morphology among different groups are presented in Table 2. Variations of HF were observed in 30 (20.8%) of the 144 epilepsy patients. Of these, five were MTLE-HS patients (16.7% of the patients with MVHF and 7.4% of all MTLE-HS patients) and 13, MCD patients (43.3% of the patients with MVHF and 38.2% of all patients with MCD). The other 12 cases presented MVHF without any other structural abnormality (40% of all patients with MVHF). None of the 30 controls showed HF abnormalities. The frequency of each aspect of HF dysmorphism (shape, orientation or positioning) differed among groups. Morphological variations of hippocampal formation were significantly more frequent in the MCD group when compared to controls (Table 2). When the side of MVHF was evaluated, we noted a trend to a higher frequency of abnormalities in the left when compared to the right temporal lobe, although this did not reach statistical significance. Regarding the five patients with MTLE-HS plus MVHF, one presented HF abnormalities ipsilateral to the side of HS, one presented HF abnormalities contralateral to the side of HS, and the remaining three patients had unilateral HS but bilateral HF abnormalities.
2.4. Statistical analysis
3.1. Clinical characteristics of patients with MVHF
Categorical variables were assessed by the chi-square test or Fisher's exact test. The magnitudes of associations were measured by the odds ratio with the respective confidence intervals (O.R., 95% CI). Mean differences of numerical variables were analyzed by ANOVA with Tukey's honestly significant difference as a post hoc test. All data were analyzed using SPSS, Windows® (SPSS Inc.) and GraphPad Instat®, Windows® (GraphPad Software Inc.). In order to
Patients with all forms of MVHF (MTLE-HS plus MVHF, MCD plus MVHF, or pure MVHF) were compared to patients with MTLE-HS without MVHF. This later group of patients was chosen for comparison since MTLE-HS represents the most frequent epileptic syndrome in adults. Clinical data are presented in Table 3. Patients with MCD plus MVHF were younger, and their seizures started earlier. Twenty-one patients in the MTLE-HS without MVHF group (33.3%)
2.3. Clinical and neurophysiological data
Table 1 Demographic data.
Age — mean (SD) Sex (M/F), n
Control (n = 30)
MTLE-HS (n = 68)
MCD (n = 34)
Pure MVHF (n = 12)
Total (n = 144)
32.80 (8.90) 15/15
35.16 (9.53) 28/40
16.03 (11.10)⁎ 15/19
28.92 (13.85) 6/6
29.63 (12.75) 64/80
MTLE: mesial temporal lobe epilepsy; HS: hippocampal sclerosis; MCD: malformations of cortical development; MVHF: morphological variations of hippocampal formation; M: male; F: female. ⁎ Statistically significant (p b 0.0001).
A.P.A. Hamad et al. / Epilepsy & Behavior 26 (2013) 67–70 Table 2 Variation of hippocampal formation morphology among different groups. Groups Shape Controls (n = 30) MTLE-HS (n = 68) MCD (n = 34) Pure MVHF (n = 12) Orientation Controls (n = 30) MTLE-HS (n = 68) MCD (n = 34) Pure MVHF (n = 12) Position Controls (n = 30) MTLE-HS (n = 68) MCD (n = 34) Pure MVHF (n = 12)
69
Table 4 Ictal onset of seizures in MVHF groups.
No variation
Variation
p
30 (100%) 63 (92.7%) 23 (67.6%) 0 (0%)
0 (0%) 5 (7.3%) 11 (32.3%) 12 (100%)
0.32 0.0005⁎ b0.0001⁎
30 (100%) 66 (97.1%) 23 (67.6%) 5 (41.7%)
0 (0%) 2 (2.9%) 11 (32.3%) 7 (58.3%)
1.00 0.0005⁎ b0.0001⁎
30 (100%) 64 (94.1%) 24 (70.6%) 3 (25.0%)
0 (0%) 4 (5.9%) 10 (29.4%) 9 (75.0%)
0.31 0.0011⁎ b0.0001⁎
Seizure onset groups
Seizures recorded (n)
Temporal ipsilateral
Extratemporal
MTLE-HS/MVHF (n = 5) MDC/MVHF (n = 13) Pure MVHF (n = 12)
3 6 6
2 (66.7%) 0 2 (33.3%)
1 (33.3%) 6 (100%) 4 (66.7%)
MTLE: mesial temporal lobe epilepsy; HS: hippocampal sclerosis; MCD: malformations of cortical development; MVHF: morphological variations of hippocampal formation.
MTLE: mesial temporal lobe epilepsy; HS: hippocampal sclerosis; MCD: malformations of cortical development; MVHF: morphological variations of hippocampal formation. ⁎ Statistically significant (p b 0.05).
