Focal cortical dysplasias in temporal lobe epilepsy surgery: Challenge in defining unusual variants according to the last ILAE classification

Epilepsy & Behavior 45 (2015) 212–216

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Focal cortical dysplasias in temporal lobe epilepsy surgery: Challenge in defining unusual variants according to the last ILAE classification Matteo Martinoni a,⁎,1, Gianluca Marucci b,1, Guido Rubboli e,g, Lilia Volpi e, Patrizia Riguzzi e, Federica Marliani f, Francesco Toni f, Ilaria Naldi d, Francesca Bisulli c,d, Paolo Tinuper c,d, Roberto Michelucci e, Agostino Baruzzi c,d, Marco Giulioni a a

IRCCS Institute of Neurological Science of Bologna, Division of Neurosurgery, Bellaria Hospital, Bologna, Italy Department of Biomedical and NeuroMotor Sciences (DiBiNeM), Section of Pathology “M.Malpighi”, Bellaria Hospital, University of Bologna, Bologna, Italy c IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy d Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy e IRCCS Institute of Neurological Sciences of Bologna, Division of Neurology, Bellaria Hospital, Bologna, Italy f IRCCS Institute of Neurological Sciences of Bologna, Section of Neuroradiology, Bellaria Hospital, Bologna, Italy g Danish Epilepsy Centre, Dianalund, Denmark b

a r t i c l e

i n f o

Article history: Received 6 November 2014 Revised 10 January 2015 Accepted 12 January 2015 Available online 23 March 2015 Keywords: Temporal lobe epilepsy Focal cortical dysplasia Hippocampal sclerosis Glioneuronal tumors Dual pathology Double pathology

a b s t r a c t Objective: Focal cortical dysplasias (FCDs) represent a common architectural cortical disorder underlying pharmacoresistant focal epilepsy. The recent ILAE classification defines different types of FCDs based on their histopathological features, MRI imaging, and presumed pathogenesis; however, their clinical features and their prognostic significance are still incompletely defined. In addition, the combination of different histopathological abnormalities can represent “unusual” subtypes that can be difficult to classify. The aim of our study was to analyze the incidence and the significance of these “unusual” subtypes of FCDs in drug-resistant mesial temporal lobe epilepsy (MTLE). Methods: We retrospectively analyzed 133 patients consecutively submitted to tailored anteromesial temporal lobe resection for pharmacoresistant MTLE. Seizure onset, seizure duration, age at surgery, and postoperative seizure outcome were evaluated in relation to the different neuropathological groups defined according to the new ILAE classification. Results: Focal cortical dysplasias were found in 80 out of 133 patients. Six patients were affected by isolated FCD type I, 12 patients by FCD type II, and 44 patients by FCD type III. Furthermore, we found 18 “atypical” cases (20.5% of all FCD cases and 26.6% of FCDs associated with a principal lesion): 10 cases of associated FCD type II–hippocampal sclerosis (HS) and 8 cases associated with FCD II–epilepsy-associated tumors (EATs). Conclusion: Our results indicate that “unusual” subtypes of FCDs, in particular associated FCD type II, are not uncommon findings, suggesting that they deserve a classification recognition. Similarities in seizure outcome and immunohistochemical and molecular evidences, shared by FCD type II + EATs and EATs, suggest a common pathogenic link. The choice to create a specific unifying class or, on the contrary, to also include “associated FCD type II” in the definition of the new unifying class FCD type III should be further discussed. © 2015 Elsevier Inc. All rights reserved.

1. Introduction Focal cortical dysplasias (FCDs) are a group of highly epileptogenic localized cortical lesions responsible for focal epileptic seizures rarely controlled by pharmacotherapy [1–9]. In 2011, the new International

⁎ Corresponding author at: IRCCS Institute of Neurological Sciences of Bologna, Department of Neurosurgery, Bellaria Hospital, Via Altura 3, 40100 Bologna, Italy. Tel.: +39 051 6225111; fax: +39 051 6225347. E-mail address: [email protected] (M. Martinoni). 1 M. Martinoni and G. Marucci equally contributed to the study.

http://dx.doi.org/10.1016/j.yebeh.2015.01.022 1525-5050/© 2015 Elsevier Inc. All rights reserved.

