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Anterior corpus callosotomy in school-aged children with Lennox–Gastaut syndrome: A prospective study
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 4 ) 1 e7
Official Journal of the European Paediatric Neurology Society
Original Article
Anterior corpus callosotomy in school-aged children with LennoxeGastaut syndrome: A prospective study Shuli Liang a,*, Shaohui Zhang b, Xiaohong Hu c, Zhiwen Zhang d, Xiangping Fu d, Hong Jiang e, Yu Xiaoman b a
Department of Neurosurgery, Capital Epilepsy Therapy Center, First Affiliated Hospital of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China b Capital Epilepsy Therapy Center, First Affiliated Hospital of PLA General Hospital, Beijing, China c Department of Pediatrics, First Affiliated Hospital of PLA General Hospital, Beijing, China d Department of Neurosurgery, First Affiliated Hospital of PLA General Hospital, Beijing, China e Department of Psychology, First Affiliated Hospital of PLA General Hospital, Beijing, China
article info
abstract
Article history:
Aims: To compare outcomes of anterior corpus callosotomy (CCT) with anti-epileptic drugs
Received 7 October 2013
(AEDs) treatment in school-aged children with LennoxeGastaut syndrome (LGS).
Received in revised form
Methods: Sixty school-aged children with LGS were prospectively enrolled and divided into
11 March 2014
either the medicine or surgery group according the choice of the patients' caregivers. Cases
Accepted 10 May 2014
in the medicine group were treated with multiple rational AEDs and patients in the surgery
Available online xxx
group underwent anterior CCT. Seizure control at 1e5 years after enrollment and changes of intelligence quotient (IQ) and quality of life (QOL) from pre-treatment to the 2-year
Keywords:
follow-up were compared between the two groups.
Anterior corpus callosotomy
Results: The percentages of patients who were totally seizure-free in the surgery group were
Anti-epilepsy drugs
17.4% at the 1-year follow-up, 13.0% at the 2-year follow-up and 8.7% at the 5-year follow
Epileptic surgery
up, and the data for patients in the medicine group were 2.9%, 5.9% and 2.9%, respectively.
LennoxeGastaut syndrome
Significant differences were found in total seizure control between the two groups at 1, 2, and 5-year follow-up (personal c2 test). Significant differences were found in mean changes of IQ and overall QOL between the medicine and surgery groups at the 2-year follow-up, showing positive results for the surgery group, but these changes were not related to postoperative outcomes of seizure control (t-test). Conclusion: Anterior CCT is a promising treatment for school-aged children with LGS, and can present marked seizure control and improvement in QOL and IQ, all of which were significantly better than the effects of treatment with multiple AEDs. © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Department of Neurosurgery, First Affiliated Hospital of PLA General Hospital, No. 51, Fucheng Road, Beijing 100048, China. Tel.: þ86 10 68989063. E-mail address: [email protected] (S. Liang). http://dx.doi.org/10.1016/j.ejpn.2014.05.004 1090-3798/© 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Liang S, et al., Anterior corpus callosotomy in school-aged children with LennoxeGastaut syndrome: A prospective study, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.05.004
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1.
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 4 ) 1 e7
Introduction
LennoxeGastaut syndrome (LGS) is one of the most common types of epileptic encephalopathy in childhood and adolescence, and prevalence rates vary widely, having been reported to comprise between 1 and 10% of all childhood epilepsies. LGS is an intractable form of epilepsy with multiple seizure attack types. It begins in childhood, and seldom responds to any of the current anti-epilepsy drugs.1 Cognitive stagnation and behavioral problems are seen in almost all patients with LGS and lead to a life of dependency. It is reported that complete or partial neurological and neuropsychological function of patients with epileptic encephalopathy can be recovered after seizure frequency decreases or stops altogether.2 Reports have recently been published on surgical operations to ameliorate LGS. The results of those operations were promising, and showed obvious seizure reduction and exciting cognitive improvement.1,3,4 LGS has a very heterogeneous etiology. Previous research has confirmed that some focal lesions, such as hypothalamic hamartoma and cortical dysplasia, were epileptogenic foci of LGS, and total resection of those lesions could render freedom from seizures.4e6 However, even comprehensive preoperative assessments were unable to localize the epileptogenic foci in most of the patients with LGS, including high-resolution magnetic resonance imaging (MRI), positron emission tomography, longterm video-electroencephalography (EEG) and exhaustive seizure semiology analysis. Corpus callosotomy (CCT), which incorporates anterior CCT, posterior CCT and one-stage or two-stage total CCT,7 is a classic approach for patients with LGS without focal lesion.1,8 Nevertheless, CCT has typically been the last choice for treating patients with LGS. Until recently, before CCT was taken into consideration, all kinds of multiple anti-epilepsy drugs (AEDs) and pharmaceutical management would be repeatedly attempted for a long period of time, despite of poor results. Childhood is a critical period in which the compensatory mechanisms of the brain are highly functional and frequent epileptic seizures provide more detrimental effects on maturating brains in childhood than in adult brains. After this age, cerebral impairment caused by recurrent epileptic attacks on the developing brain would be permanent, even if the attacks were controlled after the critical period.9,10 Therefore, early surgical intervention in children with intractable epilepsy could prevent or mitigate longterm impairment on intelligence due to seizure attack, reduce unfavorable effects of frequent seizures on cognition, as well as psychological and behavioral problems, and bypass permanent neuropsychological complications.5,11 Although it has been reported that total CCT was more effective,12,13 anterior CCT has still been used in many studies because of its high efficacy and lower risk.3,14,15 Another important consideration for the use of anterior CCT is that it seldom has complications, in contrast to total CCT.16 Finally, two-stage total CCT can be considered when patients fail to respond to the anterior method and it is safer than one-stage CCT.12,13 However, prospective trials studying the therapeutic outcome of school-aged children with LGS after CCT vs. treatment with multiple AEDs are scarce. We therefore designed a prospective uncontrolled trial for CCT in primary
school-aged children with LGS, in order to study the effects of early surgical intervention.
2.
Patients and methods
2.1.
Patients
The trial commenced in September 2004 and ended in March 2007 (Fig. 1). Sixty primary school-aged children with LGS were enrolled the study by the multidisciplinary specialist team of the Capital Epilepsy Therapy Center in Beijing, according to the criteria listed in Table 1. The patients were divided into medicine and surgery groups, by the choice of the patients and caregivers, after doctors explained the aims of the trial with their families and discussed the different therapeutic approaches. Final results were compiled in February 2012. The ethics committee of the First Affiliated Hospital of PLA General Hospital approved this prospective investigation in March 2004.
2.2.
Preoperative assessment
Pre-operative evaluations included neurological examination, long-term Video-EEG recording, MRI, 2-deoxy-2[18F] fluoro-Dglucose positron emission tomography and a neuropsychological test. Scalp video-EEG was recorded with a 64-channel video recorder, and the recordings were taken after gradual withdrawal of AEDs. There were at least five seizures recorded by video-EEG. The MRI scan included axial T1, T2, fluid attenuation inversion recovery and diffusion weighted imaging, sagittal T1-weighted imaging and coronal T2 and fluid attenuation inversion recovery imaging. PET scan examination was performed after the patient had fasted for 12 h, dieted for 24 h and been seizure-free for 24 h. Neuropsychological tests (by J.H. and Y.X.) included full-scale IQ, verbal IQ and performance IQ assessments on the Wechsler Child Intelligence Scale (Chinese Revision) (WCIS-CR), and overall subscale of QOL in the epilepsy inventory-31 (QOLIE-31), and were performed by patients with the help of caregivers. Baselines included full-scale IQ, verbal IQ and performance IQ and overall QOL scores of patients in the 3 months before surgery, as well as seizure frequency during the 6-month preoperative Children with LGS (n=95)
Enrolled Patients with LGS (n=60)
Anterior corpus callosotomy (n=23)
Rational multiple AEDs therapy (n=37)
5 years follow-up in surgery group (n=23)
5 years follow-up in medicine group (n=34)
35 patients exclude for: -Age (11) -Decline to study (7) -Decline to therapy (6) -LGS diagnosis criteria not met (6) -Focal lesion on MRI image (5)
3 patients droppe out: -Accepted surgery (1)
-Changed AEDs in the first year for disappointed in seizure control (2)
Fig. 1 e Consort flow diagram. AEDs ¼ anti-epilepsy drugs; LGS ¼ LennoxeGastaut syndrome.
