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Clinicopathological associations in temporal lobe epilepsy patients utilising the current ILAE focal cortical dysplasia classification
Epilepsy Research (2014) 108, 1345—1351
journal homepage: www.elsevier.com/locate/epilepsyres
Clinicopathological associations in temporal lobe epilepsy patients utilising the current ILAE focal cortical dysplasia classification Alexandra M. Johnson a,b,∗, Ella Sugo c,d, Daniela Barreto a, Anne M. Cunningham a,b, Chee-Chung Hiew d, John A. Lawson a,b, Ernest R. Somerville d,b, Anne M. Connolly a,b, Annie M.E. Bye a,b a
Sydney Children’s Hospitals Network (Randwick), High St, Randwick, Sydney, NSW 2031, Australia University of New South Wales, NSW 2052, Australia c South Eastern Area Laboratory Services, Barker St, Randwick, Sydney, NSW 2031, Australia d Prince of Wales Hospital, High St, Randwick, Sydney, NSW 2031, Australia b
Received 17 February 2014; received in revised form 9 May 2014; accepted 13 June 2014 Available online 7 July 2014
KEYWORDS Temporal lobe epilepsy; FCD IIIA; Surgery
Summary Objectives: This study utilised the revised 2011 ILAE classification of focal cortical dysplasia (FCD) (Blümcke et al., 2011) to examine pathology in a cohort of children and adults who underwent temporal lobe epilepsy (TLE) surgery, and to describe the electroclinical and imaging features associated with these pathologies. Methods: The sample population were children (n = 26) and adults (n = 47) who underwent TLE surgery between 2002 and 2011 at our institutions. Neuropathology and MRI studies were rereviewed by experts blinded to the original diagnosis. EEG and clinical data including current seizure outcome were determined by patient file review and/or patient contact. Pre-operative data, post-operative outcome and pathological diagnoses were compared. Results: The commonest pathology in the adult cohort was isolated hippocampal sclerosis (HS) (n = 24, 51.1%) and in the paediatric cohort, isolated tumour (n = 10, 38.5%). Overall, HS with
∗ Corresponding author at: Neurology Department, Level 4 Emergency Wing, Sydney Children’s Hospitals Network (Randwick), High St, Randwick, Sydney, NSW 2031, Australia. Tel.: +61 2 9382 1111; fax: +61 2 9382 1580. E-mail addresses: [email protected] (A.M. Johnson), [email protected] (E. Sugo), [email protected] (D. Barreto), [email protected] (A.M. Cunningham), [email protected] (C.-C. Hiew), [email protected] (J.A. Lawson), [email protected] (E.R. Somerville), [email protected] (A.M. Connolly), [email protected] (A.M.E. Bye).
http://dx.doi.org/10.1016/j.eplepsyres.2014.06.013 0920-1211/Crown Copyright © 2014 Published by Elsevier B.V. All rights reserved.
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A.M. Johnson et al. associated FCD (FCD IIIA) was the third most common pathology (n = 12, 16.4%). Temporal grey matter signal changes on MRI were associated with FCD IIIA (p = 0.035). FCD IIIA had the poorest post-surgical seizure outcome compared to all other pathologies (p = 0.026). A history of bilateral convulsive seizures was more common in adults (n = 40, p < 0.0005), and was associated with failure to achieve postoperative seizure freedom (p = 0.045). Postoperatively, paediatric TLE had higher rates of seizure freedom (p = 0.005) and more children had ceased medication (p < 0.0005). Significance: FCD IIIA is a comparatively common pathological subtype in TLE, with a poor postsurgical outcome. Pre-operative recognition of FCD IIIA may be feasible through grey matter signal change on MRI. Paediatric patients had a higher rate of seizure freedom than adults. Pre-operative bilateral convulsive seizures were associated with poor outcome after surgery. Crown Copyright © 2014 Published by Elsevier B.V. All rights reserved.
Introduction Focal cortical dysplasia (FCD) is associated with intractable epilepsy, and occurs either in isolation or in combination with other pathologies. There have been multiple previous attempts to introduce uniformity to the pathological classification of FCD (Mischel et al., 1995; Palmini et al., 2004). However, inter-rater reliability of previous classifications has been poor (Chamberlain et al., 2009). Electroclinical features and post-operative outcome vary between cohorts for some subtypes of FCD. FCD IIB has well described clinical and imaging features which predict pathology and outcome (Lawson et al., 2005). However, features of FCD I are not well distinguished on clinical presentation, neuroimaging, or histopathology (Chamberlain et al., 2009) and there is variable post-surgical outcome (Fauser et al., 2004; Krsek et al., 2009; Tassi et al., 2010). A revised classification was formulated by an International League Against Epilepsy (ILAE) task force (Blümcke et al., 2011) to address the poor interobserver reliability of the previous classifications and aimed to lessen the clinicopathological discrepancies (Chamberlain et al., 2009). The 2011 classification is considered to provide good inter-observer reliability of pathological diagnoses (Coras et al., 2012). The new ILAE classification introduced a third category of dysplasia associated with another primary lesion (FCD type III) (Blümcke et al., 2011). FCD III is now considered a distinct entity to FCD I. Previous studies have shown its clinical characteristics reflected its primary pathology (e.g. hippocampal sclerosis (HS) in FCD IIIA) rather than the associated dysplasia (Tassi et al., 2009, 2010). We aimed to determine the frequency of FCD type IIIA pathology in a cohort of temporal lobe epilepsy (TLE) surgical patients and whether FCD IIIA has a distinct electroclinical phenotype with identifying imaging features and prognostic implications. This has not been previously established. Prediction of outcome after temporal lobe surgery is known to be influenced both by underlying pathology and pre-operative clinical factors, such as presence of bilateral convulsive seizures (McIntosh et al., 2004; Ozkara et al., 2008) Atypical HS (ILAE type 2 and 3) has also been associated with poorer post-surgical outcome (Blümcke et al., 2013). Some studies have demonstrated that earlier operation is correlated with better seizure and psychosocial outcomes (Lindsay et al., 1984; Jeong et al., 1999;
Sirven et al., 2000; Zarroli et al., 2011). It has not been established if these findings apply to FCD IIIA.
Materials and methods Cohort and ethics A retrospective review of adult and paediatric patients who underwent TLE surgery at Sydney Children’s Hospitals Network (Randwick) and Prince of Wales Hospital between January 2002 and December 2011 was undertaken. Ethics approval was granted by the Sydney Children’s Hospitals Network Human Research Ethics Committee. Eligible participants were invited by mail with follow-up phone call to determine interest. Written informed consent was obtained. Of the eligible cohort 13 were not contactable and 11 did not give written consent. Data from 73 patients (47 adults, 26 children) were included in the study. The median time since operation was 4.2 years (range 1.1—10.9 years), and was not significantly different between children and adults (p = 0.662). All underwent a tailored anterior temporal lobectomy or temporal lesionectomy (46% left sided), with no patients undergoing a selective amygdalohippocampectomy. Six children and five adults required a repeat operation.