but no patient in the other groups had a past history of febrile seizure, with the difference being highly significant (OR = 30.86; 95% CI = 1.80 to 529.69; p b 0.0001). All patients with MTLE-HS without MVHF and those with MTLE-HS plus MVHF had clinical seizures suggestive of temporal lobe onset, while only seven patients (58.3%) with pure MVHF and four patients (30.8%) with MDC plus MVHF had clinical findings suggestive of temporal lobe seizure onset (O.R. = 172.74; 95% CI = 9.62 to 3102.80; p b 0.0001). All patients with MTLE-HS had seizures resistant to medical treatment. This finding contrasts with the observation that only three patients with pure MVHF (17.6%) and only four patients with MCD plus MVHF (44.4%) were pharmacologically resistant. Patients with MTLE-HS, with or without MVHF, were significantly more likely to be refractory to clinical treatment (O.R. = 55.54; 3.03 to 1018.70; p b 0.0001). 3.2. Neurophysiological findings of patients with MVHF Video-EEG monitoring was performed in 26 of the 30 patients with MVHF. The remaining four patients (one with MTLE-HS plus MVHF, two with MCD plus MVHF, and one with pure MVHF) had only EEG recordings. Interictal epileptic discharges (IEDs) were assessed in all patients. Seizures were registered in 15 (50%) patients during VEEG monitoring, with results presented in Table 4. Two patients with MTLE-HS plus bilateral MVHF presented ictal seizure onset ipsilateral to HS as evidenced by MRI. 4. Discussion In this study, we compared neuroimaging HF morphological findings and clinical variables in groups of patients with MTLE-HS, MCD, or pure MVHF. Neuroimaging findings of control individuals without epilepsy were also analyzed. Morphological variations of
hippocampal formation were significantly more frequent in patients with MCD than in patients with MTLE-HS or in normal individuals. The relevance of MRI for assessment of TLE was consolidated since the well-accepted characterization of HS findings [15–17]. Additionally, MCD findings in the temporal lobe, including abnormalities of mesial temporal structures, were demonstrated by MRI [7]. Later on, variations of HF shape, orientation or positioning were further described in patients with epilepsy [8–11,13,14]. The term “malformation” was first and only utilized by Baulac et al. based on the knowledge of the embryological development of the HF as well as on the presence of these findings in patients with well-defined MCD [8]. However, other authors later abandoned the term because there were no clear histopathological correlations available [9–14]. Some authors have reported the occurrence of MVHF in 6 to 18% of healthy individuals [9,10,12]. However, similar to our findings, other authors did not observe HF abnormalities in healthy individuals [8,11]. Differences in MVHF definition might account for this discrepancy. However, in a large study on 497 non-epilepsy patients, none of them fulfilled the criteria for HF malrotation [18]. The authors concluded that MVHF are a rare finding in patients without seizures and that HF malrotation is probably a pathological finding [18]. Thus, although some variations in HF might be observed in healthy individuals [19], more severe MVHF are probably pathological and more frequently observed in patients with epilepsy. Indeed, depending on the series, anatomical HF variations were observed in 14–25% of TLE patients, including those with MTLE-HS [9,12], and in 29.5% to 49% of MCD patients [10,11,14]. In our series, we observed HF abnormalities in 7.4% of MTLE-HS patients and in 38.2% of MCD patients. In agreement with other authors, we observed higher frequency of MVHF in MCD patients, suggesting that MVHF could be viewed as part of the MCD spectrum, as first suggested by Baulac et al. [8] and supported by others [12,14]. The development of HF is complete after 18 gestational weeks, when it assumes its ovoid shape and horizontal orientation. The HF is anatomically similar to the adult HF after 30 weeks of gestation [6,8], although its maturity and organization take place slower, spanning the second year of life, in parallel with the rest of cortical development [20,21]. Since MVHF might co-exist with different forms of MCD, it is tempting to suggest that HF abnormalities might occur at any time during gestation or even during the early post-gestational period. However, the number of patients studied was not sufficient to accurately correlate the type of HF variation
Table 3 Clinical characteristics in pure MTLE-HS without MVHF, MTLE-HS plus MVHF, pure MVHF, and MCD plus MVHF. Group variables
MTLE-HS without MVHF (n = 63)
MTLE-HS plus MVHF (n = 5)
Pure MVHF (n = 12)
MCD plus MVHF (n = 13)
p
Age — mean (SD) Sex (M/F), n Age of epilepsy onset — mean (SD) Febrile seizure (Y/N), n Clinical localization — T/ET Seizures control (Y/N), n
35.5 (9.3) 25/38 10.7 (9.2) 21/42⁎ 63/0 0/63
31.0 (13.0) 3/2 15.0 (11.0) 0/5 5/0⁎ 0/5⁎
28.9 (13.8) 5/7 15.9 (13.0) 0/12 7/5 3/9
11.1 (10.9)⁎ 7/6 4.6 (5.1) 0/13 4/9 4/9
b0.001⁎ 0.68 0.022 b0.005⁎ b0.001⁎ b0.0001⁎
MTLE: mesial temporal lobe epilepsy; HS: hippocampal sclerosis; MCD: malformations of cortical development; MVHF: morphological variations of hippocampal formation; M: male; F: female; Y: yes; N: no; T: temporal; ET: extratemporal. ⁎ Statistically significant (p b 0.05).