Please cite this article in press as: Liang S, et al., Anterior corpus callosotomy in school-aged children with LennoxeGastaut syndrome: A prospective study, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.05.004
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Table 1 e Inclusion criteria. (1) Male or female patients, 6e12 years old at surgery. (2) Age at first seizure onset: 2e10 years. (3) Patients who had their epilepsy treated by more than three types of anti-epilepsy drugs for at least 2 years with no response or poor response. (4) Patients who had multiple type seizure attacks, including over 12 tonic or atonic seizures in last 3-month. (5) Patients whose recent EEG showing a slow background, bursts of slow spike-and-wave in interictal period, paroxysmal bursts of fast rhythm during sleeping, and generalized or diffusive epileptiform discharge during ictal period [121]. (6) Patient who can perform IQ, and QOL test. (7) Patient whose MRI revealed diffusive abnormality or normal image, without focal lesion. (8) Positron emission tomography image revealed hypometabolism or normal. (9) Patients that were not candidates for respective surgery. (10) Patient who was not included into another research group.15 (11) Patients who were able to follow the investigational study procedures and whose family members were willing to give written consent for the study.
period. Epilepsy classification was made according to the official document of the ILAE from 1989, and was based on findings from MRI, video-EEG recording and detailed description of seizure semiology from patients and caregivers.
2.3.
Surgical methods
Each patient in the surgical group was placed in a supine position. A “U”-type right frontal incision was made anterior to the coronal suture and mesial edge, adjacent to the sagittal sinus. The anterior extent of dissection was defined by the dorsal surface of the anterior cerebral arteries, as well as the anterior commissure. The posterior border was the thinning seen at the junction of the posterior body and the splenium and the apposition of the fornices to the ventral aspect of the posterior corpus callosum. The corpus callosum was disconnected until the ependyma was visible. It was important to extend the resection through all commissural fibers to ensure surgical efficacy. Furthermore, in order to reduce complications, veins draining to the superior and inferior sagittal sinuses and branches of pericallosal artery were preserved. The distance of the section was 5e7 cm, according to age, or approximately two thirds of the corpus callosum. The anterior commissure and hippocampal commissure were spared.7 Post-surgery MRI scans were performed to confirm the extent of CCT in all patients in surgery group.
2.4.
Medicinal treatments
All of the medicinal therapeutic programs for each patient were created by members of the research team, and the numbers of AEDs were recorded. For at least the first year after the operation, the patients in the surgery group took the same anti-epileptic drugs as preoperative patients. Levetiracetam, valproate, topiramate and lamotrigine were the most common AEDs in both the medicine and surgical groups, and levetiracetam (May, 2006 to March, 2007) or topiramate (September, 2004 to April, 2006), adjunctive to valproate were the most common medicinal therapeutic programs for the two groups.
2.5.
Follow-up
All children were followed up for 5 years, and completed 1, 2 and 5-year follow-up visits in the hospital, as well as a
telephone visit every 3e6 months. Also, a seizure log, including seizure frequency, seizure type, numbers of AEDs, medicinal side effects and surgical complications were recorded by both the patient and the caregiver, who had been instructed by doctors. Post-treatment assessments included changes in IQ and overall QOL, reduction in seizure frequency and surgical complications. Improvement was defined as post-treatment to pretreatment changes of IQ and QOL over than 10% of pre-treatment scores, and decrease was defined as the changes less than 10% f pre-treatment scores. Seizure reduction was based on the number of seizures during the preceding 6 months, at the 1, 2 and 5-year follow-up visits. Because CCT is essentially a palliative procedure, seldom providing the patient seizure freedom, the Engel classification for seizure outcome is less applicable. Therefore, outcomes of overall seizure control were divided into 3 classes: seizurefree (no seizure in the last year, with or without auras), S50% reduction and <50% reduction in overall seizures. Surgical complications were described as transient or permanent. A nurse in the hospital recorded transient complications and permanent complications were registered by caregivers.
2.6.
Statistical analysis
Statistical analyses were performed with the SPSS statistical program (version 11.0; SPSS, Inc., Chicago, Ill., USA). The outcomes were described by percentages, means and standard deviations. Quantitative data were analyzed using either an F-test or t-test. Qualitative data were analyzed by a personal c2 or KruskaleWallis test. The KruskaleWallis and F tests were adopted for analysis of variance among over 2 groups. Results were considered significant for values of p < 0.05.
3.
Results
3.1.
Pretreatment data
This cohort included 60 children: 23 (M:F ¼ 16:7) in the surgery group and 37 (M:F ¼ 22:15) in the medicine group. The demographic and clinical characteristics of the two groups are summarized in Table 2. Each child experienced two or more types of seizures and tonic seizures (or atonic seizures) were
Please cite this article in press as: Liang S, et al., Anterior corpus callosotomy in school-aged children with LennoxeGastaut syndrome: A prospective study, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.05.004
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Table 2 e Children's demographical and clinical characteristics. Characteristics Age at first seizure History of seizure Age at enrolled Full scale IQ Abnormal MRI Abnormal PET Number of AEDs in last 1-month Seizure times in last 1-month Seizure types in last 6 months Tonic or atonic seizure Atypical absence seizure Toniceclonic seizure Clonic seizure Myoclonic seizure
Surgery group Medicine group P value (n ¼ 23) (n ¼ 37) 5.13 ± 1.68 4.35 ± 2.08 9.48 ± 2.21 56.09 ± 10.27 7 (30.4%) 11 (47.8%) 2.96 ± 0.93
5.43 ± 1.92 4.30 ± 2.16 9.73 ± 2.39 55.32 ± 10.14 8 (21.6%) 16 (43.2%) 2.76 ± 0.93
0.5420 0.9299 0.6868 0.7770 0.6456 0.9632 0.4291
92.52 ± 14.35
86.11 ± 14.19
0.0957
23 (100%)
37 (100%)
1.0000
21 (91.3%)
32 (86.5%)
0.8795
16 (69.6%)
23 (62.2%)
0.7595
7 (30.4%) 6 (26.0%)
10 (27.0%) 18 (48.6%)
0.9922 0.1434
found in 100% of the 60 children, and were the most frequent seizure type. There were 10 (43.5%) children with moderate mental retardation (full scale IQ < 50) in the surgery group and 14 (37.8%) cases in the medicine group. Significant differences were not found in age at first seizure, age at surgery, pretreatment full scale IQ, percentage of abnormal MRI, percentage of male patients, mean number of AEDs or seizure type distribution between the surgery and medicine groups.
3.2.
