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Long-term developmental outcome in patients with West syndrome after epilepsy surgery
Brain & Development 34 (2012) 731–738 www.elsevier.com/locate/braindev
Original article
Long-term developmental outcome in patients with West syndrome after epilepsy surgery Yoshiko Iwatani a, Kuriko Kagitani-Shimono a,b,⇑, Koji Tominaga a,c, Takeshi Okinaga a, Ikuko Mohri b,c, Haruhiko Kishima d, Amami Kato e, Wakako Sanefuji c, Tomoka Yamamoto c, Aika Tatsumi c, Emi Murata c, Masako Taniike b,c, Toshisaburo Nagai f, Keiichi Ozono a a
Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan United Graduate School of Child Development, Osaka University Graduate School of Medicine, Osaka, Japan c Department of Molecular Research Center for Children’s Mental Development, Osaka University Graduate School of Medicine, Osaka, Japan d Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan e Department of Neurosurgery, Kinki University Faculty of Medicine, Osaka, Japan f Division of Health Science, Osaka University Graduate School of Medicine, Osaka, Japan b
Received 28 October 2011; received in revised form 11 January 2012; accepted 11 January 2012
Abstract It has been hypothesized that early seizure control may prevent children with intractable epileptic spasms (ES) from developmental regression and may contribute to better developmental outcome. The effectiveness of surgery for ES has been reported. We investigated long-term post-operative outcomes of seizure control and development in patients with symptomatic West syndrome (S-WS) who underwent epilepsy surgery. Six children who underwent surgical intervention for intractable ES were retrospectively investigated. Cortical malformations were observed on pre-operative MRI in all patients, with hemispheric or multilobar involvement in four children and focal lesions in two. Following surgery, we measured motor function, developmental age (DA), language skills, and sociopsychological function for up to 7 years (mean, 4.9 years). Post-operative seizure outcome was Engel Class I (n = 4) or III (n = 2). Motor function and DA was increased following surgery in six and five patients, respectively. Two patients started to speak in sentences following focal resection. Autistic features were noted in four of the five examined patients post-operatively. None of the patients showed developmental regression following surgery. Epilepsy surgery for S-WS with ES may result in good seizure control and improvement in motor development. Improvement in cognitive function was modest in this small cohort of children and autistic features were noted post-operatively in a substantial proportion of the children. While seizure control can be obtained by epilepsy surgery, early intervention for sociopsychological comorbidities may be warranted in children with S-WS. Ó 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Autism; Developmental outcome; Epilepsy surgery; Spasms; West syndrome
1. Introduction
⇑ Corresponding author at: Department of Pediatrics, Osaka Uni-
versity Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Fax: +81 6 6879 3939. E-mail address: [email protected] (K. KagitaniShimono).
West syndrome (WS) is characterized by epileptic spasms (ES), hypsarrhythmia, and mental regression. Symptomatic WS (S-WS) with cortical dysplasia frequently remains resistant to antiepileptic drugs (AEDs) including adrenocorticotrophic hormone (ACTH), and
0387-7604/$ - see front matter Ó 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2012.01.008
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progressively manifests marked mental and motor retardation. In addition, intractable WS may reveal varying degrees of impaired social relationships resulting in severe behavioral disorders [1,2]. WS is thus sometimes referred to as ‘catastrophic epilepsy’ or ‘epileptic encephalopathy’ [3]. Recent advances in various neuroimaging techniques, which can more exactly detect the localization of cortical dysplasia or malformations, has facilitated earlier surgical intervention [4–7]. It has been hypothesized that early surgical intervention could prevent children with intractable WS from developmental regression and that such early intervention might result in better developmental outcome and quality of life [8–10]. However, in terms of mental and social development, the most appropriate time for surgery remains controversial [11,12]. We investigated the long-term prognosis of seizure control and developmental improvement among patients with S-WS who underwent epilepsy surgery for ES. Developmental outcome was evaluated not only in terms of motor development but also in terms of cognitive function such as developmental age (DA), language constitution, and sociopsychological development. 