Journal of Clinical Neuroscience 21 (2014) 2170–2174
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Clinical Study
Clinical characteristics of 92 patients with temporal lobe focal cortical dysplasia identified by pathological examination Jiang Wu a, Wenling Li b, Yao Chen a, Lin Kang c, Wenqing Zhao a,b,⇑ a
Department of Neurosurgery, Hebei Medical University, Shijiazhuang, China Department of Functional Neurosurgery, Hebei General Hospital, No. 348 Heping West Road, Shijiazhuang 050000, China c Department of Pathology, Hebei General Hospital, Shijiazhuang, China b
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Article history: Received 22 August 2013 Accepted 21 April 2014
Keywords: Clinical characteristics Focal cortical dysplasia Pathological subtypes Temporal lobe epilepsy
a b s t r a c t Focal cortical dysplasia (FCD) is frequently associated with focal epilepsy, and a broad spectrum of histopathology is included in the diagnosis of FCD. In 2011, an International League Against Epilepsy (ILAE) task force proposed an international consensus for a classification system to better characterise specific clinicopathological FCD entities. The clinical characteristics of patients with FCD should be confirmed according to the new ILAE classification. We retrospectively analysed 92 patients who had undergone surgical treatment for temporal lobe epilepsy and received a pathological diagnosis of FCD. The pathological sections were re-examined and diagnosed according to the 2011 ILAE classification. The clinical data from patients with different FCD subtypes were evaluated, including a detailed history regarding spontaneous abortions, trauma, ischaemic injury, encephalitis, and febrile seizures at an early age. The age of epilepsy onset, duration of epilepsy, age at surgery, seizure frequency, history of febrile seizures, and seizure type, particularly whether the seizures were secondarily generalised tonic-clonic seizures, were recorded. Clinical differences were found in the patients with temporal lobe FCD. The associated FCD subtypes have unique clinical characteristics, including a later age of epilepsy onset and a shorter duration of epilepsy, especially in FCD Type IIIc; and a high susceptibility to febrile seizures was observed in FCD Type IIIa. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction Focal cortical dysplasia (FCD) was first described as a distinct neuropathological entity in 1971 by Taylor [1]. FCD is a common neuropathological finding in patients with refractory epilepsy that is increasingly diagnosed with the development of high-resolution MRI [2,3]. The term ‘‘FCD’’ is widely used to describe a large spectrum of malformative lesions comprising cortical dyslamination and cytoarchitectural lesions; the morphological spectrum of FCD variants is not well classified. A number of FCD classification systems have been proposed that rely on histopathological examination [4], imaging and genetic findings [5], or a combination of clinical and histopathological features [3,6]. The repeatability is low and results in inconsistent diagnoses between different centres [7]. In 2011, the International League Against Epilepsy (ILAE) proposed a novel three-tiered classification system for FCD that distinguishes isolated forms (FCD Type I and II) from those cortical abnormalities associated with another principal lesion (FCD Type ⇑ Corresponding author. Tel./fax: +86 311 8598 8643. E-mail address: [email protected] (W. Zhao). http://dx.doi.org/10.1016/j.jocn.2014.04.022 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.
III) [8]; this new system is based on standardised laboratory protocols. The determination of the clinical characteristics of FCD has been limited and less comparable among studies because the cohorts of studies have been mixed, with cases involving different lobes, paediatric versus adult patients, and isolated versus associated FCD types [9–11]. The clinical characteristics of the subtypes according to this new classification system have not been clarified, especially those of the newly classified associated FCD type (FCD Type III). Because almost 50% of FCD occurrences are in the temporal lobe [3,12–14], the purpose of this study was to elucidate the clinical characteristics of different temporal lobe FCD subtypes, according to the 2011 ILAE classification. 2. Patients and methods 2.1. Patients The medical charts of 241 consecutive paediatric and adult patients with temporal lobe epilepsy (TLE) were retrospectively analysed. All of the patients had surgery at Hebei General Hospital in China between June 2006 and June 2011. The pathological sections
J. Wu et al. / Journal of Clinical Neuroscience 21 (2014) 2170–2174
were re-examined and diagnosed according to the 2011 ILAE classification. Ninety-two patients were selected using the following inclusion criteria: (1) the patient underwent a temporal lobectomy; (2) surgical specimens were sufficiently preserved for evaluation of the neocortex and hippocampus; (3) final diagnosis was FCD according to the 2011 ILAE classification; and (4) they were not suffering from any other neurological disorder. Patients with dual pathology (for example, FCD Type II with hippocampal sclerosis [HS], or FCD Type IIIb, c, d with HS) and multilobar FCD were excluded. The clinical records of each patient were reviewed, including a detailed history regarding spontaneous abortions, trauma, ischaemic injury, encephalitis, and febrile seizures (FS) at an early age. The age of epilepsy onset, duration of epilepsy, age at surgery, seizure frequency, history of FS, and seizure type, particularly whether the seizures were secondarily generalised tonic-clonic seizures (sGTCS), were recorded. 2.2. Surgery The surgical resections were performed for strictly therapeutic reasons and were planned based on the clinical, neuroimaging, and electrophysiological results. In patients for whom MRI was unrevealing, resection was planned using electroclinical and invasive electroencephalography data. The extent of resection was planned pre-operatively in each case, after considering the severity of the epilepsy and the risk of post-surgical deficits. 2.3. Pathological examinations The specimens were fixed in a 4% buffered formaldehyde solution, dehydrated and embedded in paraffin. The standard stains on each tissue block included haematoxylin and eosin. Specific stains and immunohistochemistry were used according to the practical diagnostic guidelines for the neuropathological assessment of FCD recommended by the European Confederation of Neuropathological Societies Research Committee [15]. The pathological sections were re-examined and diagnosed according to the 2011 ILAE classification system. The isolated FCD include FCD Type I, broken down into FCD with abnormal radial cortical lamination (FCD Type Ia), FCD with abnormal tangential cortical lamination (FCD Type Ib), FCD with abnormal radial and tangential cortical lamination (FCD Type Ic), and FCD Type II, broken down into FCD with dysmorphic neurons (FCD Type IIa), and FCD with dysmorphic neurons and balloon cells (FCD Type IIb). The associated FCD category is FCD Type III, broken down into cortical lamination abnormalities in the temporal lobe associated with HS (FCD Type IIIa), cortical lamination abnormalities adjacent to a glial or glioneuronal tumour (FCD Type IIIb), cortical lamination abnormalities adjacent to a vascular malformation (FCD Type IIIc), and cortical lamination abnormalities adjacent to a lesion acquired during early life, for example, from trauma, ischaemic injury, or encephalitis (FCD Type IIId) [8]. The slides were independently re-examined by two neuropathologists, one of whom had not been involved in the initial diagnoses. If any disagreements occurred, they were discussed, and the cases were excluded if a consensus diagnosis was not achieved. The tumours were assigned to histopathological subtypes according to the 2007 World Health Organization Classification of Tumours of the Central Nervous System [16]. HS was diagnosed in the presence of diffused gliosis associated with pyramidal cell loss in the CA1, CA3 and CA4 sectors of Ammon’s horn [17]. 2.4. Statistical procedures The Kruskal–Wallis test and the Mann–Whitney test were used as non-parametric tests for the comparison of age at epilepsy
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onset, duration of epilepsy, age at surgery and seizure frequency in the different subgroups. The chi-squared test or Fisher’s exact test were used for comparison of the categorical data on the occurrence of FS and sGTCS in patients with different subtypes. In the analyses, p < 0.05 was regarded as statistically significant. All of the analyses were performed with the Statistical Package for the Social Sciences version 17.0 (SPSS, Chicago, IL, USA).
