Individually tailored extratemporal epilepsy surgery in children: Anatomo-electro-clinical features and outcome predictors in a population of 53 cases

Epilepsy & Behavior 25 (2012) 68–80

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Individually tailored extratemporal epilepsy surgery in children: Anatomo-electro-clinical features and outcome predictors in a population of 53 cases Alexandra Liava a,⁎, Stefano Francione b, Laura Tassi b, Giorgio Lo Russo b, Massimo Cossu b, Roberto Mai b, Francesca Darra c, Elena Fontana c, Bernardo Dalla Bernardina c a b c

Infantile Neurology Service, Complex Unit of Infantile Neuropsychiatry, Niguarda Ca'Granda Hospital, Milan, Italy “Claudio Munari” Epilepsy Surgery Centre, Niguarda Ca'Granda Hospital, Milan, Italy Infantile Neurology Service, Complex Unit of Infantile Neuropsychiatry, University Hospital G.B. Rossi, Verona, Italy

a r t i c l e

i n f o

Article history: Received 20 January 2012 Revised 2 May 2012 Accepted 3 May 2012 Available online 17 August 2012 Keywords: Extratemporal lobe epilepsy Epilepsy surgery Pediatric epilepsy Epileptogenic zone Children with epilepsy

a b s t r a c t Surgery for refractory extratemporal lobe epilepsy (ETLE) in the pediatric age group has been reported to be associated with a high percentage of failure and relapse. We performed a retrospective study of 53 consecutive patients with epilepsy onset before 12 years of age, who underwent, mostly at a pediatric age, an individually tailored ETLE surgery (32 in frontal and 21 in posterior cerebral areas) for pharmacoresistant seizures; these patients were selected and followed by a single national tertiary care pediatric center. Mean age at seizure onset was 3.14 years, and mean age at surgery was 11.23 years. Complete seizure freedom was achieved in 75% of the subjects. Short duration of illness before surgery, MRI features, no invasive pre‐surgical evaluation, a localized interictal and ictal pattern as well as the presence of ictal fast activity on scalp EEG, localized interictal fast rhythms and absence of a diffuse initial ictal modification during SEEG, a complete resection of the epileptogenic zone, a type II FCD, and the absence of acute postoperative seizures correlated in a statistically significant way with a seizure‐free outcome. We conclude that the seizure outcome of ETLE surgery in a carefully selected pediatric population can be excellent. © 2012 Elsevier Inc. All rights reserved.

1. Introduction Surgical treatment of extratemporal lobe epilepsy (ETLE) concerns about 40% of resections among large pediatric series [1,2]. Despite the progressive development of neuroimaging, electrophysiological, and operative techniques, incidence of ETLE surgical failure in children is reported to be relatively high [3–11], and could be attributed, not only to the major complexity in localizing the epileptogenic zone (EZ) and to the presence of eloquent areas, but also to the fact that selection criteria for children who could benefit from ETLE surgery are still not completely defined. Furthermore, despite the fact that focal non-idiopathic ETLE is more frequent in childhood than in adults, there have been relatively few studies characterizing the features and exploring the prognostic factors influencing the outcome of ETLE surgery within a pediatric population, an essential element for counseling families for epilepsy surgery. In this regard, the aim of this study was to characterize a population of patients with pharmacoresistant ETLE, whose diagnosis and indication for individually tailored resective epilepsy surgery were ⁎ Corresponding author. E-mail addresses: [email protected], [email protected] (A. Liava). 1525-5050/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2012.05.008

achieved at a single national tertiary care pediatric center, and to identify the prognostic factors associated with a favorable postoperative seizure outcome. 2. Patients and methods We retrospectively studied the medical records of 53 consecutive patients suffering from pharmacoresistant ETLE with onset before 12 years of age, all recruited and followed by the Infantile NeuroPsychiatry Service of the University Hospital of Verona; these patients received individually tailored resective surgery for resistant seizures at the “Claudio Munari” Epilepsy Surgery Centre of the Niguarda Hospital, Milano, between 1996 and 2010. In order to obtain a semiologically homogeneous population, the age limit of 12 years at seizure onset was chosen, since adolescents tend to show clinical ictal patterns superimposable to adults [12]. Pre-surgical evaluation protocol included a detailed neurologic and neuropsychological (IQ: intelligence quotient or DQ: developmental quotient, attention, problem solving, linguistic, amnestic, visuo-constructive function assessment, behavioral profile) examination, prolonged scalp video-EEG monitoring with scalp electrodes placed according to the International 10–20 system, a neuroradiological investigation by a 1.5 T MRI using a dedicated epilepsy protocol [13] and, when necessary, functional imaging.

A. Liava et al. / Epilepsy & Behavior 25 (2012) 68–80

In cases where the data obtained by non-invasive pre-surgical evaluation were discordant, or MRI was unremarkable, or highly functional regions were located immediately close to the presumed EZ, stereo-electroencephalography (SEEG) monitoring was performed; implantation strategy, aiming to explore the areas putatively involved in the seizure onset and early propagation, was based on an individual electro‐clinical hypothesis (the technique for placement of intracerebral electrodes employed in SEEG has been previously reported [14]).