2. Methods Patients undergoing epilepsy surgery for ES were recruited from the Department of Pediatrics at Osaka University Hospital between 2002 and 2007. Informed consent was obtained to use clinical data from the parents of each patient. Pre-operative evaluations included interictal and ictal electroencephalography (EEG) (EEG-1000 NIHON KODEN System, Nihon Koden, Tokyo, Japan), magnetic resonance imaging (MRI) (Signa HD, 1.5 T, GE Medical Systems, Milwaukee, WI, USA), ictal and interictal 99mTc-ethylcysteinate dimer single photon emission computed tomography (SPECT), 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), and magnetoencephalography (MEG) (NeuroSQUID Model 100, CTF Systems Inc., Port Coquitlam, Canada). Medical records were retrospectively reviewed for age at onset of seizures, age at surgery, seizure types, and preand post-surgical outcomes for both seizures and development. Post-operative seizure control was assessed at 6 months, 2 years, and 5 years after surgery using Engel’s classification [13]. Pre- and post-operative developmental quotients (DQs) and DA were evaluated using the Tsumori-Inage Development Scale [14] or the Kyoto Scale of Psychological Development [15]. Language, mental, and motor assessments were also performed pre- and post-operatively. According to previous reports [10,16], all patients were divided into six groups: 0, no language; 1, fewer than 20 words; 2, more than 20 words, but no word combinations; 3, short telegraphic utterances; 4, beyond the telegraphic stage, with only occa-
sional Japanese grammatical errors, using particles; and 5, fluent speech with mature grammar. Social reciprocity and communication were evaluated using the Autism Diagnostic Observation Schedule-Generic (ADOS-G) module 1 [17]. 3. Results 3.1. Patient information Tables 1 and 2 show the demographic and clinical characteristics, and seizure and development outcomes of the patients, respectively. The patients comprised six children (3 boys, 3 girls) with intractable spasms who were resistant to ACTH treatment and many AEDs (mean 7.8, SD 2.2). Mean duration of follow-up was 4.9 years (range, 2.8–7.1 years). Mean age at last examination was 6.3 years (range, 3.8–9.3 years). Mean ages at spasm onset and surgery were 4.7 months (range, 1– 10 months) and 1.4 years (range, 11 months–2.2 years), respectively. The mean period between seizure onset and surgery was 1.0 years (range, 8 months–2 years). Complex partial seizures (CPS) appeared before spasms in four patients and appeared following spasms until surgery in the other two patients. Pre-operative neurological deficits such as mild hemiplegia were found in three patients. At the time of surgery, all patients revealed spasms daily with or without CPS. 3.2. Pre-operative evaluations Although interictal EEG at spasm onset revealed hypsarrhythmia in all patients, two patients showed asymmetrical hypsarrhythmia. Following ACTH or AED treatment, hypsarrhythmia was transformed into focal spikes or spike-and-wave complexes in patients 1, 2, and 4. In patient 3, after total callosotomy, asymmetry of hypsarrhythmia became obvious in the left hemisphere. Malformation was detected in six patients by means of brain MRI: focal cortical dysplasia (n = 4), hemimegalencephaly (n = 1), and pachygyria in the right temporal lobe with mild atrophy of the frontal lobes bilaterally (n = 1). FDG-PET showed lateralized or localized hypometabolism corresponding with MRI abnormalities in all six patients. Patient 5 showed left diffuse hemispheric hypometabolism and focal hypometabolism in the right occipital area, which were consistent with the distribution of abnormal lesions on MRI (Fig. 1). Interictal SPECT of three patients revealed hypoperfusion consistent with MRI lesions. Ictal SPECT of spasms was performed in patients 1 and 4, and that of CPS was evaluated in patient 2. Patients 1 and 2 showed hyperperfusion corresponding to focal cortical dysplasia. Patient 4 showed hyperperfusion of bilateral frontal regions, that were concordant with MRI lesions. Interictal MEG was performed in four patients. Equiva-
Bil, bilateral; CD, cortical dysplasia; CPS, complex partial seizures; EEG, electroencephalogram; F, female; Fr, frontal; FDG-PET, F-fluorodeoxyglucose positron emission tomography; hemi, hemispheric; HEC, hemiencephalomalacia; HME, hemimegalencephaly; hyper, hyperperfusion; hypo, hypometabolism (FDG-PET) or hypoperfusion (SPECT); Hyps, hypsarrhythmia; Lt, left; M, male; MEG, magnetoencephalography MRI, magnetic resonance imaging; ND, not done; O, occipital; P, parietal; Rt, right; Sp, spike; SPECT, 99mTc-ethylcysteinate dimer single photon emission computed tomography; Sp-w, spike and wave; synch, synchronized; T, temporal.
Lt functional hemispherotomy (HME) Lt O ND Lt hemi hypo Lt hemi hypo Lt hemi hyps Spasm ! spasm + CPS Rt hemiplegia 11 m 3m F 6
18
Lt multilobar dissection (HEC) Lt O Lt P-O-T hypo Lt hemi hypo, Rt O hypo Lt hemi hyps CPS ! spasm Rt hemiplegia 1 y7 m F 5
10 m
F 4
4m
1 y0 m
None
CPS ! spasm
Hyps ! Sp + Sp-w at bil Fp-F
Bil Fr mild atrophy, Rt T pachygyria Lt P-O-T CD, Rt O CD, atrophy of Lt hemi white matter Lt HME
Rt Fr hypo
ND
Total callosotomy, Lt functional hemispherotomy (CD) Total callosotomy (–) Rt PT
Rt O lesionectomy (CD)
Rt Fr hypo
Bil Fr hyper
ND
ND
Lt F-P hypo
ND
Normal
Lt hemi hypo
Rt O CD Spasm ! spasm + CPS None
Rt hemiplegia 5 m, 10 m
2 y1 m
M 3
2m
M 2
1m
CPS ! spasm
Lt O-T CD M 1
8m
2 y2 m
None
CPS ! spasm
Hyps (synch) ! sharp waves at Lt T Hyps ! Sp at Rt O-mT-pT and Lt aT, O, pT Hyps ! Lt hemi hyps
Lt hemi CD
Rt O hypo
Rt O hyper
Lt T ND Lt O-T hypo
Lt T hyper
Interictal SPECT Interictal FDG-PET MRI EEG (interictal)
Pre-operative evaluation Seizure type Pre-operative neurological deficit Age at surgery Spasm onset Sex No.
Table 1 Clinical profile of patients with S-WS who underwent epilepsy surgery.