League Against Epilepsy (ILAE) Diagnostic Methods Commission [10] proposed a new classification of FCDs that represents an effort to overcome the recognized limits of the previous classifications. In addition, proposals to provide a reproducible and reliable histopathological FCD characterization between laboratories have been published [11,12]. Three types of FCDs according to histopathological and neuroradiological features have been defined [10]. The major change was represented by the introduction of FCD type III that consists of the association of architectural dysplasia with another lesion type, the latter considered to be the major contributor to the disease characteristics and seizure outcome.

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all the patients submitted to tailored surgery for drug-resistant MTLE between April 2001 and December 2011. Presurgical neurophysiological assessment was performed by means of noninvasive long-term video-EEG monitoring for seizure recording. Electroencephalographic signals were collected by means of silver– silver chloride electrodes applied to the scalp according to the international 10–20 system; in selected cases, additional electrodes (zygomatic or supraorbital) were used. Patients underwent 1.5-T MRI scans until 2005 (50 patients) and 3-T scans since 2006 (83 patients). The MRI protocol consisted of sagittal spoiled gradient-recalled acquisition T1weighted, axial T2-weighted, axial and coronal FLAIR T2-weighted, coronal gradient echo, coronal T2*-weighted, and coronal T1 inversion recovery sequences, and when necessary, axial, sagittal, and coronal T1-weighted sequences with gadolinium were performed. Computed tomography was carried out when necessary (for instance, when calcifications were suspected). All patients underwent neuropsychological evaluation. All patients have been followed up for at least 2 years. Seizure outcome was defined according to the Engel classification [14]. 2.1. Pathological examination

Fig. 1. Surgical specimen correctly oriented for pathological examination.

However, some histopathological substrates may represent “unusual” findings that may be still difficult to classify, such as the association between FCD type II and other structural abnormalities, namely hippocampal sclerosis or epilepsy-associated tumors (EATs). According to the ILAE Task Force, the combination of these pathological findings has been reported as a rare association and should not be classified as a FCD type III variant but as dual (FCD type II–HS) and double (FCD type II–EATs) pathology [10]. However, even if the terminology has been defined in the text of the new ILAE classification [10], the terms “dual” and “double” are often considered interchangeable and can be misleading and confusing [13]. In the present study, we investigated the incidence and the features of the different types of FCDs in temporal lobe epilepsy, focusing in particular on the “unusual” structural abnormalities in patients who underwent temporal lobectomy for pharmacoresistant mesial temporal lobe epilepsy (MTLE). 2. Materials and methods We retrospectively retrieved, from the register of the epilepsy surgery center at the IRCCS Institute of Neurological Sciences of Bologna,

All surgical specimens were appropriately oriented. Polar temporal specimens were cut perpendicular to the pial surface in 3- to 5-mm sections (Fig. 1). Hippocampal specimens were dissected along the anterior–posterior axis. Tissue was fixed in 10% buffered formalin and embedded in paraffin. Paraffin sections of 4 mm were serially cut and treated with hematoxylin and eosin (H&E), Nissl, Kluver, and reticulin staining. Serial, 3-μm-thick, paraffin sections mounted on precoated slides were processed by standardized automated procedures (BenchMark Ultra® immunostainer by VentanaMedical System; Ultraview Universal DAB® detection kit) using prediluted antibodies (GFAP, CD34, neurofilament protein, vimentin, Ki67) with the exception of anti-NeuN (clone A60, dilution of 1:500, Chemicon/Millipore Corp.) and anti-IDH1 R132H (clone H09, dilution of 1:100, Histonova, Dianova GmbH) antibodies. Appropriate positive and negative controls were performed. All cases were histologically reviewed according to the WHO classification of tumors of the central nervous system [15] and the more recent classifications for FCD [10] and hippocampal sclerosis (HS) [16] diagnoses. The areas identified as dysplastic were carefully evaluated with CD34, Ki67, and IDH1 antisera in order to rule out the possibility of tumor infiltration misdiagnosed as dysplastic tissue [17]. 3. Results One hundred thirty-three patients were submitted to tailored anteromesial temporal lobe resection from 2001 to 2011. We selected 80 patients with a proven diagnosis of FCDs at neuropathological examination. In 18 cases, FCDs were isolated: in this group, we observed 6 patients with FCD type I and 12 with FCD II. In the remaining 62 cases,

Table 1 Clinical features and outcome of temporal FCD series. FCD type

Number of patients.

