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Improvement of language development after successful hemispherotomy
Seizure 30 (2015) 70–75
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Improvement of language development after successful hemispherotomy Gudrun Gro¨ppel a, Christian Dorfer b, Angelika Mu¨hlebner-Fahrngruber a, Anastasia Dressler a, Barbara Porsche a, Thomas Czech b, Martha Feucht a,* a b
Epilepsy Monitoring Unit, Department of Pediatrics and Adolescence Medicine, MUW/AKH Vienna, Austria Department of Neurosurgery, MUW/AKH Vienna, Austria
A R T I C L E I N F O
A B S T R A C T
Article history: Received 30 December 2014 Received in revised form 17 May 2015 Accepted 30 May 2015
Purpose: To investigate language development after functional hemispherotomy and to evaluate prognostic factors for (un-)favourable outcomes. Methods: Children and adolescents who had vertical perithalamic hemispherotomy at the Medical University Wien (MUW) paediatric epilepsy centre were identified from a prospectively maintained database. Inclusion criteria were: complete clinical, neurophysiological and neuropsychological data, seizure freedom and a minimum follow-up of 12 months after surgery. The language quotients (LQ) prior to surgery and at last follow-up were calculated for each child. In addition, associations between pre- to post-surgical changes in LQ and the following variables were examined: age at epilepsy-onset, age at surgery and duration of epilepsy prior to surgery, aetiology, side of surgery, interictal EEG including sleep organization before and 12 months after surgery and antiepileptic-drug (AED) withdrawal state at last follow-up. Analyses were carried out in SPSS version 20.0 (SPSS Inc., Chicago, IL, USA). Nonparametric Wilcoxon and chi-square tests were applied, as required. Results: Data from 28 children (14 female) were analyzed. The median age at epilepsy surgery was 64.5 months. The median follow-up after surgery was 3.0 years (2.6 years, range 12 months to 12 years). Significant gains in LQs at last follow-up were found in 31% of the children (p = 0.008). Short disease duration prior to surgery, acquired pathology, lack of epileptiform EEG discharges in the contralateral hemisphere and/or normalization of EEG sleep patterns after surgery, and successful AED withdrawal were linked to favourable language outcomes. Conclusion: Successful and early hemispherotomy results in improvement of language function in the intact hemisphere. ß 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Epilepsy surgery Children Language developmental
1. Introduction Epilepsy has the highest incidence in the first year of life with a rate of 118 of 100,000 new patients per year [6]. These early-onset symptomatic epilepsies are often associated with multilobar or hemispheric pathology, neurological deficits and severe developmental impairment [11,12,27]. Most, if not all of these epilepsies
Abbreviations: LQ, language quotient; ESES, electrical status epilepticus in sleep; PMG, polymicrogyria; FCD, focal cortical dysplasia; SWS, Sturge–Weber syndrome; RE, Rasmussen encephalitis; MCD, mild cortical dysplasia. * Corresponding author at: Martha Feucht, Head of the Epilepsy Service and EEG Laboratory, Department of Pediatrics and Adolescence Medicine, Medical University of Vienna, Wa¨hringer Gu¨rtel, A-1090 Vienna, Austria. Tel.: +43 01 40400 33850; fax: +43 01 40400 22770. E-mail address: [email protected] (M. Feucht).
are resistant to antiepileptic drug (AED) treatment [7,11,13]. Multilobar/hemispheric epilepsy surgery has been found to be a safe and highly effective alternative treatment option for appropriately selected children, leading to seizure freedom in up to 90% of patients after surgery [12,13,20,27,35]. In addition, cognitive, especially language abilities may improve in these patients, even after surgery in the dominant hemisphere [9,22]. However, most reports published so far on language outcomes following hemispheric surgery have concentrated on anatomic hemispherectomy [8–10,21,22,31,35]. These studies concluded that seizure freedom [8–10,16] may be a favourable predictor whereas developmental pathologies may be linked with unfavourable language outcomes. The effects of functional hemispherotomy on development have been less extensively studied and the results are inconsistent [1,24,26,27]. One possible reason for this may be that functional hemispherotomy is a comparatively new surgical
http://dx.doi.org/10.1016/j.seizure.2015.05.018 1059-1311/ß 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
G. Gro¨ppel et al. / Seizure 30 (2015) 70–75
technique and postsurgical follow-up is therefore generally limited. In addition, most patients undergoing hemispheric surgery are infants and young children and many of them have a very low level of global and language development, making standardized neuropsychological assessment difficult [1,16]. Adequate test inventories and more extensive follow-up may be required in order to establish the full developmental impact of surgery in patients with low baseline and slow progress. The primary aim of this study was to investigate the impact of disconnective hemispheric surgery, i.e. vertical perithalamic hemispherotomy, on long-term language development. We concentrated on language development because it is the most difficult developmental step and also the most vulnerable. Further, language impairment is associated with severe drawbacks across the lifespan. The secondary aim was to detect additional prognostic risk factors (e.g. duration of epilepsy, age at surgery, pathological EEG pattern, etc.) linked with (un-)favourable language development. 2. Methods This study was approved by the Medical University of Vienna Clinical Research Ethics Board. Written informed consent was obtained from all patients and/or caregivers in accordance with the standards of the Declaration of Helsinki. Prospectively collected data from a longitudinal observational electronic database containing the medical records of all paediatric patients who had presurgical evaluation and epilepsy surgery at the study clinic were screened. Data from all patients who fulfilled the following criteria were analyzed: (1) presurgical evaluation and vertical perithalamic hemispherotomy performed at the study centre; (2) age <18 years at surgery; (3) complete presurgical and follow-up data for at least 12 months after surgery, including complete language developmental data, and (4) seizure freedom after surgery (outcome class 1a [34]). Presurgical evaluation followed a standardized protocol [13] including neurological, ophthalmologic, and neuropsychological assessment as well as intensive video EEG monitoring, FDG-PET and high-resolution MRI. All surgeries were performed by one neurosurgeon (T.C.) using the same technique, i.e. vertical perithalamic hemispherotomy introduced by Delalande in 1992 [12,13]. Histopathology was classified by one of the authors (AM) according to the ILAE criteria [4,25]. Post-operative follow-up visits were scheduled at 3 months after surgery and then once per year after surgery. Post-operative follow-up examinations included thorough neurologic, psychological, psychiatric and neuro-ophthalmologic assessment