70
A.P.A. Hamad et al. / Epilepsy & Behavior 26 (2013) 67–70
with a specific time-related MCD process. Studies on larger patient series are necessary to further clarify these aspects. Regarding clinical differences, we observed that patients with MCD/MVHF presented seizures earlier in life when compared to other patients, in agreement with previous reports. It has already been established that the age at seizure onset varies according to the type of MCD and that the malformation defect itself can justify earlier seizure onset in this group of patients [8,22–25]. Febrile seizure (FS) is the most frequent initial precipitant injury (IPI) associated with MTLE-HS [3,22]. This association is well-known, but a cause–effect relationship is still a matter of intense research. It is still unclear if febrile seizure is the cause of HS or if there are pre-existent HF abnormalities that predispose patients to seizures [26,27]. In our cohort, we observed febrile seizures only in MTLE-HS patients. Also, it is interesting to observe that in one patient, the sclerotic hippocampus was contralateral to HF abnormalities. Thus, our findings support the hypothesis that febrile seizures cause MTLE-HS, whether or not the HF is dimorphic. Of course, this hypothesis does not exclude the possibility that some HF abnormalities might be a risk factor for HS development after febrile seizures or after other IPIs. Studies that followed children under 5 years of age after their first febrile status epilepticus (FS) have shown signal abnormality in 23% and some dysmorphology of HF (shape, position, internal architecture) in 17.19% [28,29]. Recently, it has been suggested that FS might lead to HS [30] or to HF abnormalities [31] but not to epilepsy [31]. Thus, to date, this question of the relationship between HF dysmorphism, FS and HS remains open. Regarding interictal EEG findings in MVHF patients, we observed that the frequency of temporal interictal epileptiform discharges in all groups was lower than that previously described for TLE [32,33]. This finding is probably justified for patients with MCD but is somewhat unexpected for MTLE/MVHF or pure MVHF patients. However, previous studies on MVHF patients observed the same finding, showing no linear correlation between the irritative zone and the morphological HF abnormalities [8,10]. The same was also observed for the ictal pattern. While MCD plus MVHF patients expectedly presented more extratemporal seizure onset, patients with pure MVHF showed a somewhat unexpected higher frequency of extratemporal seizure onset as well. Indeed, although MRI visible lesions are located in the temporal lobes, only 33.3% of seizures were suggestive of temporal lobe seizure onset. For this reason, these patients were not considered eligible for surgery. The methodological limitation with noninvasive EEG monitoring should be taken into account for this. Overall, our findings agree with previous reports [8,10] and should alert about the difficulty of presurgical evaluation of these patients. 5. Conclusions Taken together with previous findings, our data further suggest that refractoriness in patients with epilepsy with MVHF seems to be more associated with other abnormalities, like HS or occult MRI cortical dysplastic lesions, than with the HF variation itself. Thus, although morphological HF abnormalities might play a role in epileptogenicity, they seem to contribute less to refractoriness. We expect that reports on larger series of patients with epilepsy and controls with improved neuroimaging technique and detailed correlation with clinical, neurophysiological, and histopathological findings will clarify many of the questions that still remain open. References [1] Foldvary N, Klem G, Hammel J, Bingaman W, Najm I, Lüders H. The localizing value of ictal EEG in focal epilepsy. Neurology 2001;57:2022-8. [2] Babb TL. Pathology of the temporal lobe: hippocampal sclerosis. In: Lüders HO, Comair YG, editors. Epilepsy surgery. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2001. p. 901-6.
[3] Wieser HG, for the ILAE Commission on Neurosurgery of Epilepsy. ILAE Commission Report: mesial temporal lobe epilepsy with hippocampal sclerosis. Epilepsia 2004;45:695-714. [4] Sumi SM. Brain malformations in the trisomy 18 syndrome. Brain 1970;93: 821-30. [5] Atlas SW, Zimmerman RA, Bilaniuk LT, et al. Corpus callosum and limbic system: neuroanatomic MR evaluation of developmental anomalies. Radiology 1986;160: 355-62. [6] Baker LL, Barkovich AJ. The large temporal horn: MR analysis in developmental brain anomalies versus hydrocephalus. AJNR Am J Neuroradiol 1992;13: 115-22. [7] Lehéricy S, Dormont D, Sémah F, et al. Developmental abnormalities of the medial temporal lobe in patients with temporal lobe epilepsy. AJNR Am J Neuroradiol 1995;16:617-26. [8] Baulac M, De Grissac N, Hasboun D, et al. Hippocampal developmental change in patients with partial epilepsy: magnetic resonance imaging and clinical aspects. Ann Neurol 1998;44:223-33. [9] Peltier B, Hurtevent P, Trehan G, Derambure P, Pruvo JP, Soto-Ares G. MRI of hippocampal malformations in patients with intractable temporal lobe epilepsy. J Radiol 2005;86:69-75. [10] Bernasconi N, Kinay D, Andermann F, Antel S, Bernasconi A. Analysis of shape and positioning of the hippocampal formation: a MRI study in patients with partial epilepsy and healthy controls. Brain 2005;128:2442-52. [11] Montenegro MA, Kinay D, Cendes F, et al. Patterns of hippocampal abnormalities in malformations of cortical development. J Neurol Neurosurg Psychiatry 2006;77:367-71. [12] Bajic D, Kumlien E, Mattsson P, Lundberg S, Wang C, Raininko R. Incomplete hippocampal inversion—is there a relation to epilepsy? Eur Radiol 2009;19: 2544-50. [13] Gama HP, da Rocha AJ, Valério RM, da Silva CJ, Garcia LA. Hippocampal abnormalities in an MR imaging