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ACTH therapy for Taiwanese children with West syndrome—efficacy and impact on long-term prognosis
Brain & Development 28 (2006) 196–201 www.elsevier.com/locate/braindev
Original article
ACTH therapy for Taiwanese children with West syndrome—efficacy and impact on long-term prognosis Haung-Chi Lina,*, Chainllie Youngb,d, Pen-Jung Wangc, Wang-Tso Leed, Yu-Zen Shend a
Department of Pediatrics, En Chu Kong Hospital, 399, Fuhsing Road, San-Shia Town, Taipei County, Taiwan, ROC b Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA c Department of Pediatrics, Buddhist Tzu Chi University Hospital, Hua-Lien, Taiwan, ROC d Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan, ROC Received 21 January 2005; received in revised form 28 June 2005; accepted 22 July 2005
Abstract To study the efficacy of adrenocorticotrophic hormone (ACTH) in treating Taiwanese children with West syndrome (WS) and the impact on long-term prognosis, 66 patients with WS (54 symptomatic and 12 cryptogenic) were collected from 1987 to 1998 in a medical center in Taiwan. A total of 53 patients were enrolled in this study and treated with ACTH at the dosage of 2.5 IU/kg daily for 2 weeks with gradual tapering in subsequent 6 weeks. Immediate responses, side effects of ACTH and long-term outcomes of the patients including seizure and developmental status were evaluated during the average follow-up period of 35.6 months. The spasm-free percentage after one or two courses of ACTH treatment was 77.4%. Nine (17%) patients encountered severe side effects such as major infections, which prompted us to stop ACTH. At the end of follow-up, 22 (41.5%) patients had intractable seizures but 25 (47.2%) patients remained seizure free with or without anticonvulsants. The ACTH-responders had a better chance of remaining seizure free (P!0.05). Regarding the long-term developmental outcome, 12 (22.6%) patients had normal or borderline development; two thirds of them belonged to the crytpogenic group. Six (11.3%) patients expired and 24 (45.3%) were severely retarded; all but one of them belonged to the symptomatic group. The prognosis of WS heavily relies on whether a patient is cryptogenic or symptomatic (P!0.001). Good response to therapy or short treatment lag did not favorably affect the developmental outcomes of the symptomatic cases. We conclude that the long-term outcomes of WS in Taiwan were generally poor despite of treatment. Only cryptogenic patients had favorable prognosis. For symptomatic patients, ACTH therapy may be used to control the spasms and decrease the incidence of subsequent epilepsy, but it will not improve developmental outcome. Considering a high percentage of severe side effects in our study, a lower dosage of ACTH with adequate therapeutic efficacy but less side effects should be considered for treating Taiwanese children with WS. q 2005 Published by Elsevier B.V. Keywords: Infantile spasms; Adrenocorticotropic hormone; Long-term outcome; Prognosis
1. Introduction West syndrome (WS) is a severe epileptic syndrome during infancy with distinctive clinical and electroencephalographic (EEG) features. Most WS is refractory to conventional anticonvulsant therapy and the reported long-term outcome is generally poor. In 1958, Sorel and
* Corresponding author. Tel.: C886 2 26723456x6957; fax: C886 2 86710550. E-mail address: [email protected] (H.-C. Lin).
0387-7604/$ - see front matter q 2005 Published by Elsevier B.V. doi:10.1016/j.braindev.2005.07.002
Dusaucy-Bauloye [1] reported that adrenocorticotropic hormone (ACTH) successfully stopped the spasms of patients with WS and improved their EEGs. Until the end of 20th century, ACTH has since remained the treatment of choice in many countries despite its significant adverse effects. As new anticonvulsants effective in treating WS become available, the optimal approach in treating patients of West syndrome raises debate. Evidence and data regarding the efficacy of ACTH and its impact on longterm outcome of patients with West syndrome should be revised. Most reports regarding the efficacy of ACTH in WS or the prognosis of WS, however, were from Western countries and Japan. Data from non-Japanese Asian children with WS are quite limited. In this study, we examined
H.-C. Lin et al. / Brain & Development 28 (2006) 196–201
the efficacy of ACTH in treating Taiwanese children with WS in the past decade and studied their long-term outcomes.