as well as 48 h-EEG-Video Monitoring and MRI. Seizure outcome was classified according to the ILAE criteria [34] (Table 1), because the classification proposed by Wieser is based on annual data evaluation and therefore overcomes several disadvantages of the widely used Engel outcome classification [14]. Neuropsychological tests were performed during the presurgical evaluation process (baseline) and at all scheduled follow-up visits after surgery. The tests administered depended on the age of the patient and date of assessment. Language skills were assessed using Denver Scales II [15] in severely handicapped children and the German versions of the Wechsler Intelligence Scales (HAWIWA, HAWIK and HAWIE) [33] in all other patients. We extracted the scores of the subtests vocabulary, description of concept, finding communalities and general knowledge and on this basis the language quotient (LQ) was calculated for each patient in order to make results comparable within and between patients. LQ was defined as that portion of the developmental age divided by chronological language age all multiplied by 100 [17,18]. The maximum quotient is 100, LQ 85 stands for normal
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Table 1 classification of Wieser et al. [34]. Class 1a 1 2 3 4 5 6
Complete seizure free since surgery, no auras Complete seizure free, no auras within the last evaluated yeara Only auras, no other seizures 1–3 seizures per year auras 4 seizure daysb per year to 50% reduction of baseline seizure daysc <50% reduction of baseline seizure days to 100% increase of baseline seizure days auras >100% increase of baseline seizure days auras
Seizure days during the first month after surgery are not counted. a Seizure outcome class is determined for each year at annual intervals after surgery. Patients may change from one class to another from year to year. b A seizure day is a 24 h period with one or more seizures. This may include an episode of status epilepticus. c The number of baseline seizure days is calculated by determining the seizureday frequency during the 12 months before surgery.
development, a value between 84 and 71 refers to mild to moderate delay whereas a score of 70 or below indicates severe delay [17,18,23]. LQs prior to surgery were compared with those obtained at the last follow-up visit after surgery (minimum 12 months, longest observation 12 years). To explore clinical predictors of language outcome after surgery, possible associations between the pre-/post-operative changes in LQ within the following clinical parameters were evaluated as shown in Table 2. The patient cohort was divided according to above-mentioned parameters into two subgroups (details of the subgroups are defined in Table 2). The LQ for each subgroup was then assessed according to the above-mentioned parameters, once prior to surgery, and once at the last follow-up visit. Using statistical analysis (described below), we then calculated the change in LQ following surgery within the two subgroups (pre- to postoperative) of each parameter and compared the changes in LQ between the subgroups. 2.1. Statistical analysis For statistical analysis of continuous data the nonparametric Wilcoxon test was used. To identify associations between categorical data (group comparison) the chi-square test was used. Data were analyzed with SPSS WIN 20.0 software (SPSS Inc., Chicago, IL, USA). The minimum coincidence level to prove the significant differences of our results was p < 0.05. 3. Results 3.1. Description of the study group and patient characteristics Since 1999 a total of 245 children had epilepsy surgery at our centre: 42 patients had vertical perithalamic hemispherotomies. We included 28 patients (14 girls), 14 did not meet the inclusion criteria: five patients were excluded because of incomplete followup data (two of them also were not seizure free). Four patients were excluded because of follow-up periods shorter than 12 months (one of them was also not seizure free). Three patients were excluded because they were older than 18 years of age at surgery. One additional patient was excluded because of ongoing seizures after surgery. One further patient was excluded because the child died on the fourth day following surgery due to brain oedema. The median age (Table 3) at seizure onset was 13.5 months 30.9 months. The reason for the variability was the ranging from one to 112.0 months. In 46.4% of the patients (13/28) the seizure onset was before the age of 12 months. The median age at
G. Gro¨ppel et al. / Seizure 30 (2015) 70–75
72 Table 2 possible prognostic variables. Variable
Group 1
Group 2
Age at epilepsy onset Duration of epilepsy Age at surgery Aetiology Interictal preoperative activity (contralateral to the lesion) Interictal post-operative activity (contralateral to the lesion) Preoperative sleep pattern Postoperative sleep pattern AED treatment at last follow-up Side of surgery
Younger than 1 year Younger than 2 years Younger than 4 years Acquired pathologyb Spike activity Spike activity Normal sleep Normal sleep On medication Right
Older than 1 year Older than 2 years Older than 4 years Developmental pathologyc No spikes No spikes Pathological sleep patterna Pathological sleep patterna Medication withdrawn Left
a Either ESES (electrical status epilepticus during sleep) with spikes covering more than 85% of the slow wave sleep and the lack of sleep spindles or disturbance of sleep organization. b E.g. peri/postnatal stroke, cavernoma, Rasmussen encephalitis. c E.g. malformation of cortical development.
epilepsy surgery was 64.5 months 66.0 months (range: 6–222 months). 60.7% of the children (17/28) were older than 4 years at the time of surgery. The median duration of epilepsy before surgery was 35.5 months 47.9 months (range: 4–202 months). In 32.1% of the children (9/28) the disease duration was longer than 2 years. The median seizure frequency prior to surgery was 365 seizure days per year 140.1 seizure days (range: three seizure days per year to 365 seizure days per year). Most of our patients had more than ten seizures per day. In 67.9% of the patients (19/28) surgery was in the left hemisphere. Both surgical technique and intra/perioperative data were described in detail recently [13]. There were no major complications. Only one patient needed blood transfusion. One patient developed high intracranial pressure and needed a
temporary CSF drainage. The median follow-up after surgery was 3.0 years 2.6 years (range: 1–12 years). All 28 children were seizure free at the last follow up, 39.3% of them (11/28) were off medication, with a median time of 3.0 years (2.4, range 1–9 years) since AED withdrawal. Developmental pathologies were found in 35.7% of the patients (10/28). Malformations of cortical development occurred in 28.4% of the patients (8/28): type Ib in one patient, type IIb in two patients, mild cortical dysplasia in two patients and polymicrogyria in three patients [4,25,28]. Two patients had Sturge–Weber syndrome. With respect to acquired pathology (18/28 children) the most frequent histopathology was perinatal infarction in 57.1% of the patients (16/28). In 7.1% of the patients (2/28) other pathologies (cavernoma, Rasmussen encephalitis) were found.