series of patients with tuberous sclerosis. AJNR Am J Neuroradiol 2010;31:1059-62. [14] Kuchukhidze G, Koppelstaetter F, Unterberger I, Dobesberger J, Walser G, Zamarian L, et al. Hippocampal abnormalities in malformations of cortical development: MRI study. Neurology 2010;74:1575-82. [15] Jackson GD, Berkovic SF, Tress BM, Kalnins RM, Fabinyi GLA, Bladin PF. Hippocampal sclerosis can be reliably detected by magnetic resonance imaging. Neurology 1990;40:1869-75. [16] Jackson GD. The diagnosis of hippocampal sclerosis: other techniques. Magn Reson Imaging 1995;13:1081-93. [17] Diehl B, Najm I, Mohamed A, et al. Fluid-attenuation inversion recovery: correlations of hippocampal cell densities with signal abnormalities. Neurology 2001;57: 1029-32. [18] Gamss RP, Slasky SE, Bello JA, Miller TS, Shinnar S. Prevalence of hippocampal malrotation in a population without seizures. AJNR Am J Neuroradiol 2009;30: 1571-3. [19] Bajic D, Wang C, Kumlien E, et al. Incomplete inversion of the hippocampus—a common developmental anomaly. Eur Radiol 2008;18:138-42. [20] Rakic P. Specification of cerebral areas. Science 1988;241:170-6. [21] Rakic P. Principles of neural cell migration. Experientia 1990;46:882-91. [22] French JA, Williamson PD, Thadani VM, et al. Characteristics of medial temporal lobe epilepsy: I. Results of history and physical examination. Ann Neurol 1993;34:774-80. [23] Cascino GD, Trenerry MR, So EL, et al. Routine EEG and temporal lobe epilepsy: relation to long-term EEG monitoring, quantitative MRI, and operative outcome. Epilepsia 1996;37:651-6. [24] Janszky J, Rásonyi G, Clemens Z, et al. Clinical differences in patients with unilateral hippocampal sclerosis and unitemporal or bitemporal epileptiform discharges. Seizure 2003;12:550-4. [25] Hardy SG, Miller JW, Holmes MD, et al. Factors predicting outcome of surgery for intractable epilepsy with pathologically verified mesial temporal sclerosis. Epilepsia 2003;44:565-8. [26] Jefferys JG. Hippocampal sclerosis and temporal lobe epilepsy: cause or consequence? Brain 1999;122:1007-8. [27] Tarkka R, Pääkkö E, Pyhtinen J, Uhari M, Rantala H. Febrile seizures and mesial temporal sclerosis: no association in a long term follow-up study. Neurology 2003;60:215-8. [28] Lewis DV, Bello JA, Chan S, et al. Hippocampal abnormalities subsequent to febrile status epilepticus: findings on early post-ictal MRI imaging. Epilepsia 2005;46(Suppl. 8):52. [29] Shinnar S, Hesdorffer DC, Nordli Jr DR, et al. Phenomenology of prolonged febrile seizures: results of the FEBSTAT study. Neurology 2008;71:170-6. [30] Provenzale JM, Barboriak DP, VanLandingham K, MacFall J, Delong D, Lewis DV. Hippocampal MRI signal hyperintensity after febrile status epilepticus is predictive of subsequent mesial temporal sclerosis. AJR Am J Roentgenol 2008;190:976-83. [31] Auer T, Barsi P, Bone B, et al. History of simple febrile seizures is associated with hippocampal abnormalities in adults. Epilepsia 2008;49:1562-9. [32] Williamson PD, French JA, Thadani VM, et al. Characteristics of medial temporal lobe epilepsy: II. Interictal and ictal scalp electroencephalography, neuropsychological testing, neuroimaging results, surgical results and pathology. Ann Neurol 1993;34: 781-7. [33] Caboclo LO, Garzon E, Oliveira PA, et al. Correlation between temporal pole MRI abnormalities and surface ictal EEG patterns in patients with unilateral mesial temporal lobe epilepsy. Seizure 2007;16:8–16.
Contents lists available at SciVerse ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Morphological variations of hippocampal formation in epilepsy: Image, clinical and electrophysiological data Ana Paula Andrade Hamad a,⁎, Henrique Carrete Jr. b, Marino Muxfeldt Bianchin c, Taissa Ferrari-Marinho a, Katia Lin a, Elza Márcia Targas Yacubian a, Luiz Celso Pereira Vilanova a, Eliana Garzon a, Luís Otávio Caboclo a, Américo Ceiki Sakamoto a, c a
Departamento de Neurologia e Neurocirurgia, Hospital São Paulo, Universidade Federal de São Paulo, Rua Napoleão de Barros, 865, Vila Clementino, São Paulo/SP, Brazil Departamento de Diagnóstico por Imagem, Universidade Federal de São Paulo, Rua Napoleão de Barros, 800, Vila Clementino, São Paulo/SP, Brazil c Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Av. dos Bandeirantes, 3900, Monte Alegre, Ribeirão Preto/SP, Brazil b
a r t i c l e
i n f o
Article history: Received 4 October 2012 Revised 12 October 2012 Accepted 15 October 2012 Available online 7 December 2012 Keywords: Hippocampal formation Hippocampal sclerosis Malformation of cortical development Magnetic resonance imaging Morphological variations Epilepsy
a b s t r a c t Morphological variations of hippocampal formation (MVHF) are observed in patients with epilepsy but also in asymptomatic individuals. The precise role of these findings in epilepsy is not yet fully understood. This study analyzes the hippocampal formation (HF) morphology of asymptomatic individuals (n=30) and of patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis (MTLE-HS) (n=68), patients with malformations of cortical development (MCD) (n=34), or patients with pure morphological variations of hippocampal formation (pure MVHF) (n=12). Main clinical and electrophysiological data of patients with MVHF were also analyzed. Morphological variations of hippocampal formation are more frequently observed in patients with MCD than in patients with MTLE-HS or in asymptomatic individuals. Patients with pure morphological variations of hippocampal formation showed higher incidence of extratemporal seizure onset. Refractoriness seems to be more associated with other abnormalities, like HS or MCD, than with the HF variation itself. Thus, although morphological HF abnormalities might play a role in epileptogenicity, they seem to contribute less to refractoriness. © 2012 Elsevier Inc. All rights reserved.