2. Patients and methods Children diagnosed as West syndrome or Infantile spasms (IS) at National Taiwan University Hospital between 1987 and 1998 were enrolled for this study if they met the following criteria: (1) clinical diagnosis by experienced child neurologists of WS or IS with compatible EEG pattern, including hypsarrythmia or modified hypsarrhythmia; (2) never been treated with ACTH or corticosteroids for WS before; (3) availability of follow-up information, including developmental status and EEGs. Every patient received a three-day trial of pyridoxine (30–50 mg/kg/day) before ACTH was administered. If the patients responded to pyridoxine, there was no need for ACTH therapy. The interval between the onset of spasms and the initiation of ACTH treatment was termed as treatment lag. Treatment lag was regarded as short if it was less than one month, and long if more than 1 month. According to the classification of Epilepsy and Epileptic Syndromes of the International League Against Epilepsy (ILAE) [2], patients were classified into symptomatic and cryptogenic groups. For etiological investigation, every patient received thorough clinical history evaluation, developmental and neurological assessments, neuroimage studies such as computed tomography (CT) or magnetic resonance image (MRI) of the head, chromosomal studies, and metabolic studies including serum amino acids and urine organic acids. Cryptogenic group was defined as (1) normal pregnancy and birth, (2) normal development before the onset of spasms and absence of neurological abnormalities at the onset of spasms, (3) absence of any other types of seizure before the onset of spasms, and (4) negative laboratory and neuroimage findings after adequate investigation [3]. When the criteria for cryptogenic group were not fulfilled, the patient was classified as symptomatic group.
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treatment. Patients were examined for evidence of infection daily during hospital stay. Blood pressure elevations were treated with fluid restriction and/or antihypertensive drugs such as nifedipine and hydralazine if necessary. In case of severe side effects such as serious infection or lifethreatening bleeding, ACTH therapy was stopped immediately. Patients with cessations of spasms and disappearance of hypsarrhythmia at the end of treatment were considered as responders. Those patients whose spasms persisted after 2 weeks of ACTH were non-responders and ACTH was discontinued. If spasms stopped in the first two weeks but relapsed during tapering period or in the follow-up period, a second course of ACTH or oral prednisolone (1– 2 mg/kg/day) was given. 2.2. Assessment of long-term outcomes The patients were followed up at the pediatric neurologic clinic regularly. Seizure outcomes were categorized as seizure free, rare seizure or intractable seizure. Intractable seizure was defined as residual seizure with the mean frequency of at least once per month. Developmental outcomes were presented as degrees of developmental delay or retardation. A ‘developmental age’ was assessed according to the Chinese Child Developmental Inventory and Early Inventory Developmental Profile [4]. A patient was considered severely retarded if the developmental age was less than 35% of the chronological age; 35–49%, moderately delayed; 50–69%, mildly delayed; 70–84%, borderline development; and R85%, normal development. 2.3. Statistics Data were presented as meanGSEM. For statistical analysis, we used Statistical Analysis System (SAS) Version 8.2. A P value %0.05 was considered significant.