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Six months after surgery, all subjects had a first follow-up visit with EEG, MRI, and neuropsychological evaluation; further follow-ups were obtained annually until at least 5 years from surgery. Postoperative outcome was classified according to Engel's classification [15]. In all cases, at least one seizure was recorded, and semiological features were analyzed for each patient. For the purpose of the study, subjective manifestations and the initial objective ictal clinical sign were taken into account.

Table 1 Patients' features. Age onset: age at seizure onset (months), age surgery: age at surgery (months), exam (neurologic/neuropsychologic/psychiatric): n: normal/m: moderate/s: severe, MRI+: positive, MRI −: negative, freq: frequency, CPS: complex partial seizures, SPS: simple partial seizures, S: spasms, D: daily, W: weekly, M: monthly, A: annual, pf: partial functional resection, t: total resection, def postop: de novo permanent postoperative deficits, R: right, L: left, F: frontal, P: parietal, O: occipital, T: temporal, C: central, Operc: opercular, Ins: insular, OpercIns: opercular-insular, cing: cingular, FU: follow-up (years), AED: antiepileptic drugs, t: AEDs tapered, m: monotherapy, p: polytherapy, d: deceased, crypto: cryptogenic, TSC: tuberous sclerosis complex, FCD: focal cortical dysplasia, FCDI: FCD type I, FCDII: FCD type II, DNET: dysembryoplastic neuroepithelial tumour, PMG: polymicrogyria, astrocyt: astrocytoma, ganglio: ganglioglioma, oligod: oligodendroglioma, heterot: heterotopia, HH: homonymous hemianopsia, HQ: homonymous quadrantanopsia, hp: hemiparesis, mp: monoparesis, contr: contralateral, ipsil: ipsilateral. Pt

Age onset

Age surgery

Exam

Seizures type/freq

Status

MRI

SEEG

Excision

Etiology

FU (years) /AED

Engel class

Def postop

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52

0.6 41 60 48 55 9 4 42 68 12 11 1 72 26 6 11 60 12 9 25 32 108 90 96 16 0.1 22 60 13 1 0.3 48 48 144 24 89 72 5 6 30 23 36 116 18 51 144 0.6 1 0.16 58 2 72

76 151 156 96 133 75 144 114 132 156 85 13 273 162 203 41 215 211 114 60 122 288 180 219 48 312 84 117 103 41 26 87 120 276 87 288 78 146 12 63 47 95 180 168 188 204 204 61 51 240 80 276

m/m/n n/n/n n/n/n n/n/n n/n/n n/n/n n/m/n n/m/n n/n/n n/m/n n/m/m n/n/n n/n/n m/m/n n/n/n n/n/n n/n/n n/s/m m/m/m m/m/m n/n/n n/n/n n/n/n n/m/m n/n/n m/n/n m/n/m n/m/n m/m/n m/m/m m/m/m n/n/n n/n/n n/n/n n/n/n n/m/m n/n/n m/m/m n/n/n n/n/n n/m/n n/n/n n/n/n n/n/n n/n/n n/n/n n/m/m m/m/m m/m/m n/n/n n/m/n n/n/n

CPS/W SPS, CPS/D SPS, CPS/A CPS/D SPS, CPS/W SPS, CPS/D SPS, CPS/D SPS, CPS/W CPS/W CPS/A SPS, CPS/D S, CPS/W SPS, CPS/D SPS/M SPS, CPS/M SPS, CPS/D SPS, CPS/W CPS/W S, CPS/W SPS, CPS/M CPS/W SPS, CPS/W SPS, CPS/W CPS/D SPS, CPS/W SPS, CPS/M SPS, CPS, reflex/D SPS, CPS/D SPS,CPS/W SPS, CPS/D SPS, CPS/W SPS, CPS/W SPS, CPS/D SPS, CPS/M SPS, CPS/D SPS, CPS/W SPS, CPS/W SPS, CPS/D S, CPS/W SPS, CPS/D S, CPS/D CPS/D SPS, CPS/W CPS/M SPS, CPS/D SPS, CPS/W SPS, CPS/M CPS, S/W S, CPS/D SPS, CPS/W CPS/D SPS, CPS/W

Yes No No No No Yes No No No No Yes No No No No No No No No No No Yes No No No No Yes No Yes Yes No Yes No No No No No No No No No No No No No No No No No No No No

+ − + + − − + − + + + + + + − + + − + + − + + − + + + + + + + + + + + + + − + + + + + + + + + + + + + −

Yes Yes No Yes Yes Yes Yes Yes Yes No No No Yes No Yes Yes No Yes Yes Yes Yes Yes No Yes Yes No Yes Yes Yes Yes Yes No Yes Yes Yes Yes No No Yes No Yes No No No No Yes Yes No No No Yes Yes

L F dorsolateral R F mesial L F2 R F mesial + dorsal L F mesial + dorsal (pf → t)a R F orbito-frontal R F1 + F2 + cingular R F1 L F3 R F1, F2, F3 L F1 + mesial R F polar + cing + operc R F OpercIns L F Operc R F OpercIns L F OpercIns R F Ins R F mesiala R F dorsolateral (pf) R F (SMA + operc + cingular + orbital) (pf)a R F mesial L F mesial C (pf) L F mesial L fronto-orbital R FC L FCT R FCT L FCT (pf → t)a R FCP R FCP a R FCP (pf → hemisph)a R FCP (pf → t)a R P (pf → t)a RP R PC RP LP L P (pf) R PT R PT LO R OT L OT R OT R OT R OT (pf → t)a L OT L TPO R TPO R TO R TPO L TPO (pf)