3. Results The 92 patients included 36 females and 56 males. The surgical resections were performed on the right side in 52 patients and on the left in 40 patients. Isolated FCD and associated FCD were found in 36 (39.1%) and 56 (60.9%) patients, respectively. FCD Type IIIa (26 patients, 28.3%) was the most frequently found subtype, and FCD Type IIb (five patients, 5.4%) was the most rarely observed subtype (Table 1). Regarding the 10 patients with FCD Type IIIb, the principal lesions of eight patients were gangliogliomas, whereas two patients presented with dysembryoplastic neuroepithelial tumours. Of the nine patients with FCD Type IIIc, the principal lesions of seven patients were cavernomas, and two patients presented with arteriovenous malformations. Regarding the principal lesions of the 11 patients with FCD Type IIId, six patients had traumatic brain injury, three patients had glial scarring after perinatal ischaemic injury, and two patients had infections. The mean age at epilepsy onset was 16.8 years (median 15.0; range 1–36). The mean age at epilepsy onset in isolated FCD patients was 13.1 years (median 12.0; range 1–36). The mean age at epilepsy onset in associated FCD patients was 19.2 years (median 17.0; range 1–50), significantly later than isolated FCD (p = 0.038). In the associated FCD patients, the mean age at epilepsy onset of Type IIIc patients was 30.7 years (median 31.0; range 4–46), significantly later than that of other associated subtypes (p = 0.007 versus IIIa, IIIb and IIId) (Fig. 1). The mean duration of epilepsy was 9.5 years (median 9.5, range 1–29). The mean duration of epilepsy in isolated FCD patients was 12.1 years (median 10.0; range 2–29). The mean duration of epilepsy in associated FCD patients was 7.8 years (median 6.5; range 1–24), significantly shorter than patients with isolated FCD (p = 0.003). In the associated FCD patients, the mean duration of epilepsy in Type IIIb patients was 3.5 years (median 2.0; range 1–10), significantly shorter than the other associated subtypes (p = 0.016 versus IIIa, IIIc and IIId). The mean duration of epilepsy in Type IIIc patients was 5.3 years (median 1.0; range 1–24), significantly shorter than in the other associated subtypes (p = 0.041 versus IIIa, IIIb and IIId) (Fig. 2). The mean age at surgery was 26.5 years (median 23.5; range 3– 51). The mean age at surgery of isolated FCD patients was 25.2 years (median 23.5; range 10–45). The mean age at surgery of associated FCD patients was 27.4 years (median 23.5; range 3– 51), and this was not significantly different to isolated FCD patients. In associated FCD patients, the mean age at surgery for Type IIIc patients was 35.8 years (median 42; range 21–47), which was significantly later than that in the other associated subtypes (p = 0.014 versus IIIa, IIIb and IIId) (Fig. 3). The mean seizure frequency at surgery was 17.7 per month (median 10.0; range 1–330), which was not significantly different between isolated and associated FCD, and there was no significant difference between the subtypes (Fig. 4). A history of FS was present in 38 (41.3%) patients. In the 56 patients with associated FCD, 25 (44.6%) patients had a history of FS, and there was no difference in the patients with isolated FCD. In associated FCD patients, 18 Type IIIa patients had a history of FS, which was significantly more frequent than the other associ-
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Table 1 Clinical characteristics of 92 focal cortical dysplasia patients FCD Type
n
Mean age at epilepsy onset, years
Mean duration of epilepsy, years
Mean age at surgery, years
Mean seizure frequency (per month)
Mean
Median
Range
Mean
Median
Range
Mean
Median
Range
Mean
Median
Range
Isolated FCD (I + II) I Ia Ib Ic
36 23 6 10 7
13.1 13.7 10.7 14.9 14.7
12.0 12.0 12.0 12.5 12.0
1–36 2–36 2–19 2–36 6–29
12.1 10.0 10.7 8.5 11.6
10.0 10.0 7.5 9.0 10.0
2–29 2–29 2–29 2–14 2–25
25.2 23.7 21.3 23.5 26.1
23.5 22.0 17.5 22.5 26.0
10–45 10–41 14–33 10–41 14–41
12.3 12.8 18.5 13.0 7.9
10.0 10.0 8.5 11.0 8.0
1–60 2–60 2–60 3–40 3–15
II IIa IIb
13 8 5
12.1 12.9 10.8
11.0 15.5 10.0
1–27 1–27 7–16
15.8 16.6 14.4
18.0 18.5 12.0
5–23 5–23 5–23
27.9 29.5 25.2
26.0 28.5 24.0
19–45 19–45 19–33
11.2 8.7 15.2
10.0 7.0 12.0
1–35 1–20 4–35
Associated FCD (III) IIIa IIIb IIIc IIId
56 26 10 9 11
19.2a 17.5 18.7 30.7b 14.1
17.0 15.5 20.0 31.0 8.0
1–50 4–50 1–30 4–46 1–43
7.8c 8.4 3.5d 5.3e 12.6
6.5 6.5 2.0 1.0 10.0
1–24 1–20 1–10 1–24 3–24
27.4 25.9 23.5 35.8f 27.6
23.5 21.5 23.5 42.0 26.0
3–51 15–51 3–45 21–47 13–45
21.2 17.5 17.2 50.3 10.0
10.0 8.5 14.5 5.0 10.0
1–330 1–150 1–50 1–330 2–30
Total
92
16.8
15.0
1–50
9.5
9.5
1–29
26.5
23.5
3–51
17.7
10.0
1–330
a
p = 0.038 versus isolated FCD. p = 0.007 Type IIIc versus Type IIIa, IIIb c p = 0.003 versus isolated FCD. d p = 0.016 Type IIIb versus Type IIIa, IIIc e p = 0.041 Type IIIc versus Type IIIa, IIIb f p = 0.014 Type IIIc versus Type IIIa, IIIb FCD = focal cortical dysplasia. b
and IIId. and IIId. and IIId. and IIId.