Table 3 demographic data of the study group. Pat./ sex
Epilepsy onset
Duration of epilepsy
Age at surgery
Seizure baseline
Pathology
Side of surgery
Followup
Lateralization of spikes – preoperative
Spikes in the contralateral hemisphere– post-operative
Sleep pattern – post-operative
LQ – preoperative
LQ – postoperative
1m 2w 3w 4w 5w 6m 7w 8w 9m 10 m 11 m 12 m 13 m 14 w 15 w 16 m 17 w 18 m 19 m 20 m 21 w 22 m 23 w 24 w 25 w 26 m 27 m 28 w
14 28 69 1 6 1 16 1 30 16 3 19 73 112 6 73 13 3 3 76 7 49 24 8 8 1 3 73
24 36 30 20 121 16 10 5 35 112 70 202 31 92 4 90 12 10 84 147 52 58 18 33 51 11 75 50
38 64 99 21 127 16 26 6 65 128 73 209 103 204 10 222 25 13 87 216 58 107 42 41 59 12 78 123
1–6/week 1–6/week 1–3/month >10/day 1–3/day >10/day >10/day >10/day 4–10/day 1–3/day >10/day 1–3/month 1–3/day 1–6/week >10/day 1–6/week 4–11/year 4–11/year >10/day 1–3/month 1–3/day 1–6/week >10/day >10/day >10/day 1–6/week >10/day 4–10/day
PMG PMG Stroke FCD IB Stroke Stroke Stroke FCD IIB Stroke Stroke FCD IIB Stroke Stroke Cavernoma MCD Stroke Stroke SWS Stroke Stroke Stroke PMG RE Stroke Stroke SWS MCD Stroke
Left Right Right Left Right Left Left Right Left Right Left Left Right Right Left Left Right Left Left Left Left Left Right Left Left Left Left Left
1 3 2 5 1 1 2 5 3 4 12 3 2 1 3 5 2 2 5 2 5 5 4 5 11 1 2 4
Left Bilateral Right Bilateral Bilateral Left Bilateral Bilateral Left Right Bilateral Left Bilateral Right Left Left Right Left Bilateral Left Bilateral Bilateral Bilateral Left Bilateral Left Bilateral Left
No spikes No spikes No spikes No spikes Left No spikes No spikes No spikes No spikes Left No spikes No spikes No spikes Left No spikes No spikes No spikes No spikes No spikes No spikes No spikes No spikes Left No spikes Right No spikes Right No spikes
Normal Pathological Normal Pathological Pathological Pathological Pathological Pathological Normal Pathological Pathological Normal Normal Pathological Pathological Normal Pathological Pathological Pathological Normal Pathological Pathological Pathological Normal Pathological Normal Pathological Normal
71 – mild 61 – severe 91 – normal 30 – severe 27 – severe 40 – severe 67 – severe 25 – severe 38 – severe 16 – severe 13 – severe 45 – severe 99 – normal 77 – mild 40 – severe 92 – normal 85 – normal 54 – severe 42 – severe 43 – severe 62 – severe 82 – mild 31 – severe 9 – severe 11 – severe 67 – severe 12 – severe 100 – normal
73 – mild 68 – severe 100 – normal 75 – mild 35 – severe 41 – severe 40 – worse 81 – mild 100 – normal 57 – severe 3 – worse 54 – severe 100 – normal 71 – mild 47 – severe 99 – normal 61 – worse 66 – severe 99 – normal 60 – severe 97 – normal 100 – normal 73 – mild 23 – severe 45 – severe 64 – severe 5–severe 94 – normal
Measure of time in the variable epilepsy onset and duration of epilepsy and age at surgery is in months. Measure of time in the variable follow-up is in years. PMG, polymicrogyria; FCD, focal cortical dysplasia; SWS, Sturge–Weber syndrome; RE, Rasmussen encephalitis; MCD, mild cortical dysplasia.
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The electroencephalography data relating to pre-/post-operative time points are summarized in Table 3. Prior to surgery 46.4% of the patients (13/28) had bilateral interictal epileptiform discharges. One year after surgery only 21.4% (6/28) still showed epileptiform discharges in the contralateral hemisphere. In 64.3% of the patients (18/28) pathological sleep patterns occurred prior to surgery (ESES and/or no sleep spindles and/or no proper sleep organization), only 35.7% (10/28) had normal sleep patterns. All 28 patients showed normal sleep patterns in the contralateral hemisphere 12 months after surgery.