1. Introduction Temporal lobe epilepsy (TLE) is the most frequent focal epileptic syndrome in adults [1], and hippocampal sclerosis (HS) its most common pathological substrate [2]. Mesial temporal lobe epilepsy associated with hippocampal sclerosis (MTLE-HS) is a well-defined syndrome with seizures originating in the hippocampal formation (HF) and, occasionally, in the amygdala [3]. Some authors have also reported that variations in shape, orientation, and position of the HF can be observed in patients with malformations of cortical development (MCD), corpus callosum agenesis, congenital hydrocephaly, chromosomal disorders, or MTLE-HS [4–6]. Lehéricy et Abbreviations: MVHF, morphological variations of hippocampal formation; HF, hippocampal formation; MTLE-HS, mesial temporal lobe epilepsy associated with hippocampal sclerosis; MCD, malformations of cortical development; PHFD, pure hippocampal formation dysmorphism; TLE, temporal lobe epilepsy; HS, hippocampal sclerosis; MRI, magnetic resonance imaging. ⁎ Corresponding author at: Departamento de Neurologia e Neurocirurgia, Rua Napoleão de Barros, 865, Vila Clementino, São Paulo/SP, Brazil. Fax: +55 11 3888 2220. E-mail addresses: [email protected] (A.P.A. Hamad), [email protected] (H. Carrete), [email protected] (M.M. Bianchin), [email protected] (T. Ferrari-Marinho), [email protected] (K. Lin), [email protected] (E.M.T. Yacubian), [email protected] (L.C.P. Vilanova), [email protected] (E. Garzon), [email protected] (L.O. Caboclo), [email protected] (A.C. Sakamoto). 1525-5050/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2012.10.028
al. previously suggested that HF abnormalities might be the consequence of cortical developmental disorders in some patients [7]. This hypothesis was later reconsidered by other authors who observed that MVHF could be seen in patients with MTLE-HS, MCD, or even in healthy subjects [8–14]. However, the impact of these structural variations on clinical and neurophysiological aspects has been poorly explored. The objective of the present study was to observe the HF morphology of healthy individuals, of patients with MTLE-HS, of patients with MCD, and of patients with morphological HF variation without any other structural signs (pure MVHF). We also analyzed clinical and neurophysiological findings in patients with MVHF in order to improve our understanding of epilepsy associated with this HF variation. 2. Methods 2.1. Patients We analyzed the neuroimaging findings of 114 consecutive patients with MTLE-HS (n = 68), MCD (n = 34), or pure MVHF (n = 12), focusing on HF morphology. Data were also seen in a voluntary group of 30 healthy controls. From the selected group of patients with MVHF, we also analyzed the neurophysiological and clinical findings and compared them to those of patients with MTLE-HS. Patients and controls were selected at the Epilepsy Outpatient Clinic
68
A.P.A. Hamad et al. / Epilepsy & Behavior 26 (2013) 67–70
Fig. 1. Variations of HF morphology among different groups. A) Bilateral abnormalities of the hippocampal formations with globular shape, verticalization, and position, in the presence of malformation of cortical development — lissencephaly. B) The right side is normal, but there is left-sided abnormal hippocampal formation: a rounded, medially displaced left side of the hippocampus, a vertical collateral sulcus and an enlarged-appearing temporal horn. C) Bilateral abnormalities of the hippocampal formations with globular shape and verticalization, in the presence of a right hippocampus sclerosis.
of Hospital São Paulo, Universidade Federal de São Paulo. The study was approved by the Ethics Committee of our institution.
avoid type I error due to the large number of comparisons, results were considered significant only if p b 0.01.
2.2. Neuroimaging data
3. Results
All patients were scanned using 1.5-T MRI equipment (Gyroscan; Philips Medical System, Eindhoven, The Netherlands or Magneton Sonata; Siemens, Erlangen, Germany). Acquisition protocol included FLAIR, sagittal T1 and axial T2 sequences as well as coronal T2, FLAIR and IR sequences with slices perpendicular to the longest axis of the hippocampus. Images were independently analyzed by two neuroradiologists with expertise in epilepsy neuroimaging. Patients were defined as having MVHF when they presented at least one of the criteria previously suggested by Baulac et al. [8] and also used by Bernasconi et al. [10] — round or pyramidal in shape, in vertical orientation or medial positioning with respect to the temporal horn (Fig. 1). Patients were classified in four groups according to the etiology and the presence of MVHF: 1) MTLE-HS plus MVHF; 2) MCD plus MVHF; 3) pure MVHF; and 4) MTLE-HS without MVHF. Patients with MCD without MVHF were excluded from further analyses.
Demographic and clinical data were obtained from hospital charts. Interictal and ictal EEG findings and seizure data were collected from video-EEG recordings, lasting from 12 to 120 h, with scalp plus sphenoidal electrodes.
Table 1 shows the demographic data of the patients. Patients with MCD were significantly younger (p b 0.0001) when compared to the other patients. Variations of HF morphology among different groups are presented in Table 2. Variations of HF were observed in 30 (20.8%) of the 144 epilepsy patients. Of these, five were MTLE-HS patients (16.7% of the patients with MVHF and 7.4% of all MTLE-HS patients) and 13, MCD patients (43.3% of the patients with MVHF and 38.2% of all patients with MCD). The other 12 cases presented MVHF without any other structural abnormality (40% of all patients with MVHF). None of the 30 controls showed HF abnormalities. The frequency of each aspect of HF dysmorphism (shape, orientation or positioning) differed among groups. Morphological variations of hippocampal formation were significantly more frequent in the MCD group when compared to controls (Table 2). When the side of MVHF was evaluated, we noted a trend to a higher frequency of abnormalities in the left when compared to the right temporal lobe, although this did not reach statistical significance. Regarding the five patients with MTLE-HS plus MVHF, one presented HF abnormalities ipsilateral to the side of HS, one presented HF abnormalities contralateral to the side of HS, and the remaining three patients had unilateral HS but bilateral HF abnormalities.
2.4. Statistical analysis
3.1. Clinical characteristics of patients with MVHF
Categorical variables were assessed by the chi-square test or Fisher's exact test. The magnitudes of associations were measured by the odds ratio with the respective confidence intervals (O.R., 95% CI). Mean differences of numerical variables were analyzed by ANOVA with Tukey's honestly significant difference as a post hoc test. All data were analyzed using SPSS, Windows® (SPSS Inc.) and GraphPad Instat®, Windows® (GraphPad Software Inc.). In order to
Patients with all forms of MVHF (MTLE-HS plus MVHF, MCD plus MVHF, or pure MVHF) were compared to patients with MTLE-HS without MVHF. This later group of patients was chosen for comparison since MTLE-HS represents the most frequent epileptic syndrome in adults. Clinical data are presented in Table 3. Patients with MCD plus MVHF were younger, and their seizures started earlier. Twenty-one patients in the MTLE-HS without MVHF group (33.3%)
2.3. Clinical and neurophysiological data
Table 1 Demographic data.