Fig. 1. Box and whisker plot showing age of epilepsy onset in focal cortical dysplasia subtypes. ILAE = International League Against Epilepsy, 1 = FCD Type Ia, 2 = FCD Type Ib, 3 = FCD Type Ic, 4 = FCD Type IIa, 5 = FCD Type IIb, 6 = FCD Type IIIa, 7 = FCD Type IIIb, 8 = FCD Type IIIc, 9 = FCD Type IIId. The box represents the mean ± one interquartile range, the whiskers represent the range.
ated subtypes (p = 0.005 versus IIIb, IIIc and IIId). A total of 54 (58.7%) patients had sGTCS; there was no significant difference between isolated and associated FCD patients, and no significant difference between the subtypes (Table 2). 4. Discussion Most FCD studies have focused on patients who underwent surgery for drug resistant epilepsy, and it was difficult to confirm FCD without a pathological examination. Reported frequencies of FCD in TLE patients identified by pathological examination range from 9% to 29% according to different classifications and at different centres [18–20], and the proportions have increased in recent studies [12–14]. According to the 2011 ILAE classification, we found that 45% (92/240) of our TLE patients had FCD, and in a series of
Fig. 2. Box and whisker plot showing duration of epilepsy in focal cortical dysplasia subtypes. ILAE = International League Against Epilepsy, 1 = FCD Type Ia, 2 = FCD Type Ib, 3 = FCD Type Ic, 4 = FCD Type IIa, 5 = FCD Type IIb, 6 = FCD Type IIIa, 7 = FCD Type IIIb, 8 = FCD Type IIIc, 9 = FCD Type IIId. The box represents the mean ± one interquartile range, the whiskers represent the range, the circles are mild outliers out of the interquartile range.
patients with associated FCD, previously diagnosed as tumour, vascular malformation and scar, the coexistence of subtle cortical dysplasia was frequently overlooked. Many studies have focused on the adjacent FCD of these lesions, and in 19–35% of FCD patients, FCD occurs with HS [21–23]; approximately 80% of long-term epilepsy-associated tumours are located in the temporal lobe, and coexistent FCD are identified in approximately 10.6–17.8% of these patients [17,24,25]. FCD is frequently present in association with cavernous angiomas in patients with chronic epilepsy [26]. In our study, isolated FCD were present in 39.1% of 92 FCD patients, and associated FCD were present in 60.8% of 92 patients. A recent report studied 215 consecutive patients with Type I FCD (according to Palmini’s classification) and distinguished isolated FCD or FCD associated with HS and tumours [23], with isolated
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Table 2 History of febrile seizure and second generalized tonic-clonic seizures in focal cortical dysplasia patients FCD Type
n
FS (%)
sGTCS (%)
Isolated FCD (I + II) I Ia Ib Ic
36 23 6 10 7
13 (36.1) 9 (39.1) 2 (33.3) 4 (40.0) 3 (42.9)
21 (58.3) 14 (60.9) 4 (66.7) 6 (60.0) 4 (57.1)
II IIa IIb
13 8 5
4 (30.8) 3 (37.5) 1 (20.0)
7 (53.8) 5 (62.5) 2 (40.0)
Associated FCD (III) IIIa IIIb IIIc IIId
56 26 10 9 11
25 (44.6) 18 (69.2)a 2 (20.0) 1 (11.1) 4 (36.4)
33 (58.9) 17 (65.4) 5 (50.0) 6 (66.7) 5 (45.5)
Total
92
41 (44.6)
54 (58.7)
a
Fig. 3. Box and whisker plot showing age at surgery in focal cortical dysplasia subtypes. ILAE = International League Against Epilepsy, 1 = FCD Type Ia, 2 = FCD Type Ib, 3 = FCD Type Ic, 4 = FCD Type IIa, 5 = FCD Type IIb, 6 = FCD Type IIIa, 7 = FCD Type IIIb, 8 = FCD Type IIIc, 9 = FCD Type IIId. The box represents the mean ± one interquartile range, the whiskers represent the range, the circles are mild outliers out of the interquartile range, and the stars are extreme outliers exceeding three times the interquartile range.
