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Age at epilepsy onset in patients with focal cortical dysplasias, gangliogliomas and dysembryoplastic neuroepithelial tumours
Accepted Manuscript Title: Age at epilepsy onset in patients with focal cortical dysplasias, gangliogliomas and dysembryoplastic neuroepithelial tumours Authors: Attila R´acz, Andreas-Markus Muller, ¨ Johannes Schwerdt, Albert Becker, Hartmut Vatter, Christian E. Elger PII: DOI: Reference:
S1059-1311(17)30860-9 https://doi.org/10.1016/j.seizure.2018.04.002 YSEIZ 3157
To appear in:
Seizure
Received date: Revised date: Accepted date:
28-12-2017 1-4-2018 3-4-2018
Please cite this article as: R´acz Attila, Muller ¨ Andreas-Markus, Schwerdt Johannes, Becker Albert, Vatter Hartmut, Elger Christian E.Age at epilepsy onset in patients with focal cortical dysplasias, gangliogliomas and dysembryoplastic neuroepithelial tumours.SEIZURE: European Journal of Epilepsy https://doi.org/10.1016/j.seizure.2018.04.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Age at epilepsy onset in patients with focal cortical dysplasias, gangliogliomas and dysembryoplastic neuroepithelial tumours
Attila Rácza*, Andreas-Markus Müllera*, Johannes Schwerdtb, Albert Beckerb, Hartmut
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Vatterc, Christian E. Elgera
aDepartment
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Affiliations:
of Epileptology, University of Bonn Medical Centre, Bonn, Germany
of Neuropathology, University of Bonn Medical Centre, Bonn, Germany
cDepartment
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Sigmund Freud Str. 25, 53105 Bonn, Germany
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bDepartment
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Sigmund Freud Str. 25, 53105 Bonn, Germany
of Neurosurgery, University of Bonn Medical Centre, Bonn, Germany
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Sigmund Freud Str. 25, 53105 Bonn, Germany
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*These authors contributed equally to this work
*Corresponding
author: Attila Rácz
Email: [email protected]
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Department of Epileptology University of Bonn Medical Centre Sigmund Freud Str. 25 53105 Bonn,Germany
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Highlights
Age at epilepsy onset was investigated in patients with FCDs and neuroglial tumors. The spectrum of age at epilepsy onset is very broad in both patient groups.
FCDs cause epilepsy earlier than neuroglial tumours.
Positive family history for epileptic seizures is more frequent in FCD-patients.
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Abstract Purpose:
The age at epilepsy onset in patients with inborn or very early acquired brain lesions
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depends on the epileptogenic potential of the lesion and the patients’ individual
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“susceptibility” to epileptic seizures. To gain insight into these determinants, we
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analysed the case history of patients with focal cortical dysplasias (FCDs) and
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neuroglial tumours.
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Methods:
In a systematic, retrospective analysis comprised of 233 patients who underwent
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surgery (116 with FCDs and 117 with neuroglial tumours), we evaluated the age at epilepsy onset according to histopathologic subgroups, lesion location and family
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history.
Results:
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Epilepsy onset was significantly earlier in patients with FCD than for those with neuroglial tumours (FCDs: 8.06 ± 0.74 years, gangliogliomas: 15.86 ± 1.24 years, dysembryoplastic neuroepithelial tumours (DNTs): 19.18 ± 2.47 years; p < 0.00001). FCDs were most frequently located in the frontal, whereas neuroglial tumours most frequently in the temporal lobe. For FCD patients, the age at epilepsy onset was not dependent on lesion location, whereas DNTs in a temporal location were associated 2
with a later epilepsy onset than gangliogliomas and extratemporal DNTs. A positive family history for epilepsy or epileptic seizures was found more frequently among patients with FCDs (FCDs: 20.4%, neuroglial tumours: 8.1%; p=0.013).
Conclusion: We postulate that the age difference at epilepsy onset between patients with FCDs
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and neuroglial tumours can be attributed – at least partially – to unidentified genetic factors underlying the epileptogenic potential of the brain tissue. Additionally, the large
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variance in the age at epilepsy onset is possibly also genetically determined.
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Keywords: focal cortical dysplasia, ganglioglioma, dysembryoplastic neuroepithelial
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Introduction
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tumour, epilepsy, age, genetics.
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Age at epilepsy onset varies characteristically among distinct etiologic groups of epilepsy. Well-known examples include age-related epilepsy syndromes such as benign partial epilepsy of childhood, childhood absence epilepsy (CAE) and juvenile
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myoclonic epilepsy (JME), etc (Wirrell et al., 2011; Hantus, 2011). Whereas these examples supposedly have a genetic background, symptomatic epilepsies are rarely coupled to specific ages, and generally show a broader distribution regarding age at epilepsy onset. However, inborn brain lesions, either vascular or inflammatory in origin,
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or malformations of cortical and brain development may also show a strong connection to certain age groups with respect to epilepsy onset. Focal cortical dysplasias (FCDs) are generally interpreted as a subgroup of malformations of cortical development (MCD), and are supposedly related to early developmental defects in the brain. Anomalies in proliferation of neuronal precursor
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cells, neuronal migration and cortical organisation can all contribute to the development of FCDs (Taylor et al., 1971; Palmini et al., 2004; Lim & Crino, 2013). The
currently
accepted
histopathologic
classification
scheme
(Palmini-Taylor
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classification, Palmini et al., 2004) underlies the diversity of FCDs at a cellular level and the different grades of disorganization in cortical structure; types Ia and Ib display cortical lamination defects and facultatively giant neurons, while type IIa and IIb exhibit
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dysmorphic and/or balloon cells (Palmini et al., 2004). Recent research has revealed
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possible genetic mechanisms which, in rare instances, underlie the formation of FCDs,
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especially the DEPDC5-pathway and its components NPRL2, NPRL3, PI3K and AKT
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(Schick et al., 2007a; Lim and Crino, 2013; Scheffer et al., 2014; Jansen et al., 2015; Scerri et al, 2015; Sim et al., 2016; reviewed by Neubauer and Hahn, 2016). An
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overlap between the described genetic factors and the genetic background of tuberous sclerosis (TS) leading to overactivation of the mTOR-signalling pathway is also well
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known, and reflects similarities in cellular abnormalities found both in FCD type IIb and TS lesions (TS cells referring to balloon cells in the histopathologic terminology, Lim &
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Crino, 2013). The epileptogenic potential of FCDs is thought to be different according to histopathologic subtypes (Rosenow et al., 1998). This is partly because of the differential electrical activity of distinct cellular constituents (dysmorphic neurons are
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electrically active; balloon cells are silent, Palmini, 2000), and most likely due to the extent and form of the "wiring" that connects pathologic with normal brain tissue. The versatility of FCDs is also reflected by the various epilepsy surgery outcomes (Keene et al., 1998; Chassoux et al., 2000; Kloss et al., 2002; Tassi et al., 2002; Fauser et al., 2004). 4
Neuroglial (or glioneural) tumours are also thought to arise during the early stages of brain maturation. The two main histopathologic types - gangliogliomas and dysembryoplastic
neuroepithelial
tumours
(DNT)
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are
frequent
causes
of
pharmacoresistant epilepsy (Daumas-Duport et al., 1988; Otsubo et al., 1991). As with FCDs, epilepsy surgery often results in seizure freedom for patients with neuroglial
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tumours (Morris et al., 1998; Thom et al., 2011; Bonney et al., 2015; Fallah et al., 2015; Radhakrishnan et al., 2016; Tandon et al., 2016; Tomita et al., 2016). Over the past few years, investigations have revealed possible genetic factors underlying the
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development of neuroglial tumours, especially that of the BRAF- (Schindler et al., 2011; Koelsche et al. 2013; Martinoni et al., 2015) and PI3K-pathway (Schick et al., 2007b) for gangliogliomas, and the FGFR1-pathway for DNTs (Qaddoumi et al., 2016;
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Rivera et al., 2016). Apart from these molecular signalling routes, distinct profiles of
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chromosomal copy number aberrations have also been described in neuroglial
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tumours (Prabowo et al., 2015).
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Even though the clinical practice clearly distinguishes between FCDs and neuroglial tumours, there is emerging evidence that the development of FCDs and neuroglial
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tumours may share common pathways (Samadani et al., 2007; Schick et al., 2007a; Schick et al., 2007b), and gangliogliomas may be interpreted in the context of
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mTORpathies as well (reviewed by Lim & Crino, 2013). This notion is also supported by histopathologic findings wherein neuroglial tumours and FCDs coexist in close
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proximity (Prayson, 2010), thus leading to the formation of a so-called FCD III (Blümcke et al., 2011). The epileptogenic potential of these lesions, and as a consequence the age at epilepsy
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onset, however, cannot be directly deduced from the above described genetic factors. Additionally, common experience reflects a broad age distribution with respect to age at
epilepsy
onset
in
respective
patients.
Further
determinants
influencing
epileptogenicity can be genetic as well as non-genetic mechanisms. In this study, we aimed at unveiling the variables influencing age at epilepsy onset, and gaining further 5
insight into possible, but yet unknown, genetic and non-genetic mechanisms influencing the development of epilepsy.
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Methods
We retrospectively evaluated the clinical history of 233 patients who underwent epilepsy surgical resection between 2000 and 2016 in the Epilepsy Centre of Bonn,
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Germany, and in whom a histopathologic evaluation confirmed the diagnosis of either an FCD or neuroglial tumour. The histopathologic (i.e. neuropathologic) evaluation was performed in the Department of Neuropathology of the University of Bonn Medical
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Centre, Germany. For the classification of FCDs, the Palmini-Taylor system was
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adopted (Palmini et al., 2004). In patients undergoing surgery before 2004, the
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histopathologic evaluation of the FCDs relied on the documented presence of TS-cells
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and additional characteristics described in the histopathology protocol. Gangliogliomas and DNTs were further subclassified according to the WHO system (see review of
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Holthausen and Blümcke, 2016).