Age — mean (SD) Sex (M/F), n
Control (n = 30)
MTLE-HS (n = 68)
MCD (n = 34)
Pure MVHF (n = 12)
Total (n = 144)
32.80 (8.90) 15/15
35.16 (9.53) 28/40
16.03 (11.10)⁎ 15/19
28.92 (13.85) 6/6
29.63 (12.75) 64/80
MTLE: mesial temporal lobe epilepsy; HS: hippocampal sclerosis; MCD: malformations of cortical development; MVHF: morphological variations of hippocampal formation; M: male; F: female. ⁎ Statistically significant (p b 0.0001).
A.P.A. Hamad et al. / Epilepsy & Behavior 26 (2013) 67–70 Table 2 Variation of hippocampal formation morphology among different groups. Groups Shape Controls (n = 30) MTLE-HS (n = 68) MCD (n = 34) Pure MVHF (n = 12) Orientation Controls (n = 30) MTLE-HS (n = 68) MCD (n = 34) Pure MVHF (n = 12) Position Controls (n = 30) MTLE-HS (n = 68) MCD (n = 34) Pure MVHF (n = 12)
69
Table 4 Ictal onset of seizures in MVHF groups.
No variation
Variation
p
30 (100%) 63 (92.7%) 23 (67.6%) 0 (0%)
0 (0%) 5 (7.3%) 11 (32.3%) 12 (100%)
0.32 0.0005⁎ b0.0001⁎
30 (100%) 66 (97.1%) 23 (67.6%) 5 (41.7%)
0 (0%) 2 (2.9%) 11 (32.3%) 7 (58.3%)
1.00 0.0005⁎ b0.0001⁎
30 (100%) 64 (94.1%) 24 (70.6%) 3 (25.0%)
0 (0%) 4 (5.9%) 10 (29.4%) 9 (75.0%)
0.31 0.0011⁎ b0.0001⁎
Seizure onset groups
Seizures recorded (n)
Temporal ipsilateral
Extratemporal
MTLE-HS/MVHF (n = 5) MDC/MVHF (n = 13) Pure MVHF (n = 12)
3 6 6
2 (66.7%) 0 2 (33.3%)
1 (33.3%) 6 (100%) 4 (66.7%)
MTLE: mesial temporal lobe epilepsy; HS: hippocampal sclerosis; MCD: malformations of cortical development; MVHF: morphological variations of hippocampal formation.
MTLE: mesial temporal lobe epilepsy; HS: hippocampal sclerosis; MCD: malformations of cortical development; MVHF: morphological variations of hippocampal formation. ⁎ Statistically significant (p b 0.05).
but no patient in the other groups had a past history of febrile seizure, with the difference being highly significant (OR = 30.86; 95% CI = 1.80 to 529.69; p b 0.0001). All patients with MTLE-HS without MVHF and those with MTLE-HS plus MVHF had clinical seizures suggestive of temporal lobe onset, while only seven patients (58.3%) with pure MVHF and four patients (30.8%) with MDC plus MVHF had clinical findings suggestive of temporal lobe seizure onset (O.R. = 172.74; 95% CI = 9.62 to 3102.80; p b 0.0001). All patients with MTLE-HS had seizures resistant to medical treatment. This finding contrasts with the observation that only three patients with pure MVHF (17.6%) and only four patients with MCD plus MVHF (44.4%) were pharmacologically resistant. Patients with MTLE-HS, with or without MVHF, were significantly more likely to be refractory to clinical treatment (O.R. = 55.54; 3.03 to 1018.70; p b 0.0001). 3.2. Neurophysiological findings of patients with MVHF Video-EEG monitoring was performed in 26 of the 30 patients with MVHF. The remaining four patients (one with MTLE-HS plus MVHF, two with MCD plus MVHF, and one with pure MVHF) had only EEG recordings. Interictal epileptic discharges (IEDs) were assessed in all patients. Seizures were registered in 15 (50%) patients during VEEG monitoring, with results presented in Table 4. Two patients with MTLE-HS plus bilateral MVHF presented ictal seizure onset ipsilateral to HS as evidenced by MRI. 4. Discussion In this study, we compared neuroimaging HF morphological findings and clinical variables in groups of patients with MTLE-HS, MCD, or pure MVHF. Neuroimaging findings of control individuals without epilepsy were also analyzed. Morphological variations of
hippocampal formation were significantly more frequent in patients with MCD than in patients with MTLE-HS or in normal individuals. The relevance of MRI for assessment of TLE was consolidated since the well-accepted characterization of HS findings [15–17]. Additionally, MCD findings in the temporal lobe, including abnormalities of mesial temporal structures, were demonstrated by MRI [7]. Later on, variations of HF shape, orientation or positioning were further described in patients with epilepsy [8–11,13,14]. The term “malformation” was first and only utilized by Baulac et al. based on the knowledge of the embryological development of the HF as well as on the presence of these findings in patients with well-defined MCD [8]. However, other authors later abandoned the term because there were no clear histopathological correlations available [9–14]. Some authors have reported the occurrence of MVHF in 6 to 18% of healthy individuals [9,10,12]. However, similar to our findings, other authors did not observe HF abnormalities in healthy individuals [8,11]. Differences in MVHF definition might account for this discrepancy. However, in a large study on 497 non-epilepsy patients, none of them fulfilled the criteria for HF malrotation [18]. The authors concluded that MVHF are a rare finding in patients without seizures and that HF malrotation is probably a pathological finding [18]. Thus, although some variations in HF might be observed in healthy individuals [19], more severe MVHF are probably pathological and more frequently observed in patients with epilepsy. Indeed, depending on the series, anatomical HF variations were observed in 14–25% of TLE patients, including those with MTLE-HS [9,12], and in 29.5% to 49% of MCD patients [10,11,14]. In our series, we observed HF abnormalities in 7.4% of MTLE-HS patients and in 38.2% of MCD patients. In agreement with other authors, we observed higher frequency of MVHF in MCD patients, suggesting that MVHF could be viewed as part of the MCD spectrum, as first suggested by Baulac et al. [8] and supported by others [12,14]. The development of HF is complete after 18 gestational weeks, when it assumes its ovoid shape and horizontal orientation. The HF is anatomically similar to the adult HF after 30 weeks of gestation [6,8], although its maturity and organization take place slower, spanning the second year of life, in parallel with the rest of cortical development [20,21]. Since MVHF might co-exist with different forms of MCD, it is tempting to suggest that HF abnormalities might occur at any time during gestation or even during the early post-gestational period. However, the number of patients studied was not sufficient to accurately correlate the type of HF variation