Ictal SPECT
MEG (dipoles)
Surgical procedure (histopathology)
Lt T-O lesionectomy (CD)
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lent current dipoles (ECD) were congregated in regions of cortical dysplasia for three of these patients. In patient 4, however, ECD did not correspond to the hypometabolism identified on FDG-PET or the hyperperfusional area on ictal SPECT. 3.3. Surgical procedures and etiology Results of neuroimaging, such as brain MRI, interictal FDG-PET, interictal and ictal SPECT, and MEG, were consistent in all patients except one (patient 4). Patient 1 is shown as a representative example in Fig. 2. As a result, these five patients underwent cortical resection (n = 3), functional hemispherotomy (n = 1), or functional hemispherotomy following total callosotomy (n = 1). As inconsistency of abnormalities of various neuroimaging modalities suggested more than one epileptogenic focus in patient 4, total callosotomy was performed as palliative surgery. The most frequent histopathology was cortical dysplasia (n = 3), followed by periventricular leukomalacia (n = 1) and hemimegalencephaly (n = 1). 3.4. Post-operative seizure prognosis Table 2 shows seizure outcome for spasms at 6 months, 2 years, and 5 years after surgery. The latest seizure outcomes were Class I (spasm-free) in four patients and Class III in two patients. In patient 1, for whom control for spasms was judged as Class I, CPS appeared 5.3 years after surgery. In patient 2, CPS had persisted daily for 4 months after surgery and disappeared for a period of time; it relapsed 1 year after surgery, but was again controlled 2.6 years after surgery. In patient 5, classified as Class III, simple partial seizures appeared 3 months after surgery and persisted weekly. 3.5. Developmental facilitation after epilepsy surgery Post-operative DA was improved and no regression was seen in any patients post-operatively. However, post-operative DQs were not likely to be improved to the normal range because patients do not develop at the same speed as normal children (Table 2). Patient 1, who was able to walk independently before surgery, was able to run 5 months after surgery, and patient 2, who was unable to walk without assistance before surgery, became able to walk 2 weeks after surgery. Motor development in patient 5 improved slowly and she gained the ability to walk independently more than 5 years after surgery. On the other hand, in patients 3, 4, and 6, who received surgery earlier than patients 1 and 2, motor development improved markedly soon after surgery, but they never achieved walking without assistance at final follow-up (Fig. 3). Patients 1 and 2 also gained the ability to speak in sentences post-opera-
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Table 2 Seizure outcome and developmental prognosis after surgery. No.
1
Follow-up
Prognosis of spasms
Developmental quotient/developmental
Language
period
(Engel Class)
age (chronological age)
score
7 y1 m
6m
2y
5y
Pre-surgical
IA
IA
IAa
30/7 m (1 y11 m)
2
5 y5 m
IA
IAb
IA
42/5 m (12 m)
3
3 y0 m
IA
IA
–
48/5 m (10 m)
4
2 y9 m
IIIA
IIIA
–
–
5
5 y3 m
IIIAc
IIIAc
IIIAc
32/6 m (1 y7 m)
6
6 y0 m
IA
IA
IA
26/3 m (11 m)
ADOS-G
Post-surgical 34/17 m (4 y2 m) 31/26 m (7 y1 m) 44/15 m (2 y9 m) 37/28 m (6 y3 m) 39/7 m (1 y5 m) 29/8 m (2 y4 m) 27/5 m (1 y6 m) 21/8 m (2 y11 m) 19/11 m (4 y9 m) 29/7 m (2 y0 m)
Class 3
Autism
Class 3
No autism
Class 0
ASD
Class 0
ND
Class 1
Autism
Class 1
Autism
ADOS-G, Autism Diagnostic Observation Schedule-Generic; ASD, autism spectrum disorder; CPS, complex partial seizure; m, month; ND, not able to be determined; y, year. a CPS appeared from daily to weekly 5 years and 3 months after surgery. b CPS had persisted daily for 4 months after surgery and relapsed for a period of time, but then disappeared 2.6 years after surgery. c Simple partial seizures appeared 3 months after surgery and persisted weekly.
Fig. 1. Pre-operative neuroimaging findings in patient 5. (A) T1-weighted MRI showing atrophy of white matter (arrow) without the globus pallidus, putamen, caudate nucleus, and thalamus on the left hemisphere. (B) Interictal FDG-PET showing prominent left parieto-occipito-temporal (arrow) and right occipital (triangle) hypometabolism. (C) Interictal SPECT showing left parieto-occipito-temporal hypoperfusion (arrow). (D) MEG showing ECD accumulated in the left occipital region. The findings of interictal FDG-PET, interictal SPECT, and MEG were consistent with those of MRI.
tively (Table 2): the others had not developed communicative language by final follow-up, although two of them could utter words incompletely. Patient 4 could not be
fully evaluated in the social developmental trajectory because of severe mental and motor retardation. Of the five remaining patients, three were diagnosed as aut-
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Fig. 2. Pre-operative neuroimaging findings in patient 1. (A) T1-weighted MRI showing abnormality of the left occipito-temporal lobe (arrow). (B) Interictal FDG-PET showing hypometabolism of the left occipito-temporal lobe (arrow). (C) Ictal SPECT demonstrating hyperperfusion (arrow) of the left temporal lobe. (D) MEG showing ECD converging to the left temporal region. The findings of interictal FDG-PET, ictal SPECT, and MEG were consistent with those of MRI.