Fig. 4. Box and whisker plot showing seizure frequency in focal cortical dysplasia subtypes. ILAE = International League Against Epilepsy, 1 = FCD Type Ia, 2 = FCD Type Ib, 3 = FCD Type Ic, 4 = FCD Type IIa, 5 = FCD Type IIb, 6 = FCD Type IIIa, 7 = FCD Type IIIb, 8 = FCD Type IIIc, 9 = FCD Type IIId. The box represents the mean ± one interquartile range, the whiskers represent the range, the circles are mild outliers out of the interquartile range, and the stars are extreme outliers exceeding three times the interquartile range.
p = 0.005 versus Type IIIb, IIIc and IIId. FCD = focal cortical dysplasia, FS = febrile seizure, sGTCS = second generalized tonicclonic seizure.
decades of life. Reports comparing the age at epilepsy onset of different FCD subtypes show that the age at epilepsy onset in FCD Type I patients is significantly later than Type II patients, with cytologic abnormalities [11,27] and cytologic abnormalities are always present with severe epileptogenicity. In this cohort, the mean age at epilepsy onset of associated FCD was 19.5 years, later than that of isolated FCD, perhaps because associated FCD with cortical lamination abnormalities adjacent to principal lesions, does not involve cytologic abnormalities, and is associated with mild epileptogenicity. In the associated FCD patients, the mean age at epilepsy onset of Type IIIc was 30.7 years, significantly later than other associated subtypes. The reports of 53 patients who underwent microsurgical resection of supratentorial cavernomas show that the first seizure occurred at a mean age of 30.4 years [28], and a recent report of patients with temporal lobe cavernomas reported a median age at presentation of 37 years [29]. Other cohorts have also shown late age at epilepsy onset [30–32]. A cohort focused on arteriovenous malformations of the temporal lobe showed a late age at surgery [33]. Another study reported significant alterations of cortical thickness, neuronal cell density, the shortest neuronal diameter and diameter of neuronal nucleus among FCD Type IIIc patients in a group associated with vascular malformations in comparison to the other FCD Type III subtypes (FCD Type IIIa, b, and d) [34]. The finding suggests that FCD Type IIIc has the characteristic of late age at epilepsy onset similar to that of vascular malformations in the temporal lobe and is different from other FCD Type III subtypes. 4.2. Duration of epilepsy
FCD observed in 31% patients, and associated FCD being observed in 69% patients, similar to our result. In associated FCD patients, Type IIIa, previously diagnosed as temporal lobe sclerosis or as a dual pathology of FCD with HS, was the most frequent subtype, present in 28.3% of our patients, which was similar to a recent finding of 35% FCD with HS in temporal lobe FCD patients [23]. 4.1. Age at epilepsy onset The age at epilepsy onset plays an important role in the manifestation of epilepsy and the development of intelligence. In the majority of FCD patients, epilepsy onset occurred in the first two
The duration of epilepsy of associated FCD was shorter than that of isolated FCD in this cohort, perhaps because the principal lesion was easily identified on MRI for presurgical assessment. In the patients with associated FCD, the duration of epilepsy of FCD Type IIIb and Type IIIc was significantly shorter than that of other associated subtypes. A study focused on 30 children with focal epilepsy associated with low-grade tumours showed the mean duration of epilepsy was 4.5 years, and the duration of epilepsy of 43.3% patients was 1 year or less [35]. Several studies have confirmed that patients with cavernomas have a short duration of epilepsy before surgery of approximately 3 years [28–32]. FCD Type IIIb and Type IIIc have similar characteristics to epilepsy associated with principal lesions.
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4.3. FS FS occur predominantly in patients with dual pathology, especially in FCD with additional HS [27]. The data of Tassi et al. suggest that patients with FCD are more prone to FS than other patients and that the highest prevalence of FS is found in patients with FCD Type I (48%) [12]; the data conclude that FS are statistically relevant in patients with malformative lesions plus HS. A recent study of temporal lobe sclerosis (TLS) shows that FS occur in 73% of patients with TLS compared with 36% without TLS [36]. TLS is regarded as FCD Type IIIa according to the 2011 ILAE classification. FS was reported to be more frequent in patients with dual pathology than isolated FCD [10]. In the study by Fauser et al. [37], a history of FS was found more frequently in FCD Type IIIa according to the new classification. Our data showed that FS were present in 36% of the cohort and significantly more frequent in FCD Type IIIa (p = 0.005) than other subtypes, supporting the findings of previous studies, and suggesting that FCD Type IIIa has a high susceptibility to the occurrence of FS. Clinical differences were found in the patients with temporal lobe FCD. Associated FCD has a later epilepsy onset and shorter duration of epilepsy, especially FCD Type IIIc. The subtypes of associated FCD have unique clinical characteristics, including FCD Type IIIa, which is associated with a high susceptibility to FS. Associated FCD might occur during postnatal development and the maturation period, developing from different pathomechanisms. Whether FCD Type III is an acquired pathology from a principal lesion or a distinct pathological entity should be determined, and the clinical characteristics of FCD subtypes require further confirmation according to this unified new classification in a multicentre study. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgements The authors are grateful to the staff of the Department of Pathology and Department of Neuroradiology of Hebei General Hospital for their assistance in this study. References [1] Taylor DC, Falconer MA, Bruton CJ, et al. Focal dysplasia of the cerebral cortex in epilepsy. J Neurol Neurosurg Psychiatry 1971;34:369–87. [2] Kuzniecky R, Powers R. Epilepsia partialis continua due to cortical dysplasia. J Child Neurol 1993;8:386–8. [3] Tassi L, Colombo N, Garbelli R, et al. Focal cortical dysplasia: neuropathological subtypes, EEG, neuroimaging and surgical outcome. Brain 2002;125:1719–32. [4] 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. [5] Barkovich AJ, Kuzniecky RI, Jackson GD, et al. A developmental and genetic classification for malformations of cortical development. Neurology 2005;65:1873–87. [6] Palmini A, Najm I, Avanzini G, et al. Terminology and classification of the cortical dysplasias. Neurology 2004;62:S2–8. [7] Chamberlain WA, Cohen ML, Gyure KA, et al. Interobserver and intraobserver reproducibility in focal cortical dysplasia (malformations of cortical development). Epilepsia 2009;50:2593–8. [8] Blümcke I, Thom M, Aronica E, et al. The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia 2011;52:158–74.