Table 3 Clinical characteristics in pure MTLE-HS without MVHF, MTLE-HS plus MVHF, pure MVHF, and MCD plus MVHF. Group variables
MTLE-HS without MVHF (n = 63)
MTLE-HS plus MVHF (n = 5)
Pure MVHF (n = 12)
MCD plus MVHF (n = 13)
p
Age — mean (SD) Sex (M/F), n Age of epilepsy onset — mean (SD) Febrile seizure (Y/N), n Clinical localization — T/ET Seizures control (Y/N), n
35.5 (9.3) 25/38 10.7 (9.2) 21/42⁎ 63/0 0/63
31.0 (13.0) 3/2 15.0 (11.0) 0/5 5/0⁎ 0/5⁎
28.9 (13.8) 5/7 15.9 (13.0) 0/12 7/5 3/9
11.1 (10.9)⁎ 7/6 4.6 (5.1) 0/13 4/9 4/9
b0.001⁎ 0.68 0.022 b0.005⁎ b0.001⁎ b0.0001⁎
MTLE: mesial temporal lobe epilepsy; HS: hippocampal sclerosis; MCD: malformations of cortical development; MVHF: morphological variations of hippocampal formation; M: male; F: female; Y: yes; N: no; T: temporal; ET: extratemporal. ⁎ Statistically significant (p b 0.05).
70
A.P.A. Hamad et al. / Epilepsy & Behavior 26 (2013) 67–70
with a specific time-related MCD process. Studies on larger patient series are necessary to further clarify these aspects. Regarding clinical differences, we observed that patients with MCD/MVHF presented seizures earlier in life when compared to other patients, in agreement with previous reports. It has already been established that the age at seizure onset varies according to the type of MCD and that the malformation defect itself can justify earlier seizure onset in this group of patients [8,22–25]. Febrile seizure (FS) is the most frequent initial precipitant injury (IPI) associated with MTLE-HS [3,22]. This association is well-known, but a cause–effect relationship is still a matter of intense research. It is still unclear if febrile seizure is the cause of HS or if there are pre-existent HF abnormalities that predispose patients to seizures [26,27]. In our cohort, we observed febrile seizures only in MTLE-HS patients. Also, it is interesting to observe that in one patient, the sclerotic hippocampus was contralateral to HF abnormalities. Thus, our findings support the hypothesis that febrile seizures cause MTLE-HS, whether or not the HF is dimorphic. Of course, this hypothesis does not exclude the possibility that some HF abnormalities might be a risk factor for HS development after febrile seizures or after other IPIs. Studies that followed children under 5 years of age after their first febrile status epilepticus (FS) have shown signal abnormality in 23% and some dysmorphology of HF (shape, position, internal architecture) in 17.19% [28,29]. Recently, it has been suggested that FS might lead to HS [30] or to HF abnormalities [31] but not to epilepsy [31]. Thus, to date, this question of the relationship between HF dysmorphism, FS and HS remains open. Regarding interictal EEG findings in MVHF patients, we observed that the frequency of temporal interictal epileptiform discharges in all groups was lower than that previously described for TLE [32,33]. This finding is probably justified for patients with MCD but is somewhat unexpected for MTLE/MVHF or pure MVHF patients. However, previous studies on MVHF patients observed the same finding, showing no linear correlation between the irritative zone and the morphological HF abnormalities [8,10]. The same was also observed for the ictal pattern. While MCD plus MVHF patients expectedly presented more extratemporal seizure onset, patients with pure MVHF showed a somewhat unexpected higher frequency of extratemporal seizure onset as well. Indeed, although MRI visible lesions are located in the temporal lobes, only 33.3% of seizures were suggestive of temporal lobe seizure onset. For this reason, these patients were not considered eligible for surgery. The methodological limitation with noninvasive EEG monitoring should be taken into account for this. Overall, our findings agree with previous reports [8,10] and should alert about the difficulty of presurgical evaluation of these patients. 5. Conclusions Taken together with previous findings, our data further suggest that refractoriness in patients with epilepsy with MVHF seems to be more associated with other abnormalities, like HS or occult MRI cortical dysplastic lesions, than with the HF variation itself. Thus, although morphological HF abnormalities might play a role in epileptogenicity, they seem to contribute less to refractoriness. We expect that reports on larger series of patients with epilepsy and controls with improved neuroimaging technique and detailed correlation with clinical, neurophysiological, and histopathological findings will clarify many of the questions that still remain open. References [1] Foldvary N, Klem G, Hammel J, Bingaman W, Najm I, Lüders H. The localizing value of ictal EEG in focal epilepsy. Neurology 2001;57:2022-8. [2] Babb TL. Pathology of the temporal lobe: hippocampal sclerosis. In: Lüders HO, Comair YG, editors. Epilepsy surgery. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2001. p. 901-6.