Age at epilepsy onset (years), mean (SD)

Seizure duration (years), mean (SD)

Age at surgery (years), mean (SD)

Class I, number of patients (%)

Class Ia, number of patients (%)

FCD I FCD IIa FCD IIb FCD IIIa FCD IIa + HS FCD IIb + HS FCD IIIb FCD IIa + EATs FCD IIb + EATs FCD IIIc FCD IIId

6 12 – 33 9 1 9 7 1 1 1

13.3 (3.8) 21.5 (9.8) – 11 (8.4) 9.2 (11.3) 28 9.3 (5.3) 11.6 (8.4) 30 11 35

21.8 (10.9) 12.5 (8.5) – 26 (11.2) 24.3 (11.3) 12 15.7 (11.2) 6 (9.4) 14 7 7

35.2 (8.9) 33.5 (7.5) – 37.8 (9.1) 36.3 (9.6) 40 25.2 (7.7) 17.4 (15.5) 44 18 42

2 (33.3%) 8 (66.6%) – 28 (84.8%) 8 (88.8%) – 8 (88.8%) 6 (85.7%) 1 1 1

1 (16.6%) 7 (58.3%) – 25 (75.7%) 5 (55.5%) – 6 (66.6%) 5 (71.4%) 1 1 1

FCD: focal cortical dysplasia.

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Fig. 2. Case of HS + FCD type IIa. A: HS type 1 evidenced by significant pyramidal cell loss in both CA1 and CA4 sectors (NeuN, 20× magnification); B: FCD: dysmorphic neurons in focal cortical displasia type IIa (H&E, 200× magnification); C: FCD: dysmorphic neurons are highlighted by antineurofilament protein antiserum (neurofilament protein, 200× magnification).

FCDs were associated with other pathological entities. In the majority of cases (43 patients), the associated pathological finding was HS. Interestingly, in this group of subjects, the FCD type was FCD IIIa (FCD I + HS), according to the ILAE classification, in 33 cases (76.7%) while there was a combination of FCD II and HS in the remaining 10 cases (23.3%) (see Table 1 and Fig. 2). In 17 cases, FCDs were associated with EATs. In this group, the FCD type was FCD IIIb (FCD I + EATs) in 9 cases (53%) whereas EATs were associated with FCD type II in 8 cases (47%) (see Tables 2 and 3 and Fig. 3). Therefore, we found 18 “atypical” cases (20.5% of all FCD cases and 26.6% of FCDs associated with a principal lesion): 10 cases of FCD II– HS (1 case of FCD IIb–HS and 9 cases of FCD IIa–HS) and 8 cases of FCD II–EATs (1 case of FCD IIb–EAT and 7 cases of FCD IIa–EATs). Furthermore, we observed 1 case of FCD type I associated with a cavernous angioma (FCD IIIc) and another case associated with posttraumatic gliosis (FCD IIId). Age at epilepsy onset, seizure duration, age at surgery, and postoperative seizure outcome for the different groups are reported in Table 1 as mean and standard deviation. 3.1. Correlation of FCD subtypes and postoperative seizure outcome FCD type I: considering cases of isolated FCD type I, only 1 out of 6 patients (16.6%) was in Class Ia; FCD type II: 7 out of 12 patients (58.3%), carrying isolated FCD type II, were in Class Ia; FCD type III: patients with FCD types IIIa and IIIb (75.7% and 66.6% of cases, respectively), presenting an abnormal cortical lamination associated with HS and EATs, were completely seizure-free (Class Ia). “Unusual” cases (i.e., FCD type II + HS and FCD type II + EATs): 5 out of 10 patients (50%) with FCD type II + HS were in Class Ia whereas 6 out of 8 patients (75%) with FCD type II + EATs were completely seizure-free. 4. Discussion Although the etiology and pathogenesis of each FCD subtype are yet to be elucidated, in 2011, the ILAE Task Force issued a consensus proposal attempting to provide criteria to evaluate and classify