ism, one as autism spectrum disorders (ASD), and the other was not diagnosed as autistic (Table 2). Patients 1, 3, 5, and 6 used poorly modulated eye contact, but occasionally directed facial expression toward another person for communicating affect. Patients 3, 5, and 6 did not have spontaneous functional play and pretend play. Patients 1 and 3 showed no stereotyped behavior or restricted interest, but patient 5 had unusual sensory response and patient 6 unusually showed repetitive or stereotyped behavior. According to post-operative interviews with parents, all patients showed increased smiling, more interest in objects such as books and television, more frequent babbling, and improved quality of life. 4. Discussion Cognitive impairment is well known as a comorbidity of WS [8,18]. We investigated the long-term prognosis of cognitive function and association with sociopsychological comorbidity after surgical treatment for S-WS. A few reports have examined surgical treatment for ES in WS, and fewer still have provided long-term follow-
up. Evaluation of results following epilepsy surgery with regard to mental and motor development or language are occasionally reported, but sociopsychological assessments such as ADOS-G have never been evaluated. This study represents the first to report sociopsychological analysis and may therefore provide some useful insights. Several reports have examined the effects of surgery for WS in controlling seizures. Chugani et al. [4] reported that spasms disappeared in 13 of 17 patients (76.5%) who underwent cortical resection or hemispherectomy, and that CPS still persisted in three patients (17.6%) whose spasms had stopped after surgery (mean follow-up, 2.3 years). Kramer et al. [19] reported that, in nine WS patients who underwent surgical treatment for infantile spasms (IS) or partial seizures, seizures disappeared in six (67%), remained in two (22%), and one patient died during hemispherectomy. In our study, the patients whose epileptogenic foci were identified obtained good seizure control. Four of five patients (80%) who underwent hemispherotomy or cortical resection had no spasms. In our study, FDG-PET was useful for detecting the epileptogenic area in combination with MRI, as also reported by Chugani et al. [4]. In other
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words, seizure control depended on whether the epileptogenic zone was totally resected or dissected. When hypometabolism in FDG-PET was localized to one area or one hemisphere, epilepsy surgery was considered to provide seizure control. The reported mortality rate from epilepsy surgery in children is 0–1.7% [10,20–22]. In our study, none of the patients died post-operatively or experienced serious peri-operative complications. With regard to developmental outcome, improved post-operative motor development has been reported in patients who underwent epilepsy surgery for IS [4,23,24]. Kang et al. [24] reported two patients who underwent surgery in early infancy obtained catch-up in motor development. Chugani et al. [4] reported ten of 17 patients could walk at final evaluation, although motor skills were not described prior to surgery. In our study, the improvement in motor developmental outcome was not as good as that of their study. Poor seizure control in patient 4 and pre-operative low motor development level in patients 3 and 6 might be associated with their post-operative motor developmental outcome. On the other hand, Asarnow et al. [8] reported that developmental level at 2 years post-operatively for intractable IS was better than the pre-operative level and also that developmental outcome was better than that previously reported for children with IS without surgical intervention [25]. Developmental outcome was better in children who achieved and preserved a higher pre-operative developmental level and received surgery at an earlier stage [8]. None of our patients showed mental deterioration post-operatively and DA was improved after surgery. However, none of our patients reached DA equivalent to chronological age and post-operative DA was not always better with younger age at surgery. As the plasticity of neurons facilitates recovery from brain damage caused by IS, early control of intractable spasms is thought to be effective in promoting development [10]. From the perspective of plasticity in infancy, surgery such as hemispherotomy at an earlier stage may have been better in patients 3 and 6. However, performing surgery in early infancy also increases the risk of peri-operative complications. Our study included a small cohort of patients studied retrospectively. Therefore, considering seizure outcome, developmental outcome, and risk of complications all together, we can not conclude the appropriate timing of epilepsy surgery. Regarding language acquisition, verbal ability was preserved regardless of the laterality of hemispherectomy/hemispheric surgery [10,16,21,22]. On the other hand, while large individual differences exist in language acquisition following surgery for IS, the average outcome is reportedly poor [2]. In our study, only two patients, whose lesion is limited in a narrow area and had babbling before surgery, reached the level of uttering sentences. However, communicative language was not obtained in
the others, including patients 3 and 6, in whom seizures disappeared, even though post-surgical seizure control has been reported to correlate with acquiring language in hemimegalencephaly and cortical dysplasia [16]. Moreover, we are unable to discuss the relationship between the laterality of surgical lesions and language acquisition outcome due to the small number of patients. Regardless of the timing of surgery and seizure control, good language development would not be expected in ES patients who undergo extensive surgery and/or who already had severe impairment before surgery. According to the social developmental trajectory, four of five patients in our study were diagnosed as autism or ASD after surgery. The prevalence of ASD among children with IS obviously exceeds that of ASD in the general population and autism has been recognized as one of the comorbidities of IS [18,26]. In a case report of a child with tuberous sclerosis who did not show autistic features before the onset of spasms and secondary generalized partial seizures [27], the patient developed autistic regression after persisting spasms for 3 months and subsequently continued to show marked autistic features. This case indicates that the onset of epilepsy might lead to autistic regression. Furthermore, it has been reported that, in patients with tuberous sclerosis who had partial seizures and ES, autistic behavior was only induced by ES and not by partial seizures alone [28]. These cases demonstrate a more negative effect on cognition by ES than that by partial seizures. Thus, children with ES might develop features of autism even after a short period of ES. However, no previous studies have evaluated autistic features following surgery for ES. In our study, we could not prevent four patients from developing autistic symptomatology in spite of good seizure control and postoperative improvements in psychomotor development. Whether a shorter duration of spasms could prevent autistic regression is unclear. Also, as this study did not compare developmental outcomes of patients with WS who underwent epilepsy surgery with those of patients treated with medication alone in an agematched control group, we could not determine whether earlier intervention by epilepsy surgery might prevent severe autistic regression. A recent study has indicated that early psychosocial intervention is effective when autism is diagnosed by 3–4 years of age [29,30]. Thus, the evaluation of autistic features from an early postoperative stage and the early intervention may be necessary even in patients with good seizure control and improvement of psychomotor development. In conclusion, post-operative evaluation of patients with ES is important not only for assessment of seizure control and psychomotor development but also for social developmental trajectory. Early treatment intervention for autistic features might improve the prognosis of social adjustment.
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Fig. 3. The course of motor development. All patients showed marked catch-up after surgery. Triangle: onset of spasms; Arrow: age at surgery.
Acknowledgements This work was supported in part by the Core Research for Evolutional Science and Technology (CREST) on Bio-medical-photonic LSI from Japan Science and Technology Agency (JST), and a Grant-in-Aid for Scientific Research (20300199) from the Japan Society for the Promotion of Science (JSPS).