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Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Clinical characteristics of 92 patients with temporal lobe focal cortical dysplasia identified by pathological examination Jiang Wu a, Wenling Li b, Yao Chen a, Lin Kang c, Wenqing Zhao a,b,⇑ a
Department of Neurosurgery, Hebei Medical University, Shijiazhuang, China Department of Functional Neurosurgery, Hebei General Hospital, No. 348 Heping West Road, Shijiazhuang 050000, China c Department of Pathology, Hebei General Hospital, Shijiazhuang, China b
a r t i c l e
i n f o
Article history: Received 22 August 2013 Accepted 21 April 2014
Keywords: Clinical characteristics Focal cortical dysplasia Pathological subtypes Temporal lobe epilepsy
a b s t r a c t Focal cortical dysplasia (FCD) is frequently associated with focal epilepsy, and a broad spectrum of histopathology is included in the diagnosis of FCD. In 2011, an International League Against Epilepsy (ILAE) task force proposed an international consensus for a classification system to better characterise specific clinicopathological FCD entities. The clinical characteristics of patients with FCD should be confirmed according to the new ILAE classification. We retrospectively analysed 92 patients who had undergone surgical treatment for temporal lobe epilepsy and received a pathological diagnosis of FCD. The pathological sections were re-examined and diagnosed according to the 2011 ILAE classification. The clinical data from patients with different FCD subtypes were evaluated, including a detailed history regarding spontaneous abortions, trauma, ischaemic injury, encephalitis, and febrile seizures at an early age. The age of epilepsy onset, duration of epilepsy, age at surgery, seizure frequency, history of febrile seizures, and seizure type, particularly whether the seizures were secondarily generalised tonic-clonic seizures, were recorded. Clinical differences were found in the patients with temporal lobe FCD. The associated FCD subtypes have unique clinical characteristics, including a later age of epilepsy onset and a shorter duration of epilepsy, especially in FCD Type IIIc; and a high susceptibility to febrile seizures was observed in FCD Type IIIa. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction Focal cortical dysplasia (FCD) was first described as a distinct neuropathological entity in 1971 by Taylor [1]. FCD is a common neuropathological finding in patients with refractory epilepsy that is increasingly diagnosed with the development of high-resolution MRI [2,3]. The term ‘‘FCD’’ is widely used to describe a large spectrum of malformative lesions comprising cortical dyslamination and cytoarchitectural lesions; the morphological spectrum of FCD variants is not well classified. A number of FCD classification systems have been proposed that rely on histopathological examination [4], imaging and genetic findings [5], or a combination of clinical and histopathological features [3,6]. The repeatability is low and results in inconsistent diagnoses between different centres [7]. In 2011, the International League Against Epilepsy (ILAE) proposed a novel three-tiered classification system for FCD that distinguishes isolated forms (FCD Type I and II) from those cortical abnormalities associated with another principal lesion (FCD Type ⇑ Corresponding author. Tel./fax: +86 311 8598 8643. E-mail address: [email protected] (W. Zhao). http://dx.doi.org/10.1016/j.jocn.2014.04.022 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.
III) [8]; this new system is based on standardised laboratory protocols. The determination of the clinical characteristics of FCD has been limited and less comparable among studies because the cohorts of studies have been mixed, with cases involving different lobes, paediatric versus adult patients, and isolated versus associated FCD types [9–11]. The clinical characteristics of the subtypes according to this new classification system have not been clarified, especially those of the newly classified associated FCD type (FCD Type III). Because almost 50% of FCD occurrences are in the temporal lobe [3,12–14], the purpose of this study was to elucidate the clinical characteristics of different temporal lobe FCD subtypes, according to the 2011 ILAE classification. 2. Patients and methods 2.1. Patients The medical charts of 241 consecutive paediatric and adult patients with temporal lobe epilepsy (TLE) were retrospectively analysed. All of the patients had surgery at Hebei General Hospital in China between June 2006 and June 2011. The pathological sections
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were re-examined and diagnosed according to the 2011 ILAE classification. Ninety-two patients were selected using the following inclusion criteria: (1) the patient underwent a temporal lobectomy; (2) surgical specimens were sufficiently preserved for evaluation of the neocortex and hippocampus; (3) final diagnosis was FCD according to the 2011 ILAE classification; and (4) they were not suffering from any other neurological disorder. Patients with dual pathology (for example, FCD Type II with hippocampal sclerosis [HS], or FCD Type IIIb, c, d with HS) and multilobar FCD were excluded. The clinical records of each patient were reviewed, including a detailed history regarding spontaneous abortions, trauma, ischaemic injury, encephalitis, and febrile seizures (FS) at an early age. The age of epilepsy onset, duration of epilepsy, age at surgery, seizure frequency, history of FS, and seizure type, particularly whether the seizures were secondarily generalised tonic-clonic seizures (sGTCS), were recorded. 2.2. Surgery The surgical resections were performed for strictly therapeutic reasons and were planned based on the clinical, neuroimaging, and electrophysiological results. In patients for whom MRI was unrevealing, resection was planned using electroclinical and invasive electroencephalography data. The extent of resection was planned pre-operatively in each case, after considering the severity of the epilepsy and the risk of post-surgical deficits. 2.3. Pathological examinations The specimens were fixed in a 4% buffered formaldehyde solution, dehydrated and embedded in paraffin. The standard stains on each tissue block included haematoxylin and eosin. Specific stains and immunohistochemistry were used according to the practical diagnostic guidelines for the neuropathological assessment of FCD recommended by the European Confederation of Neuropathological Societies Research Committee [15]. The pathological sections were re-examined and diagnosed according to the 2011 ILAE classification system. The isolated FCD include FCD Type I, broken down into FCD with abnormal radial cortical lamination (FCD Type Ia), FCD with abnormal tangential cortical lamination (FCD Type Ib), FCD with abnormal radial and tangential cortical lamination (FCD Type Ic), and FCD Type II, broken down into FCD with dysmorphic neurons (FCD Type IIa), and FCD with dysmorphic neurons and balloon cells (FCD Type IIb). The associated FCD category is FCD Type III, broken down into cortical lamination abnormalities in the temporal lobe associated with HS (FCD Type IIIa), cortical lamination abnormalities adjacent to a glial or glioneuronal tumour (FCD Type IIIb), cortical lamination abnormalities adjacent to a vascular malformation (FCD Type IIIc), and cortical lamination abnormalities adjacent to a lesion acquired during early life, for example, from trauma, ischaemic injury, or encephalitis (FCD Type IIId) [8]. The slides were independently re-examined by two neuropathologists, one of whom had not been involved in the initial diagnoses. If any disagreements occurred, they were discussed, and the cases were excluded if a consensus diagnosis was not achieved. The tumours were assigned to histopathological subtypes according to the 2007 World Health Organization Classification of Tumours of the Central Nervous System [16]. HS was diagnosed in the presence of diffused gliosis associated with pyramidal cell loss in the CA1, CA3 and CA4 sectors of Ammon’s horn [17]. 2.4. Statistical procedures The Kruskal–Wallis test and the Mann–Whitney test were used as non-parametric tests for the comparison of age at epilepsy
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onset, duration of epilepsy, age at surgery and seizure frequency in the different subgroups. The chi-squared test or Fisher’s exact test were used for comparison of the categorical data on the occurrence of FS and sGTCS in patients with different subtypes. In the analyses, p < 0.05 was regarded as statistically significant. All of the analyses were performed with the Statistical Package for the Social Sciences version 17.0 (SPSS, Chicago, IL, USA).