Overall, 116 patients with FCDs (25 with FCD IIa and 81 with FCD IIb; in the remaining
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10 cases the histopathology either revealed FCD I or was not informative enough for further classification), 89 patients with gangliogliomas, and 28 patients with DNTs were
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included in our analysis. For the evaluation, we excluded patients with dual pathologies (for instance, associated hippocampal sclerosis in conjunction with neuroglial tumours in the temporal lobe); patients where the result of histopathologic examinations was
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discordant with that of previous interventions (in a few cases, resective surgery or a biopsy prior to surgery in our centre); and patients with alternative etiologies for epilepsy (i.e. one patient with coexistent SCN1A-mutation). The age at epilepsy onset (i.e. index seizure) was assessed based on patient charts and records. In most cases, at least two independent sources with concordant results were required for inclusion in 6
our study. Statistical analysis was performed with the statistical toolbox of MATLAB (MathWorks, Natick, USA). Within the framework of the descriptive statistics, cumulative and differential distribution functions (histograms) were computed to evaluate the age spectrum of the index seizure in different histopathologic categories. The statistical significance of differences between age distributions were evaluated
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with T-test, Mann-Whitney-U-test, Kruskal-Wallis test, and 2-way ANOVA depending on distribution characteristics of the examined variables and the number of compared distributions. Data were presented as mean values and standard errors of the mean, if
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not otherwise indicated. P-values below 0.05 were accepted as significant. Normality of distributions was assessed with a Lilliefors-test. As the majority of FCDs were located in the frontal lobe and most of the neuroglial tumours were within the temporal
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lobe, lesions in other lobes were summed up as “nonfrontal” and “extratemporal”
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respectively in order to avoid larger differences in sampling size. Differences in
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interregional distributions of lesions and in the family history of the respective patients
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were evaluated with Pearson’s Chi2 statistics.
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Results
We evaluated the clinical history of 116 patients with FCDs, 89 patients with
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gangliogliomas and 28 patients with DNTs who underwent epilepsy surgery between 2000 and 2016 after an extensive presurgical evaluation at the Department of Epileptology,
University
of
Bonn
Medical
Centre,
Germany.
Characteristic
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histopathologic features of these lesions are shown in Figure 1. Basic characteristics of the patient groups (sex, age at epilepsy onset, exact histopathologic type of lesion, location) are outlined in Table 1. Age at epilepsy onset displays a wide spectrum ranging from the first up to 43rd years of age for FCDs, and from the first up to the 60th years of age for neuroglial tumours (Figure 2A and B, displaying histograms for FCDs 7
and neuroglial tumours). In both cases, the evaluation of the histograms suggests that diverse subgroups may exist. Compared to patients with gangliogliomas and DNTs, the age at epilepsy onset was significantly earlier for patients with FCDs. However, the difference was not significant between the two histopathologic categories of neuroglial tumours (8.06 ± 0.74 years for 116 patients with FCD; 15.86 ± 1.24 years for 88
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patients with ganglioglioma and 19.18 ± 2.47 years for 28 patients with DNT; p < 0.00001, Kruskal-Wallis test with post hoc Tukey-Kramer adjustment for multiple comparisons; see Figures 3A and B).
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To evaluate the relevance of different histopathologic FCD subgroups as a possible variable influencing age at epilepsy onset, we also examined the variables in the groups with FCD type IIa and IIb, but this analysis did not reveal any differences (9.08
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± 1.66 years for 25 patients with FCD IIa and 7.60 ± 0.90 years for 81 patients with
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FCD IIb; p = 0.22, Mann-Whitney-U-test). Among neuroglial tumours the overwhelming
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majority belonged to WHO grade I (112 patients), higher grade developmental tumours
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were very rare (from the group of gangliogliomas 4 with grade II, 1 with grade III, DNTs were all grade I).
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There was no hint at gender differences regarding age at epilepsy onset in distinct histopathologic subgroups (p = 0.71 for FCDs, Mann-Whitney-U-test; p = 0.07 for
see Table 1).
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gangliogliomas, Mann-Whitney-U-test; and p = 0.80 for DNTs, T-test; for more detail
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FCDs were predominantly localized to the frontal lobe and appeared less frequently in temporal and occipital locations (71 frontal, 16 parietal, 9 temporal, 3 occipital, 16 multilobar or insular FCDs), whereas the preferential location of both gangliogliomas
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and DNTs was the temporal lobe (82 temporal, 11 frontal, 5 parietal, 4 occipital and 15 multilobar or insular locations). Differences in regional distributions of FCDs and neuroglial tumours also reached a statistical significance (p < 0.000001, Pearson's Chi2-test). Regional distributions of FCDs for types IIa and IIb did not differ significantly (p = 0.50, Pearson's Chi2-test; FCD IIa: 16 frontal, 3 parietal, 3 temporal, 1 occipital 8
and 2 multilobar or insular locations; FCD IIb: 50 frontal, 13 parietal, 3 temporal, 2 occipital and 12 multilobar or insular locations). On the other hand, regional distributions in the group of neuroglial tumours were somewhat different. Even though gangliogliomas and DNTs were most frequently located in the temporal lobe, frontal locations among DNTs were found relative frequently (p < 0.01, Pearson's Chi2-test;
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gangliogliomas: 67 temporal, 3 frontal, 3 parietal, 3 occipital and 13 multilobar or insular locations; DNTs: 15 temporal, 8 frontal, 2 parietal, 1 occipital and 2 multilobar locations).
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Lesions of the same histological subgroup may have different epileptogenic potentials according to their distinct location in the brain, and the properties of the network with which they interact. Therefore, we examined the age at epilepsy onset in the
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“preferential” and “non-preferential” locations of FCDs and neuroglial tumours. Even
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though the difference between FCDs in frontal versus nonfrontal locations was not
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significant (7.52 ± 0.83 years for 71 patients with frontal and 8.93 ± 1.42 years for 44
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patients with nonfrontal FCDs; p = 0.89, Mann-Whitney-U-test; subtype-specific analysis with 7.44 ± 1.18 years for 16 frontal FCD type IIa, 12.00 ± 4.08 years for 9
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nonfrontal FCD IIa, 7.22 ± 1.06 years for 50 frontal FCD IIb and 8.23 ± 1.66 years for 30 nonfrontal FCD IIb; p = 0.31 for histology effect, p = 0.15 for location effect and p =
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0.36 for interaction effects, 2-way ANOVA), there was a trend to develop epilepsy earlier in patients with neuroglial tumours in extratemporal versus temporal locations
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(17.68 ± 1.20 years for 81 patients with neuroglial tumours in temporal and 14.31 ± 2.42 years for 35 patients with extratemporal locations; p = 0.02, Mann-Whitney-Utest). Further analysis revealed that this effect was due to the relatively late epilepsy
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onset in patients with DNTs in temporal locations (15.97 ± 1.32 years for 66 temporal gangliogliomas, 15.55 ± 3.08 years for 22 extratemporal gangliogliomas, 25.20 ± 2.08 years for 15 temporal DNTs and 12.23 ± 4.01 years for 13 extratemporal DNTs; p = 0.26 for histology effect, p = 0.012 for location effect, and p = 0.019 for interaction effects, 2-way ANOVA with post hoc multiple comparisons). Because FCDs in the 9
temporal and occipital lobes and neuroglial tumours in parietal and occipital locations were rare, we were unable to perform a more detailed analysis for distinct lobes. In order to gain more insight into possible genetic components determining age at epilepsy onset, we also evaluated the family history for epileptic seizures or epilepsy in the respective patient collectives. For 98 of the 116 patients with FCD, we had reliable
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information on the family anamnesis, with 20 patients (20.4 %) displaying a positive family history. In patients with neuroglial tumours (117 cases), reliable information could be obtained in 99 cases, in which 8 patients (8.1 %) had a history of epilepsy or
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epileptic seizures in their family. Further details on patients with a positive family history are outlined in Table 2. The trend for more frequent positive family history in the group of FCD patients reached statistical significance (p = 0.013, Pearson’s Chi2-test).
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On the other hand, no statistically significant differences were found when comparing
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the age at epilepsy onset with positive versus negative family history either for FCDs
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(8.55 ± 2.15 years with positive and 8.68 ± 0.90 years with negative family history; p =
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0.32, Mann-Whitney-U-test) or neuroglial tumours (14.63 ± 3.45 years with positive and 17.59 ± 1.33 years with negative family history; p = 0.57, Mann-Whitney-U-test).
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This held also true when we performed a subtype-specific analysis for FCDs (5.50 ± 2.04 years for 8 FCD IIa in patients with positive, 12.08 ± 2.69 years for 13 FCD IIa in
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patients with negative, 10.58 ± 3.26 years for 12 FCD IIb in patients with positive and 7.86 ± 0.99 years for 59 FCD IIb in patients with negative family history; p = 0.85 for
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histology effect, p = 0.40 for family history effect and p = 0.046 for interaction effects, 2-way ANOVA, post hoc comparisons not revealing any statistically significant difference). Since there were only 2 patients with DNT and a positive family history for
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epileptic seizures, we did not perform a more detailed analysis of neuroglial tumours.