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patterns before surgery (18/28 patients) and normal sleep patterns after surgery showed a significantly higher gain in LQ at the last follow-up visit than children with normal pre- and postsurgical sleep patterns (p = 0.043). Children in whom AEDs had been successfully withdrawn (11/28 patients) showed a significantly higher increase in LQ at last follow-up than those still on medication (p = 0.003). Pre- to post-surgical change in language function was not associated with age at epilepsy onset or side of surgery. 4. Discussion
3.2. Pre to post-surgical gains and losses in language performance The results in Table 3 outline the detailed pre- to post-surgical changes in the language quotient (LQ). The median LQ before surgery was 44.0 (28.6). A total of 82.1% of the children (23/28) showed language delay prior to surgery: in only 10.7% of the patients (3/28) this delay was mild, in 71.2% of the patients (20/28) language delay was severe. As few as 17.8% of the children (5/28) showed normal LQs prior to surgery. A total of 53.6% of the children (15/28) had preoperative LQs < 50. The median LQ at last follow-up after surgery was 69.5 28.9. A sum of 4/5 children with normal language development before surgery showed normal language development also after surgery. One child (a girl with perinatal stroke) with normal development prior to surgery had a significant pre- to post-operative decrement of more than 10 points in LQ, showing severe developmental delay at the last follow up visit. Two children with preoperative mild delay showed mild delay also after surgery. One child with preoperative mild delay had a gain in LQ of more than 10 points and therefore showed normal language development at last follow-up. A number of 70.0% of the patients (14/20) with preoperative severe developmental delay had this delay also after surgery. Five children had an increase of more than 10 points but still had a severe delay, two children had a decrease of more than 10 points. Some patients (6/20) with preoperative severe developmental delay had an increase of more than 10 points and achieved a normal post-operative language development (three patients) or a post-operative mild developmental delay (three patients). About a third of the children (32.1%, 9/28) had a post-operative LQ < 50. A quantity of 31% of patients with preoperative language delay (7/23 patients) had a post-operative improvement of language abilities (increase of LQ more than 10 points). Hence, a statistically significant gain (p = 0.008) in LQ was observed between pre- and post-surgical evaluation. Although we saw no significant loss in language function at last follow up compared to presurgical levels, decline of LQ was seen in individual patients. 3.3. Predictors for post-operative changes in language performance Children with duration of epilepsy shorter than 2 years prior to surgery (9/28 patients) presented a significantly higher increase in LQ than those with a longer disease duration (p = 0.004). Children older than 4 years at the time of surgery (17/28 patients) showed a significantly higher increase in LQ than those operated at a younger age (p = 0.011). Additionally, patients with epilepsy due to acquired pathologies (18/28 patients) showed a significantly higher increase in LQ than patients with developmental pathologies (p = 0.022). Children without epileptiform discharges in the contralateral hemisphere (22/28 patients) after surgery showed a significantly higher increase in LQ at last follow-up than those with persisting spikes (p = 0.025). All patients had normal sleep patterns in the remaining hemisphere after surgery. Patients with pathological sleep
Functional hemispherotomy is a relatively new surgical technique for children suffering from drug resistant seizures due to multilobar or hemispheric epilepsies. In this procedure, the affected hemisphere is disconnected without physically being removed, thus minimizing significantly the side effects associated with anatomical hemispherectomy [12,13]. This report focuses on long-term language outcome of seizurefree paediatric patients who underwent hemispheric surgery for drug-resistant epileptic encephalopathies. We provide positive evidence for the efficacy of hemispherotomy, in this case vertical perithalamic hemispherotomy, in improving language skills, which underscores further the technique’s safety. These results might stand true also for other techniques of functional hemispherotomy. So far, only few studies have concentrated on progress in language skills following functional hemispherotomy [24,27]. These studies reported that gains in language development were seen primarily in children achieving seizure freedom after surgery [1,12,24,27]. In the present study only patients who were seizure free after surgery were included, and we were able to demonstrate improvement in language functions in 31% of our patients, albeit their language abilities were delayed compared to healthy children. In general progress in language development was slow, requiring that the observation time be long enough to detect any small steps of improvement. In our study the post-operative observation time extended to 12 years. However, since factors other than surgery might also influence language development following surgery, thereby biasing our result, we investigated additional predictors for positive long-term language outcome. We found a significant increase in LQ in patients with shorter duration of epilepsy (p = 0.004). Other reports have previously found that a shorter period of overt seizures might be positive for better general developmental progress [2,12,24,27], which also holds true for language abilities [8,9,16]. Additionally, our results corroborate the finding that children who were off medication after surgery showed significantly better language outcomes (p = 0.003). Similarly, children who had AED withdrawal after successful surgery showed better psychomotor development than those on AED treatment [5,19,32]. In our study children who were older than 4 years at surgery showed a higher increase of post-operative LQ compared to those operated at an earlier age (p = 0.011). This result appeared counterintuitive, since language acquisition in healthy children, including attaining native accents in foreign languages, takes place very early. We argue that the reason for our finding was that precisely those children undergoing surgery at a later age were afflicted by acquired pathologies, with milder seizure loads thereby delaying carer consent for surgery. On the other hand, surgical intervention would have taken place a great deal earlier for children with developmental pathologies, since parent consent would have been more forthcoming due to child morbidity and care burden [1,9,24,27,29,30]. In our study we found that epileptic discharges in the contralateral hemisphere recorded after surgery seemed to be
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significant predictors of long-term language outcome (p = 0.025). Indeed, even seizure-free children with remaining interictal discharges in the contralateral hemisphere showed smaller increases in post-operative LQ and therefore less favourable language outcomes than those without such alterations. In our study group, children with pathological sleep patterns prior to surgery and normalization thereafter showed a significantly higher gain in LQ (p = 0.043) than children with normal preand post-surgical sleep patterns. In this respect, altered sleep patterns have been described for patients with Landau–Kleffner Syndrome, who suffer from electrical status epilepticus during sleep (ESES) in combination with severe language retardation. However, patients with unilateral brain lesions may also develop ESES and, therefore, might benefit from disconnective surgery [3,23]. Pre- to post-surgical change in language function was not associated with the side of surgery. This finding is congruent with other studies and may be due to brain plasticity and both pre- and post-surgical compensatory mechanisms in infants and young children [9,16,22]. 5. Conclusion Vertical perithalamic hemispherotomy leads to seizure freedom in a high number of patients, and also significantly improves language development in these patients, especially in children with short disease duration prior to surgery, those with acquired pathologies and provided that AEDs can be successfully withdrawn. 5.1. Study strengths and limitations Although data collection was prospective and, in a structured manner, the design was that of a retrospective cross sectional observational study. In addition, the number of patients evaluated was low and inhomogeneous with respect to clinical variables (i.e. age at surgery, underlying pathology, etc.). Improvement in language development after surgery is reported by many parents, but quantification with standardized neuropsychological tests is difficult. However, special psychological screening methods for severely handicapped children and adolescents currently do not exist [1,31]. In this study, LQ was calculated based on the language scores of two standardized methods (Denver Scales II and the German Version of the Wechsler Intelligence Scales), which made results comparable between and within subjects. These tests might not be the ideal methods, but most children included in this study were severely handicapped and their language performance was poor. Additionally, no tool for measuring the impact of rehabilitation on the language development exists. The strength of our study was the relatively long observation time after surgery (median 3.0 years; range 1–12 years), which facilitated the detection of developmental progress even when it was slow. Conflict of interest The authors have stated that they had no interests, which might be perceived as posing a conflict or bias. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Acknowledgments The work of A. Mu¨hlebner-Fahrngruber and G. Gro¨ppel was supported by the Anniversary Fund of the Central Bank of the ¨ NB-12036 dedicated to M. Feucht: Republic of Austria (O