Seizure control
All of the 23 patients from the surgery group and 34 cases from the medical group finished the 5 years of follow-up appointments (Fig. 1). One child underwent an operation after 3 years of medical therapy and 2 of the patients dropped out due to disappointment in seizure control. Therefore, 57 children were included in the post-treatment analysis. The seizure outcomes are shown in Figs. 2 and 3. When all types of seizures are considered as a whole, the percentage of patients who were seizure-free in the surgery group was 17.4% at the 1-year follow-up, 13.0% at the 2-year follow-up and 8.7% at 5 years Those percentages were 2.9%,
5.9% and 2.9%, respectively, for the medicine group. The best seizure control was seen in children from the surgery group at 1-year post-procedure; 87% of this group reached at least 50% seizure reduction. Significant differences were found in overall seizure control between the two groups at 1-year, 2 years, and 5 years. While seizure control was seen in every type of seizure, the greatest seizure reduction was seen in tonic seizures, with an 81% reduction at 1-year, 77% at 2 years and 75% at 5 years after operation in the surgery group. The smallest seizure reduction in the surgery group was seen with myoclonic seizures, which showed a 42% reduction at 1-year, 40% at 2 years and 39% at 5 years after surgery. Significant differences were not found in seizure reduction of any type of seizure between the 3 periods of follow-up in the surgery group. However, significant differences were found between groups in seizure control of tonic, tonic-clonic and atypical absence seizure at all of three follow-ups, clonic seizures at 1 and 2 years follow-up (P < 0.01) and myoclonic seizures at 1-year follow-up (P < 0.05).
3.3.
IQ and QOL
IQ and overall QOL tests were performed in all of the 57 cases at the 2-year follow-up appointment. Each child was grouped into one of the three categories (improvement, unchanged or impairment), based on the score change from the pretreatment scores of full scale IQ and overall QOL, when compared with the scores at the 2-year follow-up. Full scale IQ improvement was present in 10 (43.5%) cases from the surgery group and 2 (5.9%) children from the medicine group. A decline in IQ was seen in 2 (8.7%) patients from the surgery group and 13 (38.2%) cases in the medical therapy group. Overall QOL improvement showed in 13 (60.9%) children in the surgery group and 2 (5.9%) cases from the medicine group, and changes of overall QOL were grouped into impairment in 1 boy (4.3%) from the surgery group and 15 children (44.1%) from the medicine group. The significant differences between the two groups were found in the change of overall QOL and full scale IQ. When the mean changes of IQ and overall QOL were compared for the different groups, from pretreatment scores to the 2-year follow up assessment (see Table 3), significant differences were found in full scale IQ, verbal IQ, performance IQ and overall QOL (P < 0.01). Additionally, the change in the surgery group presented positive outcomes. In the surgery group, preoperative full scale IQ, postoperative seizure control and age at enrollment had no effects on the mean changes of
Fig. 2 e Overall seizure reduction in surgery group and medicine group.
Please cite this article in press as: Liang S, et al., Anterior corpus callosotomy in school-aged children with LennoxeGastaut syndrome: A prospective study, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.05.004
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Fig. 3 e Reductions of different types of seizures in two groups at 1FU, 2FU and 5FU.
full scale IQ, verbal IQ, performance IQ and overall QOL. However, significant differences were found in mean changes of full scale IQ, verbal IQ, performance IQ and overall QOL between children with at least 50% seizure reduction and those with less than 50% seizure reduction (P < 0.01) in the medicine group. Also, the children who were less than 10 years old at enrollment and those with less than 50% seizure reduction presented mean performance IQ impairment after 2 years of treatment with anti-seizure drugs.
3.4.
AEDs among before operation,2 years and 5 years after operation (Table 4).
3.5.
Complications in surgery group
There was no postoperative death or development of permanent complications in any of the children in the surgery group. Transient complications appeared in 4 patients, including two cases of urinary incontinence, 1 case of aphasia and 1 cases of apraxia.
Numbers of AEDs
The preoperative patients in surgery group took most numbers of AEDs, and the number was 2.96 ± 0.93. Significant differences were not found in number of AEDs between surgery group and medicine group before operation and 2 or 5 years after operation. Furthermore, neither surgery group nor medicine group, there was significant difference in number of
4.
Discussion
To the best of our knowledge, this paper reports on the first prospective study on anterior CCT in school-aged children with LGS. Percentages of patients who were seizure free and who experienced >50% reduction in seizure frequency
Table 3 e Means changes of IQ and overall QOL at 2 years follow-up. Factors
Full scale IQ Baseline
Total surgery group Seizure reduction S50% (n ¼ 16) <50% (n ¼ 7) Pre-operative IQ S50 (n ¼ 16) <50 (n ¼ 7) Age at enrolled S10 (n ¼ 11) <10 (n ¼ 12) Total medicine group Seizure reduction S50% (n ¼ 11) <50% (n ¼ 23) Pre-treatment IQ S50 (n ¼ 22) <50 (n ¼ 12) Age at enrolled S10 yrs (n ¼ 19) <10 yrs (n ¼ 15)
Verbal IQ a
Change
Baseline
Performance IQ a
Change
Baseline
Overall QOL a
Change
Baseline
Changea
56.09
5.13##
57.00
3.26##
56.17
7.13b##
44.78
6.26b##
56.50 55.14
5.44 4.43
57.63 55.57
3.25 3.29
56.38 55.71
7.69b 5.86b
44.56 45.29
6.19b 6.43b
61.69 43.29
4.88 5.71b
64.00 41.00
3.06 4.00
60.38 46.57
6.88 7.43
47.63 36.29
5.63b 8.00b
55.00 57.05
3.82 6.33b
55.64 58.25
2.18 4.25
55.55 56.75
5.64 8.50b
44.55 45.00
4.18 8.17b
55.32
3.56
55.38
3.12
56.76
4.02
43.44
2.71
57.69 54.54
0.64** 5.59
56.60 54.81
0.55** 4.87
60.20 55.13
0.73** 6.32b
45.50 42.58
0.73** 4.35
61.68 44.33
3.09 4.42
60.64 45.75
2.59 4.08
63.77 49.32
3.64 4.75
47.68 35.67
2.64 2.83
53.95 57.6
2.26 5.20
53.74 57.47
2.47 3.93
55.26 58.67
2.11* 6.47b
42.95 44.07
1.84 3.80
##
P < 0.01 mean change in surgery group VS. mean change in medicine group at 2 years follow-up. *P < 0.05, **P < 0.01, Change in this group versus change in the other group. a Change from baseline to 2-year follow-up visit (score for 2FU minus baseline score). b Change from baseline to 2-year follow-up visit >10% of baseline score.