Discussion
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FCDs and neuroglial tumours are presumed to be either inborn brain lesions or lesions which are acquired at a very early age. Both types of lesions frequently result in an epilepsy which is difficult-to-treat from a pharmacological standpoint. Even though the epileptogenic lesion resides in the brain from an early age on, the question arises as to why some patients develop seizures very early while others only at a relatively “old”
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age. In this study, we analysed the age at epilepsy onset in patients with histologically proven FCDs, gangliogliomas and DNTs.
Some epileptic events might not be immediately recognised as epilepsy. One reason
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for this is that patients often wait longer before seeking for further medical evaluation (Firkin et al., 2015), and this phenomenon can lead to biases in epidemiological observational studies. Patients in our centre are interviewed by specialists who are
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well-trained in epileptology and the interview is always comprised of a very detailed
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description of seizures and seizure semiologies. Therefore, it is rather unlikely that
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significant discrepancies exist between the reported and exact onset of epilepsy in the
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respective cohorts.
Whereas the age spectrum is quite broad in each case (ranging from the first to the
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43rd years in patients with FCDs and from the first to the 60th years in patients with neuroglial tumours), patients with FCD tended to develop epilepsy earlier than patients
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with neuroglial tumours, as also reported in the literature (Hirabayashi et al., 1993; Blümcke et al., 2017). In addition, one might speculate that in each group different
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patient subgroups exist with different “predilection” age for epilepsy onset. As also described in the literature, preferential locations of FCDs are the frontal (meaning frontal and precentral locations) (Hirabayashi et al., 1993; Kloss et al., 2002), and that
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of neuroglial tumors are the temporal lobes (Otsubo et al., 1991; Thom et al., 2011; Radhakrishnan et al., 2016; Tomita et al., 2016; Blümcke et al., 2017). Different lesion locations (lobes) did not have a statistically significant impact on the age at epilepsy onset in case of FCDs, and were associated with a later age at epilepsy onset in case of temporal DNTs. A significantly different relation of distinct histopathologic subtypes 11
of FCDs (type IIa and IIb) to epilepsy onset seems – based on the actual results – not reasonable. However, at this point we need to emphasise that our study has a couple of restrictions. First of all, lesions in “non-canonical” locations (meaning FCDs outside the frontal and neuroglial tumours outside the temporal lobe) were infrequent and difficult
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to handle in a reasonable manner for statistics. Besides, FCD type II (meaning type IIa and IIb) is overrepresented among our patients, so our conclusions refer only to patients with these histopathological subgroups. This bias and the high percentage of
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FCD type IIb may be explained by circumstances in the presurgical evaluation, where patients with well-defined or more circumscribed lesions on MRI and more circumscribed focal epileptiform activity in EEG studies could have been preferentially
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selected as “optimal” candidates for epilepsy surgery. In addition, the groups with FCD
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type IIa and DNT were significantly smaller than those with FCD IIb and ganglioglioma,
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therefore results concerning these groups need to be interpreted cautiously.
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One possible reason as to why FCDs tend to cause epilepsy at earlier age may be related to the fact that FCDs are inborn malformations of cortical development (MCD)
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where the lesion has an epileptogenic potential from early ages on. On the other hand, neuroglial tumours might show a slight growth tendency and require more time to
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reach a certain “epileptogenic threshold”. An alternative explanation for the observed differences could be that neural elements of FCDs can be integrated in electrically
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active networks and cause network dysfunction and epileptic seizures in a direct manner, while cellular elements of neuroglial tumours are considered rather inactive, and the epileptogenic potential of these tumours resides in their indirect interaction
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with neighbouring brain tissue (reviewed by Fernández and Loddenkemper, 2017). Supporting this hypothesis, the intrinsic epileptogenicity of cortical dysplasias seems much higher than that of neuroglial tumours (Palmini et al., 1995; Rosenow et al., 1998; Aubert et al., 2009). Another possible explanation for the observed effects involves the ongoing maturation of brain regions and of subcortical connections which 12
often extends into adulthood, and the diverse kinetics of these processes in distinct anatomical structures (Lebel et al., 2008). Parallel to physiological networks, the time necessary for the development of pathological and epileptogenic networks may vary according to the type of lesion and its location. Our analysis does not satisfactorily explain the huge variability in age at epilepsy onset
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among the examined groups. Interestingly, a positive family history for epilepsy or epileptic seizures was observed more frequently in the patient group with FCDs than for the neuroglial tumour group. This observation must be interpreted with precaution
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in view of the relatively small number of cases and the heterogeneity of the epileptic manifestations in the affected families. However, it also supports the hypothesis that besides the above described and well-known, but also rather rare genetic defects -
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further genetic factors may influence the epileptogenic potential of lesions, the
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individual susceptibility of patients to seizures and as a consequence of these the age
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at epilepsy onset in patients with FCDs and neuroglial tumours. A recent report also
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emphasizes that genetic alterations of the mTOR-pathway as well as of SCN1A and GABRG2 genes are relatively common in patients with non-lesional focal epilepsy and
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a positive family history for epileptic seizures, and the age at epilepsy onset shows a correlation with the presence of these alterations (Perucca et al., 2017). In addition to
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genetic routes, epigenetic mechanisms can also contribute to the different epileptogenic potential of these lesions (reviewed by Kobow and Blümcke, 2017).
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In summary, further intense investigations are warranted to precisely identify the genetic and non-genetic influences shaping the evolution of epilepsy in patients with FCDs and neuroglial tumours. The broad spectrum of age at epilepsy onset not only
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reflects the differences in the epileptogenic potential of these lesions, but also the differences in individual patient susceptibility to epileptic seizures. Altogether we assume that besides the above mentioned and supposed genetic and non-genetic variables, several other factors influence the evolution of epilepsy.
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Conclusion
The age at epilepsy onset in patients with structural epilepsy can vary remarkably according to the underlying pathology. In this study, we evaluated patients who
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underwent surgery for histologically proven FCDs and neuroglial tumours. According to our results, FCDs lead to an earlier epilepsy onset than neuroglial tumours. Nevertheless, the age spectrum of epilepsy onset is very broad for both of these
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patient groups. At present, we could not positively identify further variables for determining age at epilepsy onset in these patient groups. However, the higher relative incidence of a positive family history for epileptic seizures or epilepsy in patients with
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FCDs suggests possible and unknown genetic factors influencing the epileptogenic
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potential of these brain alterations and the individual susceptibility of patients to
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epileptic seizures. Further clarification of these mechanisms and detailed analysis of
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currently known pathways (such as the mTOR-pathway) can lead to a better
therapeutic avenues.
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understanding of the pathophysiology of these patients and could open new
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Conflict of interest statement
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The authors have no conflicts of interest to declare.
Acknowledgements
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We are very grateful to Karen Wörmann for proficient English revision of the manuscript.
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Fallah A, Weil AG, Sur S, Miller I, Jayakar P, MOrrison G, Bhatia S, Ragheb J. (2015) Epilepsy surgery related to pediatric brain tumors: Miami Children's Hospital experience. J Neurosurg Pediatr, 16:675-80. Fernández IS, Loddenkemper T. (2017) Seizures caused by brain tumors in children. Seizure, 44:98107. Firkin AL, Marco DJT, Saya S, Newton MR, O’Brien TJ, Berkovic SF, McIntosh AM. (2015) Mind the gap: Multiple events and lengthy delays before presentation with a “first seizure”. Epilepsia, 56:15341541.
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Hantus S. Idiopathic generalized epilepsy syndromes of childhood and adolescence. 2011 In Wyllie's Treatment of Epilepsy - Principles and Practice, 2011, Fifth Edition, Wolters Kluwer, Lippincott Williams & Wilkins. pp: 258-268. Hirabayashi S, Binnie CD, Janota I, Polkey CE. (1993) Surgical treatment of epilepsy due to cortical dysplasia: clinical and EEG findings. J Neurol Neurosurg Psychiatry, 56:765-770. Holthausen H, Blümcke I. (2016) Epilepsy-associated tumors: what epileptologists should know about neuropathology, terminology, and classification systems. Epileptic Disord, 18:240-251.
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Lim KC, Crino PB. (2013) Focal malformations of cortical development: new vistas for molecular pathogenesis. Neuroscience, 252:262-276.
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Martinoni M, Marucci G, de Biase D, Rubboli G, Volpi L, Riguzzi P, Marliani F, Toni F, Naldi I, Bisulli F, Tinuper P, Michelucci R, Baruzzi A, Tallini G, Giulioni M. (2015) BRAF V600E mutation in neocortical posterior temporal epileptogenic gangliogliomas. J Clin Neurosci, 22:1250-1253.
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Neubauer BA, Hahn A. (2016) Fokale genetisch bedingte Epilepsiesyndrome - Neue Erkenntnisse in der Entstehung. Z Epileptol, 29:57-62. Otsubo H, Hoffmann HJ, Humphreys RP, Hendrick EB, Drake JM, Hwang PA, Becker LE, Chuang SH. (1990-1991) Evaluation, surgical approach and outcome of seizure patients with gangliogliomas. Pediatr Neurosurg, 16:208-212. Palmini A, Gambardella A, Andermann F, Dubeau F, da Costa JC, Olivier A, Tampieri D, Gloor P, Quesney F, Andermann E, Paglioli E, Paglioli-Neto E, Coutinho L, Leblanc R, Kim HI. (1995) Intrinsic epileptogenicity of human dysplastic cortex as suggested by corticography and surgical results. Annals of Neurology, 37: 476-487.