3. Results The 92 patients included 36 females and 56 males. The surgical resections were performed on the right side in 52 patients and on the left in 40 patients. Isolated FCD and associated FCD were found in 36 (39.1%) and 56 (60.9%) patients, respectively. FCD Type IIIa (26 patients, 28.3%) was the most frequently found subtype, and FCD Type IIb (five patients, 5.4%) was the most rarely observed subtype (Table 1). Regarding the 10 patients with FCD Type IIIb, the principal lesions of eight patients were gangliogliomas, whereas two patients presented with dysembryoplastic neuroepithelial tumours. Of the nine patients with FCD Type IIIc, the principal lesions of seven patients were cavernomas, and two patients presented with arteriovenous malformations. Regarding the principal lesions of the 11 patients with FCD Type IIId, six patients had traumatic brain injury, three patients had glial scarring after perinatal ischaemic injury, and two patients had infections. The mean age at epilepsy onset was 16.8 years (median 15.0; range 1–36). The mean age at epilepsy onset in isolated FCD patients was 13.1 years (median 12.0; range 1–36). The mean age at epilepsy onset in associated FCD patients was 19.2 years (median 17.0; range 1–50), significantly later than isolated FCD (p = 0.038). In the associated FCD patients, the mean age at epilepsy onset of Type IIIc patients was 30.7 years (median 31.0; range 4–46), significantly later than that of other associated subtypes (p = 0.007 versus IIIa, IIIb and IIId) (Fig. 1). The mean duration of epilepsy was 9.5 years (median 9.5, range 1–29). The mean duration of epilepsy in isolated FCD patients was 12.1 years (median 10.0; range 2–29). The mean duration of epilepsy in associated FCD patients was 7.8 years (median 6.5; range 1–24), significantly shorter than patients with isolated FCD (p = 0.003). In the associated FCD patients, the mean duration of epilepsy in Type IIIb patients was 3.5 years (median 2.0; range 1–10), significantly shorter than the other associated subtypes (p = 0.016 versus IIIa, IIIc and IIId). The mean duration of epilepsy in Type IIIc patients was 5.3 years (median 1.0; range 1–24), significantly shorter than in the other associated subtypes (p = 0.041 versus IIIa, IIIb and IIId) (Fig. 2). The mean age at surgery was 26.5 years (median 23.5; range 3– 51). The mean age at surgery of isolated FCD patients was 25.2 years (median 23.5; range 10–45). The mean age at surgery of associated FCD patients was 27.4 years (median 23.5; range 3– 51), and this was not significantly different to isolated FCD patients. In associated FCD patients, the mean age at surgery for Type IIIc patients was 35.8 years (median 42; range 21–47), which was significantly later than that in the other associated subtypes (p = 0.014 versus IIIa, IIIb and IIId) (Fig. 3). The mean seizure frequency at surgery was 17.7 per month (median 10.0; range 1–330), which was not significantly different between isolated and associated FCD, and there was no significant difference between the subtypes (Fig. 4). A history of FS was present in 38 (41.3%) patients. In the 56 patients with associated FCD, 25 (44.6%) patients had a history of FS, and there was no difference in the patients with isolated FCD. In associated FCD patients, 18 Type IIIa patients had a history of FS, which was significantly more frequent than the other associ-
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Table 1 Clinical characteristics of 92 focal cortical dysplasia patients FCD Type
n
Mean age at epilepsy onset, years
Mean duration of epilepsy, years
Mean age at surgery, years
Mean seizure frequency (per month)
Mean
Median
Range
Mean
Median
Range
Mean
Median
Range
Mean
Median
Range
Isolated FCD (I + II) I Ia Ib Ic
36 23 6 10 7
13.1 13.7 10.7 14.9 14.7
12.0 12.0 12.0 12.5 12.0
1–36 2–36 2–19 2–36 6–29
12.1 10.0 10.7 8.5 11.6
10.0 10.0 7.5 9.0 10.0
2–29 2–29 2–29 2–14 2–25
25.2 23.7 21.3 23.5 26.1
23.5 22.0 17.5 22.5 26.0
10–45 10–41 14–33 10–41 14–41
12.3 12.8 18.5 13.0 7.9
10.0 10.0 8.5 11.0 8.0
1–60 2–60 2–60 3–40 3–15
II IIa IIb
13 8 5
12.1 12.9 10.8
11.0 15.5 10.0
1–27 1–27 7–16
15.8 16.6 14.4
18.0 18.5 12.0
5–23 5–23 5–23
27.9 29.5 25.2
26.0 28.5 24.0
19–45 19–45 19–33
11.2 8.7 15.2
10.0 7.0 12.0
1–35 1–20 4–35
Associated FCD (III) IIIa IIIb IIIc IIId
56 26 10 9 11
19.2a 17.5 18.7 30.7b 14.1
17.0 15.5 20.0 31.0 8.0
1–50 4–50 1–30 4–46 1–43
7.8c 8.4 3.5d 5.3e 12.6
6.5 6.5 2.0 1.0 10.0
1–24 1–20 1–10 1–24 3–24
27.4 25.9 23.5 35.8f 27.6
23.5 21.5 23.5 42.0 26.0
3–51 15–51 3–45 21–47 13–45
21.2 17.5 17.2 50.3 10.0
10.0 8.5 14.5 5.0 10.0
1–330 1–150 1–50 1–330 2–30
Total
92
16.8
15.0
1–50
9.5
9.5
1–29
26.5
23.5
3–51
17.7
10.0
1–330
a
p = 0.038 versus isolated FCD. p = 0.007 Type IIIc versus Type IIIa, IIIb c p = 0.003 versus isolated FCD. d p = 0.016 Type IIIb versus Type IIIa, IIIc e p = 0.041 Type IIIc versus Type IIIa, IIIb f p = 0.014 Type IIIc versus Type IIIa, IIIb FCD = focal cortical dysplasia. b
and IIId. and IIId. and IIId. and IIId.