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Original article
Long-term developmental outcome in patients with West syndrome after epilepsy surgery Yoshiko Iwatani a, Kuriko Kagitani-Shimono a,b,⇑, Koji Tominaga a,c, Takeshi Okinaga a, Ikuko Mohri b,c, Haruhiko Kishima d, Amami Kato e, Wakako Sanefuji c, Tomoka Yamamoto c, Aika Tatsumi c, Emi Murata c, Masako Taniike b,c, Toshisaburo Nagai f, Keiichi Ozono a a
Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan United Graduate School of Child Development, Osaka University Graduate School of Medicine, Osaka, Japan c Department of Molecular Research Center for Children’s Mental Development, Osaka University Graduate School of Medicine, Osaka, Japan d Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan e Department of Neurosurgery, Kinki University Faculty of Medicine, Osaka, Japan f Division of Health Science, Osaka University Graduate School of Medicine, Osaka, Japan b
Received 28 October 2011; received in revised form 11 January 2012; accepted 11 January 2012
Abstract It has been hypothesized that early seizure control may prevent children with intractable epileptic spasms (ES) from developmental regression and may contribute to better developmental outcome. The effectiveness of surgery for ES has been reported. We investigated long-term post-operative outcomes of seizure control and development in patients with symptomatic West syndrome (S-WS) who underwent epilepsy surgery. Six children who underwent surgical intervention for intractable ES were retrospectively investigated. Cortical malformations were observed on pre-operative MRI in all patients, with hemispheric or multilobar involvement in four children and focal lesions in two. Following surgery, we measured motor function, developmental age (DA), language skills, and sociopsychological function for up to 7 years (mean, 4.9 years). Post-operative seizure outcome was Engel Class I (n = 4) or III (n = 2). Motor function and DA was increased following surgery in six and five patients, respectively. Two patients started to speak in sentences following focal resection. Autistic features were noted in four of the five examined patients post-operatively. None of the patients showed developmental regression following surgery. Epilepsy surgery for S-WS with ES may result in good seizure control and improvement in motor development. Improvement in cognitive function was modest in this small cohort of children and autistic features were noted post-operatively in a substantial proportion of the children. While seizure control can be obtained by epilepsy surgery, early intervention for sociopsychological comorbidities may be warranted in children with S-WS. Ó 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Autism; Developmental outcome; Epilepsy surgery; Spasms; West syndrome
1. Introduction
⇑ Corresponding author at: Department of Pediatrics, Osaka Uni-
versity Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Fax: +81 6 6879 3939. E-mail address: [email protected] (K. KagitaniShimono).
West syndrome (WS) is characterized by epileptic spasms (ES), hypsarrhythmia, and mental regression. Symptomatic WS (S-WS) with cortical dysplasia frequently remains resistant to antiepileptic drugs (AEDs) including adrenocorticotrophic hormone (ACTH), and
0387-7604/$ - see front matter Ó 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2012.01.008
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progressively manifests marked mental and motor retardation. In addition, intractable WS may reveal varying degrees of impaired social relationships resulting in severe behavioral disorders [1,2]. WS is thus sometimes referred to as ‘catastrophic epilepsy’ or ‘epileptic encephalopathy’ [3]. Recent advances in various neuroimaging techniques, which can more exactly detect the localization of cortical dysplasia or malformations, has facilitated earlier surgical intervention [4–7]. It has been hypothesized that early surgical intervention could prevent children with intractable WS from developmental regression and that such early intervention might result in better developmental outcome and quality of life [8–10]. However, in terms of mental and social development, the most appropriate time for surgery remains controversial [11,12]. We investigated the long-term prognosis of seizure control and developmental improvement among patients with S-WS who underwent epilepsy surgery for ES. Developmental outcome was evaluated not only in terms of motor development but also in terms of cognitive function such as developmental age (DA), language constitution, and sociopsychological development. 