Pathological review A pathologist (ES) reviewed the existing pathology slides of hippocampus and temporal lobe for each patient, blinded to the previous report. When several operations had occurred, pathological sections were reviewed from each operation when available. Section thickness was 5 m. Histochemistry with haematoxylin and eosin (H&E) was available for every patient. Luxol fast blue/Cresyl violet (LFB/CV) and immunostaining with antibodies to glial fibrillary acidic protein (GFAP) and neuronal nuclei (NeuN) were performed according to the current laboratory protocol, using a Leica Bond III automated immunostainer (Leica Autostainer XL, Leica Microsystems, Newcastle, UK). De-paraffinisation and rehydration were followed by enzymatic antigen retrieval for 10 min (GFAP) or heat retrieval for 30 min (NeuN). Slides were incubated with primary (rabbit) polyclonal antibody against GFAP (currently 1 in 4000, previously 1 in 10,000,
FCD IIIA correlates in TLE DAKO) and primary (mouse) monoclonal antibody against NeuN (clone A60, 1 in 200, Millipore) for 30 min. Antibody binding was detected by means of the respective Bond Polymer Refine Detection kit (Leica Microsystems), which uses HRP1 conjugated secondary antibodies and DAB2 as the chromagen. Mayer’s haematoxylin was used as the counter-stain. Markers for cellular proliferaton and epilepsy-associated tumours (e.g. Ki-67, CD-34) were also available. In patients with isolated HS and FCD IIIA, the majority had previously performed immunostaining with either NeuN (n = 30/42) and/or GFAP (n = 35/42), and further recutting and immunohistochemistry were performed if there was doubt as to the underlying diagnosis. A primary diagnostic category was assigned to each patient based on their pathology, using recent definitions for hippocampal sclerosis (HS) and tumours (Louis et al., 2007). Accompanying dysplasia (FCD III) was diagnosed on the basis of the ILAE 2011 classification of FCD (Blümcke et al., 2011). FCD IIIA was identified if HS was accompanied by vertical and/or horizontal dyslamination or temporal lobe sclerosis.
Clinical, radiological and electrophysiological review Demographic data were collected on seizure onset, duration and type, and precipitating events. Seizure type was determined using the ILAE classification (Berg et al., 2010). Seizure frequency was recorded for the six months prior to operation. Three patients had surgery soon after seizure onset due to suspicion of tumour. They were excluded from the analysis of seizure frequency. In cases where more than one operation had occurred, clinical details were analysed prior to the first epilepsy surgery when tissue was available for review. Documentation of duration of epilepsy prior to surgery was limited to those undergoing a single surgery. Pre-operative magnetic resonance images (MRI) (majority 1.5 T) were independently reviewed by a neuroradiologist (CH) and neurologist (JL), blinded to the original reports. Data were recorded using a standardised protocol, based on the features of FCD described by Krsek et al. (2009). Individual, independent features examined included (1) hippocampal size, shape and signal change; (2) temporal lobe signal change (T2 and FLAIR) in grey or white matter; (3) temporal lobe grey-white matter blurring; and (4) extra-hippocampal atrophy and location. Disagreement was resolved by discussion. When hippocampal tissue was not available for pathological analysis (n = 3), the presence of HS was determined by the presence of hippocampal volume reduction and/or increased signal intensity (FLAIR and T2) on MRI (Jackson et al., 1990). In these patients, FCD IIIA was diagnosed if the pathology showed evidence of FCD in the temporal lobe with HS on MRI. Pre-operative EEG data were recorded using a standardised protocol documenting ictal and interictal localisation as either (1) focal (anterior temporal); (2) regional (involving other ipsilateral temporal or frontal leads); or (3) bilateral and/or generalised discharges.
1 2
HRP = horseradish peroxidase. DAB = 3,3 diaminobenzidine tetrahydrochloride.
1347 Post-operative seizure outcome was graded according to the Engel classification (Engel, 1992). This was assessed for one, three and five years post-operatively and current status (December 2012). Patients were not included unless more than one year had elapsed since their operation. Postoperative anti-epileptic medication use and cessation were recorded.
Statistical analysis SPSS was used for statistical analysis. Categorical variables were compared using Pearson Chi-squared and Fisher’s exact tests. Continuous, non-parametric variables were analysed using Mann—Whitney U analysis with independent samples. Significance level was set at p < 0.05. Subgroup analysis was performed on the basis of age group (paediatric patients defined as less than 18 years at time of operation) and pathological groupings. Inter-rater agreement was assessed through percentage agreement and kappa statistic.
Results Description of common pathologies in TLE utilising ILAE classification of FCD The most common pathologies in the cohort were isolated HS, isolated tumour and FCD IIIA (Table 1). Isolated HS was the most common pathology in adults (n = 24/47, 51.1%). Of those where HS type could be determined, only two patients were confirmed to have atypical patterns of HS (ILAE type 3), whilst the remainder (n = 40) had ILAE type I (typical HS). Isolated tumour was the most common pathology in paediatric patients (n = 10/26, 38.5%). FCD IIIA was the third most common pathology, and had a similar frequency in adult and paediatric patients (p = 0.651). Of the patients with FCD IIIA (n = 12), the majority had horizontal dyslamination (n = 7) of varying severity (see Fig. 1) including three with temporal lobe sclerosis. In three patients the lamination abnormality lacked a clear direction (both horizontal and vertical dyslamination). No patients were noted to have lentiform heterotopias. Seventeen patients had FCD III, including 12 with FCD IIIA, one with FCD IIIB, one with FCD IIIC and three with a combination of tumour, HS and FCD.