[3] Wieser HG, for the ILAE Commission on Neurosurgery of Epilepsy. ILAE Commission Report: mesial temporal lobe epilepsy with hippocampal sclerosis. Epilepsia 2004;45:695-714. [4] Sumi SM. Brain malformations in the trisomy 18 syndrome. Brain 1970;93: 821-30. [5] Atlas SW, Zimmerman RA, Bilaniuk LT, et al. Corpus callosum and limbic system: neuroanatomic MR evaluation of developmental anomalies. Radiology 1986;160: 355-62. [6] Baker LL, Barkovich AJ. The large temporal horn: MR analysis in developmental brain anomalies versus hydrocephalus. AJNR Am J Neuroradiol 1992;13: 115-22. [7] Lehéricy S, Dormont D, Sémah F, et al. Developmental abnormalities of the medial temporal lobe in patients with temporal lobe epilepsy. AJNR Am J Neuroradiol 1995;16:617-26. [8] Baulac M, De Grissac N, Hasboun D, et al. Hippocampal developmental change in patients with partial epilepsy: magnetic resonance imaging and clinical aspects. Ann Neurol 1998;44:223-33. [9] Peltier B, Hurtevent P, Trehan G, Derambure P, Pruvo JP, Soto-Ares G. MRI of hippocampal malformations in patients with intractable temporal lobe epilepsy. J Radiol 2005;86:69-75. [10] Bernasconi N, Kinay D, Andermann F, Antel S, Bernasconi A. Analysis of shape and positioning of the hippocampal formation: a MRI study in patients with partial epilepsy and healthy controls. Brain 2005;128:2442-52. [11] Montenegro MA, Kinay D, Cendes F, et al. Patterns of hippocampal abnormalities in malformations of cortical development. J Neurol Neurosurg Psychiatry 2006;77:367-71. [12] Bajic D, Kumlien E, Mattsson P, Lundberg S, Wang C, Raininko R. Incomplete hippocampal inversion—is there a relation to epilepsy? Eur Radiol 2009;19: 2544-50. [13] Gama HP, da Rocha AJ, Valério RM, da Silva CJ, Garcia LA. Hippocampal abnormalities in an MR imaging series of patients with tuberous sclerosis. AJNR Am J Neuroradiol 2010;31:1059-62. [14] Kuchukhidze G, Koppelstaetter F, Unterberger I, Dobesberger J, Walser G, Zamarian L, et al. Hippocampal abnormalities in malformations of cortical development: MRI study. Neurology 2010;74:1575-82. [15] Jackson GD, Berkovic SF, Tress BM, Kalnins RM, Fabinyi GLA, Bladin PF. Hippocampal sclerosis can be reliably detected by magnetic resonance imaging. Neurology 1990;40:1869-75. [16] Jackson GD. The diagnosis of hippocampal sclerosis: other techniques. Magn Reson Imaging 1995;13:1081-93. [17] Diehl B, Najm I, Mohamed A, et al. Fluid-attenuation inversion recovery: correlations of hippocampal cell densities with signal abnormalities. Neurology 2001;57: 1029-32. [18] Gamss RP, Slasky SE, Bello JA, Miller TS, Shinnar S. Prevalence of hippocampal malrotation in a population without seizures. AJNR Am J Neuroradiol 2009;30: 1571-3. [19] Bajic D, Wang C, Kumlien E, et al. Incomplete inversion of the hippocampus—a common developmental anomaly. Eur Radiol 2008;18:138-42. [20] Rakic P. Specification of cerebral areas. Science 1988;241:170-6. [21] Rakic P. Principles of neural cell migration. Experientia 1990;46:882-91. [22] French JA, Williamson PD, Thadani VM, et al. Characteristics of medial temporal lobe epilepsy: I. Results of history and physical examination. Ann Neurol 1993;34:774-80. [23] Cascino GD, Trenerry MR, So EL, et al. Routine EEG and temporal lobe epilepsy: relation to long-term EEG monitoring, quantitative MRI, and operative outcome. Epilepsia 1996;37:651-6. [24] Janszky J, Rásonyi G, Clemens Z, et al. Clinical differences in patients with unilateral hippocampal sclerosis and unitemporal or bitemporal epileptiform discharges. Seizure 2003;12:550-4. [25] Hardy SG, Miller JW, Holmes MD, et al. Factors predicting outcome of surgery for intractable epilepsy with pathologically verified mesial temporal sclerosis. Epilepsia 2003;44:565-8. [26] Jefferys JG. Hippocampal sclerosis and temporal lobe epilepsy: cause or consequence? Brain 1999;122:1007-8. [27] Tarkka R, Pääkkö E, Pyhtinen J, Uhari M, Rantala H. Febrile seizures and mesial temporal sclerosis: no association in a long term follow-up study. Neurology 2003;60:215-8. [28] Lewis DV, Bello JA, Chan S, et al. Hippocampal abnormalities subsequent to febrile status epilepticus: findings on early post-ictal MRI imaging. Epilepsia 2005;46(Suppl. 8):52. [29] Shinnar S, Hesdorffer DC, Nordli Jr DR, et al. Phenomenology of prolonged febrile seizures: results of the FEBSTAT study. Neurology 2008;71:170-6. [30] Provenzale JM, Barboriak DP, VanLandingham K, MacFall J, Delong D, Lewis DV. Hippocampal MRI signal hyperintensity after febrile status epilepticus is predictive of subsequent mesial temporal sclerosis. AJR Am J Roentgenol 2008;190:976-83. [31] Auer T, Barsi P, Bone B, et al. History of simple febrile seizures is associated with hippocampal abnormalities in adults. Epilepsia 2008;49:1562-9. [32] Williamson PD, French JA, Thadani VM, et al. Characteristics of medial temporal lobe epilepsy: II. Interictal and ictal scalp electroencephalography, neuropsychological testing, neuroimaging results, surgical results and pathology. Ann Neurol 1993;34: 781-7. [33] Caboclo LO, Garzon E, Oliveira PA, et al. Correlation between temporal pole MRI abnormalities and surface ictal EEG patterns in patients with unilateral mesial temporal lobe epilepsy. Seizure 2007;16:8–16.