2. Methods Patients undergoing epilepsy surgery for ES were recruited from the Department of Pediatrics at Osaka University Hospital between 2002 and 2007. Informed consent was obtained to use clinical data from the parents of each patient. Pre-operative evaluations included interictal and ictal electroencephalography (EEG) (EEG-1000 NIHON KODEN System, Nihon Koden, Tokyo, Japan), magnetic resonance imaging (MRI) (Signa HD, 1.5 T, GE Medical Systems, Milwaukee, WI, USA), ictal and interictal 99mTc-ethylcysteinate dimer single photon emission computed tomography (SPECT), 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), and magnetoencephalography (MEG) (NeuroSQUID Model 100, CTF Systems Inc., Port Coquitlam, Canada). Medical records were retrospectively reviewed for age at onset of seizures, age at surgery, seizure types, and preand post-surgical outcomes for both seizures and development. Post-operative seizure control was assessed at 6 months, 2 years, and 5 years after surgery using Engel’s classification [13]. Pre- and post-operative developmental quotients (DQs) and DA were evaluated using the Tsumori-Inage Development Scale [14] or the Kyoto Scale of Psychological Development [15]. Language, mental, and motor assessments were also performed pre- and post-operatively. According to previous reports [10,16], all patients were divided into six groups: 0, no language; 1, fewer than 20 words; 2, more than 20 words, but no word combinations; 3, short telegraphic utterances; 4, beyond the telegraphic stage, with only occa-
sional Japanese grammatical errors, using particles; and 5, fluent speech with mature grammar. Social reciprocity and communication were evaluated using the Autism Diagnostic Observation Schedule-Generic (ADOS-G) module 1 [17]. 3. Results 3.1. Patient information Tables 1 and 2 show the demographic and clinical characteristics, and seizure and development outcomes of the patients, respectively. The patients comprised six children (3 boys, 3 girls) with intractable spasms who were resistant to ACTH treatment and many AEDs (mean 7.8, SD 2.2). Mean duration of follow-up was 4.9 years (range, 2.8–7.1 years). Mean age at last examination was 6.3 years (range, 3.8–9.3 years). Mean ages at spasm onset and surgery were 4.7 months (range, 1– 10 months) and 1.4 years (range, 11 months–2.2 years), respectively. The mean period between seizure onset and surgery was 1.0 years (range, 8 months–2 years). Complex partial seizures (CPS) appeared before spasms in four patients and appeared following spasms until surgery in the other two patients. Pre-operative neurological deficits such as mild hemiplegia were found in three patients. At the time of surgery, all patients revealed spasms daily with or without CPS. 3.2. Pre-operative evaluations Although interictal EEG at spasm onset revealed hypsarrhythmia in all patients, two patients showed asymmetrical hypsarrhythmia. Following ACTH or AED treatment, hypsarrhythmia was transformed into focal spikes or spike-and-wave complexes in patients 1, 2, and 4. In patient 3, after total callosotomy, asymmetry of hypsarrhythmia became obvious in the left hemisphere. Malformation was detected in six patients by means of brain MRI: focal cortical dysplasia (n = 4), hemimegalencephaly (n = 1), and pachygyria in the right temporal lobe with mild atrophy of the frontal lobes bilaterally (n = 1). FDG-PET showed lateralized or localized hypometabolism corresponding with MRI abnormalities in all six patients. Patient 5 showed left diffuse hemispheric hypometabolism and focal hypometabolism in the right occipital area, which were consistent with the distribution of abnormal lesions on MRI (Fig. 1). Interictal SPECT of three patients revealed hypoperfusion consistent with MRI lesions. Ictal SPECT of spasms was performed in patients 1 and 4, and that of CPS was evaluated in patient 2. Patients 1 and 2 showed hyperperfusion corresponding to focal cortical dysplasia. Patient 4 showed hyperperfusion of bilateral frontal regions, that were concordant with MRI lesions. Interictal MEG was performed in four patients. Equiva-
Bil, bilateral; CD, cortical dysplasia; CPS, complex partial seizures; EEG, electroencephalogram; F, female; Fr, frontal; FDG-PET, F-fluorodeoxyglucose positron emission tomography; hemi, hemispheric; HEC, hemiencephalomalacia; HME, hemimegalencephaly; hyper, hyperperfusion; hypo, hypometabolism (FDG-PET) or hypoperfusion (SPECT); Hyps, hypsarrhythmia; Lt, left; M, male; MEG, magnetoencephalography MRI, magnetic resonance imaging; ND, not done; O, occipital; P, parietal; Rt, right; Sp, spike; SPECT, 99mTc-ethylcysteinate dimer single photon emission computed tomography; Sp-w, spike and wave; synch, synchronized; T, temporal.
Lt functional hemispherotomy (HME) Lt O ND Lt hemi hypo Lt hemi hypo Lt hemi hyps Spasm ! spasm + CPS Rt hemiplegia 11 m 3m F 6
18
Lt multilobar dissection (HEC) Lt O Lt P-O-T hypo Lt hemi hypo, Rt O hypo Lt hemi hyps CPS ! spasm Rt hemiplegia 1 y7 m F 5
10 m
F 4
4m
1 y0 m
None
CPS ! spasm
Hyps ! Sp + Sp-w at bil Fp-F
Bil Fr mild atrophy, Rt T pachygyria Lt P-O-T CD, Rt O CD, atrophy of Lt hemi white matter Lt HME
Rt Fr hypo
ND
Total callosotomy, Lt functional hemispherotomy (CD) Total callosotomy (–) Rt PT
Rt O lesionectomy (CD)
Rt Fr hypo
Bil Fr hyper
ND
ND
Lt F-P hypo
ND
Normal
Lt hemi hypo
Rt O CD Spasm ! spasm + CPS None
Rt hemiplegia 5 m, 10 m
2 y1 m
M 3
2m
M 2
1m
CPS ! spasm
Lt O-T CD M 1
8m
2 y2 m
None
CPS ! spasm
Hyps (synch) ! sharp waves at Lt T Hyps ! Sp at Rt O-mT-pT and Lt aT, O, pT Hyps ! Lt hemi hyps
Lt hemi CD
Rt O hypo
Rt O hyper
Lt T ND Lt O-T hypo
Lt T hyper
Interictal SPECT Interictal FDG-PET MRI EEG (interictal)
Pre-operative evaluation Seizure type Pre-operative neurological deficit Age at surgery Spasm onset Sex No.
Table 1 Clinical profile of patients with S-WS who underwent epilepsy surgery.