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Palmini A. (2000) Disorders of cortical development. Curr Opin Neurol, 13:183-192. Palmini A, Najm I, Avanzini G, Babb T, Guerrini R, Foldvary-Schaefer N, Jackson G, Lüders HO, Prayson R, Spreafico R, Vinters HV. (2004) Terminology and classification of the cortical dysplasias. Neurology, 62 (Suppl 3):S2-S8. Perucca P, Scheffer IE, Harvey AS, James PA, Lunke S, Thorne N, Gaff C, Regan BM, Damiano JA, Hildebrand MS, Berkovic SF, O’Brien TJ, Kwan P. (2017) Real-world utility of whole exome sequencing with targeted gene analysis for focal epilepsy. Epilepsy Research, 131:1-8.
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Prabowo AS, van Thuijl HF, Scheinin I, Sie D, van Essen HF, Iver AM; Spliet WG, Ferrier CH, van Rijen PC, Veersema TJ, Thom M, Schouten-van Meeteren AY, Reijneveld JC, Ylstra B, Wesseling P, Aronica E. (2015) Landscape of chromosomal copy number aberrations in gangliogliomas and dysembryoplastic neuroepithelial tumours. Neuropathol Appl Neurobiol, 41:743-755.
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Prayson RA. (2010) Tumours arising in the setting of paediatric chronic epilepsy. Pathology, 42:426431.
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Qaddoumi I, Orisme W, Wen J, Santiago T, Gupta K, Dalton JD, Tang B, Haupfear K, Punchihewa C, Easton J, Mulder H, Boggs K, Shao Y, Rusch M, Becksfort J, Gupta P, Wang S, Lee RP, Brat D, Peter Collins V, Dahiya S, George D, Konomos W, Kurian KM, McFadden K, Serafini LN, Nickols H, Perry A, Shurtleff S, Gajjar A, Boop FA, Klimo PD Jr, Mardis ER, Wilson RK, Baker SJ, Zhang J, Wu G, Downing JR, Tatevossian RG, Ellison DW. (2016) Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology. Acta Neuropathol, 131:833-845.
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Radhakrishnan A, Abraham M, Vilanilam G, Menon R, Menon D, Kumar H, Cherian A, Radhakrishnan N, Kesavadas C, Thomas B, Sarma SP, Thomas SV. (2016) Surgery for "Long-term epilepsy associated tumors (LETAs)": Seizure outcome and its predictors. Clin Neurol Neurosurg, 141:98-105.
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Rivera B, Gayden T, Carrot-Zhang J, Nadaf J, Boshari T, Faury D, Zeinieh M, Blanc R, Burk DL, Fahiminiya S, Bareke E, Schüller U, Monoranu CM, Sträter R, Kerl K, Niederstadt T, Kurlemann G, Ellezam B, Michalak Z, Thom M, Lockhart PJ, Leventer RJ, Ohm M, MacGregor D, Jones D, Karamchandani J, Greenwood CM, Berghuis AM, Bens S, Siebert R, Zakrzewska M, Liberski PP, Zakrzewski K, Sisodiya SM, Paulus W, Albrecht S, Hasselblatt M, Jabado N, Foulkes WD, Majewski J. (2016) Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors. Acta Neuropathol, 131:847-863. Rosenow F, Lüders HO, Dinner DS, Prayson RA, Mascha E, Wolgamuth BR, Comair YG, Bennett G. (1998) Histopathological correlates of epileptogenicity as expressed by electrocorticographic spiking and seizure frequency. Epilepsia, 39:850-856.
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Samadani U, Judkins AR, Akpalu A, Aronica E, Crino PB (2007) Differential cellular gene expression in ganglioglioma. Epilepsia, 48:646-653. Scerri T, Riseley JR, Gillies G, Pope K, Burgess R, Mandelstam SA, Dibbens L, Chow CW, Maixner W, Harvey AS, Jackson GD, Amor DJ, Delatycki MB, Crino PB, Berkovic SF, Scheffer IE, Bahlo M, Lockhart PJ, Leventer RJ. (2015) Familial cortical dysplasia type IIA caused by a germline mutation in DEPDC5. Ann Clin Transl Neurol, 2:575-580. Scheffer IE, Heron SE, Regan BM, Mandelstam S, Crompton DE, Hodgson BL, Licchetta L, Provini F, Bisulli F, Vadlamudi L, Gecz J, Connelly A, Tinuper P, Ricos MG, Berkovic SF, Dibbens LM. (2014)
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Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations. Ann Neurol, 75:782-787. Schick V, Majores M, Engels G, Hartmann W, Elger CE, Schramm J, Schoch S, Becker AJ (2007a) Differential Pi3K-pathway activation in cortical tubers and focal cortical dysplasias with balloon cells. Brain Pathol, 17:165-173. Schick V, Majores M, Koch A, Elger CE, Schramm J, Urbach H, Becker AJ (2007b) Alterations of phosphatidylinositol 3-kinase pathway components in epilepsy-associated glioneuronal lesions. Epilepsia, 48(Suppl. 5):65-73.
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Schindler G, Capper D, Meyer J, Janzarik W, Omran H, Herold-Mende C, Schmieder K, Wesseling P, Mawrin C, Hasselblatt M, Louis DN, Korshunov A, Pfister S, Hartmann C, Paulus W, Reifenberger G, von Deimling A (2011) Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol, 121:397-405.
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Sim JC, Scerri T, Fanjul-Fernández M, Riseley JR, Gillies G, Pope K, van Roozendaal H, Heng JI, Mandelstam SA, McGillivray G, MacGregor D, Kannan L, Maixner W, Harvey AS, Amor DJ, Delatycki MB, Crino PB, Bahlo M, Lockhart PJ, Leventer RJ. (2016) Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3. Ann Neurol, 79:132-137.
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Tandon V, Bansal S, Chandra PS, Suri A, Tripathi M, Sharma MC, Sarkari A, Mahapatra AK. (2016) Ganglioglioma: single-institutional experience of 24 cases with review of literature. Asian J Neurosurg, 11:407-411.
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Tassi L, Colombo N, Garbelli R, Francione S, Lo Russo G, Mai R, Cardinale F, Cossu M, Ferrario A, Galli C, Bramerio M, Citterio A, Spreafico R. (2002) Focal cortical dysplasia: neuropathological subtypes, EEG, neuroimaging and surgical outcome. Brain, 125:1719-1732.
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Taylor DC, Falconer MA, Bruton CJ, Corsellis JAN. (1971) Focal dysplasia of the cerebral cortex in epilepsy. J Neurol Neurosurg Psychiatry, 34:369-387.
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Thom M, Toma A, An S, Martinian L, Hadjivassiliou G, Ratilal B, Dean A, McEvoy A, Sisodiya SM, Brandner S. (2011) One hundred and one dysembryoplastic neuroepithelial tumors: An adult epilepsy series with immunohistochemical, molecular genetic, and clinical correlations and a review of the literature. J Neuropathol Exp Neurol, 70:859-878. Tomita T, Volk JM, Shen W, Pundy T. (2016) Glioneural tumors of cerebral hemisphere in children: correlation of surgical resection with seizure outcomes and tumor recurrences. Childs Nerv Syst, 32:1839-1848.
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Wirrell EC, Camfield CS, Camfiled PR. Idiopathic and benign partial epilepsies of childhood. 2011 In Wyllie's Treatment of Epilepsy - Principles and Practice, 2011, Fifth Edition, Wolters Kluwer, Lippincott Williams & Wilkins. pp: 243-257.
18
Figure legends Figure 1. The histopathology of focal cortical dysplasias (FCDs), gangliogliomas and dysembryoplastic neuroepithelial tumours (DNTs). A, B FCDs type IIb are
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characterized by the presence of dysplastic neurons (black arrows) and characteristic balloon cells (white arrows) scattered within normal brain tissue. Dysplastic neurons present with enlarged cell and nucleus diameters and perimembranous Nissl
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aggregation (arrowheads), whereas balloon cells show opalescent glassy eosinophilic cytoplasm and no Nissl substance. FCDs type IIa (not shown) are characterized by similar dysplastic neurons, but lack balloon cells. C Gangliogliomas (WHO grade I)
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present with clusters of enlarged dysplastic neurons (black arrows) within a matrix of
N
neoplastic astroglia. Occasional binucleation is encountered (arrowhead). D The
A
simple DNT variant (WHO grade I) is characterized by specific glioneural elements
M
consisting of floating neurons (black arrow) and columns of oligodendrocyte-like tumour cells (OLCs) (arrowheads) within an abundant myxoid matrix. H&E stainings.
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Scale bar in D for A–D 100 µm.
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Figure 2. Distribution of age at epilepsy onset in the analysed patient groups. Histograms of age at epilepsy onset in patients with FCDs (A) and neuroglial tumours
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(B).
Figure 3. FCDs cause epilepsy earlier than neuroglial tumours.
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Cumulative distribution plots of age at epilepsy onset in patients with FCDs and neuroglial tumours (A). Age at epilepsy onset is significantly earlier in patients with FCDs, compared to those with gangliogliomas and DNTs (B, Kruskal-Wallis test, with Tukey-Kramer correction for multiple comparisons).
19
A ED
PT
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U
N
A
M
Fig 1
20
A ED
PT
CC E
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U
N
A
M
Fig 2
21
A ED
PT
CC E
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U
N
A
M
Fig 3
22
Table 1. Basic characteristics of the analysed patient groups with histologically proven FCDs, gangliogliomas and DNTs. * In a few cases FCDs were classified as FCD I or a precise classification was not possible. ** In one case the precise location of an FCD of central location could not be determined unequivocally (precentral versus postcentral).
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*** As WHO grades II and III were very rare among gangliogliomas, age at onset was not analysed separately for WHO grades. DNTs were all grade I. Age at onset is
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shown for precise classifications only.
Table 2. Details on positive family history for epilepsy and epileptic seizures in patients
A
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PT
ED
M
A
N
U
with FCDs and neuroglial tumours.