10/t 6/t 6/t 7.5/t 6.5/t 13.5/t 1.5/m 5/t 6.5/t 5/t 8/t 4/t 6.5/t 4/m 2/m 11.5/t 2.5/m 9/p 10/p 7/p 2/p 11/p 11.5/p d 2.5/m 4/p 12/t 3.5/p 5/t 6/t 7.5/t 6.5/t 11.5/m 11/t 2/m 7/t 5/t 8.5/p 13/t 10.5/t 3/m 5/t 4.5/t 3.5/t 10/t 5/m 9.5/p 4/t 6/t 9.5/t 2/p 7.5/p

Ia Ia Ia Ia Ia Ia Ic Ia Ia Ia Ia Ia Ia Ia Ia Ia Ia II II II II II IV d Ia III Ic III Ia Ia Ia Ic Ic Ia Ia Ia Ia III Ia Ia Ia Ia Ia Ia Ia Ia IV Ia Ia Ia III IV

No No No No No No No No No No No No No No No No No No No No No No No No No No No Hp No Hp Mp No No No No No No No HQ HH No No HQ HH HH HH No No HQ No HH

53

4

43

m/s/m

S, CPS/D

No

−

Yes

L TPO

FCDIIB FCDIIA TSC FCDI FCDIIB FCDI PMG FCDIIB Gliosis FCDIIB TSC FCDIIA FCDIIA DNET FCDI FCDIIB FCDI FCDI FCDI FCDI Gliosis DNET Astrocyt FCDIIA FCDIIB Gliosis Gliosis FCDIIIA FCDIIA FCDIIA FCDIIB Astrocyt DNET DNET FCDI Ganglio Oligod FCDIIA TSC Ganglio FCDIIA Gliosis DNET FCDIIB Gliosis Ganglio FCDI FCDIIA FCDIIB FCDIIIB crypto Laminar Heterot Gliosis

5/p

IV

No

a

Re-operation.

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Ictal electrophysiological patterns as well as interictal discharges were classified according to their extent (localized, diffused, or generalized) and their morphology (spikes/polyspikes, spike-waves/sharp waves, slow waves: delta–theta band, fast activity: superior to alpha band). Patients were classified as MRI-negative, when the preoperative MRI was unremarkable or showed an abnormality not concordant with the electro‐clinical picture, and MRI-positive, when the MRI demonstrated a focal lesion possibly coherent with the electroclinical picture. The surgical resection in terms of EZ was judged as complete when all the cerebral areas defined by the anatomo-electro-clinical features of each single patient were removed; in lesional cases, this did not necessarily imply the total resection of the MRI-identifiable lesion. Localization of the excision permitted the subdivision of the original population in a frontal-epilepsy group (FEG): when excisions involved the frontal lobes, and in a posterior-epilepsy group (PEG): when the frontal lobes were not involved by the resection. Similarly, the histological examination allowed us to subdivide the patients in the following etiological subgroups: malformations of cortical development, tumors, vascular malformations, and encephalomalacic/ gliotic lesions. Only low grade tumors with refractory epilepsy were included in the study. Acute postoperative seizures (APOS), as defined by seizures occurring within the first postoperative week, were noted. Finally, electro‐clinical and neuroradiological features, as shown in Table 3, were analyzed in relation to postsurgical seizure outcome by interferential statistical analysis: univariate binomial analysis and univariate T test, the latter for the variants: age at epilepsy onset and duration of epilepsy.

ischemic insults, 1 hemorrhagic infarct), while none presented febrile convulsions. Neurological examination was normal for 39 subjects; 14 patients presented a motor deficit. Twenty-one subjects presented a neuropsychological impairment of moderate degree and 2 of severe degree; neuropsychological evaluation was normal for 30 patients. Age at epilepsy onset varied from 3 days to 12 years (mean: 3.14 years). Forty-six children (87%) had a seizure onset within the first 6 years of age. No substantial difference on age at epilepsy onset was observed between symptomatic (38.67 months) and MRInegative patients (35.07 months). Pre-surgical MRI study was positive for a focal lesion in 85% (42/53) of patients. Magnetic resonance imaging was negative in 8 cases among FEG and in 3 cases among PEG (25% of FEG and 28.6% of PEG). Eleven patients additionally underwent functional imaging (6 fMRI, 2 PET, 3 SPECT). The majority of patients, despite differences in age and localization of the EZ, had a high frequency of seizures: 20 daily, 23 weekly, 7 monthly, and 2 sporadic (less than 1/month). A high percentage of children (58.5% of the whole population, 37% of children below 6 years of age) reported subjective ictal symptoms, well correlated to the topography of the EZ. Dizziness as well as cephalic sensations concerned exclusively the FEG; 37% of patients of the FEG reported this symptom. Sensation of unreality, visual, and auditory hallucinations concerned almost exclusively the PEG, while viscerosensitive/autonomic as well as somatosensory symptoms were more frequent among the FEG. Fear (4 cases, all aged below 6 years) concerned equally the FEG and PEG, likely not reflecting an Table 3 Outcome predictors. SF: seizure‐free, s: spikes, shw: sharp waves, sw: spike-waves, slw: slow waves, EZ: epileptogenic zone. P value minor 0.05.