Please cite this article in press as: Liang S, et al., Anterior corpus callosotomy in school-aged children with LennoxeGastaut syndrome: A prospective study, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.05.004
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Table 4 e Mean numbers of AEDs in surgery group and medicine group. Time Pre-operation 2 years follow-up 5 years follow-up
Surgery group (n ¼ 23)
Medicine group (n ¼ 34)
P value
2.96 ± 0.93 2.57 ± 0.90 2.52 ± 0.67
2.71 ± 0.87 2.68 ± 0.98 2.76 ± 1.05
0.3059 0.6693 0.3366
reached 17.4% and 87%, respectively, in the surgery group at 1year after CCT. The seizure control in the group was significantly better than for those under multiple AEDs treatments at the 1e5 year follow-ups. When each type of seizure was compared, CCT demonstrated good control for tonic seizure, tonic-clonic seizure and atypical absence seizure. Therefore, we point that school-aged children with LGS, whose main types of seizures were tonic/atonic and tonic-clonic, would be excellent first candidates for CCT. LGS is a well-known epileptic encephalopathy, and over 40% of patients present moderate to severe mental retardation, in which frequent epileptic seizures and epileptiform discharges play an important role.1,17,18 At the same time, childhood, though a short period of time, is a very key stage in the development of intelligence and recognition. Therefore, freedom from seizures or good seizure control in childhood is ultimately very important to intelligence and recognition levels in adult patients with LGS.19,20 In our cohort, full scale IQ and overall QOL improved in 44% and 61%, of patients, respectively, 2 years after anterior CCT. These findings align with previous reports,14,21,22 and were substantially higher than the changes in patients who received only medicinal treatment. Thereby, once no-lesion LGS is diagnosed in school-aged children, anterior CCT should been taken into account before the child becomes an adult and time is wasted trying, adjusting and readjusting AEDs, to prevent the loss of invaluable time for brain development. The anti-epileptic drugs given to the surgery group in this study did not change in the first year after operation, and there was no significant difference in the numbers of AEDs in between pre-operative time and 2 or 5 years after operation in surgery group. At the same time, we found that postoperative improvement of IQ and QOL was not related to postoperative seizure control or preoperative full scale IQ level. Therefore, these improvements should be caused by the surgical blockage of abnormal electrical activity dissemination between bilateral hemispheres, due to the corpus callosotomy. By removing the means of signaling, the overexcited activity related to abnormal behavior or emotions is inhibited and, consequently, the suppressed normal nerve signal conductions are restored.15,23e25 Concurrently, children experience superior brain plasticity and increased opportunities for special education after surgery, as compared with an adult.26 Furthermore, the improvements in patients with mental retardation were related to a high incidence of motor and behavioral problems, as well as more attention from caregivers to patients in order to improve these problems, which would greatly alleviate their burden. As a conceptual framework for treating patients with LGS, the purpose of treatment with CCT is not only the control of seizures, but also the
opportunity for more normal intellectual development and quality of life.9,27 Anterior CCT in these specific patients meets these needs. Vagus nerve stimulation, anterior CCT and one- or twostage total CCT have all been reported in the treatment of LGS and other generalized epilepsy.12,22,28 Although callosotomy is an intracranial procedure, compared to stimulation of the vagus nerve, which is an extracranial procedure, we preferred anterior CCT to vagus nerve stimulation. The three reasons are as follows: first, CCT was more effective in reducing seizure frequency than vagus nerve stimulation,13,22,29 secondly, vagus nerve stimulation is much more expensive than anterior CCT and, third, anterior CCT has the same rare permanent surgical complications as vagus nerve stimulation.13 Anterior CCT, but not total CCT, was used in this cohort because of its high efficacy and safety.15 The genu of the corpus callosum connects mainly the prefrontal, premotor and motor cortex which are areas with particularly rich interhemispheric connections representing the majority of fibers. The anterior body of callosum connects additional and frontal and parietal areas. Therefore, anterior CCT disconnects the majority of fibers. At the same time, anterior CCT has fewer complications than total CCT. Lastly, two-stage total CCT can always be considered for patients who fail anterior CCT, and will be safer than one-stage total CCT.15
4.1.
Study limitations
It was a prospective study to compare outcomes of anterior CCT with AEDs in school-aged children with LGS. However, because of its limited design, the patients didn't be divided into surgery group and medicine group randomly, but according the choice of the patients' caregivers. In addition, it is of note that neural plasticity in childhood can work to the disadvantage of the patient, in that epilepsy may find new pathways to spread in the brain after anterior CCT. Therefore, an even longer follow-up is necessitated to fully demonstrate the advantages of anterior callosotomy over medical management in children with LGS.
5.
Conclusion:
Anterior CCT confers an obvious reduction in seizure frequency and improvement in overall QOL and IQ in schoolaged children with LGS, which were significantly better than multiple drug therapy. Additionally, the procedure proved to be quite safe for the children in this study. Therefore, anterior CCT could be performed for carefully selected primary schoolaged children with LGS, before the trial and failure of all antiepileptic drugs.
Disclosure None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Please cite this article in press as: Liang S, et al., Anterior corpus callosotomy in school-aged children with LennoxeGastaut syndrome: A prospective study, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.05.004
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Fund This research was funded by Beijing Technology & Science New-star Training Project (2010B084).
Acknowledgments The authors would like to show gratitude to the patients and their families for their long-term cooperation. We also appreciate the contribution provided by the following people: Dr SB Yao from the Neurosurgery Department; and Dr SS Liang, Dr. YJ Sun and all technicians in the Neurophysiologic Laboratory of Capital Epilepsy Therapy Center.
references
1. Camfield PR. Definition and natural history of Lennox-Gastaut syndrome. Epilepsia 2011;52:S3e9. 2. Teutonico F, Mai R, Devinsky O, Lo Russo G, Weiner HL, Borrelli P, Balottin U, Veggiotti P. Epilepsy surgery in tuberous sclerosis complex: early predictive elements and outcome. Childs Nerv Syst 2008;24:1437e45. 3. Lassonde M, Sauerwein C. Neuropsychological outcome of corpus callosotomy in children and adolescents. J Neurosurg Sci 1997;41:67e73. 4. Lee YJ, Kang HC, Lee JS, Kim SH, Kim DS, Shim KW, Lee YH, Kim TS, Kim HD. Resective padiatric epilepsy surgery in Lennox-Gastaut Syndrome. Pediatrics 2010;125:58e66. 5. Ng YT, Hastriter EV, Wethe J, Chapman KE, Prenger EC, Prigatano GP, Oppenheim T, Varland M, Rekate HL, Kerrigan JF. Surgical resection of hypothalamic hamartomas for severe behavioral symptoms. Epilepsy Behav 2011;20:75e8. 6. You SJ, Lee JK, Ko TS. Epilepsy surgery in a patient with Lennox-Gastaut syndrome and cortical dysplasia. Brain Dev 2007;29:167e70. 7. Asadi-Pooya AA, Sharan A, Nei M, Sperling MR. Corpus callosotomy. Epilepsy Behav 2007;13:271e8. 8. Harvey S, Cross JH, Shinnar S, Mathern BW, ILAE Pediatric Epilepsy Surgery Survey Taskforce. Defining the spectrum of international practice in pediatric epilepsy surgery patients. Epilepsia 2008;49:146e55. 9. Hermann B, Seidenber M. Epilepsy and cognition. Epilepsy Curr 2007;7:1e6. 10. Oguni H, Mukahira K, Tanaka T, Awaya Y, Saito K, Shimizu H, Oda M, Arai N, Suzuki I, Osawa M. Surgical indication for refractory childhood epilepsy. Epilepsia 2000;41:S21e5. 11. van Empelen R, Helders PJ, van Rijen PC, JennekensSchinkel A, van Nieuwenhuizen O. No deterioration in epilepsy and motor function in children with medically intractable epilepsy ineligible for surgery. Dev Med Child Neurol 2007;49:214e8.