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Improvement of language development after successful hemispherotomy Gudrun Gro¨ppel a, Christian Dorfer b, Angelika Mu¨hlebner-Fahrngruber a, Anastasia Dressler a, Barbara Porsche a, Thomas Czech b, Martha Feucht a,* a b
Epilepsy Monitoring Unit, Department of Pediatrics and Adolescence Medicine, MUW/AKH Vienna, Austria Department of Neurosurgery, MUW/AKH Vienna, Austria
A R T I C L E I N F O
A B S T R A C T
Article history: Received 30 December 2014 Received in revised form 17 May 2015 Accepted 30 May 2015
Purpose: To investigate language development after functional hemispherotomy and to evaluate prognostic factors for (un-)favourable outcomes. Methods: Children and adolescents who had vertical perithalamic hemispherotomy at the Medical University Wien (MUW) paediatric epilepsy centre were identified from a prospectively maintained database. Inclusion criteria were: complete clinical, neurophysiological and neuropsychological data, seizure freedom and a minimum follow-up of 12 months after surgery. The language quotients (LQ) prior to surgery and at last follow-up were calculated for each child. In addition, associations between pre- to post-surgical changes in LQ and the following variables were examined: age at epilepsy-onset, age at surgery and duration of epilepsy prior to surgery, aetiology, side of surgery, interictal EEG including sleep organization before and 12 months after surgery and antiepileptic-drug (AED) withdrawal state at last follow-up. Analyses were carried out in SPSS version 20.0 (SPSS Inc., Chicago, IL, USA). Nonparametric Wilcoxon and chi-square tests were applied, as required. Results: Data from 28 children (14 female) were analyzed. The median age at epilepsy surgery was 64.5 months. The median follow-up after surgery was 3.0 years (2.6 years, range 12 months to 12 years). Significant gains in LQs at last follow-up were found in 31% of the children (p = 0.008). Short disease duration prior to surgery, acquired pathology, lack of epileptiform EEG discharges in the contralateral hemisphere and/or normalization of EEG sleep patterns after surgery, and successful AED withdrawal were linked to favourable language outcomes. Conclusion: Successful and early hemispherotomy results in improvement of language function in the intact hemisphere. ß 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Epilepsy surgery Children Language developmental
1. Introduction Epilepsy has the highest incidence in the first year of life with a rate of 118 of 100,000 new patients per year [6]. These early-onset symptomatic epilepsies are often associated with multilobar or hemispheric pathology, neurological deficits and severe developmental impairment [11,12,27]. Most, if not all of these epilepsies
Abbreviations: LQ, language quotient; ESES, electrical status epilepticus in sleep; PMG, polymicrogyria; FCD, focal cortical dysplasia; SWS, Sturge–Weber syndrome; RE, Rasmussen encephalitis; MCD, mild cortical dysplasia. * Corresponding author at: Martha Feucht, Head of the Epilepsy Service and EEG Laboratory, Department of Pediatrics and Adolescence Medicine, Medical University of Vienna, Wa¨hringer Gu¨rtel, A-1090 Vienna, Austria. Tel.: +43 01 40400 33850; fax: +43 01 40400 22770. E-mail address: [email protected] (M. Feucht).
are resistant to antiepileptic drug (AED) treatment [7,11,13]. Multilobar/hemispheric epilepsy surgery has been found to be a safe and highly effective alternative treatment option for appropriately selected children, leading to seizure freedom in up to 90% of patients after surgery [12,13,20,27,35]. In addition, cognitive, especially language abilities may improve in these patients, even after surgery in the dominant hemisphere [9,22]. However, most reports published so far on language outcomes following hemispheric surgery have concentrated on anatomic hemispherectomy [8–10,21,22,31,35]. These studies concluded that seizure freedom [8–10,16] may be a favourable predictor whereas developmental pathologies may be linked with unfavourable language outcomes. The effects of functional hemispherotomy on development have been less extensively studied and the results are inconsistent [1,24,26,27]. One possible reason for this may be that functional hemispherotomy is a comparatively new surgical
http://dx.doi.org/10.1016/j.seizure.2015.05.018 1059-1311/ß 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
G. Gro¨ppel et al. / Seizure 30 (2015) 70–75
technique and postsurgical follow-up is therefore generally limited. In addition, most patients undergoing hemispheric surgery are infants and young children and many of them have a very low level of global and language development, making standardized neuropsychological assessment difficult [1,16]. Adequate test inventories and more extensive follow-up may be required in order to establish the full developmental impact of surgery in patients with low baseline and slow progress. The primary aim of this study was to investigate the impact of disconnective hemispheric surgery, i.e. vertical perithalamic hemispherotomy, on long-term language development. We concentrated on language development because it is the most difficult developmental step and also the most vulnerable. Further, language impairment is associated with severe drawbacks across the lifespan. The secondary aim was to detect additional prognostic risk factors (e.g. duration of epilepsy, age at surgery, pathological EEG pattern, etc.) linked with (un-)favourable language development. 2. Methods This study was approved by the Medical University of Vienna Clinical Research Ethics Board. Written informed consent was obtained from all patients and/or caregivers in accordance with the standards of the Declaration of Helsinki. Prospectively collected data from a longitudinal observational electronic database containing the medical records of all paediatric patients who had presurgical evaluation and epilepsy surgery at the study clinic were screened. Data from all patients who fulfilled the following criteria were analyzed: (1) presurgical evaluation and vertical perithalamic hemispherotomy performed at the study centre; (2) age <18 years at surgery; (3) complete presurgical and follow-up data for at least 12 months after surgery, including complete language developmental data, and (4) seizure freedom after surgery (outcome class 1a [34]). Presurgical evaluation followed a standardized protocol [13] including neurological, ophthalmologic, and neuropsychological assessment as well as intensive video EEG monitoring, FDG-PET and high-resolution MRI. All surgeries were performed by one neurosurgeon (T.C.) using the same technique, i.e. vertical perithalamic hemispherotomy introduced by Delalande in 1992 [12,13]. Histopathology was classified by one of the authors (AM) according to the ILAE criteria [4,25]. Post-operative follow-up visits were scheduled at 3 months after surgery and then once per year after surgery. Post-operative follow-up examinations included thorough neurologic, psychological, psychiatric and neuro-ophthalmologic assessment as well as 48 h-EEG-Video Monitoring and MRI. Seizure outcome was classified according to the ILAE criteria [34] (Table 1), because the classification proposed by Wieser is based on annual data evaluation and therefore overcomes several disadvantages of the widely used Engel outcome classification [14]. Neuropsychological tests were performed during the presurgical evaluation process (baseline) and at all scheduled follow-up visits after surgery. The tests administered depended on the age of the patient and date of assessment. Language skills were assessed using Denver Scales II [15] in severely handicapped children and the German versions of the Wechsler Intelligence Scales (HAWIWA, HAWIK and HAWIE) [33] in all other patients. We extracted the scores of the subtests vocabulary, description of concept, finding communalities and general knowledge and on this basis the language quotient (LQ) was calculated for each patient in order to make results comparable within and between patients. LQ was defined as that portion of the developmental age divided by chronological language age all multiplied by 100 [17,18]. The maximum quotient is 100, LQ 85 stands for normal
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Table 1 classification of Wieser et al. [34]. Class 1a 1 2 3 4 5 6
Complete seizure free since surgery, no auras Complete seizure free, no auras within the last evaluated yeara Only auras, no other seizures 1–3 seizures per year auras 4 seizure daysb per year to 50% reduction of baseline seizure daysc <50% reduction of baseline seizure days to 100% increase of baseline seizure days auras >100% increase of baseline seizure days auras
Seizure days during the first month after surgery are not counted. a Seizure outcome class is determined for each year at annual intervals after surgery. Patients may change from one class to another from year to year. b A seizure day is a 24 h period with one or more seizures. This may include an episode of status epilepticus. c The number of baseline seizure days is calculated by determining the seizureday frequency during the 12 months before surgery.