3. Results 3.1. Anatomo-electro-clinical features (Tables 1 and 2) Nine children had a family history of epilepsy; all but 4 children had no significant personal antecedents (3 perinatal hypoxic–

Table 2 A. Ictal subjective semiology; B. Ictal objective semiology. Frontal 19 pts

Posterior 12 pts

A Aura 31 pts Dizziness Somatosensory Autonomic/viscerosensitive Cephalic sensation Fear Sensation of unreality, jamais vu Forced thoughts Visual hallucinations Visual illusions Auditory hallucinations/illusions

3 4 4 4 2 0 1 1 1 0

0 2 1 0 2 3 0 4 1 2

B Leading ictal sign Slow head and eye version Tonic head and eye deviation Staring Focal contralateral dystonia Focal hypertonia (contr/ipsil) Focal clonias Autonomic Ictal paresis Blinking Nystagmus Eye deviation Spasm

0 9 2 4 6 (5/1) 4 1 1 0 0 1 2

5 0 1 2 2 2 2 0 3 1 3 1

Outcome predictors

SF (39 patients)

Non‐SF (13 patients)

p Value

Age seizure onset (months) Duration epilepsy (months) MRI‐positive Type of seizure Complex partial seizures Simple partial seizures Spasms Frequency of seizures Daily Weekly Monthly EEG interictal discharges S Shw, sw Slw EEG interictal diffusion EEG ictal pattern Fast Slow EEG ictal generalization SEEG (No. of patients) SEEG interictal discharges S Shw, sw Slw Localized fast rhythms SEEG interictal diffusion SEEG ictal generalization Topography EZ Frontal Posterior Histology FCDI FCDII FCD tot Tumor Total exeresis APOS

38.08 81.62 34/39 (87.17%)

32.23 133.38 5/13 (38.46%)

0.6386 0.0261 0.0004

38/39 (97.44%) 28/39 (71.79%) 4/39 (10.26%)

13/13 (100%) 9/13 (69.23%) 1/13 (7.69%)

0.1555 0.4307 0.3859

16/39 (41.03%) 17/39 (43.59%) 4/39 (10.26%)

4/13 (30.77%) 6/13 (46.15%) 3/13 (23.08%)

0.2475 0.4361 0.1555

19/39 (48.72%) 33/39 (84.62%) 12/39 (30.77%) 2/39 (5.13%)

9/13 (69.23%) 12/13 (92.31%) 4/13 (30.77%) 4/13 (30.77%)

0.0871 0.2061 0.500 0.0267

37/39 (94.87%) 2/39 (5.12%) 8/39 (20.51%) 22/39 (56.41%)

7/13 (53.85%) 6/13 (46.15%) 9/13 (69.23%) 11/13 (84.61%)

0.0020 0.0020 0.0003 0.0136

19/21 (90.48%) 14/21 (66.67%) 12/21 (57.14%) 7/21 (33.33%) 6/21 (28.57%) 1/21 (4.76%)

8/11 8/11 7/11 0 8/11 9/11

(72.72%) (81.82%)

0.1164 0.3601 0.3598 0.0006 0.0136 0.0000

22/39 (56.41%) 17/39 (43.59%)

8/13 (61.54%) 5/13(38.46%)

0.3716 0.3716

6/39 (15.38%) 16/39 (41.02%) 22/39 (56.41%) 10/39 (25.64%) 39/39 (100%) 1/39 (2.56%)

5/13 1/13 6/13 2/13 8/13 6/13

0.0580 0.0010 0.2600 0.2004 0.0022 0.0010

(72.73%) (72.73%) (63.64%)

(38.46%) (7.69%) (46.15%) (15.38%) (61.54%) (46.15%)

A. Liava et al. / Epilepsy & Behavior 25 (2012) 68–80

ictal emotional change but reflecting the child’s reaction to the perception of seizure onset. Blinking, nystagmus, and slow eye–head version represented the leading objective ictal signs exclusively among the PEG, whereas tonic head–eye deviation and ictal paresis concerned exclusively the FEG; focal clonic movements, focal dystonia, and hypertonia, mostly contralateral, were more frequent in the FEG (Fig. 1). In all cases, long-term scalp EEG, either interictal and/or ictal, was correctly lateralizing. Interictal abnormalities were localized/regional in 47 cases (89%). Ictal pattern was generalized/non-localized in 18 cases (34% of FEG and 33% of PEG). Interictal focal slow activities were found in 30% of cases, interictal spikes and spike-waves in 96%; slow-band ictal activity was observed in 21% and fast-band ictal pattern in 75% of cases. For 19 children, the data collected from imaging and electroclinical analysis were fully concordant and guided a tailored resection of the EZ; the remaining 34 subjects (64%, 11 of them MRI-negative) underwent SEEG evaluation, well tolerated in all. Patients whose evaluation required a SEEG procedure represented 72% of FEG and 52% of PEG.