Electroclinical and imaging correlations for FCD IIIA and other pathologies When FCD IIIA and isolated HS were compared, there were no significant differences in the frequency of initial precipitating events (p = 1.000), the age at precipitating event (p = 0.711), the frequency of febrile seizures (p = 0.719), the age at epilepsy onset (p = 0.858), or the presence of aura (p = 0.565). Precipitating events included febrile seizures/status, central nervous system infection and head trauma. Focal EEG ictal and interictal discharges were found in similar proportions in isolated HS and FCD IIIA (respectively p = 0.689, p = 0.443). The electroclinical phenotype of isolated HS and FCD IIIA was significantly different to the other pathologies in
1348 Table 1
A.M. Johnson et al. Pathological diagnosis in TLE. Pathological diagnosis (n = 70)
HS on MRIa (n = 3)
Total (n = 73)
Isolated HS FCD IIIA (HS with FCD)
29 (41.4%) 10 (14.3%)
1 2b
30 12
Isolated tumour FCD IIIB (tumour with FCD) Tumour with HS Tumour, HS and FCD
13 (18.6%) 1 5 (7.1%) 3
N/A
Total tumour n = 22
Vascular/cavernoma FCD/tuber Non-diagnostic
6 (8.6%) 2 1
N/A
6 2 1
a Radiological evidence for hippocampal sclerosis, but no hippocampus identified in the surgical specimen, despite successful surgical removal confirmed by post-operative MRI. b FCD in temporal lobe on pathological assessment, but no hippocampus contained in the surgical specimen. Radiological appearance consistent with hippocampal sclerosis.
the cohort. Precipitating events (p < 0.0005), febrile seizures (p = 0.002) and aura (p = 0.031) were significantly more common in HS and FCD IIIA when compared to the other pathologies. MRI changes associated with the presence of HS on pathology included hippocampal atrophy (n = 31/41, 75.6%, p < 0.0005), hippocampal T2 signal change (n = 25/36, 69.4%, p < 0.0005), temporal grey-white matter blurring (n = 15/39, 38.5%, p = 0.022), temporal white matter volume loss (n = 16/41, 39%, p = 0.012) and extra-hippocampal atrophy (n = 20/41, 48.8%, p = 0.014). There was no difference
regarding grey-white matter blurring, white matter volume loss or atrophy between isolated HS and FCD IIIA. On MRI, increased temporal grey matter signal on FLAIR (Fig. 2a) was significantly associated with FCD IIIA (n = 4/11 available, 36.4%) compared to other pathologies when tumour patients were excluded (n = 2/30 available, 6.7%, p = 0.035). Increased T2 signal over the temporal grey matter (Fig. 2b) was exclusively found in FCD IIIA (n = 3/11 available, 27.3%, tumour patients excluded). Changes were noted on contiguous coronal slices and also on the axial plane. Hyperintensity was not associated with other changes such as
Figure 1 Comparison of cortical lamination in isolated HS and FCD IIIA. The samples show a normal pattern of cortical lamination (a), demonstrated through immunoreactivity against neuronal nuclei (NeuN) in a patient with isolated HS. Different extremes of horizontal dyslamination in FCD IIIA were demonstrated in the cohort. Milder changes are shown in (b), and included clustering and lining up of neurones in layer II with a relative sparsity immediately below this. Relatively severe lamination abnormalities are shown in (c), with neuronal sparsity throughout the cortex, but particularly in layer III. Two low power fields (50×) were tiled together to create a—c. Scale bar measures 500 m.
FCD IIIA correlates in TLE
1349 (n = 16, 61.5%) compared to adults (n = 13, 27.7%, p = 0.005). Of those with isolated HS, more paediatric patients achieved complete post-operative seizure freedom (Engel IA) than adults, although this did not reach significance (p = 0.156). Significantly more children (n = 10, 38.5%) successfully ceased anti-epileptic medications post-operatively than adults (n = 2, 4.3%, p < 0.0005). There was a trend for post-operative seizure freedom (Engel IA) to be associated with a shorter duration of epilepsy (p = 0.056, one outlier excluded). No significant relationship was found within a pathological group between epilepsy duration and outcome. More patients with pre-operative status epilepticus had a poor post-operative seizure outcome (Engel II—IV) at current assessment (n = 6/8, 75% p = 0.045). Patients with poor post-operative outcome (n = 27) had a higher number of pre-operative bilateral convulsive seizures (median n = 3) than those with a good outcome (median n = 1, p = 0.045). No significant relationship was found within a pathological group between bilateral convulsive seizures or status epilepticus and outcome.
Discussion Figure 2 Temporal grey matter FLAIR and T2 increased signal in FCD IIIA. (a) Increased grey matter FLAIR signal over left temporal lobe in FCD IIIA (slice thickness 5 mm). (b) Increased grey matter T2 signal over right temporal lobe in FCD IIIA (slice thickness 5 mm).
grey-white blurring. Initial independent agreement on grey matter changes was reached in 74% (FLAIR) and 77% (T2) of cases. Overall agreement was 85% for all MRI features, with ‘moderate’ agreement on temporal lobe changes (kappa 0.418). Complete agreement on grey matter changes was reached on consensus. Bilateral convulsive seizures occurred in a similar proportion of patients with isolated HS (n = 21/30, 70.0%) and FCD IIIA (n = 10/12, 83.3%). Convulsive seizures occurred in a comparable percentage of patients with other pathologies (vascular n = 5/6, 83.3%; tumour with HS n = 3/5, 60%). Bilateral convulsive seizures were associated with a longer duration of epilepsy (p = 0.002) and were found in more adult patients than paediatric (p < 0.0005).
Pathological and independent predictors of post-surgical outcome At the time of current assessment, 63.0% of patients (n = 46/73) had an Engel Class 1 outcome (Table 2). Poor outcome (Engel III or IV) was seen in more patients with FCD IIIA (n = 6/12, 50%) than in other pathologies (n = 11/61, 18%, p = 0.026). Patients with temporal lobe sclerosis (n = 3/12, 25%) did not have a significantly different outcome (Engel III or IV, n = 2/3, 66.6%) to other patients with FCD IIIA identified with vertical and/or horizontal dyslamination (n = 4/9, 44.4%, p = 1.00). Patients with atypical patterns of HS (ILAE type 3) and those where mesial structures were not present in the specimen did not have poorer outcome in this series (respectively Engel I, n = 2/2; Engel I—II in n = 2/3. More children were completely seizure free (without auras, Engel IA) for the entire post-operative follow-up
This study provides support for the clinical application of the recent 2011 FCD classification (Blümcke et al., 2011). FCD IIIA was the third commonest pathology after isolated hippocampal sclerosis and isolated tumour in our temporal lobe series, though further larger studies are required to confirm the prevalence. The diagnosis of FCD IIIA has implications for surgical outcome. There was no difference between FCD IIIA and isolated HS in many electroclinical comparisons. These included frequency of precipitating events, age at precipitating events, occurrence of febrile seizures, age of epilepsy onset and presence of aura. Temporal grey matter signal changes on MRI were associated with FCD IIIA and may be a pre-operative marker of this pathology. Importantly, patients with FCD IIIA had the worst postoperative seizure outcome compared to those with other major pathologies in our series (isolated HS and isolated tumour). Our finding is in contrast to reports in the recent literature, including patients with HS and FCD, where the outcome was reported to be similar to isolated HS and better than FCD I (Tassi et al., 2009, 2010; Thom et al., 2009). There were methodological differences in cohort selection between our study and both Tassi et al. (2009, 2010) and Thom et al. (2009), which may explain these disparate findings. Thom et al. (2009) excluded all patients with associated FCD, aside from a specific subgroup with temporal lobe sclerosis. Tassi et al. (2009, 2010) used previous classifications, potentially altering pathological subgroup allocation. In addition, Tassi et al. (2010) compared a group of HS and FCD (largely temporal) with isolated FCD which was extra-temporal and/or multilobar. Some authors have criticised this comparison due to the worse outcome in extra-temporal resections, regardless of pathology (Fauser et al., 2013). A recent report by Fauser et al. (2013) described no difference between the post-surgical outcome for temporal FCD I and FCD IIIA. Our findings support those described by Fauser et al. (2013) and suggest that the prognosis for FCD IIIA is not equivalent to isolated HS, but similar to temporal FCD I. The poorer outcome for FCD IIIA
1350 Table 2
A.M. Johnson et al. Engel I outcome at current post-operative assessment versus pathology.