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12. Spencer SS, Spencer DD, Sass K, Westerveld M, Katz A, Mattson R. Anterior, total, and two-stage corpus callosum section: differential and incremental seizure responses. Epilepsia 1993;34:561e7. 13. Rathore C, Abraham M, Rao RM, George A, Sankara Sarma P, Radhakrishnan K. Outcome after corpus callosotomy in children with injurious drop attacks and severe mental retardation. Brain Dev 2007;29:577e85. 14. Yang TF, Wong TT, Kwan SY, Chang KP, Lee YC, Hsu TC. Quality of life and life satisfaction in families after a child has undergone corpus callosotomy. Epilepsia 1996;37:76e80. 15. Liang SL, Li AM, Jiang H, Meng XL, Zhao M, Zhang JW, Sun YJ. Anterior corpus callosotomy in patients with intractable generalized epilepsy and mental retardation. Stereotact Funct Neurosurg 2010;88:246e52. 16. Gleissner U, Johanson K, Helmstaedter C, Elger CF. Surgical outcome in a group of low-IQ patients with focal epilepsy. Epilepsia 1999;40:553e9. 17. Crumrine PK. Management of seizures in Lennox-Gastaut syndrome. Paediatr Drugs 2011;13:107e18. 18. Montouris GD. Rational approach to treatment options for Lennox-Gastaut syndrome. Epilepsia 2011;52:S10e20. 19. Francione S, Vigliano P, Tassi L, Cardinale F, Mai R, Lo Russo G, Munari C. Surgery for drug resistant partial epilepsy in children with focal cortical dysplasia: anatomicaleclinical correlations and neurophysiological data in 10 patients. J Neurol Neurosurg Psychiatr 2003;74:1493e501. 20. Duchowny M. Epilepsy surgery in the first three years of life. Epilepsia 1998;39:717e43. 21. Maehara T, Shimizu H. Surgical outcome of corpus callosotomy in patients with drop attacks. Epilepsia 2001;42:67e71. 22. Cukiert A, Burattini JA, Mariani PP, Cukiert CM, ArgentoniBaldochi M, Baise-Zung C, Forster CR, Mello VA. Outcome after extended callosal section in patients with primary idiopathic generalized epilepsy. Epilepsia 2008;49:1e4. 23. Ono T, Fujimura K, Yoshida S, Ono K. Suppressive effect of callosotomy on epileptic seizures is due to the blockade of enhancement of cortical reactivity by transcallosal volleys. Epilepsy Res 2002;51:117e21. 24. Kanner AM. Psychiatric comorbidity in children with epilepsy, or is it: epilepsy comorbidity in children with psychiatric disorders. Epilepsy Curr 2008;8:10e2. 25. Iimura Y, Sugano H, Nakajima M, Arai H. Stepwise synchronization through the corpus callosum is one cause of myoclonic jerks. World Neurosurg 2012;77:399.E5e8. 26. Johnston MV. Clinical disorders of brain plasticity. Brain Dev 2004;26:73e80. 27. Shields WD. Catastrophic epilepsy in childhood. Epilepsia 2000;41:S2e6. 28. Ardesch JJ, Buschman HPJ, Wagener-Schimmel LJ, van der Aa HE, Hageman G. Vagus nerve stimulation for medically refractory epilepsy: a long-term follow-up study. Seizure 2007;16:579e85. 29. Nei M, O'Connor M, Liporace J, Sperling MR. Refractory generalized seizures: response to corpus callosotomy and vagal nerve stimulation. Epilepsia 2006;47:115e22.
Please cite this article in press as: Liang S, et al., Anterior corpus callosotomy in school-aged children with LennoxeGastaut syndrome: A prospective study, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.05.004
Official Journal of the European Paediatric Neurology Society
Original Article
Anterior corpus callosotomy in school-aged children with LennoxeGastaut syndrome: A prospective study Shuli Liang a,*, Shaohui Zhang b, Xiaohong Hu c, Zhiwen Zhang d, Xiangping Fu d, Hong Jiang e, Yu Xiaoman b a
Department of Neurosurgery, Capital Epilepsy Therapy Center, First Affiliated Hospital of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China b Capital Epilepsy Therapy Center, First Affiliated Hospital of PLA General Hospital, Beijing, China c Department of Pediatrics, First Affiliated Hospital of PLA General Hospital, Beijing, China d Department of Neurosurgery, First Affiliated Hospital of PLA General Hospital, Beijing, China e Department of Psychology, First Affiliated Hospital of PLA General Hospital, Beijing, China
article info
abstract
Article history:
Aims: To compare outcomes of anterior corpus callosotomy (CCT) with anti-epileptic drugs
Received 7 October 2013
(AEDs) treatment in school-aged children with LennoxeGastaut syndrome (LGS).
Received in revised form
Methods: Sixty school-aged children with LGS were prospectively enrolled and divided into
11 March 2014
either the medicine or surgery group according the choice of the patients' caregivers. Cases
Accepted 10 May 2014
in the medicine group were treated with multiple rational AEDs and patients in the surgery
Available online xxx
group underwent anterior CCT. Seizure control at 1e5 years after enrollment and changes of intelligence quotient (IQ) and quality of life (QOL) from pre-treatment to the 2-year
Keywords:
follow-up were compared between the two groups.
Anterior corpus callosotomy
Results: The percentages of patients who were totally seizure-free in the surgery group were
Anti-epilepsy drugs
17.4% at the 1-year follow-up, 13.0% at the 2-year follow-up and 8.7% at the 5-year follow
Epileptic surgery
up, and the data for patients in the medicine group were 2.9%, 5.9% and 2.9%, respectively.
LennoxeGastaut syndrome
Significant differences were found in total seizure control between the two groups at 1, 2, and 5-year follow-up (personal c2 test). Significant differences were found in mean changes of IQ and overall QOL between the medicine and surgery groups at the 2-year follow-up, showing positive results for the surgery group, but these changes were not related to postoperative outcomes of seizure control (t-test). Conclusion: Anterior CCT is a promising treatment for school-aged children with LGS, and can present marked seizure control and improvement in QOL and IQ, all of which were significantly better than the effects of treatment with multiple AEDs. © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Department of Neurosurgery, First Affiliated Hospital of PLA General Hospital, No. 51, Fucheng Road, Beijing 100048, China. Tel.: þ86 10 68989063. E-mail address: [email protected] (S. Liang). http://dx.doi.org/10.1016/j.ejpn.2014.05.004 1090-3798/© 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Liang S, et al., Anterior corpus callosotomy in school-aged children with LennoxeGastaut syndrome: A prospective study, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.05.004
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1.
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Introduction
LennoxeGastaut syndrome (LGS) is one of the most common types of epileptic encephalopathy in childhood and adolescence, and prevalence rates vary widely, having been reported to comprise between 1 and 10% of all childhood epilepsies. LGS is an intractable form of epilepsy with multiple seizure attack types. It begins in childhood, and seldom responds to any of the current anti-epilepsy drugs.1 Cognitive stagnation and behavioral problems are seen in almost all patients with LGS and lead to a life of dependency. It is reported that complete or partial neurological and neuropsychological function of patients with epileptic encephalopathy can be recovered after seizure frequency decreases or stops altogether.2 Reports have recently been published on surgical operations to ameliorate LGS. The results of those operations were promising, and showed obvious seizure reduction and exciting cognitive improvement.1,3,4 LGS has a very heterogeneous etiology. Previous research has confirmed that some focal lesions, such as hypothalamic hamartoma and cortical dysplasia, were epileptogenic foci of LGS, and total resection of those lesions could render freedom from seizures.4e6 However, even comprehensive preoperative assessments were unable to localize the epileptogenic foci in most of the patients with LGS, including high-resolution magnetic resonance imaging (MRI), positron emission tomography, longterm video-electroencephalography (EEG) and exhaustive seizure semiology analysis. Corpus callosotomy (CCT), which incorporates anterior CCT, posterior CCT and one-stage or two-stage total CCT,7 is a classic approach for patients with LGS without focal lesion.1,8 Nevertheless, CCT has typically been the last choice for treating patients with LGS. Until recently, before CCT was taken into consideration, all kinds of multiple anti-epilepsy drugs (AEDs) and pharmaceutical management would be repeatedly attempted for a long period of time, despite of poor results. Childhood is a critical period in which the compensatory mechanisms of the brain are highly functional and frequent epileptic seizures provide more detrimental effects on maturating brains in childhood than in adult brains. After this age, cerebral impairment caused by recurrent epileptic attacks on the developing brain would be permanent, even if the attacks were controlled after the critical period.9,10 Therefore, early surgical intervention in children with intractable epilepsy could prevent or mitigate longterm impairment on intelligence due to seizure attack, reduce unfavorable effects of frequent seizures on cognition, as well as psychological and behavioral problems, and bypass permanent neuropsychological complications.5,11 Although it has been reported that total CCT was more effective,12,13 anterior CCT has still been used in many studies because of its high efficacy and lower risk.3,14,15 Another important consideration for the use of anterior CCT is that it seldom has complications, in contrast to total CCT.16 Finally, two-stage total CCT can be considered when patients fail to respond to the anterior method and it is safer than one-stage CCT.12,13 However, prospective trials studying the therapeutic outcome of school-aged children with LGS after CCT vs. treatment with multiple AEDs are scarce. We therefore designed a prospective uncontrolled trial for CCT in primary
school-aged children with LGS, in order to study the effects of early surgical intervention.