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Interictal SEEG determined the localization of the EZ in 53% of patients who underwent the procedure. Interictal activity constituted spikes in 82% of cases, slow activity in 59%, and localized interictal fast rhythms in 20.6%. Diffuse initial ictal modification was observed in 10 cases (29.4%). 3.2. Surgery (Table 1) Mean age at surgery was 11.23 years (range: 1–26 years). Mean duration of epilepsy before surgery was 7.92 years. A tailored resection was performed in the right hemisphere in 33 cases and in the left in 20, with the following localization: 5 frontomesial, 6 fronto-dorsolateral, 6 fronto-mesial + dorsolateral, 2 fronto-orbital, 5 fronto-operculo-insular, 1 fronto-central, 4 frontocentro-parietal, 3 fronto-centro-temporal, 5 parietal, 2 parietotemporal, 1 centro-parietal, 1 occipital, 7 occipito-temporal, and 5 temporo-parieto-occipital. In 5 cases, only a partial excision of the EZ was performed, due to its functional intersection with eloquent areas: 1 fronto-dorsolateral, 1 fronto-mesial + dorsolateral, 1 fronto-central, 1 parietal, and 1

Fig. 1. Case illustration 1: Patient 2. Female. No significant family and personal antecedents. Normal neurological exam, right‐handed; neuropsychological examination: IQ 100, difficulties in problem solving and visuo-spatial competencies. Seizure onset at 3 years, 5 months characterized by rubefaction, laughter, tachycardia, psychomotor agitation with terrified expression; if the seizure was longer, a vibratory hypertonia of both arms could follow. Contact was apparently preserved. Seizures were rare at onset; at 11 years of age, they became frequent, and semiology was characterized by fear, terrified expression, and dystonia of the left arm; phasic competencies were normal. Interictal EEG showed rare bifronto-centro-temporal (FCT) spike-waves, predominant on the right, while in the ictal EEG, a diffuse fast rhythm, predominant on the right FCT region, was observed. Magnetic resonance imaging was normal. Stereo‐electroencephalography (1a): MRI with implanted electrodes (notice that the artifacts on the MRI are consistently bigger than the real diameter of the electrodes: 0.8 mm) showing, on the lateral (a) and mesial (b) surfaces, the positions of the electrodes implanted in the right hemisphere; two other electrodes (H′, S′) were implanted also in the left frontal lobe (electrodes K, H′, S′ are not shown). Interictal SEEG during hyperventilation (1b) revealed the presence of rhythmic spikewaves and slow waves on the frontal cingulate gyrus (H1–2) and on the knee of the cingulate gyrus (G1–2). Ictal SEEG (1c): the discharge starts on the frontal cingulate gyrus (H 1–2 + G1–2) with a flattening followed by a slow rhythmic activity (first arrow); the first clinical sign (second arrow: dystonia of the left arm) appears when the discharge becomes very fast in the same positions and involves also other parts of the frontal cingulate gyrus (I1–2), and the intermediate (E1–2, F1–2) and posterior (M2–3, J1–2) frontal mesial cortices. Resection (1d) included the dorsal and mesial frontal gyri and the frontal cingulated gyrus. At FU 6 years postop, the child is in Engel class Ia and AEDs were totally tapered.

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Fig. 1 (continued).

temporo-parieto-occipital; the remaining resections were considered as complete. At histopathological analysis, a high incidence of developmental lesions was observed: focal cortical dysplasias (FCD) represented 54.7% of results (9 FCDI, 9 FCDIIA, 9 FCDIIB, 1 FCDIIIA, 1 FCDIIIB, ILAE classification, 2011) [16], followed by gliotic lesions 13.2%,

DNTs 9.4%, tubers 7.5%, gangliogliomas 7.5%, and other low-grade tumors 5.6%; finally, there were one laminar heterotopy, one right frontal polymicrogyria, and one patient who presented no definite pathologic abnormalities in the resected tissue. In frontal excisions, there was a majority of FCD (63.6%, of which FCDI: 38%, FCDII: 62%) in contrast to the posterior ones (40%, of

A. Liava et al. / Epilepsy & Behavior 25 (2012) 68–80

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Fig. 1 (continued).

Follow‐up after surgery varied from 1.5 to 13.5 years (mean 3.73 years). One patient died in the immediate postoperative period due to pulmonary complications. Permanent postoperative de novo deficits, all fully predicted and discussed with the families, occurred in 21% of the population (9.6% of FEG and 38% of PEG): 5 cases of homonymous hemianopia, 3 homonymous quadrantanopia, 2 hemiparesis, and 1 case of monoparesis. Complete seizure freedom was achieved in 75% of patients (Engel class Ia: 35, Ic: 4 patients); 77% of them have tapered antiepileptic drugs. Seizure-free (SF) subjects represented 50% (5/10) of the MRInegative and 81% (34/42) of the MRI-positive population (Fig. 2). Five patients (9.6%) are in Engel class II, 4 (7.7%) in class III and 4 (7.7%) in class IV. Among the patients who underwent SEEG, a good outcome was observed: 69% (22/32) of subjects are SF and a further 16% are in Engel class II. Subjects whose pre-surgical evaluation did not require an invasive procedure had, however, a better outcome (16/21, 76% achieved seizure freedom). Nine patients, 2 of whom with a negative MRI, required a reoperation, with 66.6% achieving success. On postoperative neuropsychological evaluation at last follow‐up, 50% of subjects had improved their global performances and one subject had worsened. Seven subjects developed de novo postoperative internalizing disorders, including anxiety and depression, in 2 cases persisting at 5 years follow‐up; interestingly, all subjects had normal intelligence and had achieved complete seizure freedom (18% of SF population), in six subjects the EZ was localized within the posterior cerebral regions, while depression and anxiety were not correlated with duration of epilepsy or with postoperative deficits.