23
FCD Females 50 8.28 ± 1.26 FCD IIb 81 7.60 ± 0.90 Nonfrontal 44 Parietal: 16 Temporal: 9 Occipital: 3 Multilobar or insular: 16 7.52 ± 0.83 8.93 ± 1.42 Positive Negative 20 78 8.55 ± 2.15 8.68 ± 0.90
U
Age at onset (years) Family history Number of patients Age at onset (years)
Ganglioglioma
M
ED PT
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15.97 ± 1.32 Positive 6 16.17 ± 4.23
Unclear 1
Unknown 18
Females 41 13.02 ± 1.43 WHO grade II 4 Extratemporal 22 Frontal: 3 Parietal: 3 Occipital: 3 Multilobar or insular: 13 15.55 ± 3.08 Negative 67 16.77 ± 1.49
Overall 89 15.86 ± 1.24 WHO grade III 1 Overall 89
Females 12 19.92 ± 4.16 Extratemporal 13 Frontal: 8 Parietal: 2 Occipital: 1 Multilobar: 2 12.23 ± 4.01 Negative
Overall 28 19.18 ± 2.47 Overall 28
N
Males 48 18.34 ± 1.91 WHO grade I 84 Temporal 67
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Gender Number of patients Age at onset (years) Histology*** Number of patients Location Number of patients
Age at onset (years) Family history Number of patients Age at onset (years)
Overall 116 8.06 ± 0.74 FCD I or no precise cl. 10
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Males 66 7.89 ± 0.89 FCD IIa 25 9.08 ± 1.66 Frontal 71
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Gender Number of patients Age at onset (years) Histology* Number of patients Age at onset (years) Location** Number of patients
15.86 ± 1.24 Unknown 14
DNT
Males 16 18.63 ± 3.09 Temporal 15
Age at onset (years) Family history
25.20 ± 2.08 Positive
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Gender Number of patients Age at onset (years) Location Number of patients
19.18 ± 2.47 Unknown 24
2 10.00 ± 6.00
22 20.18 ± 2.87
4
A
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A
N
U
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Number of patients Age at onset (years)
25
Table 2
1
Male Femal e
Temporal
14
Temporal
2
Male Femal e Male Femal e
Parietal
3
Male Male
Frontal Frontal
Male Femal e Femal e
Frontal
Male Male Male
Temporal Parietal Parietal
Parietal Occipital Frontooperculoins ular
Frontal Frontal
CC E A Ganglioglio ma
15 6 1
A
8 1 6
14
1
4 17 38
Male
Parietal
2
Male Femal e Femal e
Parietal
8
Male
Temporal
Male
Temporal
Male
Temporal
Parietal Occipital
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Frontal
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Male
U
2
father with oligoepilepsy (seizures between 12 and 27 years of age), sister with difficult-to-treat epilepsy and mental retardation, migration disorder in MRI cousin (paternal side) with epilepsy, no further details grandmother (maternal side), uncle (paternal side), no further details grandmother (maternal side) with a fever associated seizure 2 sisters (after 12 and 14 years of age), an aunt, an uncle, a cousin (paternal side) with epilepsy 2 cousins (maternal side), also hydrocephalus, neurologic syndrome classification not clarified sister with a fever associated seizure sister with seizures, treatment over 1 year, afterwards seizure free brother of grandmother (maternal side) with epilepsy during childhood mother with epilepsy, no further details aunt (maternal side) with epilepsy, no further details great-aunt and uncle with epilepsy (uncle’s epilepsy possibly related to alcohol consumption) grandmother with epilepsy after the age of 40, brother with peripartal hypoxia and status mother and grandfather (maternal side) with febrile seizures distant relative with epilepsy, no further details cousin with epilepsy, no further details father with epilepsy after 12 years of age (white spots on skin), under valproic acid seizure free, aunt (maternal side) with epilepsy or febrile seizures in childhood, cousin (maternal side) with febrile seizures younger brother with febrile seizure
N
Frontal
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FCD II b
Male
M
FCD II a
Lesion location
Onset (years) Family history
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Histology
Gend er
25 mother with epileptic seizures, no further details great-cousin (paternal side) with epilepsy, no 3 further details
17 cousin with epilepsy, no further details cousin of the grandmother (maternal side) with 23 epilepsy, no further details mother with epilepsy in later years of age, no 31 further details 26
Temporal
15 uncle with epilepsy, no further details uncle (maternal side) with grand mal epilepsy, another uncle (maternal side) with a not further classified seizure, brother with 10 myoclonic seizures uncle (paternal side) with epilepsy after the age 16 of 35
Insular Frontal Parietal
4 cousin (paternal side), no further details
A
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PT
ED
M
A
N
U
SC R
DNT
Femal e Femal e Femal e
mother with sleep associated seizures, under 1 lamotrigine seizure free
Temporal
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Femal e Femal e
27
S1059-1311(17)30860-9 https://doi.org/10.1016/j.seizure.2018.04.002 YSEIZ 3157
To appear in:
Seizure
Received date: Revised date: Accepted date:
28-12-2017 1-4-2018 3-4-2018
Please cite this article as: R´acz Attila, Muller ¨ Andreas-Markus, Schwerdt Johannes, Becker Albert, Vatter Hartmut, Elger Christian E.Age at epilepsy onset in patients with focal cortical dysplasias, gangliogliomas and dysembryoplastic neuroepithelial tumours.SEIZURE: European Journal of Epilepsy https://doi.org/10.1016/j.seizure.2018.04.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Age at epilepsy onset in patients with focal cortical dysplasias, gangliogliomas and dysembryoplastic neuroepithelial tumours
Attila Rácza*, Andreas-Markus Müllera*, Johannes Schwerdtb, Albert Beckerb, Hartmut
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Vatterc, Christian E. Elgera
aDepartment
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Affiliations:
of Epileptology, University of Bonn Medical Centre, Bonn, Germany
of Neuropathology, University of Bonn Medical Centre, Bonn, Germany
cDepartment
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Sigmund Freud Str. 25, 53105 Bonn, Germany
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bDepartment
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Sigmund Freud Str. 25, 53105 Bonn, Germany
of Neurosurgery, University of Bonn Medical Centre, Bonn, Germany
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Sigmund Freud Str. 25, 53105 Bonn, Germany
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*These authors contributed equally to this work
*Corresponding
author: Attila Rácz
Email: [email protected]
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Department of Epileptology University of Bonn Medical Centre Sigmund Freud Str. 25 53105 Bonn,Germany
1
Highlights
Age at epilepsy onset was investigated in patients with FCDs and neuroglial tumors. The spectrum of age at epilepsy onset is very broad in both patient groups.
FCDs cause epilepsy earlier than neuroglial tumours.
Positive family history for epileptic seizures is more frequent in FCD-patients.
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Abstract Purpose:
The age at epilepsy onset in patients with inborn or very early acquired brain lesions
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depends on the epileptogenic potential of the lesion and the patients’ individual
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“susceptibility” to epileptic seizures. To gain insight into these determinants, we
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analysed the case history of patients with focal cortical dysplasias (FCDs) and
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neuroglial tumours.
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Methods:
In a systematic, retrospective analysis comprised of 233 patients who underwent
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surgery (116 with FCDs and 117 with neuroglial tumours), we evaluated the age at epilepsy onset according to histopathologic subgroups, lesion location and family
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history.
Results:
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Epilepsy onset was significantly earlier in patients with FCD than for those with neuroglial tumours (FCDs: 8.06 ± 0.74 years, gangliogliomas: 15.86 ± 1.24 years, dysembryoplastic neuroepithelial tumours (DNTs): 19.18 ± 2.47 years; p < 0.00001). FCDs were most frequently located in the frontal, whereas neuroglial tumours most frequently in the temporal lobe. For FCD patients, the age at epilepsy onset was not dependent on lesion location, whereas DNTs in a temporal location were associated 2
with a later epilepsy onset than gangliogliomas and extratemporal DNTs. A positive family history for epilepsy or epileptic seizures was found more frequently among patients with FCDs (FCDs: 20.4%, neuroglial tumours: 8.1%; p=0.013).
Conclusion: We postulate that the age difference at epilepsy onset between patients with FCDs
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and neuroglial tumours can be attributed – at least partially – to unidentified genetic factors underlying the epileptogenic potential of the brain tissue. Additionally, the large
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variance in the age at epilepsy onset is possibly also genetically determined.
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Keywords: focal cortical dysplasia, ganglioglioma, dysembryoplastic neuroepithelial
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Introduction
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tumour, epilepsy, age, genetics.