3. Results 2.1. Treatment protocol 3.1. Demographic characteristics of patients Synthetic ACTH (Cortrosyn, N.V. Organon) was injected intramuscularly at a dose of 2.5 IU (0.025 mg)/kg daily for the first two weeks. If the spasms stopped, the dosing frequency was tapered to once every other day for the next 2 weeks, then twice weekly for another 2 weeks and finally once weekly for 2 weeks. The total dosage was 67.5 IU/kg in a span of 8 weeks. The patient stayed at the pediatric ward in the hospital during the first 2 weeks of treatment for close observation and evaluation. Before ACTH treatment, each patient was examined to exclude concurrent infections, renal, hepatic or immune dysfunction. Body weight, blood pressure, fluid intake, serum electrolyte, urinalysis, urine sugar, and stool occult blood were closely monitored throughout the course of ACTH
Sixty-six WS patients were diagnosed at National Taiwan University Hospital between 1987 and 1998, including 33 males and 33 females. Fifty-four patients (81.8%) were classified as symptomatic and 12 patients (18.2%), cryptogenic. In the symptomatic group, prenatal etiology could be traced in 30 patients (55.6%) while 10 patients (18.5%) were associated with perinatal factors and 11 (20.3%) with postnatal factors. The underlying diseases of the symptomatic cases were listed in Table 1. Of the 66 patients diagnosed as WS, seven did not receive ACTH and were excluded from the study. Among them, one responded to pyridoxine and the other six refused ACTH therapy for fear of the side effects or because of
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Table 1 Underlying conditions of symptomatic type West syndrome Underlying disease
Patient number
%
Neurocutaneous syndromes Tuberous sclerosis Hypomelanosis of Ito Brain malformation Neuronal migration disorder Co-morbid with systemic anomaly Other brain dysgenesis Chromosome anomaly Down syndrome Co-morbid with brain malformation Miller-Dieker syndrome 8p deletion with holoprosencephaly 9q deletion with colpocephaly Asphyxia Prematurity Neurodegenerative diseases Pelizaeus-Merzbacher disease Others Infection Bacterial meningitis Congenital Traumatic brain injury Pyridoxine dependence Hypoxic-ischemic encephalopathy, postnatal Unknown causes Co-morbid with cerebral palsy Co-morbid with early infantile epileptic Encephalopathy Total
9 8 1 6 3
16.7
2 1 4 1 3
11.1
3.2. Response and side effects of ACTH treatment 7.4
1 1 1 8 6 5 1 4 4 3 1 4 1 1
6 2 2 54
and 7 months after ACTH therapy. The average follow-up period was 35.6G3.6 months. The mean age at the time of the last follow-up was 47.8G3.9 months. Demographic characteristics including gender, age of disease onset, treatment lag, and age at initiation of ACTH therapy did not differ between the symptomatic and cryptogenic groups (PO0.05; c2-test or Wilcoxon rank sum test).
14.8 11.1 9.3
7.4
7.4 1.9 1.9
11.1
100
the grave prognosis associated with their underlying diseases (1 with Pelizaes-Merzbacher disease, 2 with lissencephaly, 1 evolving from early myoclonic encephalopathy, 1 with Ebstein anomaly and 1 with tuberous sclerosis). Six patients were lost of follow-up after ACTH treatment despite our vigorous effort of trying to contact them, but the medical information about their treatment responses and long-term outcomes or even the reason of lost of follow-up could not be obtained, so they were excluded from the analysis. A total of 53 patients, 41 symptomatic and 12 cryptogenic, were thus available for analysis. They consisted of 25 males and 28 females. The average age of disease onset was 8.2G1.2 months. The average age when ACTH treatment was started was 11.1G1.4 months. About half were treated within 1 month of spasm onset and the other half, more than 1 month after spasm onset. The average treatment lag was 2.9G0.6 months. All of the 53 patients were followed for at least 1 year to evaluate longterm outcomes, except three patients who expired between 5