neuroradiological and neuropathological findings and electroclinical features in FCDs [10]. Typical imaging features of cortical dysplasias include abnormal sulcal and/or gyral pattern, cortical thickening, blurred gray matter–white matter junction, abnormal white and gray matter signal, transmantle (down to the ventricles) subcortical signal changes, and localized cortical volume loss [18–20]. However, all specific MRI features except localized volume loss were significantly more prevalent in type II compared with type I FCD [18–20]. Consequently, a correct presurgical identification of FCD type I is rare [10,17–21]. According to the pertinent literature, the capability to detect FCD type IIa with 3 T or 1.5 T MRI remains low and even lower for FCD type I (including FCD types IIIa and IIIb) [18–20,22]. The precise mechanisms linking FCDs to epileptogenesis remain still unknown, and the pathogenesis of epilepsy associated with FCDs has been revealed to be multifactorial [1–9]. Current data indicate that seizure outcome is better for FCD type IIa or IIb than for FCD type I [20, 21,23–28]. It is well known that FCD type IIb is a frequent structural lesion in extratemporal epilepsy; on the contrary, it is very rare to be observed in the temporal lobe. According to pertinent literature [18–21, 29], our results confirm the rarity of FCD type IIb occurrence in the temporal lobe (only 1 case of FCD IIb–HS and 1 case of FCD IIb–EAT). Concerning the clinical presentation of the different types of FCDs, Fauser et al. identified some factors that differ significantly from FCD type II and FCD type IIIa (epileptic aura and febrile seizures occurred more frequently in FCD IIIa and age at surgery was higher in this FCD subtype) whereas no clear clinical differences between FCD type I isolated and FCD IIIa were observed [30]. The recent ILAE classification of FCDs [10] has showed increased interobserver and intraobserver agreement in comparison to the previous one [31,32], representing possibly an important advancement for future clinicopathological correlation studies evaluating postsurgical seizure outcomes [31,33–35]. However, after the publication of the ILAE focal cortical dysplasia classification in 2011, only a few scattered articles about the use of this classification have been published [17,20, 23,24,29,30,33,36–38]. Indeed, the major change introduced by the new ILAE classification consists in the separation of isolated FCD type I from conditions presenting with abnormal cortical lamination associated with other epileptogenic principal lesions (including HS, tumors, vascular malformations, and any other lesion acquired during early

Table 2 FCDs associated with EATs. FCDs + tumors

Number of patients

Age at epilepsy onset (years), mean

Seizure duration (years), mean

Age at surgery (years), mean

Class I, number of patients

Class Ia, number of patients

FCDs + ganglioglioma FCDs + DNT FCDs + pleomorphic xanthoastrocytoma FCDs + angiocentric glioma FCDs + neurocytoma FCDs + melanocytoma

8 2 3 2 1 1

11.6 11 15 7.5 11 19

14.1 21.5 3.3 12.5 19 6

25.7 22.5 18.3 20.5 30 25

6 2 3 2 1 1

6 1 2 1 1 1

DNT: dysembryoplastic neuroepithelial tumor; FCD: focal cortical dysplasia.

M. Martinoni et al. / Epilepsy & Behavior 45 (2015) 212–216 Table 3 Subtypes of FCDs associated with tumors. FCD type

GNT

Number of patients

Class I

FCD IIa FCD IIb FCD IIIb FCD IIa FCD IIIb FCD IIa FCD IIIb FCD IIa FCD IIIb FCD IIa FCD IIIb

GG GG GG PXA PXA AG AG DNT DNT Neu/Mel Neu/Mel

5 1 2 2 1 – 2 – 2 – 2

4/5 1 1/2 1 1 – 1 – 1 – 1

AG: angiocentric glioma; DNT: dysembryoplastic neuroepithelial tumor; FCD: focal cortical dysplasia; GG: ganglioglioma; Mel: melanocytoma; Neu: neurocytoma; PXA: pleomorphic xanthoastrocytoma.

life) that are now diagnosed as FCD type III [10]. The introduction of this new group was justified by the worse seizure outcome showed by patients with FCD type I in comparison to patients with FCD type III, which shares the same outcome typical of the associated lesion [3,25, 26,28,30]. In fact, our findings are in agreement with such evidences, showing that only 16.6% of isolated FCD type I cases were in Class Ia while 75.7% of FCD type IIIa cases and 66.6% of FCD type IIIb cases were completely seizure-free. However, this approach did not include FCD type II associated with other lesions in the new FCD type III group because these findings are considered to be rare; it was proposed to refer to them as “dual pathology” for FCD type II associated with HS and “double pathology” for FCD type II associated with EATs. Regarding seizure outcome, cases of FCD type II + HS share similar percentages of patients in Class Ia with isolated FCD type II (50% vs 58.3%), in this respect, justifying the maintenance of the class “dual pathology” as proposed by the ILAE Task Force [10]. However, in our series, we observed 18 “unusual” cases, i.e., 10 cases of FCD type II + HS (dual pathology) and 8 cases of FCD type II + EATs (double pathology), that represented 20.5% of all FCD cases and 26.6% of FCDs associated with other lesions, suggesting that these pathological entities may be less rare than previously assumed [3,23,37] and that they deserve a classification recognition. Our results comply with recent data of Cossu et al. who reported an association of FCD IIa with a tumor (double pathology) in 11% of cases [23]. In our study, the percentage of patients with FCD type II + EATs that achieved Class Ia seizure outcome was 75%, similar to the percentage observed in patients with EATs [37–41]. This finding is in keeping with the data reported by Cossu et al. [23] who demonstrated that clinical variables and postoperative seizure outcome of patients with coexisting tumors and FCDs (FCD IIIb and FCD II + EATs) were similar to those of patients with a solitary tumor and differed significantly from patients with solitary FCDs. Nevertheless, tumors associated with FCDs are characterized by a male predominance and a higher seizure frequency compared to solitary tumors. In recent years, some studies