complication with status did not correlate with outcome (7/8 subjects SF), reflecting essentially the severity of the clinical condition (Table 1). The presence of a neuroradiologically detectable lesion correlated consistently with a more favorable outcome: 81% of lesional compared to 50% of MRI-negative subjects achieved freedom from seizures, irrespective of the localization of the EZ. On pre-surgical scalp EEG, a tendency of interictal discharges, as well as of ictal pattern, to be widespread correlated with a negative outcome: regional interictal activity was observed in 95% of SF and at 69% of non-SF subjects, while a localized ictal pattern was found in 79.5% of SF compared to 31% of subjects who did not achieve freedom from seizures. Similarly, among patients who underwent SEEG evaluation, the incidence of interictal and ictal generalization was significantly higher among subjects whose seizures persisted. The presence of ictal slow-band activity on pre‐surgical scalp EEG represented a predictive element of poor outcome: in SF subjects, ictal pattern was represented by a fast-band activity in 94.87% of cases and by slow waves/delta activity in 5.12%, whereas in non-SF patients, slow waves represented 46.15% of ictal discharges (p b 0.0020). Interictal localized periodic fast rhythms on SEEG correlated with a good seizure outcome; this pattern was identified in 33.3% of the subjects rendered SF, all affected by FCD, but in none of the patients whose seizures persisted. In respect to tumor lesions, FCD was associated with a slightly lower percentage of surgical success: 78.5% (22/28) of patients affected by FCD versus 83.3% (10/12) of patients affected by tumor lesions are SF. The incidence of FCDII in respect to FCDI appeared significantly higher in SF subjects. Total excision of the EZ represented a strong positive predictive element, while an incomplete resection of the epileptogenic focus, whether it resulted from inappropriate assessment of its limits or from involvement of functional areas, did not permit cure from seizures, thus representing an absolute negative predictor of outcome. Finally, the presence of acute postoperative seizures correlated significantly with a poor outcome.

3.4. Outcome predictors (Table 3)

4. Discussion

Age at epilepsy onset did not represent a predictive element of postoperative seizure outcome, whereas duration of epilepsy correlated with postoperative outcome in a significant way. Immature seizure patterns (spasms), as well as a high frequency of seizures, did not represent negative predictive elements; similarly,

In pediatric focal non-idiopathic epilepsy, time and age play a critical role on the decision making of epilepsy treatment strategies, in order to prevent the effects of chronic epilepsy, the latter likely representing a degenerative process in terms of psychocognitive development [17].

which FCDI: 37.5%, FCDII: 62.5%). Tumor lesions concerned 12.5% of FEP and 38% of PEP. Among MRI-negative cases, FCD represented 73%, equally distributed into the subtypes FCDI: 3 subjects, FCDIIA: 3, and FCDIIB: 2 subjects. 3.3. Outcome (Table 1)

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Fig. 2. Case illustration 2: Patient 6. Male. No family and personal antecedents. Normal neurological examination, right-handed; at pre‐surgical neuropsychological examination, difficulties in problem solving, visuo-spatial and selective attention. Seizure onset at 9 months of age was characterized by hypotonia, eyes deviated to the left, drooling, and vomiting. At 5 years of age, the child reported a cephalic sensation (“like tremor”) and intense diffuse headache; aura was followed by bilateral and symmetric lip corner contraction downwards, elevation of the left arm, clonic movements mostly proximal, eyes deviated downwards to the right then upwards to the left, frequently also head oriented to the right, flexion of right arm; he could extend the legs and could fall. Interictal EEG (2a) showed bi-frontal slow waves, predominant on the right, while in the ictal EEG (2b), diffuse flattening and/or rhythmic slow waves, bi-fronto-precentral, predominant on the right, were observed. Magnetic resonance imaging was normal while ictal SPECT showed a hyperperfusion in the fronto-basal regions, predominant on the right. At SEEG (2c), spontaneous seizures as well as seizures induced by stimulations on the orbital circumvolution and gyrus rectus (Y and X internal) were recorded. Resection (2d) included the frontal orbital region and gyrus rectus. At FU of 13.5 years postop, the child is in Engel class Ia, AEDs were tapered.

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Fig. 2 (continued).