2.
Patients and methods
2.1.
Patients
The trial commenced in September 2004 and ended in March 2007 (Fig. 1). Sixty primary school-aged children with LGS were enrolled the study by the multidisciplinary specialist team of the Capital Epilepsy Therapy Center in Beijing, according to the criteria listed in Table 1. The patients were divided into medicine and surgery groups, by the choice of the patients and caregivers, after doctors explained the aims of the trial with their families and discussed the different therapeutic approaches. Final results were compiled in February 2012. The ethics committee of the First Affiliated Hospital of PLA General Hospital approved this prospective investigation in March 2004.
2.2.
Preoperative assessment
Pre-operative evaluations included neurological examination, long-term Video-EEG recording, MRI, 2-deoxy-2[18F] fluoro-Dglucose positron emission tomography and a neuropsychological test. Scalp video-EEG was recorded with a 64-channel video recorder, and the recordings were taken after gradual withdrawal of AEDs. There were at least five seizures recorded by video-EEG. The MRI scan included axial T1, T2, fluid attenuation inversion recovery and diffusion weighted imaging, sagittal T1-weighted imaging and coronal T2 and fluid attenuation inversion recovery imaging. PET scan examination was performed after the patient had fasted for 12 h, dieted for 24 h and been seizure-free for 24 h. Neuropsychological tests (by J.H. and Y.X.) included full-scale IQ, verbal IQ and performance IQ assessments on the Wechsler Child Intelligence Scale (Chinese Revision) (WCIS-CR), and overall subscale of QOL in the epilepsy inventory-31 (QOLIE-31), and were performed by patients with the help of caregivers. Baselines included full-scale IQ, verbal IQ and performance IQ and overall QOL scores of patients in the 3 months before surgery, as well as seizure frequency during the 6-month preoperative Children with LGS (n=95)
Enrolled Patients with LGS (n=60)
Anterior corpus callosotomy (n=23)
Rational multiple AEDs therapy (n=37)
5 years follow-up in surgery group (n=23)
5 years follow-up in medicine group (n=34)
35 patients exclude for: -Age (11) -Decline to study (7) -Decline to therapy (6) -LGS diagnosis criteria not met (6) -Focal lesion on MRI image (5)
3 patients droppe out: -Accepted surgery (1)
-Changed AEDs in the first year for disappointed in seizure control (2)
Fig. 1 e Consort flow diagram. AEDs ¼ anti-epilepsy drugs; LGS ¼ LennoxeGastaut syndrome.
Please cite this article in press as: Liang S, et al., Anterior corpus callosotomy in school-aged children with LennoxeGastaut syndrome: A prospective study, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.05.004
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 4 ) 1 e7
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Table 1 e Inclusion criteria. (1) Male or female patients, 6e12 years old at surgery. (2) Age at first seizure onset: 2e10 years. (3) Patients who had their epilepsy treated by more than three types of anti-epilepsy drugs for at least 2 years with no response or poor response. (4) Patients who had multiple type seizure attacks, including over 12 tonic or atonic seizures in last 3-month. (5) Patients whose recent EEG showing a slow background, bursts of slow spike-and-wave in interictal period, paroxysmal bursts of fast rhythm during sleeping, and generalized or diffusive epileptiform discharge during ictal period [121]. (6) Patient who can perform IQ, and QOL test. (7) Patient whose MRI revealed diffusive abnormality or normal image, without focal lesion. (8) Positron emission tomography image revealed hypometabolism or normal. (9) Patients that were not candidates for respective surgery. (10) Patient who was not included into another research group.15 (11) Patients who were able to follow the investigational study procedures and whose family members were willing to give written consent for the study.
period. Epilepsy classification was made according to the official document of the ILAE from 1989, and was based on findings from MRI, video-EEG recording and detailed description of seizure semiology from patients and caregivers.
2.3.
Surgical methods
Each patient in the surgical group was placed in a supine position. A “U”-type right frontal incision was made anterior to the coronal suture and mesial edge, adjacent to the sagittal sinus. The anterior extent of dissection was defined by the dorsal surface of the anterior cerebral arteries, as well as the anterior commissure. The posterior border was the thinning seen at the junction of the posterior body and the splenium and the apposition of the fornices to the ventral aspect of the posterior corpus callosum. The corpus callosum was disconnected until the ependyma was visible. It was important to extend the resection through all commissural fibers to ensure surgical efficacy. Furthermore, in order to reduce complications, veins draining to the superior and inferior sagittal sinuses and branches of pericallosal artery were preserved. The distance of the section was 5e7 cm, according to age, or approximately two thirds of the corpus callosum. The anterior commissure and hippocampal commissure were spared.7 Post-surgery MRI scans were performed to confirm the extent of CCT in all patients in surgery group.
2.4.
Medicinal treatments
All of the medicinal therapeutic programs for each patient were created by members of the research team, and the numbers of AEDs were recorded. For at least the first year after the operation, the patients in the surgery group took the same anti-epileptic drugs as preoperative patients. Levetiracetam, valproate, topiramate and lamotrigine were the most common AEDs in both the medicine and surgical groups, and levetiracetam (May, 2006 to March, 2007) or topiramate (September, 2004 to April, 2006), adjunctive to valproate were the most common medicinal therapeutic programs for the two groups.
2.5.
Follow-up
All children were followed up for 5 years, and completed 1, 2 and 5-year follow-up visits in the hospital, as well as a
telephone visit every 3e6 months. Also, a seizure log, including seizure frequency, seizure type, numbers of AEDs, medicinal side effects and surgical complications were recorded by both the patient and the caregiver, who had been instructed by doctors. Post-treatment assessments included changes in IQ and overall QOL, reduction in seizure frequency and surgical complications. Improvement was defined as post-treatment to pretreatment changes of IQ and QOL over than 10% of pre-treatment scores, and decrease was defined as the changes less than 10% f pre-treatment scores. Seizure reduction was based on the number of seizures during the preceding 6 months, at the 1, 2 and 5-year follow-up visits. Because CCT is essentially a palliative procedure, seldom providing the patient seizure freedom, the Engel classification for seizure outcome is less applicable. Therefore, outcomes of overall seizure control were divided into 3 classes: seizurefree (no seizure in the last year, with or without auras), S50% reduction and <50% reduction in overall seizures. Surgical complications were described as transient or permanent. A nurse in the hospital recorded transient complications and permanent complications were registered by caregivers.