Underlying diagnosis
Engel 1 Whole cohort (n = 73)
Engel 1 Children (n = 26)
Engel 1 Adults (n = 47)
Isolated HS FCD IIIA (HS with FCD)
18/30 (60%) 5/12 (41.7%)
5/6 (83.3%) 0/1
13/24 (54.2%) 5/11 (45.5%)
Isolated tumour FCD IIIB (tumour with FCD) Tumour with HS Tumour, HS and FCD
9/13 (69.2%) 1/1 5/5 2/3
7/10 (70%) 1/1 3/3 2/3
2/3 N/A 2/2 N/A
Vascular/cavernoma FCD/tuber Non-diagnostic
4/6 (66.7%) 1/2 1/1
1/1 1/1 N/A
3/5 0/1 1/1
in our series might potentially be related to incomplete resection, a confounder well established in the literature (Li et al., 1999; Kim et al., 2010). Our study is limited in this regard and we cannot provide data on completeness of resection, as the pathological specimens available to us histologically did not always include the margin of the resection. Not all patients had post-operative MRI’s available. The presence of FCD IIIA was significantly associated with temporal lobe grey matter signal change (FLAIR and T2) on MRI. This is a novel finding providing a potential preoperative marker of associated dysplasia. It was found in a third of FCD IIIA cases with reasonable inter-rater agreement between investigators and full agreement on consensus. Further research is required to reproduce and validate these findings. Our study was retrospective, using available scans from a 1.5 T MRI. Stronger magnets may result in a higher yield. Garbelli et al. (2011) showed altered grey matter signal in the presence of abnormal lamination (FCD type IA in TLE) using 7 T MRI in an ex vivo histopathological study using fixed post-operative specimens. Other authors have also reported that cortical architecture is detectable on in vivo MRI (Barbier et al., 2002; Bridge and Clare, 2006). Further technological improvements in MRI field strength and software are expected to improve in vivo delineation, with benefits for clinical practice (Garbelli et al., 2011). Grey matter signal has not previously been specifically reported in FCD III, though Krsek et al. (2009) noted grey matter signal changes in FCD types I and II. The new (2011) classification of FCD aimed to include electroclinical, imaging and pathological features of FCD (Blümcke et al., 2011). In our cohort, there were no differences between FCD IIIA and isolated HS with regard to clinical presentation or EEG patterns. The electroclinical phenotype of FCD IIIA therefore parallels or mimics the phenotype of isolated HS, as previously predicted (Blümcke et al., 2011). A recent study by Fauser et al. (2013) also noted the higher numbers of febrile seizures and aura in FCD IIIA in comparison to FCD I and II. This data supports the establishment of FCD IIIA as an entity distinct from FCD I and FCD II. Independent markers of poorer post-operative outcome in this cohort included: (1) pre-operative bilateral convulsive seizures; (2) pre-operative status epilepticus; with (3) a trend approaching significance for long duration of epilepsy.
These prognostic markers were not significant for outcome within pathological subgroups.
Conclusions FCD IIIA is a comparatively common pathology in TLE surgery patients, and has a poor post-operative outcome. FCD IIIA is potentially recognisable pre-operatively by grey matter signal change on MRI. Other poor prognostic markers include pre-operative bilateral convulsive seizures and status epilepticus, but these are not predictive within specific pathological groups. Children have higher rates of complete seizure freedom than adults after surgery.
Conflicts of interest None of the authors have any conflicts of interest to disclose.
Acknowledgements We have received support from Leica Biosystems regarding immunostaining. We acknowledge the support of Westfield Research Laboratories and Professor Jenny Peat (statistician). We thank Professor Ingmar Blümcke and Dr. Roland Coras (Neuropathologishes Institut, Universitatskilinikum Erlangen) for kindly providing us with support and controls for the extended project.