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Age at epilepsy onset varies characteristically among distinct etiologic groups of epilepsy. Well-known examples include age-related epilepsy syndromes such as benign partial epilepsy of childhood, childhood absence epilepsy (CAE) and juvenile
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myoclonic epilepsy (JME), etc (Wirrell et al., 2011; Hantus, 2011). Whereas these examples supposedly have a genetic background, symptomatic epilepsies are rarely coupled to specific ages, and generally show a broader distribution regarding age at epilepsy onset. However, inborn brain lesions, either vascular or inflammatory in origin,
3
or malformations of cortical and brain development may also show a strong connection to certain age groups with respect to epilepsy onset. Focal cortical dysplasias (FCDs) are generally interpreted as a subgroup of malformations of cortical development (MCD), and are supposedly related to early developmental defects in the brain. Anomalies in proliferation of neuronal precursor
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cells, neuronal migration and cortical organisation can all contribute to the development of FCDs (Taylor et al., 1971; Palmini et al., 2004; Lim & Crino, 2013). The
currently
accepted
histopathologic
classification
scheme
(Palmini-Taylor
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classification, Palmini et al., 2004) underlies the diversity of FCDs at a cellular level and the different grades of disorganization in cortical structure; types Ia and Ib display cortical lamination defects and facultatively giant neurons, while type IIa and IIb exhibit
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dysmorphic and/or balloon cells (Palmini et al., 2004). Recent research has revealed
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possible genetic mechanisms which, in rare instances, underlie the formation of FCDs,
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especially the DEPDC5-pathway and its components NPRL2, NPRL3, PI3K and AKT
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(Schick et al., 2007a; Lim and Crino, 2013; Scheffer et al., 2014; Jansen et al., 2015; Scerri et al, 2015; Sim et al., 2016; reviewed by Neubauer and Hahn, 2016). An
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overlap between the described genetic factors and the genetic background of tuberous sclerosis (TS) leading to overactivation of the mTOR-signalling pathway is also well
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known, and reflects similarities in cellular abnormalities found both in FCD type IIb and TS lesions (TS cells referring to balloon cells in the histopathologic terminology, Lim &
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Crino, 2013). The epileptogenic potential of FCDs is thought to be different according to histopathologic subtypes (Rosenow et al., 1998). This is partly because of the differential electrical activity of distinct cellular constituents (dysmorphic neurons are
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electrically active; balloon cells are silent, Palmini, 2000), and most likely due to the extent and form of the "wiring" that connects pathologic with normal brain tissue. The versatility of FCDs is also reflected by the various epilepsy surgery outcomes (Keene et al., 1998; Chassoux et al., 2000; Kloss et al., 2002; Tassi et al., 2002; Fauser et al., 2004). 4
Neuroglial (or glioneural) tumours are also thought to arise during the early stages of brain maturation. The two main histopathologic types - gangliogliomas and dysembryoplastic
neuroepithelial
tumours
(DNT)
-
are
frequent
causes
of
pharmacoresistant epilepsy (Daumas-Duport et al., 1988; Otsubo et al., 1991). As with FCDs, epilepsy surgery often results in seizure freedom for patients with neuroglial
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tumours (Morris et al., 1998; Thom et al., 2011; Bonney et al., 2015; Fallah et al., 2015; Radhakrishnan et al., 2016; Tandon et al., 2016; Tomita et al., 2016). Over the past few years, investigations have revealed possible genetic factors underlying the
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development of neuroglial tumours, especially that of the BRAF- (Schindler et al., 2011; Koelsche et al. 2013; Martinoni et al., 2015) and PI3K-pathway (Schick et al., 2007b) for gangliogliomas, and the FGFR1-pathway for DNTs (Qaddoumi et al., 2016;
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Rivera et al., 2016). Apart from these molecular signalling routes, distinct profiles of
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chromosomal copy number aberrations have also been described in neuroglial
A
tumours (Prabowo et al., 2015).
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Even though the clinical practice clearly distinguishes between FCDs and neuroglial tumours, there is emerging evidence that the development of FCDs and neuroglial
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tumours may share common pathways (Samadani et al., 2007; Schick et al., 2007a; Schick et al., 2007b), and gangliogliomas may be interpreted in the context of
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mTORpathies as well (reviewed by Lim & Crino, 2013). This notion is also supported by histopathologic findings wherein neuroglial tumours and FCDs coexist in close
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proximity (Prayson, 2010), thus leading to the formation of a so-called FCD III (Blümcke et al., 2011). The epileptogenic potential of these lesions, and as a consequence the age at epilepsy
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onset, however, cannot be directly deduced from the above described genetic factors. Additionally, common experience reflects a broad age distribution with respect to age at
epilepsy
onset
in
respective
patients.
Further
determinants
influencing
epileptogenicity can be genetic as well as non-genetic mechanisms. In this study, we aimed at unveiling the variables influencing age at epilepsy onset, and gaining further 5
insight into possible, but yet unknown, genetic and non-genetic mechanisms influencing the development of epilepsy.
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Methods
We retrospectively evaluated the clinical history of 233 patients who underwent epilepsy surgical resection between 2000 and 2016 in the Epilepsy Centre of Bonn,
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Germany, and in whom a histopathologic evaluation confirmed the diagnosis of either an FCD or neuroglial tumour. The histopathologic (i.e. neuropathologic) evaluation was performed in the Department of Neuropathology of the University of Bonn Medical
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Centre, Germany. For the classification of FCDs, the Palmini-Taylor system was
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adopted (Palmini et al., 2004). In patients undergoing surgery before 2004, the
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histopathologic evaluation of the FCDs relied on the documented presence of TS-cells
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and additional characteristics described in the histopathology protocol. Gangliogliomas and DNTs were further subclassified according to the WHO system (see review of
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Holthausen and Blümcke, 2016).
Overall, 116 patients with FCDs (25 with FCD IIa and 81 with FCD IIb; in the remaining
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10 cases the histopathology either revealed FCD I or was not informative enough for further classification), 89 patients with gangliogliomas, and 28 patients with DNTs were
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included in our analysis. For the evaluation, we excluded patients with dual pathologies (for instance, associated hippocampal sclerosis in conjunction with neuroglial tumours in the temporal lobe); patients where the result of histopathologic examinations was
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discordant with that of previous interventions (in a few cases, resective surgery or a biopsy prior to surgery in our centre); and patients with alternative etiologies for epilepsy (i.e. one patient with coexistent SCN1A-mutation). The age at epilepsy onset (i.e. index seizure) was assessed based on patient charts and records. In most cases, at least two independent sources with concordant results were required for inclusion in 6
our study. Statistical analysis was performed with the statistical toolbox of MATLAB (MathWorks, Natick, USA). Within the framework of the descriptive statistics, cumulative and differential distribution functions (histograms) were computed to evaluate the age spectrum of the index seizure in different histopathologic categories. The statistical significance of differences between age distributions were evaluated
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with T-test, Mann-Whitney-U-test, Kruskal-Wallis test, and 2-way ANOVA depending on distribution characteristics of the examined variables and the number of compared distributions. Data were presented as mean values and standard errors of the mean, if
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not otherwise indicated. P-values below 0.05 were accepted as significant. Normality of distributions was assessed with a Lilliefors-test. As the majority of FCDs were located in the frontal lobe and most of the neuroglial tumours were within the temporal
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lobe, lesions in other lobes were summed up as “nonfrontal” and “extratemporal”
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respectively in order to avoid larger differences in sampling size. Differences in
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interregional distributions of lesions and in the family history of the respective patients
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were evaluated with Pearson’s Chi2 statistics.
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Results
We evaluated the clinical history of 116 patients with FCDs, 89 patients with
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gangliogliomas and 28 patients with DNTs who underwent epilepsy surgery between 2000 and 2016 after an extensive presurgical evaluation at the Department of Epileptology,
University
of
Bonn
Medical
Centre,
Germany.
Characteristic
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histopathologic features of these lesions are shown in Figure 1. Basic characteristics of the patient groups (sex, age at epilepsy onset, exact histopathologic type of lesion, location) are outlined in Table 1. Age at epilepsy onset displays a wide spectrum ranging from the first up to 43rd years of age for FCDs, and from the first up to the 60th years of age for neuroglial tumours (Figure 2A and B, displaying histograms for FCDs 7
and neuroglial tumours). In both cases, the evaluation of the histograms suggests that diverse subgroups may exist. Compared to patients with gangliogliomas and DNTs, the age at epilepsy onset was significantly earlier for patients with FCDs. However, the difference was not significant between the two histopathologic categories of neuroglial tumours (8.06 ± 0.74 years for 116 patients with FCD; 15.86 ± 1.24 years for 88
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patients with ganglioglioma and 19.18 ± 2.47 years for 28 patients with DNT; p < 0.00001, Kruskal-Wallis test with post hoc Tukey-Kramer adjustment for multiple comparisons; see Figures 3A and B).
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To evaluate the relevance of different histopathologic FCD subgroups as a possible variable influencing age at epilepsy onset, we also examined the variables in the groups with FCD type IIa and IIb, but this analysis did not reveal any differences (9.08
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± 1.66 years for 25 patients with FCD IIa and 7.60 ± 0.90 years for 81 patients with
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FCD IIb; p = 0.22, Mann-Whitney-U-test). Among neuroglial tumours the overwhelming
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majority belonged to WHO grade I (112 patients), higher grade developmental tumours
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were very rare (from the group of gangliogliomas 4 with grade II, 1 with grade III, DNTs were all grade I).
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There was no hint at gender differences regarding age at epilepsy onset in distinct histopathologic subgroups (p = 0.71 for FCDs, Mann-Whitney-U-test; p = 0.07 for
see Table 1).
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gangliogliomas, Mann-Whitney-U-test; and p = 0.80 for DNTs, T-test; for more detail
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FCDs were predominantly localized to the frontal lobe and appeared less frequently in temporal and occipital locations (71 frontal, 16 parietal, 9 temporal, 3 occipital, 16 multilobar or insular FCDs), whereas the preferential location of both gangliogliomas
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and DNTs was the temporal lobe (82 temporal, 11 frontal, 5 parietal, 4 occipital and 15 multilobar or insular locations). Differences in regional distributions of FCDs and neuroglial tumours also reached a statistical significance (p < 0.000001, Pearson's Chi2-test). Regional distributions of FCDs for types IIa and IIb did not differ significantly (p = 0.50, Pearson's Chi2-test; FCD IIa: 16 frontal, 3 parietal, 3 temporal, 1 occipital 8
and 2 multilobar or insular locations; FCD IIb: 50 frontal, 13 parietal, 3 temporal, 2 occipital and 12 multilobar or insular locations). On the other hand, regional distributions in the group of neuroglial tumours were somewhat different. Even though gangliogliomas and DNTs were most frequently located in the temporal lobe, frontal locations among DNTs were found relative frequently (p < 0.01, Pearson's Chi2-test;
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gangliogliomas: 67 temporal, 3 frontal, 3 parietal, 3 occipital and 13 multilobar or insular locations; DNTs: 15 temporal, 8 frontal, 2 parietal, 1 occipital and 2 multilobar locations).