2.6.
Statistical analysis
Statistical analyses were performed with the SPSS statistical program (version 11.0; SPSS, Inc., Chicago, Ill., USA). The outcomes were described by percentages, means and standard deviations. Quantitative data were analyzed using either an F-test or t-test. Qualitative data were analyzed by a personal c2 or KruskaleWallis test. The KruskaleWallis and F tests were adopted for analysis of variance among over 2 groups. Results were considered significant for values of p < 0.05.
3.
Results
3.1.
Pretreatment data
This cohort included 60 children: 23 (M:F ¼ 16:7) in the surgery group and 37 (M:F ¼ 22:15) in the medicine group. The demographic and clinical characteristics of the two groups are summarized in Table 2. Each child experienced two or more types of seizures and tonic seizures (or atonic seizures) were
Please cite this article in press as: Liang S, et al., Anterior corpus callosotomy in school-aged children with LennoxeGastaut syndrome: A prospective study, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.05.004
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Table 2 e Children's demographical and clinical characteristics. Characteristics Age at first seizure History of seizure Age at enrolled Full scale IQ Abnormal MRI Abnormal PET Number of AEDs in last 1-month Seizure times in last 1-month Seizure types in last 6 months Tonic or atonic seizure Atypical absence seizure Toniceclonic seizure Clonic seizure Myoclonic seizure
Surgery group Medicine group P value (n ¼ 23) (n ¼ 37) 5.13 ± 1.68 4.35 ± 2.08 9.48 ± 2.21 56.09 ± 10.27 7 (30.4%) 11 (47.8%) 2.96 ± 0.93
5.43 ± 1.92 4.30 ± 2.16 9.73 ± 2.39 55.32 ± 10.14 8 (21.6%) 16 (43.2%) 2.76 ± 0.93
0.5420 0.9299 0.6868 0.7770 0.6456 0.9632 0.4291
92.52 ± 14.35
86.11 ± 14.19
0.0957
23 (100%)
37 (100%)
1.0000
21 (91.3%)
32 (86.5%)
0.8795
16 (69.6%)
23 (62.2%)
0.7595
7 (30.4%) 6 (26.0%)
10 (27.0%) 18 (48.6%)
0.9922 0.1434
found in 100% of the 60 children, and were the most frequent seizure type. There were 10 (43.5%) children with moderate mental retardation (full scale IQ < 50) in the surgery group and 14 (37.8%) cases in the medicine group. Significant differences were not found in age at first seizure, age at surgery, pretreatment full scale IQ, percentage of abnormal MRI, percentage of male patients, mean number of AEDs or seizure type distribution between the surgery and medicine groups.
3.2.
Seizure control
All of the 23 patients from the surgery group and 34 cases from the medical group finished the 5 years of follow-up appointments (Fig. 1). One child underwent an operation after 3 years of medical therapy and 2 of the patients dropped out due to disappointment in seizure control. Therefore, 57 children were included in the post-treatment analysis. The seizure outcomes are shown in Figs. 2 and 3. When all types of seizures are considered as a whole, the percentage of patients who were seizure-free in the surgery group was 17.4% at the 1-year follow-up, 13.0% at the 2-year follow-up and 8.7% at 5 years Those percentages were 2.9%,
5.9% and 2.9%, respectively, for the medicine group. The best seizure control was seen in children from the surgery group at 1-year post-procedure; 87% of this group reached at least 50% seizure reduction. Significant differences were found in overall seizure control between the two groups at 1-year, 2 years, and 5 years. While seizure control was seen in every type of seizure, the greatest seizure reduction was seen in tonic seizures, with an 81% reduction at 1-year, 77% at 2 years and 75% at 5 years after operation in the surgery group. The smallest seizure reduction in the surgery group was seen with myoclonic seizures, which showed a 42% reduction at 1-year, 40% at 2 years and 39% at 5 years after surgery. Significant differences were not found in seizure reduction of any type of seizure between the 3 periods of follow-up in the surgery group. However, significant differences were found between groups in seizure control of tonic, tonic-clonic and atypical absence seizure at all of three follow-ups, clonic seizures at 1 and 2 years follow-up (P < 0.01) and myoclonic seizures at 1-year follow-up (P < 0.05).
3.3.
IQ and QOL
IQ and overall QOL tests were performed in all of the 57 cases at the 2-year follow-up appointment. Each child was grouped into one of the three categories (improvement, unchanged or impairment), based on the score change from the pretreatment scores of full scale IQ and overall QOL, when compared with the scores at the 2-year follow-up. Full scale IQ improvement was present in 10 (43.5%) cases from the surgery group and 2 (5.9%) children from the medicine group. A decline in IQ was seen in 2 (8.7%) patients from the surgery group and 13 (38.2%) cases in the medical therapy group. Overall QOL improvement showed in 13 (60.9%) children in the surgery group and 2 (5.9%) cases from the medicine group, and changes of overall QOL were grouped into impairment in 1 boy (4.3%) from the surgery group and 15 children (44.1%) from the medicine group. The significant differences between the two groups were found in the change of overall QOL and full scale IQ. When the mean changes of IQ and overall QOL were compared for the different groups, from pretreatment scores to the 2-year follow up assessment (see Table 3), significant differences were found in full scale IQ, verbal IQ, performance IQ and overall QOL (P < 0.01). Additionally, the change in the surgery group presented positive outcomes. In the surgery group, preoperative full scale IQ, postoperative seizure control and age at enrollment had no effects on the mean changes of
Fig. 2 e Overall seizure reduction in surgery group and medicine group.
Please cite this article in press as: Liang S, et al., Anterior corpus callosotomy in school-aged children with LennoxeGastaut syndrome: A prospective study, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.05.004
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e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 4 ) 1 e7
Fig. 3 e Reductions of different types of seizures in two groups at 1FU, 2FU and 5FU.
full scale IQ, verbal IQ, performance IQ and overall QOL. However, significant differences were found in mean changes of full scale IQ, verbal IQ, performance IQ and overall QOL between children with at least 50% seizure reduction and those with less than 50% seizure reduction (P < 0.01) in the medicine group. Also, the children who were less than 10 years old at enrollment and those with less than 50% seizure reduction presented mean performance IQ impairment after 2 years of treatment with anti-seizure drugs.
3.4.
AEDs among before operation,2 years and 5 years after operation (Table 4).
3.5.
Complications in surgery group
There was no postoperative death or development of permanent complications in any of the children in the surgery group. Transient complications appeared in 4 patients, including two cases of urinary incontinence, 1 case of aphasia and 1 cases of apraxia.
Numbers of AEDs
The preoperative patients in surgery group took most numbers of AEDs, and the number was 2.96 ± 0.93. Significant differences were not found in number of AEDs between surgery group and medicine group before operation and 2 or 5 years after operation. Furthermore, neither surgery group nor medicine group, there was significant difference in number of
4.