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1351 surgical treatment of cortical dysplasia accompanied by hippocampal sclerosis. Epilepsia 51, 1429—1435. Krsek, P., Pieper, T., Karlmeier, A., Hildebrandt, M., Kolodziejczyk, D., Winkler, P., Pauli, E., Blümcke, I., Holthausen, H., 2009. Different presurgical characteristics and seizure outcomes in children with focal cortical dysplasia type I or II. Epilepsia 50, 125—137. Lawson, J.A., Birchansky, S., Pacheco, E., Jayakar, P., Resnick, T.J., Dean, P., Duchowny, M.S., 2005. Distinct clinicopathologic subtypes of cortical dysplasia of Taylor. Neurology 64, 55—61. Li, L.M., Cendes, F., Andermann, F., Watson, C., Fish, D.R., Cook, M.J., Dubeau, F., Duncan, J.S., Shorvon, S.D., Berkovic, S.F., Free, S., Olivier, A., Harkness, W., Arnold, D.L., 1999. Surgical outcome in patients with epilepsy and dual pathology. Brain 122, 799. Lindsay, J., Ounsted, C., Richards, P., 1984. Long-term outcome in children with temporal lobe seizures, V: indications and contraindications for neurosurgery. Dev. Med. Child Neurol. 26, 25—32. Louis, D.N., Ohgaki, H., Wiestler, O.D., Cavenee, W.K., Burger, P.C., Jouvet, A., Scheithauer, B.W., Kleihues, P., 2007. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 114, 97—109. McIntosh, A.M., Kalnins, R.M., Mitchell, L.A., Fabinyi, G.C.A., Briellmann, R.S., Berkovic, S.F., 2004. Temporal lobectomy: long-term seizure outcome, late recurrence and risks for seizure recurrence. Brain 127, 2018—2030. Mischel, P.S., Nguyen, L.P., Vinters, H.V., 1995. Cerebral cortical dysplasia associated with pediatric epilepsy. Review of neuropathologic features and proposal for a grading system. J. Neuropathol. Exp. Neurol. 54, 137—153. Ozkara, C., Uzan, M., Benbir, G., Yeni, N., Oz, B., Hano˘ glu, L., Karaa˘ gac, N., Ozyurt, E., 2008. Surgical outcome of patients with mesial temporal lobe epilepsy related to hippocampal sclerosis. Epilepsia 49, 696—699. Palmini, A., Najm, I., Avanzini, G., Babb, T., Guerrini, R., FoldvarySchaefer, N., Jackson, G., Lüders, H.O., Prayson, R., Spreafico, R., Vinters, H.V., 2004. Terminology and classification of the cortical dysplasias. Neurology 6 (Suppl. 3), S2—S8 (in this issue). Sirven, J.I., Malamut, B.L., O’Connor, M.J., Sperling, M.R., 2000. Temporal lobectomy outcome in older versus younger adults. Neurology 54, 2166—2170. Tassi, L., Garbelli, R., Colombo, N., Bramerio, M., Lo Russo, G., Deleo, F., Milesi, G., Spreafico, R., 2010. Type I focal cortical dysplasia: surgical outcome is related to histopathology. Epilep. Dis. 12, 181—191. Tassi, L., Meroni, A., Deleo, F., Villani, F., Mai, R., Russo, G.L., Colombo, N., Avanzini, G., Falcone, C., Bramerio, M., Citterio, A., Garbelli, R., Spreafico, R., 2009. Temporal lobe epilepsy: neuropathological and clinical correlations in 243 surgically treated patients. Epilep. Dis. 11, 281—292. Thom, M., Eriksson, S., Martinian, L., Caboclo, L.O., McEvoy, A.W., Duncan, J.S., Sisodiya, S.M., 2009. Temporal lobe sclerosis associated with hippocampal sclerosis in temporal lobe epilepsy: neuropathological features. J. Neuropathol. Exp. Neurol. 68, 928—938. Zarroli, K., Tracy, J.I., Nei, M., Sharan, A., Sperling, M.R., 2011. Employment after anterior temporal lobectomy. Epilepsia 52, 925—931.
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Clinicopathological associations in temporal lobe epilepsy patients utilising the current ILAE focal cortical dysplasia classification Alexandra M. Johnson a,b,∗, Ella Sugo c,d, Daniela Barreto a, Anne M. Cunningham a,b, Chee-Chung Hiew d, John A. Lawson a,b, Ernest R. Somerville d,b, Anne M. Connolly a,b, Annie M.E. Bye a,b a
Sydney Children’s Hospitals Network (Randwick), High St, Randwick, Sydney, NSW 2031, Australia University of New South Wales, NSW 2052, Australia c South Eastern Area Laboratory Services, Barker St, Randwick, Sydney, NSW 2031, Australia d Prince of Wales Hospital, High St, Randwick, Sydney, NSW 2031, Australia b
Received 17 February 2014; received in revised form 9 May 2014; accepted 13 June 2014 Available online 7 July 2014
KEYWORDS Temporal lobe epilepsy; FCD IIIA; Surgery
Summary Objectives: This study utilised the revised 2011 ILAE classification of focal cortical dysplasia (FCD) (Blümcke et al., 2011) to examine pathology in a cohort of children and adults who underwent temporal lobe epilepsy (TLE) surgery, and to describe the electroclinical and imaging features associated with these pathologies. Methods: The sample population were children (n = 26) and adults (n = 47) who underwent TLE surgery between 2002 and 2011 at our institutions. Neuropathology and MRI studies were rereviewed by experts blinded to the original diagnosis. EEG and clinical data including current seizure outcome were determined by patient file review and/or patient contact. Pre-operative data, post-operative outcome and pathological diagnoses were compared. Results: The commonest pathology in the adult cohort was isolated hippocampal sclerosis (HS) (n = 24, 51.1%) and in the paediatric cohort, isolated tumour (n = 10, 38.5%). Overall, HS with
∗ Corresponding author at: Neurology Department, Level 4 Emergency Wing, Sydney Children’s Hospitals Network (Randwick), High St, Randwick, Sydney, NSW 2031, Australia. Tel.: +61 2 9382 1111; fax: +61 2 9382 1580. E-mail addresses: [email protected] (A.M. Johnson), [email protected] (E. Sugo), [email protected] (D. Barreto), [email protected] (A.M. Cunningham), [email protected] (C.-C. Hiew), [email protected] (J.A. Lawson), [email protected] (E.R. Somerville), [email protected] (A.M. Connolly), [email protected] (A.M.E. Bye).
http://dx.doi.org/10.1016/j.eplepsyres.2014.06.013 0920-1211/Crown Copyright © 2014 Published by Elsevier B.V. All rights reserved.
1346
A.M. Johnson et al. associated FCD (FCD IIIA) was the third most common pathology (n = 12, 16.4%). Temporal grey matter signal changes on MRI were associated with FCD IIIA (p = 0.035). FCD IIIA had the poorest post-surgical seizure outcome compared to all other pathologies (p = 0.026). A history of bilateral convulsive seizures was more common in adults (n = 40, p < 0.0005), and was associated with failure to achieve postoperative seizure freedom (p = 0.045). Postoperatively, paediatric TLE had higher rates of seizure freedom (p = 0.005) and more children had ceased medication (p < 0.0005). Significance: FCD IIIA is a comparatively common pathological subtype in TLE, with a poor postsurgical outcome. Pre-operative recognition of FCD IIIA may be feasible through grey matter signal change on MRI. Paediatric patients had a higher rate of seizure freedom than adults. Pre-operative bilateral convulsive seizures were associated with poor outcome after surgery. Crown Copyright © 2014 Published by Elsevier B.V. All rights reserved.