development, a value between 84 and 71 refers to mild to moderate delay whereas a score of 70 or below indicates severe delay [17,18,23]. LQs prior to surgery were compared with those obtained at the last follow-up visit after surgery (minimum 12 months, longest observation 12 years). To explore clinical predictors of language outcome after surgery, possible associations between the pre-/post-operative changes in LQ within the following clinical parameters were evaluated as shown in Table 2. The patient cohort was divided according to above-mentioned parameters into two subgroups (details of the subgroups are defined in Table 2). The LQ for each subgroup was then assessed according to the above-mentioned parameters, once prior to surgery, and once at the last follow-up visit. Using statistical analysis (described below), we then calculated the change in LQ following surgery within the two subgroups (pre- to postoperative) of each parameter and compared the changes in LQ between the subgroups. 2.1. Statistical analysis For statistical analysis of continuous data the nonparametric Wilcoxon test was used. To identify associations between categorical data (group comparison) the chi-square test was used. Data were analyzed with SPSS WIN 20.0 software (SPSS Inc., Chicago, IL, USA). The minimum coincidence level to prove the significant differences of our results was p < 0.05. 3. Results 3.1. Description of the study group and patient characteristics Since 1999 a total of 245 children had epilepsy surgery at our centre: 42 patients had vertical perithalamic hemispherotomies. We included 28 patients (14 girls), 14 did not meet the inclusion criteria: five patients were excluded because of incomplete followup data (two of them also were not seizure free). Four patients were excluded because of follow-up periods shorter than 12 months (one of them was also not seizure free). Three patients were excluded because they were older than 18 years of age at surgery. One additional patient was excluded because of ongoing seizures after surgery. One further patient was excluded because the child died on the fourth day following surgery due to brain oedema. The median age (Table 3) at seizure onset was 13.5 months 30.9 months. The reason for the variability was the ranging from one to 112.0 months. In 46.4% of the patients (13/28) the seizure onset was before the age of 12 months. The median age at
G. Gro¨ppel et al. / Seizure 30 (2015) 70–75
72 Table 2 possible prognostic variables. Variable
Group 1
Group 2
Age at epilepsy onset Duration of epilepsy Age at surgery Aetiology Interictal preoperative activity (contralateral to the lesion) Interictal post-operative activity (contralateral to the lesion) Preoperative sleep pattern Postoperative sleep pattern AED treatment at last follow-up Side of surgery
Younger than 1 year Younger than 2 years Younger than 4 years Acquired pathologyb Spike activity Spike activity Normal sleep Normal sleep On medication Right
Older than 1 year Older than 2 years Older than 4 years Developmental pathologyc No spikes No spikes Pathological sleep patterna Pathological sleep patterna Medication withdrawn Left
a Either ESES (electrical status epilepticus during sleep) with spikes covering more than 85% of the slow wave sleep and the lack of sleep spindles or disturbance of sleep organization. b E.g. peri/postnatal stroke, cavernoma, Rasmussen encephalitis. c E.g. malformation of cortical development.
epilepsy surgery was 64.5 months 66.0 months (range: 6–222 months). 60.7% of the children (17/28) were older than 4 years at the time of surgery. The median duration of epilepsy before surgery was 35.5 months 47.9 months (range: 4–202 months). In 32.1% of the children (9/28) the disease duration was longer than 2 years. The median seizure frequency prior to surgery was 365 seizure days per year 140.1 seizure days (range: three seizure days per year to 365 seizure days per year). Most of our patients had more than ten seizures per day. In 67.9% of the patients (19/28) surgery was in the left hemisphere. Both surgical technique and intra/perioperative data were described in detail recently [13]. There were no major complications. Only one patient needed blood transfusion. One patient developed high intracranial pressure and needed a
temporary CSF drainage. The median follow-up after surgery was 3.0 years 2.6 years (range: 1–12 years). All 28 children were seizure free at the last follow up, 39.3% of them (11/28) were off medication, with a median time of 3.0 years (2.4, range 1–9 years) since AED withdrawal. Developmental pathologies were found in 35.7% of the patients (10/28). Malformations of cortical development occurred in 28.4% of the patients (8/28): type Ib in one patient, type IIb in two patients, mild cortical dysplasia in two patients and polymicrogyria in three patients [4,25,28]. Two patients had Sturge–Weber syndrome. With respect to acquired pathology (18/28 children) the most frequent histopathology was perinatal infarction in 57.1% of the patients (16/28). In 7.1% of the patients (2/28) other pathologies (cavernoma, Rasmussen encephalitis) were found.