Discussion
To the best of our knowledge, this paper reports on the first prospective study on anterior CCT in school-aged children with LGS. Percentages of patients who were seizure free and who experienced >50% reduction in seizure frequency
Table 3 e Means changes of IQ and overall QOL at 2 years follow-up. Factors
Full scale IQ Baseline
Total surgery group Seizure reduction S50% (n ¼ 16) <50% (n ¼ 7) Pre-operative IQ S50 (n ¼ 16) <50 (n ¼ 7) Age at enrolled S10 (n ¼ 11) <10 (n ¼ 12) Total medicine group Seizure reduction S50% (n ¼ 11) <50% (n ¼ 23) Pre-treatment IQ S50 (n ¼ 22) <50 (n ¼ 12) Age at enrolled S10 yrs (n ¼ 19) <10 yrs (n ¼ 15)
Verbal IQ a
Change
Baseline
Performance IQ a
Change
Baseline
Overall QOL a
Change
Baseline
Changea
56.09
5.13##
57.00
3.26##
56.17
7.13b##
44.78
6.26b##
56.50 55.14
5.44 4.43
57.63 55.57
3.25 3.29
56.38 55.71
7.69b 5.86b
44.56 45.29
6.19b 6.43b
61.69 43.29
4.88 5.71b
64.00 41.00
3.06 4.00
60.38 46.57
6.88 7.43
47.63 36.29
5.63b 8.00b
55.00 57.05
3.82 6.33b
55.64 58.25
2.18 4.25
55.55 56.75
5.64 8.50b
44.55 45.00
4.18 8.17b
55.32
3.56
55.38
3.12
56.76
4.02
43.44
2.71
57.69 54.54
0.64** 5.59
56.60 54.81
0.55** 4.87
60.20 55.13
0.73** 6.32b
45.50 42.58
0.73** 4.35
61.68 44.33
3.09 4.42
60.64 45.75
2.59 4.08
63.77 49.32
3.64 4.75
47.68 35.67
2.64 2.83
53.95 57.6
2.26 5.20
53.74 57.47
2.47 3.93
55.26 58.67
2.11* 6.47b
42.95 44.07
1.84 3.80
##
P < 0.01 mean change in surgery group VS. mean change in medicine group at 2 years follow-up. *P < 0.05, **P < 0.01, Change in this group versus change in the other group. a Change from baseline to 2-year follow-up visit (score for 2FU minus baseline score). b Change from baseline to 2-year follow-up visit >10% of baseline score.
Please cite this article in press as: Liang S, et al., Anterior corpus callosotomy in school-aged children with LennoxeGastaut syndrome: A prospective study, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.05.004
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Table 4 e Mean numbers of AEDs in surgery group and medicine group. Time Pre-operation 2 years follow-up 5 years follow-up
Surgery group (n ¼ 23)
Medicine group (n ¼ 34)
P value
2.96 ± 0.93 2.57 ± 0.90 2.52 ± 0.67
2.71 ± 0.87 2.68 ± 0.98 2.76 ± 1.05
0.3059 0.6693 0.3366
reached 17.4% and 87%, respectively, in the surgery group at 1year after CCT. The seizure control in the group was significantly better than for those under multiple AEDs treatments at the 1e5 year follow-ups. When each type of seizure was compared, CCT demonstrated good control for tonic seizure, tonic-clonic seizure and atypical absence seizure. Therefore, we point that school-aged children with LGS, whose main types of seizures were tonic/atonic and tonic-clonic, would be excellent first candidates for CCT. LGS is a well-known epileptic encephalopathy, and over 40% of patients present moderate to severe mental retardation, in which frequent epileptic seizures and epileptiform discharges play an important role.1,17,18 At the same time, childhood, though a short period of time, is a very key stage in the development of intelligence and recognition. Therefore, freedom from seizures or good seizure control in childhood is ultimately very important to intelligence and recognition levels in adult patients with LGS.19,20 In our cohort, full scale IQ and overall QOL improved in 44% and 61%, of patients, respectively, 2 years after anterior CCT. These findings align with previous reports,14,21,22 and were substantially higher than the changes in patients who received only medicinal treatment. Thereby, once no-lesion LGS is diagnosed in school-aged children, anterior CCT should been taken into account before the child becomes an adult and time is wasted trying, adjusting and readjusting AEDs, to prevent the loss of invaluable time for brain development. The anti-epileptic drugs given to the surgery group in this study did not change in the first year after operation, and there was no significant difference in the numbers of AEDs in between pre-operative time and 2 or 5 years after operation in surgery group. At the same time, we found that postoperative improvement of IQ and QOL was not related to postoperative seizure control or preoperative full scale IQ level. Therefore, these improvements should be caused by the surgical blockage of abnormal electrical activity dissemination between bilateral hemispheres, due to the corpus callosotomy. By removing the means of signaling, the overexcited activity related to abnormal behavior or emotions is inhibited and, consequently, the suppressed normal nerve signal conductions are restored.15,23e25 Concurrently, children experience superior brain plasticity and increased opportunities for special education after surgery, as compared with an adult.26 Furthermore, the improvements in patients with mental retardation were related to a high incidence of motor and behavioral problems, as well as more attention from caregivers to patients in order to improve these problems, which would greatly alleviate their burden. As a conceptual framework for treating patients with LGS, the purpose of treatment with CCT is not only the control of seizures, but also the
opportunity for more normal intellectual development and quality of life.9,27 Anterior CCT in these specific patients meets these needs. Vagus nerve stimulation, anterior CCT and one- or twostage total CCT have all been reported in the treatment of LGS and other generalized epilepsy.12,22,28 Although callosotomy is an intracranial procedure, compared to stimulation of the vagus nerve, which is an extracranial procedure, we preferred anterior CCT to vagus nerve stimulation. The three reasons are as follows: first, CCT was more effective in reducing seizure frequency than vagus nerve stimulation,13,22,29 secondly, vagus nerve stimulation is much more expensive than anterior CCT and, third, anterior CCT has the same rare permanent surgical complications as vagus nerve stimulation.13 Anterior CCT, but not total CCT, was used in this cohort because of its high efficacy and safety.15 The genu of the corpus callosum connects mainly the prefrontal, premotor and motor cortex which are areas with particularly rich interhemispheric connections representing the majority of fibers. The anterior body of callosum connects additional and frontal and parietal areas. Therefore, anterior CCT disconnects the majority of fibers. At the same time, anterior CCT has fewer complications than total CCT. Lastly, two-stage total CCT can always be considered for patients who fail anterior CCT, and will be safer than one-stage total CCT.15
4.1.
Study limitations
It was a prospective study to compare outcomes of anterior CCT with AEDs in school-aged children with LGS. However, because of its limited design, the patients didn't be divided into surgery group and medicine group randomly, but according the choice of the patients' caregivers. In addition, it is of note that neural plasticity in childhood can work to the disadvantage of the patient, in that epilepsy may find new pathways to spread in the brain after anterior CCT. Therefore, an even longer follow-up is necessitated to fully demonstrate the advantages of anterior callosotomy over medical management in children with LGS.
5.
Conclusion:
Anterior CCT confers an obvious reduction in seizure frequency and improvement in overall QOL and IQ in schoolaged children with LGS, which were significantly better than multiple drug therapy. Additionally, the procedure proved to be quite safe for the children in this study. Therefore, anterior CCT could be performed for carefully selected primary schoolaged children with LGS, before the trial and failure of all antiepileptic drugs.
Disclosure None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Please cite this article in press as: Liang S, et al., Anterior corpus callosotomy in school-aged children with LennoxeGastaut syndrome: A prospective study, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.05.004
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 4 ) 1 e7
Fund This research was funded by Beijing Technology & Science New-star Training Project (2010B084).
Acknowledgments The authors would like to show gratitude to the patients and their families for their long-term cooperation. We also appreciate the contribution provided by the following people: Dr SB Yao from the Neurosurgery Department; and Dr SS Liang, Dr. YJ Sun and all technicians in the Neurophysiologic Laboratory of Capital Epilepsy Therapy Center.
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Please cite this article in press as: Liang S, et al., Anterior corpus callosotomy in school-aged children with LennoxeGastaut syndrome: A prospective study, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.05.004