Introduction Focal cortical dysplasia (FCD) is associated with intractable epilepsy, and occurs either in isolation or in combination with other pathologies. There have been multiple previous attempts to introduce uniformity to the pathological classification of FCD (Mischel et al., 1995; Palmini et al., 2004). However, inter-rater reliability of previous classifications has been poor (Chamberlain et al., 2009). Electroclinical features and post-operative outcome vary between cohorts for some subtypes of FCD. FCD IIB has well described clinical and imaging features which predict pathology and outcome (Lawson et al., 2005). However, features of FCD I are not well distinguished on clinical presentation, neuroimaging, or histopathology (Chamberlain et al., 2009) and there is variable post-surgical outcome (Fauser et al., 2004; Krsek et al., 2009; Tassi et al., 2010). A revised classification was formulated by an International League Against Epilepsy (ILAE) task force (Blümcke et al., 2011) to address the poor interobserver reliability of the previous classifications and aimed to lessen the clinicopathological discrepancies (Chamberlain et al., 2009). The 2011 classification is considered to provide good inter-observer reliability of pathological diagnoses (Coras et al., 2012). The new ILAE classification introduced a third category of dysplasia associated with another primary lesion (FCD type III) (Blümcke et al., 2011). FCD III is now considered a distinct entity to FCD I. Previous studies have shown its clinical characteristics reflected its primary pathology (e.g. hippocampal sclerosis (HS) in FCD IIIA) rather than the associated dysplasia (Tassi et al., 2009, 2010). We aimed to determine the frequency of FCD type IIIA pathology in a cohort of temporal lobe epilepsy (TLE) surgical patients and whether FCD IIIA has a distinct electroclinical phenotype with identifying imaging features and prognostic implications. This has not been previously established. Prediction of outcome after temporal lobe surgery is known to be influenced both by underlying pathology and pre-operative clinical factors, such as presence of bilateral convulsive seizures (McIntosh et al., 2004; Ozkara et al., 2008) Atypical HS (ILAE type 2 and 3) has also been associated with poorer post-surgical outcome (Blümcke et al., 2013). Some studies have demonstrated that earlier operation is correlated with better seizure and psychosocial outcomes (Lindsay et al., 1984; Jeong et al., 1999;
Sirven et al., 2000; Zarroli et al., 2011). It has not been established if these findings apply to FCD IIIA.
Materials and methods Cohort and ethics A retrospective review of adult and paediatric patients who underwent TLE surgery at Sydney Children’s Hospitals Network (Randwick) and Prince of Wales Hospital between January 2002 and December 2011 was undertaken. Ethics approval was granted by the Sydney Children’s Hospitals Network Human Research Ethics Committee. Eligible participants were invited by mail with follow-up phone call to determine interest. Written informed consent was obtained. Of the eligible cohort 13 were not contactable and 11 did not give written consent. Data from 73 patients (47 adults, 26 children) were included in the study. The median time since operation was 4.2 years (range 1.1—10.9 years), and was not significantly different between children and adults (p = 0.662). All underwent a tailored anterior temporal lobectomy or temporal lesionectomy (46% left sided), with no patients undergoing a selective amygdalohippocampectomy. Six children and five adults required a repeat operation.
Pathological review A pathologist (ES) reviewed the existing pathology slides of hippocampus and temporal lobe for each patient, blinded to the previous report. When several operations had occurred, pathological sections were reviewed from each operation when available. Section thickness was 5 m. Histochemistry with haematoxylin and eosin (H&E) was available for every patient. Luxol fast blue/Cresyl violet (LFB/CV) and immunostaining with antibodies to glial fibrillary acidic protein (GFAP) and neuronal nuclei (NeuN) were performed according to the current laboratory protocol, using a Leica Bond III automated immunostainer (Leica Autostainer XL, Leica Microsystems, Newcastle, UK). De-paraffinisation and rehydration were followed by enzymatic antigen retrieval for 10 min (GFAP) or heat retrieval for 30 min (NeuN). Slides were incubated with primary (rabbit) polyclonal antibody against GFAP (currently 1 in 4000, previously 1 in 10,000,
FCD IIIA correlates in TLE DAKO) and primary (mouse) monoclonal antibody against NeuN (clone A60, 1 in 200, Millipore) for 30 min. Antibody binding was detected by means of the respective Bond Polymer Refine Detection kit (Leica Microsystems), which uses HRP1 conjugated secondary antibodies and DAB2 as the chromagen. Mayer’s haematoxylin was used as the counter-stain. Markers for cellular proliferaton and epilepsy-associated tumours (e.g. Ki-67, CD-34) were also available. In patients with isolated HS and FCD IIIA, the majority had previously performed immunostaining with either NeuN (n = 30/42) and/or GFAP (n = 35/42), and further recutting and immunohistochemistry were performed if there was doubt as to the underlying diagnosis. A primary diagnostic category was assigned to each patient based on their pathology, using recent definitions for hippocampal sclerosis (HS) and tumours (Louis et al., 2007). Accompanying dysplasia (FCD III) was diagnosed on the basis of the ILAE 2011 classification of FCD (Blümcke et al., 2011). FCD IIIA was identified if HS was accompanied by vertical and/or horizontal dyslamination or temporal lobe sclerosis.
Clinical, radiological and electrophysiological review Demographic data were collected on seizure onset, duration and type, and precipitating events. Seizure type was determined using the ILAE classification (Berg et al., 2010). Seizure frequency was recorded for the six months prior to operation. Three patients had surgery soon after seizure onset due to suspicion of tumour. They were excluded from the analysis of seizure frequency. In cases where more than one operation had occurred, clinical details were analysed prior to the first epilepsy surgery when tissue was available for review. Documentation of duration of epilepsy prior to surgery was limited to those undergoing a single surgery. Pre-operative magnetic resonance images (MRI) (majority 1.5 T) were independently reviewed by a neuroradiologist (CH) and neurologist (JL), blinded to the original reports. Data were recorded using a standardised protocol, based on the features of FCD described by Krsek et al. (2009). Individual, independent features examined included (1) hippocampal size, shape and signal change; (2) temporal lobe signal change (T2 and FLAIR) in grey or white matter; (3) temporal lobe grey-white matter blurring; and (4) extra-hippocampal atrophy and location. Disagreement was resolved by discussion. When hippocampal tissue was not available for pathological analysis (n = 3), the presence of HS was determined by the presence of hippocampal volume reduction and/or increased signal intensity (FLAIR and T2) on MRI (Jackson et al., 1990). In these patients, FCD IIIA was diagnosed if the pathology showed evidence of FCD in the temporal lobe with HS on MRI. Pre-operative EEG data were recorded using a standardised protocol documenting ictal and interictal localisation as either (1) focal (anterior temporal); (2) regional (involving other ipsilateral temporal or frontal leads); or (3) bilateral and/or generalised discharges.
1 2
HRP = horseradish peroxidase. DAB = 3,3 diaminobenzidine tetrahydrochloride.
1347 Post-operative seizure outcome was graded according to the Engel classification (Engel, 1992). This was assessed for one, three and five years post-operatively and current status (December 2012). Patients were not included unless more than one year had elapsed since their operation. Postoperative anti-epileptic medication use and cessation were recorded.
Statistical analysis SPSS was used for statistical analysis. Categorical variables were compared using Pearson Chi-squared and Fisher’s exact tests. Continuous, non-parametric variables were analysed using Mann—Whitney U analysis with independent samples. Significance level was set at p < 0.05. Subgroup analysis was performed on the basis of age group (paediatric patients defined as less than 18 years at time of operation) and pathological groupings. Inter-rater agreement was assessed through percentage agreement and kappa statistic.