Epileptogenesis-related developmental deterioration – whose extent will depend on the state of maturation and specialization of the brain in which it occurs – likely reflects the concept of neural plasticity that characterizes the immature brain, and there is a notion that it might be related positively to the duration of epilepsy [18]. Our study showed that duration of epilepsy correlated significantly with postoperative outcome, with patients who experienced a shorter duration of epilepsy before surgery having a more favorable seizure outcome. Our results are in line with previous studies [19,20] showing that individuals with longer duration of focal

epilepsy had significantly worse seizure prognosis after resective surgery, independently from age at seizure onset and at surgery, and this could constitute a strong argument for early surgical referral. Higher chances to achieve seizure control when surgery is performed at the very early stage of the illness, might reflect, similarly, the concept of neural plasticity, implying that deviations from normal interactions between networks, as well as more extended dysfunctional areas and/or decreased plasticity, are more likely with a longer duration of epilepsy. In this view, in the pediatric age group, failure could be ascribed to a more widespread susceptibility to seizures, in relation to

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the progressive establishment of the epileptogenic networks in the immature brain with time. Prompt referral of children to surgery might, in this way, be corroborated with higher chances of surgical success and could also lead to improved intellectual outcome. In everyday practice, however, particularly concerning ETLE, a considerable amount of time passes between onset of epilepsy and surgical treatment [21]. According to a recent survey of neurologists [22], only 43% of responders would refer for surgery patients with a MRI-negative presumed ETLE, while 30% indicated that children younger than 10 years were inappropriate surgical candidates. This attitude probably reflects the presence of rather discouraging results of ETLE surgery in children: overall outcome in patients operated for ETL foci was found to be poorer (40–63% SF) compared to TLE [4,6–8]. Seizure outcome of individually tailored ETLE surgery in our population was more favorable: 75% of subjects are in Engel class I with a mean follow‐up of 3.73 years. In addition, surgical outcome of MRI-negative patients (SF: 50%) in our small sample size appears to be more encouraging with respect to what has been previously reported, supporting

further the idea that satisfactory outcomes can be obtained in ETLE, even among cases with unremarkable neuroradiological findings. This result reflects the importance of a meticulous pre-surgical evaluation to delineate a precise topography of the EZ and to reduce the risk of surgical failure. Detailed history taking, exploration of aura symptomatology even in small children, accurate assessment of subjective and objective ictal semiological chronology – the latter obtained by prolonged video‐EEG recordings accurately studied – combined with careful assessment and interpretation of focal slowing or localized rapid rhythms on EEG, though undoubtedly more complicated in small children, are strong determinants for the estimation of the location of the seizure focus. All these parameters are fundamental for a mental visualization [23] of the spatial trajectory of the discharges within the cortex, and, finally, for the formulation of a well‐framed hypothesis, which represents the basis for the interpretation of neuroimaging results and, in cases where imaging appears little or not at all informative, guides the placement of intracranial electrodes.

Fig. 3. Case illustration 3: Patient 48. Male. No significant family and personal antecedents. Neurological examination without focal deficits, presence of a left eye convergent strabismus, right‐handed; moderate global impairment (IQ 66). Epilepsy onset at 20 days of age, with an EEG pattern of burst suppression, predominant on the left hemisphere, and clinical correlate of spasms, the latter responsive to vigabatrin. At 5 years, seizures were characterized by nystagmus to the right, immediately followed by asymmetric spasm (predominant on the right). Interictal EEG during slow sleep (3a) showed sub-continuous spikes–polyspikes localized on the left temporo-parietal-occipital (TPO) region. In the ictal EEG (3b), presence of fast rhythm localized on the left TO region, correlated with nystagmiform movements, mostly contralateral. The MRI (3c) revealed the presence of a left TPO FCD, suggestive of a picture of a posterior hemi-hemimegalencephaly. Tailored resection (3d) comprised the temporo-occipital region posterior to the Labbè vein and was associated with a temporal disconnection. Care was taken to preserve the deeper white matter containing the geniculocalcarine fibers. The child is in Engel class Ia with a FU of 4 years; AEDs were totally tapered.

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Fig. 3 (continued).

It has been reported that, in pediatric epilepsy, ictal semiology is of little localizing value, if not confounding. In our population, however, ictal semiological chronology, viewed as a part of a whole seizure pattern, appeared to correlate well with the topography of the EZ, and represented an important tool in order to distinguish frontal from posterior epilepsy, in accordance with previous contributions [24–26]. Moreover, we underline the high percentage of children below 6 years of age reporting well-localizing aura symptoms (37%); in their series, Fogarasi et al. found that 25% of a population of 14 children with frontal lobe epilepsy and 27% of a population of 18 children with posterior epilepsy, all under 7 years, reported aura. A neuroradiologically visible lesion represented a significant predictive element to a favorable seizure outcome, in accordance with previous studies [27,28]. Imaging, however, does not always provide adequate informative clinical value regarding the final decision where to operate, the structural abnormality not necessarily indicating the EZ. In this regard, SEEG in our series represented an important tool that allowed most of the complicated young patients to be treated with tailored resective surgery, which was curative for 69% of them. Stereo-EEG, well tolerated in all the small children [14], ideally permits the registration of the ictal discharge at the very initial point, as well as the evaluation of its correlations with the clinical picture [23,29], and allows one to identify electrically and semiologically a rather restricted EZ, with or without a lesion observed on MRI;