Ictal SPECT
MEG (dipoles)
Surgical procedure (histopathology)
Lt T-O lesionectomy (CD)
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lent current dipoles (ECD) were congregated in regions of cortical dysplasia for three of these patients. In patient 4, however, ECD did not correspond to the hypometabolism identified on FDG-PET or the hyperperfusional area on ictal SPECT. 3.3. Surgical procedures and etiology Results of neuroimaging, such as brain MRI, interictal FDG-PET, interictal and ictal SPECT, and MEG, were consistent in all patients except one (patient 4). Patient 1 is shown as a representative example in Fig. 2. As a result, these five patients underwent cortical resection (n = 3), functional hemispherotomy (n = 1), or functional hemispherotomy following total callosotomy (n = 1). As inconsistency of abnormalities of various neuroimaging modalities suggested more than one epileptogenic focus in patient 4, total callosotomy was performed as palliative surgery. The most frequent histopathology was cortical dysplasia (n = 3), followed by periventricular leukomalacia (n = 1) and hemimegalencephaly (n = 1). 3.4. Post-operative seizure prognosis Table 2 shows seizure outcome for spasms at 6 months, 2 years, and 5 years after surgery. The latest seizure outcomes were Class I (spasm-free) in four patients and Class III in two patients. In patient 1, for whom control for spasms was judged as Class I, CPS appeared 5.3 years after surgery. In patient 2, CPS had persisted daily for 4 months after surgery and disappeared for a period of time; it relapsed 1 year after surgery, but was again controlled 2.6 years after surgery. In patient 5, classified as Class III, simple partial seizures appeared 3 months after surgery and persisted weekly. 3.5. Developmental facilitation after epilepsy surgery Post-operative DA was improved and no regression was seen in any patients post-operatively. However, post-operative DQs were not likely to be improved to the normal range because patients do not develop at the same speed as normal children (Table 2). Patient 1, who was able to walk independently before surgery, was able to run 5 months after surgery, and patient 2, who was unable to walk without assistance before surgery, became able to walk 2 weeks after surgery. Motor development in patient 5 improved slowly and she gained the ability to walk independently more than 5 years after surgery. On the other hand, in patients 3, 4, and 6, who received surgery earlier than patients 1 and 2, motor development improved markedly soon after surgery, but they never achieved walking without assistance at final follow-up (Fig. 3). Patients 1 and 2 also gained the ability to speak in sentences post-opera-
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Table 2 Seizure outcome and developmental prognosis after surgery. No.
1
Follow-up
Prognosis of spasms
Developmental quotient/developmental
Language
period
(Engel Class)
age (chronological age)
score
7 y1 m
6m
2y
5y
Pre-surgical
IA
IA
IAa
30/7 m (1 y11 m)
2
5 y5 m
IA
IAb
IA
42/5 m (12 m)
3
3 y0 m
IA
IA
–
48/5 m (10 m)
4
2 y9 m
IIIA
IIIA
–
–
5
5 y3 m
IIIAc
IIIAc
IIIAc
32/6 m (1 y7 m)
6
6 y0 m
IA
IA
IA
26/3 m (11 m)
ADOS-G
Post-surgical 34/17 m (4 y2 m) 31/26 m (7 y1 m) 44/15 m (2 y9 m) 37/28 m (6 y3 m) 39/7 m (1 y5 m) 29/8 m (2 y4 m) 27/5 m (1 y6 m) 21/8 m (2 y11 m) 19/11 m (4 y9 m) 29/7 m (2 y0 m)
Class 3
Autism
Class 3
No autism
Class 0
ASD
Class 0
ND
Class 1
Autism
Class 1
Autism
ADOS-G, Autism Diagnostic Observation Schedule-Generic; ASD, autism spectrum disorder; CPS, complex partial seizure; m, month; ND, not able to be determined; y, year. a CPS appeared from daily to weekly 5 years and 3 months after surgery. b CPS had persisted daily for 4 months after surgery and relapsed for a period of time, but then disappeared 2.6 years after surgery. c Simple partial seizures appeared 3 months after surgery and persisted weekly.
Fig. 1. Pre-operative neuroimaging findings in patient 5. (A) T1-weighted MRI showing atrophy of white matter (arrow) without the globus pallidus, putamen, caudate nucleus, and thalamus on the left hemisphere. (B) Interictal FDG-PET showing prominent left parieto-occipito-temporal (arrow) and right occipital (triangle) hypometabolism. (C) Interictal SPECT showing left parieto-occipito-temporal hypoperfusion (arrow). (D) MEG showing ECD accumulated in the left occipital region. The findings of interictal FDG-PET, interictal SPECT, and MEG were consistent with those of MRI.
tively (Table 2): the others had not developed communicative language by final follow-up, although two of them could utter words incompletely. Patient 4 could not be
fully evaluated in the social developmental trajectory because of severe mental and motor retardation. Of the five remaining patients, three were diagnosed as aut-
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Fig. 2. Pre-operative neuroimaging findings in patient 1. (A) T1-weighted MRI showing abnormality of the left occipito-temporal lobe (arrow). (B) Interictal FDG-PET showing hypometabolism of the left occipito-temporal lobe (arrow). (C) Ictal SPECT demonstrating hyperperfusion (arrow) of the left temporal lobe. (D) MEG showing ECD converging to the left temporal region. The findings of interictal FDG-PET, ictal SPECT, and MEG were consistent with those of MRI.