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Lesions of the same histological subgroup may have different epileptogenic potentials according to their distinct location in the brain, and the properties of the network with which they interact. Therefore, we examined the age at epilepsy onset in the
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“preferential” and “non-preferential” locations of FCDs and neuroglial tumours. Even
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though the difference between FCDs in frontal versus nonfrontal locations was not
A
significant (7.52 ± 0.83 years for 71 patients with frontal and 8.93 ± 1.42 years for 44
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patients with nonfrontal FCDs; p = 0.89, Mann-Whitney-U-test; subtype-specific analysis with 7.44 ± 1.18 years for 16 frontal FCD type IIa, 12.00 ± 4.08 years for 9
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nonfrontal FCD IIa, 7.22 ± 1.06 years for 50 frontal FCD IIb and 8.23 ± 1.66 years for 30 nonfrontal FCD IIb; p = 0.31 for histology effect, p = 0.15 for location effect and p =
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0.36 for interaction effects, 2-way ANOVA), there was a trend to develop epilepsy earlier in patients with neuroglial tumours in extratemporal versus temporal locations
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(17.68 ± 1.20 years for 81 patients with neuroglial tumours in temporal and 14.31 ± 2.42 years for 35 patients with extratemporal locations; p = 0.02, Mann-Whitney-Utest). Further analysis revealed that this effect was due to the relatively late epilepsy
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onset in patients with DNTs in temporal locations (15.97 ± 1.32 years for 66 temporal gangliogliomas, 15.55 ± 3.08 years for 22 extratemporal gangliogliomas, 25.20 ± 2.08 years for 15 temporal DNTs and 12.23 ± 4.01 years for 13 extratemporal DNTs; p = 0.26 for histology effect, p = 0.012 for location effect, and p = 0.019 for interaction effects, 2-way ANOVA with post hoc multiple comparisons). Because FCDs in the 9
temporal and occipital lobes and neuroglial tumours in parietal and occipital locations were rare, we were unable to perform a more detailed analysis for distinct lobes. In order to gain more insight into possible genetic components determining age at epilepsy onset, we also evaluated the family history for epileptic seizures or epilepsy in the respective patient collectives. For 98 of the 116 patients with FCD, we had reliable
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information on the family anamnesis, with 20 patients (20.4 %) displaying a positive family history. In patients with neuroglial tumours (117 cases), reliable information could be obtained in 99 cases, in which 8 patients (8.1 %) had a history of epilepsy or
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epileptic seizures in their family. Further details on patients with a positive family history are outlined in Table 2. The trend for more frequent positive family history in the group of FCD patients reached statistical significance (p = 0.013, Pearson’s Chi2-test).
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On the other hand, no statistically significant differences were found when comparing
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the age at epilepsy onset with positive versus negative family history either for FCDs
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(8.55 ± 2.15 years with positive and 8.68 ± 0.90 years with negative family history; p =
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0.32, Mann-Whitney-U-test) or neuroglial tumours (14.63 ± 3.45 years with positive and 17.59 ± 1.33 years with negative family history; p = 0.57, Mann-Whitney-U-test).
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This held also true when we performed a subtype-specific analysis for FCDs (5.50 ± 2.04 years for 8 FCD IIa in patients with positive, 12.08 ± 2.69 years for 13 FCD IIa in
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patients with negative, 10.58 ± 3.26 years for 12 FCD IIb in patients with positive and 7.86 ± 0.99 years for 59 FCD IIb in patients with negative family history; p = 0.85 for
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histology effect, p = 0.40 for family history effect and p = 0.046 for interaction effects, 2-way ANOVA, post hoc comparisons not revealing any statistically significant difference). Since there were only 2 patients with DNT and a positive family history for
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epileptic seizures, we did not perform a more detailed analysis of neuroglial tumours.
Discussion
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FCDs and neuroglial tumours are presumed to be either inborn brain lesions or lesions which are acquired at a very early age. Both types of lesions frequently result in an epilepsy which is difficult-to-treat from a pharmacological standpoint. Even though the epileptogenic lesion resides in the brain from an early age on, the question arises as to why some patients develop seizures very early while others only at a relatively “old”
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age. In this study, we analysed the age at epilepsy onset in patients with histologically proven FCDs, gangliogliomas and DNTs.
Some epileptic events might not be immediately recognised as epilepsy. One reason
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for this is that patients often wait longer before seeking for further medical evaluation (Firkin et al., 2015), and this phenomenon can lead to biases in epidemiological observational studies. Patients in our centre are interviewed by specialists who are
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well-trained in epileptology and the interview is always comprised of a very detailed
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description of seizures and seizure semiologies. Therefore, it is rather unlikely that
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significant discrepancies exist between the reported and exact onset of epilepsy in the
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respective cohorts.
Whereas the age spectrum is quite broad in each case (ranging from the first to the
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43rd years in patients with FCDs and from the first to the 60th years in patients with neuroglial tumours), patients with FCD tended to develop epilepsy earlier than patients
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with neuroglial tumours, as also reported in the literature (Hirabayashi et al., 1993; Blümcke et al., 2017). In addition, one might speculate that in each group different
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patient subgroups exist with different “predilection” age for epilepsy onset. As also described in the literature, preferential locations of FCDs are the frontal (meaning frontal and precentral locations) (Hirabayashi et al., 1993; Kloss et al., 2002), and that
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of neuroglial tumors are the temporal lobes (Otsubo et al., 1991; Thom et al., 2011; Radhakrishnan et al., 2016; Tomita et al., 2016; Blümcke et al., 2017). Different lesion locations (lobes) did not have a statistically significant impact on the age at epilepsy onset in case of FCDs, and were associated with a later age at epilepsy onset in case of temporal DNTs. A significantly different relation of distinct histopathologic subtypes 11
of FCDs (type IIa and IIb) to epilepsy onset seems – based on the actual results – not reasonable. However, at this point we need to emphasise that our study has a couple of restrictions. First of all, lesions in “non-canonical” locations (meaning FCDs outside the frontal and neuroglial tumours outside the temporal lobe) were infrequent and difficult
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to handle in a reasonable manner for statistics. Besides, FCD type II (meaning type IIa and IIb) is overrepresented among our patients, so our conclusions refer only to patients with these histopathological subgroups. This bias and the high percentage of
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FCD type IIb may be explained by circumstances in the presurgical evaluation, where patients with well-defined or more circumscribed lesions on MRI and more circumscribed focal epileptiform activity in EEG studies could have been preferentially
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selected as “optimal” candidates for epilepsy surgery. In addition, the groups with FCD
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type IIa and DNT were significantly smaller than those with FCD IIb and ganglioglioma,
A
therefore results concerning these groups need to be interpreted cautiously.
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One possible reason as to why FCDs tend to cause epilepsy at earlier age may be related to the fact that FCDs are inborn malformations of cortical development (MCD)
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where the lesion has an epileptogenic potential from early ages on. On the other hand, neuroglial tumours might show a slight growth tendency and require more time to
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reach a certain “epileptogenic threshold”. An alternative explanation for the observed differences could be that neural elements of FCDs can be integrated in electrically
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active networks and cause network dysfunction and epileptic seizures in a direct manner, while cellular elements of neuroglial tumours are considered rather inactive, and the epileptogenic potential of these tumours resides in their indirect interaction
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with neighbouring brain tissue (reviewed by Fernández and Loddenkemper, 2017). Supporting this hypothesis, the intrinsic epileptogenicity of cortical dysplasias seems much higher than that of neuroglial tumours (Palmini et al., 1995; Rosenow et al., 1998; Aubert et al., 2009). Another possible explanation for the observed effects involves the ongoing maturation of brain regions and of subcortical connections which 12
often extends into adulthood, and the diverse kinetics of these processes in distinct anatomical structures (Lebel et al., 2008). Parallel to physiological networks, the time necessary for the development of pathological and epileptogenic networks may vary according to the type of lesion and its location. Our analysis does not satisfactorily explain the huge variability in age at epilepsy onset
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among the examined groups. Interestingly, a positive family history for epilepsy or epileptic seizures was observed more frequently in the patient group with FCDs than for the neuroglial tumour group. This observation must be interpreted with precaution
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in view of the relatively small number of cases and the heterogeneity of the epileptic manifestations in the affected families. However, it also supports the hypothesis that besides the above described and well-known, but also rather rare genetic defects -
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further genetic factors may influence the epileptogenic potential of lesions, the
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individual susceptibility of patients to seizures and as a consequence of these the age
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at epilepsy onset in patients with FCDs and neuroglial tumours. A recent report also
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emphasizes that genetic alterations of the mTOR-pathway as well as of SCN1A and GABRG2 genes are relatively common in patients with non-lesional focal epilepsy and
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a positive family history for epileptic seizures, and the age at epilepsy onset shows a correlation with the presence of these alterations (Perucca et al., 2017). In addition to
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genetic routes, epigenetic mechanisms can also contribute to the different epileptogenic potential of these lesions (reviewed by Kobow and Blümcke, 2017).