Among a total of 53 patients, 46 patients responded to the first course of ACTH therapy and 35 of them remained spasm-free thereafter. The average duration needed for spasms to disappear was 7.1G0.6 days after ACTH therapy started. Among the 46 responders, 11 (20.8%) had relapse of spasms. The mean time before relapse was 4.6G1.8 months. Eight out of these 11 whose spasms relapsed received a second course of ACTH or oral steroid and six of them achieved complete remission. The overall responding rate with spasms free after one or two courses of ACTH was 77.4% (41/53). Whether the patient was classified as symptomatic or cryptogenic did not affect clinical efficacy of ACTH. Eighty-three percent (10/12) of the cryptogenic patients stopped having spasms after ACTH, while 75.6% (31/41) of the symptomatic patients were responders (PO0.05; Fisher’s exact test). Gender, age of disease onset, treatment lag, or age at the time of ACTH therapy, none of them affected the efficacy of ACTH therapy. Most of the patients tolerated well with ACTH treatment. Nine (17%) patients, however, encountered severe side effects, which prompted us to stop ACTH. Six patients had pneumonia; two had Staphylococcus sepsis; and one had a urinary tract infection with Klebsiela and Pseudomonas. No patient expired during or shortly after ACTH therapy. 3.3. Long-term outcomes 3.3.1. Part I, seizure status During the follow-up period of 35.6G3.6 months, 22 (41.5%) patients had intractable seizures other than IS despite vigorous effort of antiepileptic drug therapy. Twenty-five patients (47.2%), all of whom were responders, remained seizure free with or without antiepileptic drugs. Thus, the responders to ACTH had a better chance of remaining seizure free, considering all cases together (P! 0.01) or within the symptomatic group (P!0.05; Fisher’s exact test). Statistical analysis for the cryptogenic group was not applicable due to small sample size. Seizure outcome was not affected by gender (c2-test), etiological classification, age of disease onset, short or long treatment lag, or age when ACTH therapy was started (Fisher’s exact test). Seizure outcomes in relation to the responses of ACTH were shown in Table 2.
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Table 2 Seizure outcomes in relation to the responses of ACTH
All cases (NZ53)
Responder, first course Responders, second course Non-responders Subtotal (% of total) Responder, first course Responder, second course Non-responders Subtotal (% of total) Responder, first course Responder, second course Non-responders Subtotal (% of total)
Symptomatic (NZ41)
Cryptogenic (NZ12)
Seizure free
Rare seizure
Intractable seizure
20 4 1 25 (47.2%) 13 3 1 17(41.5%) 7 1 0 8(66.7%)
3 2 1 6 (11.3%) 2 2 1 5(12.2%) 1 0 0 1(8.3%)
12 0 10 22 (41.5%) 11 0 8 19(46.3%) 1 0 2 3(25.0%)
P*
0.003 0.019
N/A
*Fisher’s exact test; N/A: not applicable due to small sample size.
3.4. Long-term outcomes 3.4.1. Part II, developmental status At the end of the follow-up period, 12 (22.6%) patients had normal or borderline development; two thirds of them belonged to the crytpogenic group. Twenty-four patients (45.3%) were severely retarded; all but one of them belonged to the symptomatic group. Six patients (11.3%) expired from causes not related to ACTH therapy; all of them belonged to the symptomatic group. Thus, the symptomatic group had graver developmental outcomes than the cryptogenic group (P!0.001; Fisher’s exact test). Developmental outcomes in relation to the responses of ACTH were shown in Table 3. All of the 12 patients with normal or borderline development were those who responded to the first course of ACTH without relapse; they consisted of eight cryptogenic and four symptomatic cases. Developmental outcomes were favorable for the responders to first course of ACTH without relapse when WS patients were considered altogether (P!0.05; Fisher’s exact test). However, treatment responses did not favorably predict the developmental outcomes when the patients were symptomatic (PZ0.336; Fisher’s exact test). Statistical
analysis for the cryptogenic group was not applicable due to small sample size. Again, developmental outcome was not affected by gender, age of disease onset, short or long treatment lag, or age when the ACTH therapy was started. There was a correlation between seizure outcome and developmental outcome (P!0.01).