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demonstrated that certain immunohistochemical [42–45] and molecular (namely BRAF mutation) [46] abnormalities are shared by FCD type II and EATs (especially in ganglioglioma), suggesting a common pathogenic link and a possible evolutive oncogenic progression [44,47]. Summarizing all these data, whether it should be appropriate to include the “unusual” cases of FCDs associated with other lesions in the group of FCD type IIIb or, on the contrary (in particular, considering the emerging, immunohistochemical, and molecular evidence gathered about FCD type II and EATs), to classify them as a separate class appears to be worthy of further discussion. 5. Conclusion Although these observations need to be confirmed in a larger study population, our results indicate that cases of associated FCD type II are not as rare as previously reported, suggesting a recognition for more precise classification purposes at least in TLE. Similarities in seizure outcome and immunohistochemical and molecular evidence, shared by FCD type II + EATs and EATs, suggest a common pathogenic link. The choice to create a specific unifying class or, on the contrary, to include also “associated FCD type II” in the definition of the new unifying class FCD type III should be further debated. Conflict of interest None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. References [1] Aronica E, Redeker S, Boer K, Spliet WG, van Rijen PC, Gorter JA, et al. Inhibitory networks in epilepsy-associated gangliogliomas and in the perilesional epileptic cortex. Epilepsy Res 2007;74:33–44. [2] Barkovich AJ, Kuzniecky RI, Dobyns WB, Jackson GD, Becker LE, Evrard P. A classification scheme for malformations of cortical development. Neuropediatrics 1996; 27:59–63. [3] Becker AJ, Blümcke I, Urbach H, Hans V, Majores M. Molecular neuropathology of epilepsy-associated glioneuronal malformations. J Neuropathol Exp Neurol 2006; 65:99–108. [4] Fauser S, Huppertz HJ, Bast T, Strobl K, Pantazis G, Altenmueller DM, et al. Clinical characteristics in focal cortical dysplasia: a retrospective evaluation in a series of 120 patients. Brain 2006;129:1907–16. [5] Guerrini R, Marini C. Genetic malformations of cortical development. Exp Brain Res 2006;173:322–33. [6] Mischel PS, Nguyen LP, Vinters HV. Cerebral cortical dysplasia associated with pediatric epilepsy. Review of neuropathologic features and proposal for a grading system. J Neuropathol Exp Neurol 1995;54:137–53. [7] Prayson RA, Estes ML. Cortical dysplasia: a histopathologic study of 52 cases of partial lobectomy in patients with epilepsy. Hum Pathol 1995;26:493–500. [8] Prayson RA, Spreafico R, Vinters HV. Pathologic characteristics of the cortical dysplasias. Neurosurg Clin N Am 2002;37:17–25. [9] Thom M, Blümcke I, Aronica E. Long-term epilepsy-associated tumors. Brain Pathol 2012;22:350–79. [10] Blümcke I, Thom M, Aronica E, Armstrong DD, Vnters HV, Palmini A, et al. The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification

Fig. 3. Case of EAT + FCD type IIa. A: Grade I ganglioglioma consisting of a combination of dysmorphic neurons and neoplastic glial cells (H&E, 200× magnification); B: high-power magnification of dysmorphic neurons in focal cortical displasia type IIa (H&E, 400× magnification); C: in dysmorphic neurons, Nissl substance is aggregated and displaced towards the cell membrane (Nissl, 200× magnification).

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