this understanding represents the cornerstone for completely excising the EZ and, consequently, for surgical success. We observed that the tendency of interictal and ictal discharges to remain localized, as well as the presence of ictal rapid-band pattern on scalp EEG, correlated consistently with a better seizure outcome. Our findings are in keeping with previous studies which reported a favorable surgical outcome with ictal rapid-band activity in the intracranial EEG, compared to ictal slowing [30]; ictal rapid-band activity was found to correlate with the highest density of interictal epileptiform discharges on the electrodes involved in the seizure onset, over long periods of intracranial EEG, providing in this way a marker to identify the epileptogenic area. The presence of interictal localized periodic fast rhythms, in the form of rhythmic repetitive bursting of polyspikes, on SEEG permitted us to detect an underlying dysplastic cortex and to delineate with precision its extent in 20.6% of cases, in accordance with previous contributions [31–33] (Fig. 3). Because dysplastic areas and EZ tend to overlap, the complete removal of the area circumscribed by the interictal rhythmic fast activity was sufficient, as well as necessary, in order to achieve surgical success. In 5 of the 7 cases whose interictal SEEG showed these well‐known “topographical markers” of FCD, scalp EEG also displayed interictal periodic sequences of localized fast activity with a good spatial correlation with the “irritative zone”, providing, in this way, a reliable localizing value tool to be considered carefully in the absence of any neuroimaging abnormalities.

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Fig. 3 (continued).

Undoubtedly, scalp EEG is an imprecise method for the localization of the EZ in cases with a negative MRI, due to its poor spatial resolution; however, the correlation of surgical failure with focal interictal slowing that tends to widespread, as well as with ictal slowing that tends to generalize, might suggest that the dysfunctional focal epileptic network – expression of an underlying neuronal loss and/or

synaptic re-organization and responsible for hyperexcitability – is probably more extensive than the one excised. Moreover, previous studies demonstrated that interictal slowing matches to the areas of hypometabolism on FDG-PET [34], probably delineating a regional reduction of the inhibitory synaptic activity and thus reflecting a degree of epileptogenicity.

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It is of interest that the occurrence of APOS acquired a statistical significance as a negative predictive element to seizure outcome. In this view, APOS might not reflect transient peri-operative factors but represent an immediate postoperative correlate of residual epileptogenicity following an incomplete excision. Our result is concordant with what has been previously reported by Mani et al. [35]; in their series of children and adolescents with ETL resection, 36% presented APOS, 15% of whom became seizure‐free at 2 years follow‐up, while among children without APOS, 63% achieved freedom from seizures. In concordance with previous contributions [32,36–38], the finding of a type II FCD was correlated with a more favorable outcome in respect to the FCDI subtype. It has been suggested [39] that better overall seizure outcome in patients with FCDII likely depends on better morphofunctional studies regarding FCDII; however, a difference in the detection rate by MRI for FCD type I and II is not confirmed in the literature [40]. FCDI lesions may be more extensive than FCDII, having, consequently, a major functional intersection with eloquent areas and their extent can be underestimated on MRI, though this assumption needs further exploration. In our population, FCD represented 73% of the histopathological findings of patients with negative MRI and 100% of MRI-negative subjects who achieved seizure freedom. This shows, in a certain way, the limitations of conventional high-resolution imaging to highlight dysplastic lesions [41], especially in infancy [5]. In the era of modern imaging, especially in children in whom functional neuroradiological studies are difficult to perform, our data highlight the importance of a correct appraisal of the significance of the different types of interictal activity for the identification of the EZ, as well as for the identification of other regions that might harbor a potential EZ. Our results seem to suggest that patients with a long duration of epilepsy, whose scalp EEG shows diffuse interictal abnormalities, ictal generalization, and ictal patterns of slow‐band activities, are less likely to become seizure‐free. This group of patients are candidates for extensive pre-surgical evaluation by multimodality imaging and, when necessary, invasive recording. 5. Conclusion Surgical outcome from ETLE surgery in children can be excellent; careful selection of patients is the best way for improving outcome. A correct recognition and identification of electro-clinical patterns that determine, as early as possible, patients with drug-resistant seizures is mandatory, in order to refer surgical candidates, without awaiting a “confirmation” of intractability of seizures which may require an unnecessarily long time. Identification of prognostic factors is an essential element for counseling families for epilepsy surgery. Short duration of illness, localized interictal and ictal activity on scalp EEG as well as presence of ictal rapid‐band pattern, absence of ictal generalization and localized rhythmic patterns on SEEG, a neuroradiologically identifiable lesion, the complete resection of the EZ, a type II FCD and an absence of APOS correlated significantly to a favorable postoperative seizure outcome in our population of ETLE subjects. Acknowledgments We thank Federico Calderoni for the statistical analysis. References [1] Pomata HB, Gonzalez R, Bartuluchi M, et al. Extratemporal epilepsy in children: candidate selection and surgical treatment. Childs Nerv Syst 2000;16(12):842–50. [2] Harvey S, Cross H, Shinnar S, Mathern G, ILAE Pediatric Epilepsy Surgery Survey Taskforce. Defining the spectrum of international practice in pediatric epilepsy surgery patients. Epilepsia 2008;49(1):146–55. [3] Wyllie E, Comair YG, Kotagal P, Bulacio J, Bingaman W, Ruggieri P. Seizure outcome after epilepsy surgery in children and adolescents. Ann Neurol 1998;44(5):740–8.

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