Fig. 1. Box and whisker plot showing age of epilepsy onset in focal cortical dysplasia subtypes. ILAE = International League Against Epilepsy, 1 = FCD Type Ia, 2 = FCD Type Ib, 3 = FCD Type Ic, 4 = FCD Type IIa, 5 = FCD Type IIb, 6 = FCD Type IIIa, 7 = FCD Type IIIb, 8 = FCD Type IIIc, 9 = FCD Type IIId. The box represents the mean ± one interquartile range, the whiskers represent the range.
ated subtypes (p = 0.005 versus IIIb, IIIc and IIId). A total of 54 (58.7%) patients had sGTCS; there was no significant difference between isolated and associated FCD patients, and no significant difference between the subtypes (Table 2). 4. Discussion Most FCD studies have focused on patients who underwent surgery for drug resistant epilepsy, and it was difficult to confirm FCD without a pathological examination. Reported frequencies of FCD in TLE patients identified by pathological examination range from 9% to 29% according to different classifications and at different centres [18–20], and the proportions have increased in recent studies [12–14]. According to the 2011 ILAE classification, we found that 45% (92/240) of our TLE patients had FCD, and in a series of
Fig. 2. Box and whisker plot showing duration of epilepsy in focal cortical dysplasia subtypes. ILAE = International League Against Epilepsy, 1 = FCD Type Ia, 2 = FCD Type Ib, 3 = FCD Type Ic, 4 = FCD Type IIa, 5 = FCD Type IIb, 6 = FCD Type IIIa, 7 = FCD Type IIIb, 8 = FCD Type IIIc, 9 = FCD Type IIId. The box represents the mean ± one interquartile range, the whiskers represent the range, the circles are mild outliers out of the interquartile range.
patients with associated FCD, previously diagnosed as tumour, vascular malformation and scar, the coexistence of subtle cortical dysplasia was frequently overlooked. Many studies have focused on the adjacent FCD of these lesions, and in 19–35% of FCD patients, FCD occurs with HS [21–23]; approximately 80% of long-term epilepsy-associated tumours are located in the temporal lobe, and coexistent FCD are identified in approximately 10.6–17.8% of these patients [17,24,25]. FCD is frequently present in association with cavernous angiomas in patients with chronic epilepsy [26]. In our study, isolated FCD were present in 39.1% of 92 FCD patients, and associated FCD were present in 60.8% of 92 patients. A recent report studied 215 consecutive patients with Type I FCD (according to Palmini’s classification) and distinguished isolated FCD or FCD associated with HS and tumours [23], with isolated
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Table 2 History of febrile seizure and second generalized tonic-clonic seizures in focal cortical dysplasia patients FCD Type
n
FS (%)
sGTCS (%)
Isolated FCD (I + II) I Ia Ib Ic
36 23 6 10 7
13 (36.1) 9 (39.1) 2 (33.3) 4 (40.0) 3 (42.9)
21 (58.3) 14 (60.9) 4 (66.7) 6 (60.0) 4 (57.1)
II IIa IIb
13 8 5
4 (30.8) 3 (37.5) 1 (20.0)
7 (53.8) 5 (62.5) 2 (40.0)
Associated FCD (III) IIIa IIIb IIIc IIId
56 26 10 9 11
25 (44.6) 18 (69.2)a 2 (20.0) 1 (11.1) 4 (36.4)
33 (58.9) 17 (65.4) 5 (50.0) 6 (66.7) 5 (45.5)
Total
92
41 (44.6)
54 (58.7)
a
Fig. 3. Box and whisker plot showing age at surgery in focal cortical dysplasia subtypes. ILAE = International League Against Epilepsy, 1 = FCD Type Ia, 2 = FCD Type Ib, 3 = FCD Type Ic, 4 = FCD Type IIa, 5 = FCD Type IIb, 6 = FCD Type IIIa, 7 = FCD Type IIIb, 8 = FCD Type IIIc, 9 = FCD Type IIId. The box represents the mean ± one interquartile range, the whiskers represent the range, the circles are mild outliers out of the interquartile range, and the stars are extreme outliers exceeding three times the interquartile range.