Results Description of common pathologies in TLE utilising ILAE classification of FCD The most common pathologies in the cohort were isolated HS, isolated tumour and FCD IIIA (Table 1). Isolated HS was the most common pathology in adults (n = 24/47, 51.1%). Of those where HS type could be determined, only two patients were confirmed to have atypical patterns of HS (ILAE type 3), whilst the remainder (n = 40) had ILAE type I (typical HS). Isolated tumour was the most common pathology in paediatric patients (n = 10/26, 38.5%). FCD IIIA was the third most common pathology, and had a similar frequency in adult and paediatric patients (p = 0.651). Of the patients with FCD IIIA (n = 12), the majority had horizontal dyslamination (n = 7) of varying severity (see Fig. 1) including three with temporal lobe sclerosis. In three patients the lamination abnormality lacked a clear direction (both horizontal and vertical dyslamination). No patients were noted to have lentiform heterotopias. Seventeen patients had FCD III, including 12 with FCD IIIA, one with FCD IIIB, one with FCD IIIC and three with a combination of tumour, HS and FCD.
Electroclinical and imaging correlations for FCD IIIA and other pathologies When FCD IIIA and isolated HS were compared, there were no significant differences in the frequency of initial precipitating events (p = 1.000), the age at precipitating event (p = 0.711), the frequency of febrile seizures (p = 0.719), the age at epilepsy onset (p = 0.858), or the presence of aura (p = 0.565). Precipitating events included febrile seizures/status, central nervous system infection and head trauma. Focal EEG ictal and interictal discharges were found in similar proportions in isolated HS and FCD IIIA (respectively p = 0.689, p = 0.443). The electroclinical phenotype of isolated HS and FCD IIIA was significantly different to the other pathologies in
1348 Table 1
A.M. Johnson et al. Pathological diagnosis in TLE. Pathological diagnosis (n = 70)
HS on MRIa (n = 3)
Total (n = 73)
Isolated HS FCD IIIA (HS with FCD)
29 (41.4%) 10 (14.3%)
1 2b
30 12
Isolated tumour FCD IIIB (tumour with FCD) Tumour with HS Tumour, HS and FCD
13 (18.6%) 1 5 (7.1%) 3
N/A
Total tumour n = 22
Vascular/cavernoma FCD/tuber Non-diagnostic
6 (8.6%) 2 1
N/A
6 2 1
a Radiological evidence for hippocampal sclerosis, but no hippocampus identified in the surgical specimen, despite successful surgical removal confirmed by post-operative MRI. b FCD in temporal lobe on pathological assessment, but no hippocampus contained in the surgical specimen. Radiological appearance consistent with hippocampal sclerosis.
the cohort. Precipitating events (p < 0.0005), febrile seizures (p = 0.002) and aura (p = 0.031) were significantly more common in HS and FCD IIIA when compared to the other pathologies. MRI changes associated with the presence of HS on pathology included hippocampal atrophy (n = 31/41, 75.6%, p < 0.0005), hippocampal T2 signal change (n = 25/36, 69.4%, p < 0.0005), temporal grey-white matter blurring (n = 15/39, 38.5%, p = 0.022), temporal white matter volume loss (n = 16/41, 39%, p = 0.012) and extra-hippocampal atrophy (n = 20/41, 48.8%, p = 0.014). There was no difference
regarding grey-white matter blurring, white matter volume loss or atrophy between isolated HS and FCD IIIA. On MRI, increased temporal grey matter signal on FLAIR (Fig. 2a) was significantly associated with FCD IIIA (n = 4/11 available, 36.4%) compared to other pathologies when tumour patients were excluded (n = 2/30 available, 6.7%, p = 0.035). Increased T2 signal over the temporal grey matter (Fig. 2b) was exclusively found in FCD IIIA (n = 3/11 available, 27.3%, tumour patients excluded). Changes were noted on contiguous coronal slices and also on the axial plane. Hyperintensity was not associated with other changes such as
Figure 1 Comparison of cortical lamination in isolated HS and FCD IIIA. The samples show a normal pattern of cortical lamination (a), demonstrated through immunoreactivity against neuronal nuclei (NeuN) in a patient with isolated HS. Different extremes of horizontal dyslamination in FCD IIIA were demonstrated in the cohort. Milder changes are shown in (b), and included clustering and lining up of neurones in layer II with a relative sparsity immediately below this. Relatively severe lamination abnormalities are shown in (c), with neuronal sparsity throughout the cortex, but particularly in layer III. Two low power fields (50×) were tiled together to create a—c. Scale bar measures 500 m.
FCD IIIA correlates in TLE
1349 (n = 16, 61.5%) compared to adults (n = 13, 27.7%, p = 0.005). Of those with isolated HS, more paediatric patients achieved complete post-operative seizure freedom (Engel IA) than adults, although this did not reach significance (p = 0.156). Significantly more children (n = 10, 38.5%) successfully ceased anti-epileptic medications post-operatively than adults (n = 2, 4.3%, p < 0.0005). There was a trend for post-operative seizure freedom (Engel IA) to be associated with a shorter duration of epilepsy (p = 0.056, one outlier excluded). No significant relationship was found within a pathological group between epilepsy duration and outcome. More patients with pre-operative status epilepticus had a poor post-operative seizure outcome (Engel II—IV) at current assessment (n = 6/8, 75% p = 0.045). Patients with poor post-operative outcome (n = 27) had a higher number of pre-operative bilateral convulsive seizures (median n = 3) than those with a good outcome (median n = 1, p = 0.045). No significant relationship was found within a pathological group between bilateral convulsive seizures or status epilepticus and outcome.
Discussion Figure 2 Temporal grey matter FLAIR and T2 increased signal in FCD IIIA. (a) Increased grey matter FLAIR signal over left temporal lobe in FCD IIIA (slice thickness 5 mm). (b) Increased grey matter T2 signal over right temporal lobe in FCD IIIA (slice thickness 5 mm).
grey-white blurring. Initial independent agreement on grey matter changes was reached in 74% (FLAIR) and 77% (T2) of cases. Overall agreement was 85% for all MRI features, with ‘moderate’ agreement on temporal lobe changes (kappa 0.418). Complete agreement on grey matter changes was reached on consensus. Bilateral convulsive seizures occurred in a similar proportion of patients with isolated HS (n = 21/30, 70.0%) and FCD IIIA (n = 10/12, 83.3%). Convulsive seizures occurred in a comparable percentage of patients with other pathologies (vascular n = 5/6, 83.3%; tumour with HS n = 3/5, 60%). Bilateral convulsive seizures were associated with a longer duration of epilepsy (p = 0.002) and were found in more adult patients than paediatric (p < 0.0005).