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In summary, further intense investigations are warranted to precisely identify the genetic and non-genetic influences shaping the evolution of epilepsy in patients with FCDs and neuroglial tumours. The broad spectrum of age at epilepsy onset not only
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reflects the differences in the epileptogenic potential of these lesions, but also the differences in individual patient susceptibility to epileptic seizures. Altogether we assume that besides the above mentioned and supposed genetic and non-genetic variables, several other factors influence the evolution of epilepsy.
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Conclusion
The age at epilepsy onset in patients with structural epilepsy can vary remarkably according to the underlying pathology. In this study, we evaluated patients who
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underwent surgery for histologically proven FCDs and neuroglial tumours. According to our results, FCDs lead to an earlier epilepsy onset than neuroglial tumours. Nevertheless, the age spectrum of epilepsy onset is very broad for both of these
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patient groups. At present, we could not positively identify further variables for determining age at epilepsy onset in these patient groups. However, the higher relative incidence of a positive family history for epileptic seizures or epilepsy in patients with
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FCDs suggests possible and unknown genetic factors influencing the epileptogenic
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potential of these brain alterations and the individual susceptibility of patients to
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epileptic seizures. Further clarification of these mechanisms and detailed analysis of
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currently known pathways (such as the mTOR-pathway) can lead to a better
therapeutic avenues.
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understanding of the pathophysiology of these patients and could open new
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Conflict of interest statement
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The authors have no conflicts of interest to declare.
Acknowledgements
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We are very grateful to Karen Wörmann for proficient English revision of the manuscript.
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Taylor DC, Falconer MA, Bruton CJ, Corsellis JAN. (1971) Focal dysplasia of the cerebral cortex in epilepsy. J Neurol Neurosurg Psychiatry, 34:369-387.
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Thom M, Toma A, An S, Martinian L, Hadjivassiliou G, Ratilal B, Dean A, McEvoy A, Sisodiya SM, Brandner S. (2011) One hundred and one dysembryoplastic neuroepithelial tumors: An adult epilepsy series with immunohistochemical, molecular genetic, and clinical correlations and a review of the literature. J Neuropathol Exp Neurol, 70:859-878. Tomita T, Volk JM, Shen W, Pundy T. (2016) Glioneural tumors of cerebral hemisphere in children: correlation of surgical resection with seizure outcomes and tumor recurrences. Childs Nerv Syst, 32:1839-1848.
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Wirrell EC, Camfield CS, Camfiled PR. Idiopathic and benign partial epilepsies of childhood. 2011 In Wyllie's Treatment of Epilepsy - Principles and Practice, 2011, Fifth Edition, Wolters Kluwer, Lippincott Williams & Wilkins. pp: 243-257.
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Figure legends Figure 1. The histopathology of focal cortical dysplasias (FCDs), gangliogliomas and dysembryoplastic neuroepithelial tumours (DNTs). A, B FCDs type IIb are
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characterized by the presence of dysplastic neurons (black arrows) and characteristic balloon cells (white arrows) scattered within normal brain tissue. Dysplastic neurons present with enlarged cell and nucleus diameters and perimembranous Nissl
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aggregation (arrowheads), whereas balloon cells show opalescent glassy eosinophilic cytoplasm and no Nissl substance. FCDs type IIa (not shown) are characterized by similar dysplastic neurons, but lack balloon cells. C Gangliogliomas (WHO grade I)
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present with clusters of enlarged dysplastic neurons (black arrows) within a matrix of
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neoplastic astroglia. Occasional binucleation is encountered (arrowhead). D The
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simple DNT variant (WHO grade I) is characterized by specific glioneural elements
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consisting of floating neurons (black arrow) and columns of oligodendrocyte-like tumour cells (OLCs) (arrowheads) within an abundant myxoid matrix. H&E stainings.
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Scale bar in D for A–D 100 µm.
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Figure 2. Distribution of age at epilepsy onset in the analysed patient groups. Histograms of age at epilepsy onset in patients with FCDs (A) and neuroglial tumours
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(B).
Figure 3. FCDs cause epilepsy earlier than neuroglial tumours.
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Cumulative distribution plots of age at epilepsy onset in patients with FCDs and neuroglial tumours (A). Age at epilepsy onset is significantly earlier in patients with FCDs, compared to those with gangliogliomas and DNTs (B, Kruskal-Wallis test, with Tukey-Kramer correction for multiple comparisons).
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A ED
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N
A
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Fig 1
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A ED
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CC E
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U
N
A
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Fig 2
21
A ED
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U
N
A
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Fig 3
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Table 1. Basic characteristics of the analysed patient groups with histologically proven FCDs, gangliogliomas and DNTs. * In a few cases FCDs were classified as FCD I or a precise classification was not possible. ** In one case the precise location of an FCD of central location could not be determined unequivocally (precentral versus postcentral).
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*** As WHO grades II and III were very rare among gangliogliomas, age at onset was not analysed separately for WHO grades. DNTs were all grade I. Age at onset is
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shown for precise classifications only.
Table 2. Details on positive family history for epilepsy and epileptic seizures in patients
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with FCDs and neuroglial tumours.
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FCD Females 50 8.28 ± 1.26 FCD IIb 81 7.60 ± 0.90 Nonfrontal 44 Parietal: 16 Temporal: 9 Occipital: 3 Multilobar or insular: 16 7.52 ± 0.83 8.93 ± 1.42 Positive Negative 20 78 8.55 ± 2.15 8.68 ± 0.90
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Age at onset (years) Family history Number of patients Age at onset (years)
Ganglioglioma
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ED PT
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15.97 ± 1.32 Positive 6 16.17 ± 4.23
Unclear 1
Unknown 18
Females 41 13.02 ± 1.43 WHO grade II 4 Extratemporal 22 Frontal: 3 Parietal: 3 Occipital: 3 Multilobar or insular: 13 15.55 ± 3.08 Negative 67 16.77 ± 1.49
Overall 89 15.86 ± 1.24 WHO grade III 1 Overall 89
Females 12 19.92 ± 4.16 Extratemporal 13 Frontal: 8 Parietal: 2 Occipital: 1 Multilobar: 2 12.23 ± 4.01 Negative
Overall 28 19.18 ± 2.47 Overall 28
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Males 48 18.34 ± 1.91 WHO grade I 84 Temporal 67
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Gender Number of patients Age at onset (years) Histology*** Number of patients Location Number of patients
Age at onset (years) Family history Number of patients Age at onset (years)
Overall 116 8.06 ± 0.74 FCD I or no precise cl. 10
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Males 66 7.89 ± 0.89 FCD IIa 25 9.08 ± 1.66 Frontal 71
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Gender Number of patients Age at onset (years) Histology* Number of patients Age at onset (years) Location** Number of patients
15.86 ± 1.24 Unknown 14
DNT
Males 16 18.63 ± 3.09 Temporal 15
Age at onset (years) Family history
25.20 ± 2.08 Positive
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Gender Number of patients Age at onset (years) Location Number of patients
19.18 ± 2.47 Unknown 24
2 10.00 ± 6.00
22 20.18 ± 2.87
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Number of patients Age at onset (years)
25
Table 2
1
Male Femal e
Temporal
14
Temporal
2
Male Femal e Male Femal e
Parietal
3
Male Male
Frontal Frontal
Male Femal e Femal e
Frontal
Male Male Male
Temporal Parietal Parietal
Parietal Occipital Frontooperculoins ular
Frontal Frontal
CC E A Ganglioglio ma
15 6 1
A
8 1 6
14
1
4 17 38
Male
Parietal
2
Male Femal e Femal e
Parietal
8
Male
Temporal
Male
Temporal
Male
Temporal
Parietal Occipital
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Frontal
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Male
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2
father with oligoepilepsy (seizures between 12 and 27 years of age), sister with difficult-to-treat epilepsy and mental retardation, migration disorder in MRI cousin (paternal side) with epilepsy, no further details grandmother (maternal side), uncle (paternal side), no further details grandmother (maternal side) with a fever associated seizure 2 sisters (after 12 and 14 years of age), an aunt, an uncle, a cousin (paternal side) with epilepsy 2 cousins (maternal side), also hydrocephalus, neurologic syndrome classification not clarified sister with a fever associated seizure sister with seizures, treatment over 1 year, afterwards seizure free brother of grandmother (maternal side) with epilepsy during childhood mother with epilepsy, no further details aunt (maternal side) with epilepsy, no further details great-aunt and uncle with epilepsy (uncle’s epilepsy possibly related to alcohol consumption) grandmother with epilepsy after the age of 40, brother with peripartal hypoxia and status mother and grandfather (maternal side) with febrile seizures distant relative with epilepsy, no further details cousin with epilepsy, no further details father with epilepsy after 12 years of age (white spots on skin), under valproic acid seizure free, aunt (maternal side) with epilepsy or febrile seizures in childhood, cousin (maternal side) with febrile seizures younger brother with febrile seizure
N
Frontal
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FCD II b
Male
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FCD II a
Lesion location
Onset (years) Family history
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Histology
Gend er
25 mother with epileptic seizures, no further details great-cousin (paternal side) with epilepsy, no 3 further details
17 cousin with epilepsy, no further details cousin of the grandmother (maternal side) with 23 epilepsy, no further details mother with epilepsy in later years of age, no 31 further details 26
Temporal
15 uncle with epilepsy, no further details uncle (maternal side) with grand mal epilepsy, another uncle (maternal side) with a not further classified seizure, brother with 10 myoclonic seizures uncle (paternal side) with epilepsy after the age 16 of 35
Insular Frontal Parietal
4 cousin (paternal side), no further details
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M
A
N
U
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DNT
Femal e Femal e Femal e
mother with sleep associated seizures, under 1 lamotrigine seizure free
Temporal
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Femal e Femal e
27