Fig. 4. Box and whisker plot showing seizure frequency in focal cortical dysplasia subtypes. ILAE = International League Against Epilepsy, 1 = FCD Type Ia, 2 = FCD Type Ib, 3 = FCD Type Ic, 4 = FCD Type IIa, 5 = FCD Type IIb, 6 = FCD Type IIIa, 7 = FCD Type IIIb, 8 = FCD Type IIIc, 9 = FCD Type IIId. The box represents the mean ± one interquartile range, the whiskers represent the range, the circles are mild outliers out of the interquartile range, and the stars are extreme outliers exceeding three times the interquartile range.
p = 0.005 versus Type IIIb, IIIc and IIId. FCD = focal cortical dysplasia, FS = febrile seizure, sGTCS = second generalized tonicclonic seizure.
decades of life. Reports comparing the age at epilepsy onset of different FCD subtypes show that the age at epilepsy onset in FCD Type I patients is significantly later than Type II patients, with cytologic abnormalities [11,27] and cytologic abnormalities are always present with severe epileptogenicity. In this cohort, the mean age at epilepsy onset of associated FCD was 19.5 years, later than that of isolated FCD, perhaps because associated FCD with cortical lamination abnormalities adjacent to principal lesions, does not involve cytologic abnormalities, and is associated with mild epileptogenicity. In the associated FCD patients, the mean age at epilepsy onset of Type IIIc was 30.7 years, significantly later than other associated subtypes. The reports of 53 patients who underwent microsurgical resection of supratentorial cavernomas show that the first seizure occurred at a mean age of 30.4 years [28], and a recent report of patients with temporal lobe cavernomas reported a median age at presentation of 37 years [29]. Other cohorts have also shown late age at epilepsy onset [30–32]. A cohort focused on arteriovenous malformations of the temporal lobe showed a late age at surgery [33]. Another study reported significant alterations of cortical thickness, neuronal cell density, the shortest neuronal diameter and diameter of neuronal nucleus among FCD Type IIIc patients in a group associated with vascular malformations in comparison to the other FCD Type III subtypes (FCD Type IIIa, b, and d) [34]. The finding suggests that FCD Type IIIc has the characteristic of late age at epilepsy onset similar to that of vascular malformations in the temporal lobe and is different from other FCD Type III subtypes. 4.2. Duration of epilepsy
FCD observed in 31% patients, and associated FCD being observed in 69% patients, similar to our result. In associated FCD patients, Type IIIa, previously diagnosed as temporal lobe sclerosis or as a dual pathology of FCD with HS, was the most frequent subtype, present in 28.3% of our patients, which was similar to a recent finding of 35% FCD with HS in temporal lobe FCD patients [23]. 4.1. Age at epilepsy onset The age at epilepsy onset plays an important role in the manifestation of epilepsy and the development of intelligence. In the majority of FCD patients, epilepsy onset occurred in the first two
The duration of epilepsy of associated FCD was shorter than that of isolated FCD in this cohort, perhaps because the principal lesion was easily identified on MRI for presurgical assessment. In the patients with associated FCD, the duration of epilepsy of FCD Type IIIb and Type IIIc was significantly shorter than that of other associated subtypes. A study focused on 30 children with focal epilepsy associated with low-grade tumours showed the mean duration of epilepsy was 4.5 years, and the duration of epilepsy of 43.3% patients was 1 year or less [35]. Several studies have confirmed that patients with cavernomas have a short duration of epilepsy before surgery of approximately 3 years [28–32]. FCD Type IIIb and Type IIIc have similar characteristics to epilepsy associated with principal lesions.
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4.3. FS FS occur predominantly in patients with dual pathology, especially in FCD with additional HS [27]. The data of Tassi et al. suggest that patients with FCD are more prone to FS than other patients and that the highest prevalence of FS is found in patients with FCD Type I (48%) [12]; the data conclude that FS are statistically relevant in patients with malformative lesions plus HS. A recent study of temporal lobe sclerosis (TLS) shows that FS occur in 73% of patients with TLS compared with 36% without TLS [36]. TLS is regarded as FCD Type IIIa according to the 2011 ILAE classification. FS was reported to be more frequent in patients with dual pathology than isolated FCD [10]. In the study by Fauser et al. [37], a history of FS was found more frequently in FCD Type IIIa according to the new classification. Our data showed that FS were present in 36% of the cohort and significantly more frequent in FCD Type IIIa (p = 0.005) than other subtypes, supporting the findings of previous studies, and suggesting that FCD Type IIIa has a high susceptibility to the occurrence of FS. Clinical differences were found in the patients with temporal lobe FCD. Associated FCD has a later epilepsy onset and shorter duration of epilepsy, especially FCD Type IIIc. The subtypes of associated FCD have unique clinical characteristics, including FCD Type IIIa, which is associated with a high susceptibility to FS. Associated FCD might occur during postnatal development and the maturation period, developing from different pathomechanisms. Whether FCD Type III is an acquired pathology from a principal lesion or a distinct pathological entity should be determined, and the clinical characteristics of FCD subtypes require further confirmation according to this unified new classification in a multicentre study. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgements The authors are grateful to the staff of the Department of Pathology and Department of Neuroradiology of Hebei General Hospital for their assistance in this study. References [1] Taylor DC, Falconer MA, Bruton CJ, et al. Focal dysplasia of the cerebral cortex in epilepsy. J Neurol Neurosurg Psychiatry 1971;34:369–87. [2] Kuzniecky R, Powers R. Epilepsia partialis continua due to cortical dysplasia. J Child Neurol 1993;8:386–8. [3] Tassi L, Colombo N, Garbelli R, et al. Focal cortical dysplasia: neuropathological subtypes, EEG, neuroimaging and surgical outcome. Brain 2002;125:1719–32. [4] 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. [5] Barkovich AJ, Kuzniecky RI, Jackson GD, et al. A developmental and genetic classification for malformations of cortical development. Neurology 2005;65:1873–87. [6] Palmini A, Najm I, Avanzini G, et al. Terminology and classification of the cortical dysplasias. Neurology 2004;62:S2–8. [7] Chamberlain WA, Cohen ML, Gyure KA, et al. Interobserver and intraobserver reproducibility in focal cortical dysplasia (malformations of cortical development). Epilepsia 2009;50:2593–8. [8] Blümcke I, Thom M, Aronica E, et al. The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia 2011;52:158–74.
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