Table 3 demographic data of the study group. Pat./ sex
Epilepsy onset
Duration of epilepsy
Age at surgery
Seizure baseline
Pathology
Side of surgery
Followup
Lateralization of spikes – preoperative
Spikes in the contralateral hemisphere– post-operative
Sleep pattern – post-operative
LQ – preoperative
LQ – postoperative
1m 2w 3w 4w 5w 6m 7w 8w 9m 10 m 11 m 12 m 13 m 14 w 15 w 16 m 17 w 18 m 19 m 20 m 21 w 22 m 23 w 24 w 25 w 26 m 27 m 28 w
14 28 69 1 6 1 16 1 30 16 3 19 73 112 6 73 13 3 3 76 7 49 24 8 8 1 3 73
24 36 30 20 121 16 10 5 35 112 70 202 31 92 4 90 12 10 84 147 52 58 18 33 51 11 75 50
38 64 99 21 127 16 26 6 65 128 73 209 103 204 10 222 25 13 87 216 58 107 42 41 59 12 78 123
1–6/week 1–6/week 1–3/month >10/day 1–3/day >10/day >10/day >10/day 4–10/day 1–3/day >10/day 1–3/month 1–3/day 1–6/week >10/day 1–6/week 4–11/year 4–11/year >10/day 1–3/month 1–3/day 1–6/week >10/day >10/day >10/day 1–6/week >10/day 4–10/day
PMG PMG Stroke FCD IB Stroke Stroke Stroke FCD IIB Stroke Stroke FCD IIB Stroke Stroke Cavernoma MCD Stroke Stroke SWS Stroke Stroke Stroke PMG RE Stroke Stroke SWS MCD Stroke
Left Right Right Left Right Left Left Right Left Right Left Left Right Right Left Left Right Left Left Left Left Left Right Left Left Left Left Left
1 3 2 5 1 1 2 5 3 4 12 3 2 1 3 5 2 2 5 2 5 5 4 5 11 1 2 4
Left Bilateral Right Bilateral Bilateral Left Bilateral Bilateral Left Right Bilateral Left Bilateral Right Left Left Right Left Bilateral Left Bilateral Bilateral Bilateral Left Bilateral Left Bilateral Left
No spikes No spikes No spikes No spikes Left No spikes No spikes No spikes No spikes Left No spikes No spikes No spikes Left No spikes No spikes No spikes No spikes No spikes No spikes No spikes No spikes Left No spikes Right No spikes Right No spikes
Normal Pathological Normal Pathological Pathological Pathological Pathological Pathological Normal Pathological Pathological Normal Normal Pathological Pathological Normal Pathological Pathological Pathological Normal Pathological Pathological Pathological Normal Pathological Normal Pathological Normal
71 – mild 61 – severe 91 – normal 30 – severe 27 – severe 40 – severe 67 – severe 25 – severe 38 – severe 16 – severe 13 – severe 45 – severe 99 – normal 77 – mild 40 – severe 92 – normal 85 – normal 54 – severe 42 – severe 43 – severe 62 – severe 82 – mild 31 – severe 9 – severe 11 – severe 67 – severe 12 – severe 100 – normal
73 – mild 68 – severe 100 – normal 75 – mild 35 – severe 41 – severe 40 – worse 81 – mild 100 – normal 57 – severe 3 – worse 54 – severe 100 – normal 71 – mild 47 – severe 99 – normal 61 – worse 66 – severe 99 – normal 60 – severe 97 – normal 100 – normal 73 – mild 23 – severe 45 – severe 64 – severe 5–severe 94 – normal
Measure of time in the variable epilepsy onset and duration of epilepsy and age at surgery is in months. Measure of time in the variable follow-up is in years. PMG, polymicrogyria; FCD, focal cortical dysplasia; SWS, Sturge–Weber syndrome; RE, Rasmussen encephalitis; MCD, mild cortical dysplasia.
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The electroencephalography data relating to pre-/post-operative time points are summarized in Table 3. Prior to surgery 46.4% of the patients (13/28) had bilateral interictal epileptiform discharges. One year after surgery only 21.4% (6/28) still showed epileptiform discharges in the contralateral hemisphere. In 64.3% of the patients (18/28) pathological sleep patterns occurred prior to surgery (ESES and/or no sleep spindles and/or no proper sleep organization), only 35.7% (10/28) had normal sleep patterns. All 28 patients showed normal sleep patterns in the contralateral hemisphere 12 months after surgery.