Pathological and independent predictors of post-surgical outcome At the time of current assessment, 63.0% of patients (n = 46/73) had an Engel Class 1 outcome (Table 2). Poor outcome (Engel III or IV) was seen in more patients with FCD IIIA (n = 6/12, 50%) than in other pathologies (n = 11/61, 18%, p = 0.026). Patients with temporal lobe sclerosis (n = 3/12, 25%) did not have a significantly different outcome (Engel III or IV, n = 2/3, 66.6%) to other patients with FCD IIIA identified with vertical and/or horizontal dyslamination (n = 4/9, 44.4%, p = 1.00). Patients with atypical patterns of HS (ILAE type 3) and those where mesial structures were not present in the specimen did not have poorer outcome in this series (respectively Engel I, n = 2/2; Engel I—II in n = 2/3. More children were completely seizure free (without auras, Engel IA) for the entire post-operative follow-up
This study provides support for the clinical application of the recent 2011 FCD classification (Blümcke et al., 2011). FCD IIIA was the third commonest pathology after isolated hippocampal sclerosis and isolated tumour in our temporal lobe series, though further larger studies are required to confirm the prevalence. The diagnosis of FCD IIIA has implications for surgical outcome. There was no difference between FCD IIIA and isolated HS in many electroclinical comparisons. These included frequency of precipitating events, age at precipitating events, occurrence of febrile seizures, age of epilepsy onset and presence of aura. Temporal grey matter signal changes on MRI were associated with FCD IIIA and may be a pre-operative marker of this pathology. Importantly, patients with FCD IIIA had the worst postoperative seizure outcome compared to those with other major pathologies in our series (isolated HS and isolated tumour). Our finding is in contrast to reports in the recent literature, including patients with HS and FCD, where the outcome was reported to be similar to isolated HS and better than FCD I (Tassi et al., 2009, 2010; Thom et al., 2009). There were methodological differences in cohort selection between our study and both Tassi et al. (2009, 2010) and Thom et al. (2009), which may explain these disparate findings. Thom et al. (2009) excluded all patients with associated FCD, aside from a specific subgroup with temporal lobe sclerosis. Tassi et al. (2009, 2010) used previous classifications, potentially altering pathological subgroup allocation. In addition, Tassi et al. (2010) compared a group of HS and FCD (largely temporal) with isolated FCD which was extra-temporal and/or multilobar. Some authors have criticised this comparison due to the worse outcome in extra-temporal resections, regardless of pathology (Fauser et al., 2013). A recent report by Fauser et al. (2013) described no difference between the post-surgical outcome for temporal FCD I and FCD IIIA. Our findings support those described by Fauser et al. (2013) and suggest that the prognosis for FCD IIIA is not equivalent to isolated HS, but similar to temporal FCD I. The poorer outcome for FCD IIIA
1350 Table 2
A.M. Johnson et al. Engel I outcome at current post-operative assessment versus pathology.
Underlying diagnosis
Engel 1 Whole cohort (n = 73)
Engel 1 Children (n = 26)
Engel 1 Adults (n = 47)
Isolated HS FCD IIIA (HS with FCD)
18/30 (60%) 5/12 (41.7%)
5/6 (83.3%) 0/1
13/24 (54.2%) 5/11 (45.5%)
Isolated tumour FCD IIIB (tumour with FCD) Tumour with HS Tumour, HS and FCD
9/13 (69.2%) 1/1 5/5 2/3
7/10 (70%) 1/1 3/3 2/3
2/3 N/A 2/2 N/A
Vascular/cavernoma FCD/tuber Non-diagnostic
4/6 (66.7%) 1/2 1/1
1/1 1/1 N/A
3/5 0/1 1/1
in our series might potentially be related to incomplete resection, a confounder well established in the literature (Li et al., 1999; Kim et al., 2010). Our study is limited in this regard and we cannot provide data on completeness of resection, as the pathological specimens available to us histologically did not always include the margin of the resection. Not all patients had post-operative MRI’s available. The presence of FCD IIIA was significantly associated with temporal lobe grey matter signal change (FLAIR and T2) on MRI. This is a novel finding providing a potential preoperative marker of associated dysplasia. It was found in a third of FCD IIIA cases with reasonable inter-rater agreement between investigators and full agreement on consensus. Further research is required to reproduce and validate these findings. Our study was retrospective, using available scans from a 1.5 T MRI. Stronger magnets may result in a higher yield. Garbelli et al. (2011) showed altered grey matter signal in the presence of abnormal lamination (FCD type IA in TLE) using 7 T MRI in an ex vivo histopathological study using fixed post-operative specimens. Other authors have also reported that cortical architecture is detectable on in vivo MRI (Barbier et al., 2002; Bridge and Clare, 2006). Further technological improvements in MRI field strength and software are expected to improve in vivo delineation, with benefits for clinical practice (Garbelli et al., 2011). Grey matter signal has not previously been specifically reported in FCD III, though Krsek et al. (2009) noted grey matter signal changes in FCD types I and II. The new (2011) classification of FCD aimed to include electroclinical, imaging and pathological features of FCD (Blümcke et al., 2011). In our cohort, there were no differences between FCD IIIA and isolated HS with regard to clinical presentation or EEG patterns. The electroclinical phenotype of FCD IIIA therefore parallels or mimics the phenotype of isolated HS, as previously predicted (Blümcke et al., 2011). A recent study by Fauser et al. (2013) also noted the higher numbers of febrile seizures and aura in FCD IIIA in comparison to FCD I and II. This data supports the establishment of FCD IIIA as an entity distinct from FCD I and FCD II. Independent markers of poorer post-operative outcome in this cohort included: (1) pre-operative bilateral convulsive seizures; (2) pre-operative status epilepticus; with (3) a trend approaching significance for long duration of epilepsy.
These prognostic markers were not significant for outcome within pathological subgroups.
Conclusions FCD IIIA is a comparatively common pathology in TLE surgery patients, and has a poor post-operative outcome. FCD IIIA is potentially recognisable pre-operatively by grey matter signal change on MRI. Other poor prognostic markers include pre-operative bilateral convulsive seizures and status epilepticus, but these are not predictive within specific pathological groups. Children have higher rates of complete seizure freedom than adults after surgery.
Conflicts of interest None of the authors have any conflicts of interest to disclose.
Acknowledgements We have received support from Leica Biosystems regarding immunostaining. We acknowledge the support of Westfield Research Laboratories and Professor Jenny Peat (statistician). We thank Professor Ingmar Blümcke and Dr. Roland Coras (Neuropathologishes Institut, Universitatskilinikum Erlangen) for kindly providing us with support and controls for the extended project.
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