ism, one as autism spectrum disorders (ASD), and the other was not diagnosed as autistic (Table 2). Patients 1, 3, 5, and 6 used poorly modulated eye contact, but occasionally directed facial expression toward another person for communicating affect. Patients 3, 5, and 6 did not have spontaneous functional play and pretend play. Patients 1 and 3 showed no stereotyped behavior or restricted interest, but patient 5 had unusual sensory response and patient 6 unusually showed repetitive or stereotyped behavior. According to post-operative interviews with parents, all patients showed increased smiling, more interest in objects such as books and television, more frequent babbling, and improved quality of life. 4. Discussion Cognitive impairment is well known as a comorbidity of WS [8,18]. We investigated the long-term prognosis of cognitive function and association with sociopsychological comorbidity after surgical treatment for S-WS. A few reports have examined surgical treatment for ES in WS, and fewer still have provided long-term follow-
up. Evaluation of results following epilepsy surgery with regard to mental and motor development or language are occasionally reported, but sociopsychological assessments such as ADOS-G have never been evaluated. This study represents the first to report sociopsychological analysis and may therefore provide some useful insights. Several reports have examined the effects of surgery for WS in controlling seizures. Chugani et al. [4] reported that spasms disappeared in 13 of 17 patients (76.5%) who underwent cortical resection or hemispherectomy, and that CPS still persisted in three patients (17.6%) whose spasms had stopped after surgery (mean follow-up, 2.3 years). Kramer et al. [19] reported that, in nine WS patients who underwent surgical treatment for infantile spasms (IS) or partial seizures, seizures disappeared in six (67%), remained in two (22%), and one patient died during hemispherectomy. In our study, the patients whose epileptogenic foci were identified obtained good seizure control. Four of five patients (80%) who underwent hemispherotomy or cortical resection had no spasms. In our study, FDG-PET was useful for detecting the epileptogenic area in combination with MRI, as also reported by Chugani et al. [4]. In other
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words, seizure control depended on whether the epileptogenic zone was totally resected or dissected. When hypometabolism in FDG-PET was localized to one area or one hemisphere, epilepsy surgery was considered to provide seizure control. The reported mortality rate from epilepsy surgery in children is 0–1.7% [10,20–22]. In our study, none of the patients died post-operatively or experienced serious peri-operative complications. With regard to developmental outcome, improved post-operative motor development has been reported in patients who underwent epilepsy surgery for IS [4,23,24]. Kang et al. [24] reported two patients who underwent surgery in early infancy obtained catch-up in motor development. Chugani et al. [4] reported ten of 17 patients could walk at final evaluation, although motor skills were not described prior to surgery. In our study, the improvement in motor developmental outcome was not as good as that of their study. Poor seizure control in patient 4 and pre-operative low motor development level in patients 3 and 6 might be associated with their post-operative motor developmental outcome. On the other hand, Asarnow et al. [8] reported that developmental level at 2 years post-operatively for intractable IS was better than the pre-operative level and also that developmental outcome was better than that previously reported for children with IS without surgical intervention [25]. Developmental outcome was better in children who achieved and preserved a higher pre-operative developmental level and received surgery at an earlier stage [8]. None of our patients showed mental deterioration post-operatively and DA was improved after surgery. However, none of our patients reached DA equivalent to chronological age and post-operative DA was not always better with younger age at surgery. As the plasticity of neurons facilitates recovery from brain damage caused by IS, early control of intractable spasms is thought to be effective in promoting development [10]. From the perspective of plasticity in infancy, surgery such as hemispherotomy at an earlier stage may have been better in patients 3 and 6. However, performing surgery in early infancy also increases the risk of peri-operative complications. Our study included a small cohort of patients studied retrospectively. Therefore, considering seizure outcome, developmental outcome, and risk of complications all together, we can not conclude the appropriate timing of epilepsy surgery. Regarding language acquisition, verbal ability was preserved regardless of the laterality of hemispherectomy/hemispheric surgery [10,16,21,22]. On the other hand, while large individual differences exist in language acquisition following surgery for IS, the average outcome is reportedly poor [2]. In our study, only two patients, whose lesion is limited in a narrow area and had babbling before surgery, reached the level of uttering sentences. However, communicative language was not obtained in
the others, including patients 3 and 6, in whom seizures disappeared, even though post-surgical seizure control has been reported to correlate with acquiring language in hemimegalencephaly and cortical dysplasia [16]. Moreover, we are unable to discuss the relationship between the laterality of surgical lesions and language acquisition outcome due to the small number of patients. Regardless of the timing of surgery and seizure control, good language development would not be expected in ES patients who undergo extensive surgery and/or who already had severe impairment before surgery. According to the social developmental trajectory, four of five patients in our study were diagnosed as autism or ASD after surgery. The prevalence of ASD among children with IS obviously exceeds that of ASD in the general population and autism has been recognized as one of the comorbidities of IS [18,26]. In a case report of a child with tuberous sclerosis who did not show autistic features before the onset of spasms and secondary generalized partial seizures [27], the patient developed autistic regression after persisting spasms for 3 months and subsequently continued to show marked autistic features. This case indicates that the onset of epilepsy might lead to autistic regression. Furthermore, it has been reported that, in patients with tuberous sclerosis who had partial seizures and ES, autistic behavior was only induced by ES and not by partial seizures alone [28]. These cases demonstrate a more negative effect on cognition by ES than that by partial seizures. Thus, children with ES might develop features of autism even after a short period of ES. However, no previous studies have evaluated autistic features following surgery for ES. In our study, we could not prevent four patients from developing autistic symptomatology in spite of good seizure control and postoperative improvements in psychomotor development. Whether a shorter duration of spasms could prevent autistic regression is unclear. Also, as this study did not compare developmental outcomes of patients with WS who underwent epilepsy surgery with those of patients treated with medication alone in an agematched control group, we could not determine whether earlier intervention by epilepsy surgery might prevent severe autistic regression. A recent study has indicated that early psychosocial intervention is effective when autism is diagnosed by 3–4 years of age [29,30]. Thus, the evaluation of autistic features from an early postoperative stage and the early intervention may be necessary even in patients with good seizure control and improvement of psychomotor development. In conclusion, post-operative evaluation of patients with ES is important not only for assessment of seizure control and psychomotor development but also for social developmental trajectory. Early treatment intervention for autistic features might improve the prognosis of social adjustment.
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Fig. 3. The course of motor development. All patients showed marked catch-up after surgery. Triangle: onset of spasms; Arrow: age at surgery.
Acknowledgements This work was supported in part by the Core Research for Evolutional Science and Technology (CREST) on Bio-medical-photonic LSI from Japan Science and Technology Agency (JST), and a Grant-in-Aid for Scientific Research (20300199) from the Japan Society for the Promotion of Science (JSPS).
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