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patterns before surgery (18/28 patients) and normal sleep patterns after surgery showed a significantly higher gain in LQ at the last follow-up visit than children with normal pre- and postsurgical sleep patterns (p = 0.043). Children in whom AEDs had been successfully withdrawn (11/28 patients) showed a significantly higher increase in LQ at last follow-up than those still on medication (p = 0.003). Pre- to post-surgical change in language function was not associated with age at epilepsy onset or side of surgery. 4. Discussion
3.2. Pre to post-surgical gains and losses in language performance The results in Table 3 outline the detailed pre- to post-surgical changes in the language quotient (LQ). The median LQ before surgery was 44.0 (28.6). A total of 82.1% of the children (23/28) showed language delay prior to surgery: in only 10.7% of the patients (3/28) this delay was mild, in 71.2% of the patients (20/28) language delay was severe. As few as 17.8% of the children (5/28) showed normal LQs prior to surgery. A total of 53.6% of the children (15/28) had preoperative LQs < 50. The median LQ at last follow-up after surgery was 69.5 28.9. A sum of 4/5 children with normal language development before surgery showed normal language development also after surgery. One child (a girl with perinatal stroke) with normal development prior to surgery had a significant pre- to post-operative decrement of more than 10 points in LQ, showing severe developmental delay at the last follow up visit. Two children with preoperative mild delay showed mild delay also after surgery. One child with preoperative mild delay had a gain in LQ of more than 10 points and therefore showed normal language development at last follow-up. A number of 70.0% of the patients (14/20) with preoperative severe developmental delay had this delay also after surgery. Five children had an increase of more than 10 points but still had a severe delay, two children had a decrease of more than 10 points. Some patients (6/20) with preoperative severe developmental delay had an increase of more than 10 points and achieved a normal post-operative language development (three patients) or a post-operative mild developmental delay (three patients). About a third of the children (32.1%, 9/28) had a post-operative LQ < 50. A quantity of 31% of patients with preoperative language delay (7/23 patients) had a post-operative improvement of language abilities (increase of LQ more than 10 points). Hence, a statistically significant gain (p = 0.008) in LQ was observed between pre- and post-surgical evaluation. Although we saw no significant loss in language function at last follow up compared to presurgical levels, decline of LQ was seen in individual patients. 3.3. Predictors for post-operative changes in language performance Children with duration of epilepsy shorter than 2 years prior to surgery (9/28 patients) presented a significantly higher increase in LQ than those with a longer disease duration (p = 0.004). Children older than 4 years at the time of surgery (17/28 patients) showed a significantly higher increase in LQ than those operated at a younger age (p = 0.011). Additionally, patients with epilepsy due to acquired pathologies (18/28 patients) showed a significantly higher increase in LQ than patients with developmental pathologies (p = 0.022). Children without epileptiform discharges in the contralateral hemisphere (22/28 patients) after surgery showed a significantly higher increase in LQ at last follow-up than those with persisting spikes (p = 0.025). All patients had normal sleep patterns in the remaining hemisphere after surgery. Patients with pathological sleep
Functional hemispherotomy is a relatively new surgical technique for children suffering from drug resistant seizures due to multilobar or hemispheric epilepsies. In this procedure, the affected hemisphere is disconnected without physically being removed, thus minimizing significantly the side effects associated with anatomical hemispherectomy [12,13]. This report focuses on long-term language outcome of seizurefree paediatric patients who underwent hemispheric surgery for drug-resistant epileptic encephalopathies. We provide positive evidence for the efficacy of hemispherotomy, in this case vertical perithalamic hemispherotomy, in improving language skills, which underscores further the technique’s safety. These results might stand true also for other techniques of functional hemispherotomy. So far, only few studies have concentrated on progress in language skills following functional hemispherotomy [24,27]. These studies reported that gains in language development were seen primarily in children achieving seizure freedom after surgery [1,12,24,27]. In the present study only patients who were seizure free after surgery were included, and we were able to demonstrate improvement in language functions in 31% of our patients, albeit their language abilities were delayed compared to healthy children. In general progress in language development was slow, requiring that the observation time be long enough to detect any small steps of improvement. In our study the post-operative observation time extended to 12 years. However, since factors other than surgery might also influence language development following surgery, thereby biasing our result, we investigated additional predictors for positive long-term language outcome. We found a significant increase in LQ in patients with shorter duration of epilepsy (p = 0.004). Other reports have previously found that a shorter period of overt seizures might be positive for better general developmental progress [2,12,24,27], which also holds true for language abilities [8,9,16]. Additionally, our results corroborate the finding that children who were off medication after surgery showed significantly better language outcomes (p = 0.003). Similarly, children who had AED withdrawal after successful surgery showed better psychomotor development than those on AED treatment [5,19,32]. In our study children who were older than 4 years at surgery showed a higher increase of post-operative LQ compared to those operated at an earlier age (p = 0.011). This result appeared counterintuitive, since language acquisition in healthy children, including attaining native accents in foreign languages, takes place very early. We argue that the reason for our finding was that precisely those children undergoing surgery at a later age were afflicted by acquired pathologies, with milder seizure loads thereby delaying carer consent for surgery. On the other hand, surgical intervention would have taken place a great deal earlier for children with developmental pathologies, since parent consent would have been more forthcoming due to child morbidity and care burden [1,9,24,27,29,30]. In our study we found that epileptic discharges in the contralateral hemisphere recorded after surgery seemed to be
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significant predictors of long-term language outcome (p = 0.025). Indeed, even seizure-free children with remaining interictal discharges in the contralateral hemisphere showed smaller increases in post-operative LQ and therefore less favourable language outcomes than those without such alterations. In our study group, children with pathological sleep patterns prior to surgery and normalization thereafter showed a significantly higher gain in LQ (p = 0.043) than children with normal preand post-surgical sleep patterns. In this respect, altered sleep patterns have been described for patients with Landau–Kleffner Syndrome, who suffer from electrical status epilepticus during sleep (ESES) in combination with severe language retardation. However, patients with unilateral brain lesions may also develop ESES and, therefore, might benefit from disconnective surgery [3,23]. Pre- to post-surgical change in language function was not associated with the side of surgery. This finding is congruent with other studies and may be due to brain plasticity and both pre- and post-surgical compensatory mechanisms in infants and young children [9,16,22]. 5. Conclusion Vertical perithalamic hemispherotomy leads to seizure freedom in a high number of patients, and also significantly improves language development in these patients, especially in children with short disease duration prior to surgery, those with acquired pathologies and provided that AEDs can be successfully withdrawn. 5.1. Study strengths and limitations Although data collection was prospective and, in a structured manner, the design was that of a retrospective cross sectional observational study. In addition, the number of patients evaluated was low and inhomogeneous with respect to clinical variables (i.e. age at surgery, underlying pathology, etc.). Improvement in language development after surgery is reported by many parents, but quantification with standardized neuropsychological tests is difficult. However, special psychological screening methods for severely handicapped children and adolescents currently do not exist [1,31]. In this study, LQ was calculated based on the language scores of two standardized methods (Denver Scales II and the German Version of the Wechsler Intelligence Scales), which made results comparable between and within subjects. These tests might not be the ideal methods, but most children included in this study were severely handicapped and their language performance was poor. Additionally, no tool for measuring the impact of rehabilitation on the language development exists. The strength of our study was the relatively long observation time after surgery (median 3.0 years; range 1–12 years), which facilitated the detection of developmental progress even when it was slow. Conflict of interest The authors have stated that they had no interests, which might be perceived as posing a conflict or bias. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Acknowledgments The work of A. Mu¨hlebner-Fahrngruber and G. Gro¨ppel was supported by the Anniversary Fund of the Central Bank of the ¨ NB-12036 dedicated to M. Feucht: Republic of Austria (O
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