4. Discussion Although ACTH has remained the treatment of choice in many countries for four decades, few patients with WS in Taiwan were treated with ACTH before 1980s. The necessity of hospitalization and the risks of serious side effects made it unpopular. Only two studies so far have been published to address the efficacy of ACTH treatment and the outcomes of the patients with WS in Taiwan [5,6]. The present study contained the largest number of patients and included the longest period of time among all the studies of WS in Taiwan. Symptomatic patients composed 81.8% of our cases diagnosed in the past 10 years. A retrospective national survey by the Taiwan Child Neurology Society, which evaluated West syndrome that occurred in 1998 and 1999 in
Table 3 Developmental outcomes in relation to the responses of ACTH
All cases (NZ53)
Symptomatic (NZ41)
Cryptogenic (NZ12)
Responder, first course Responder, second course Non-responder Subtotal (% of total) Responder, first course Responder, second course Non-responder Subtotal (% of total) Responder, first course Responder, second course Non-responder Subtotal (% of total)
Normal or borderline
Mild or moderate delay
Severely retarded or death
P*
12 0 0 12(22.6%) 4 0 0 4(9.8%) 8 0 0 8(66.7%)
5 3 3 11(20.8%) 5 2 1 8(19.5%) 0 1 2 3(25.0%)
18 3 9 30(56.6%) 17 3 9 29(70.7%) 1 0 0 1(8.3%)
0.034
*Fisher’s exact test; N/A: not applicable due to small sample size.
0.336
N/A
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Taiwan, revealed a similar percentage (77%) [5]. The percentage thus does not seem to change over time. In Western and Japanese studies, 70–90% of West syndrome was symptomatic and 10–30%, cryptogenic [7,8]. In terms of the underlying diseases, a large proportion of our symptomatic patients had asphyxia, which is usually the most common cause reported in other studies [9]. However, asphyxia was outnumbered in this study by brain malformations including neurocutaneous syndrome. This might reflect a higher detection rate of brain malformation and neurocutaneous syndrome by MRI in our series than in other earlier studies. Tuberous sclerosis (14.8%) was the most common single etiology in this study, which is similar to Lombroso’s study [10]. Before vigabatrin was available, hormonal therapy with ACTH and/or prednisolone remains to be the most effective treatment [8,11]. In our study, 77.4% of our WS patients became free of IS after one or two courses of ACTH. The response of Taiwanese patients to ACTH therapy is thus similar to Western or Japanese patients whose response rates are around 60–80% [8,12]. Our study also confirmed the efficacy of a second course of ACTH therapy when IS relapsed. About 75% of the patients with relapse responded and similar experience was found in other studies [8,13]. The choices for the dosage of ACTH and duration of treatment varied among different countries and medical centers. Most of earlier Western studies have used natural ACTH, at higher dosage of ACTH (40–160 units/day) and for a longer duration (3–12 months) [14,15]. When synthetic ACTH became available, it apparently had more adverse effects than natural ACTH and had been used at relatively lower dosage and for a shorter duration. In the study of Fois et al. [16], the therapeutic schedule consisted of daily administration of 2 IU/kg of corticotropin for 10 days with tapering for another 3 weeks. In a survey that investigated the treatment of WS by pediatric neurologists in the United States in 1991, most commonly used dosage of ACTH was 40 IU/day [17]. In Japan, ACTH was used in a dosage as small as 0.4–0.59 IU/kg/day, about 3.8–5.7 IU/day [18]. Our protocol is actually using a medium dose. Since, our medium dosage produced similar efficacy to Japanese protocol but higher incidence of side effects, we should consider changing our protocol to use a lower dosage to minimize the risks of side effects. Until now, there is insufficient evidence to recommend the optimum dosage and duration of treatment with ACTH for WS [19]. The outcomes of WS patients in our study were poor even though they were treated with ACTH. This is probably because most of the patients in this series are symptomatic and have congenital anomalies. Only 12 patients had normal or borderline development and 24 patients were severely retarded. Jeavons et al. [20] reported that in either steroidtreated or untreated patients, the percentage of patients with borderline to normal mentality was about 26%, and the percentage of severe retardation for both groups were both about 50%. They concluded that there was no significant
difference in long-term prognosis whether the patients were treated with steroid or not. The results of long-term prognosis in our study were similar. The overall developmental prognosis for West syndrome remains poor despite of treatment. However, when the patients were divided into symptomatic or cryptogenic groups, there was a difference in longterm prognosis. About 67% of the crytpogenic patients achieved normal or borderline development and remained seizure-free throughout the follow-up period, in contrast to 9.8% of symptomatic patients free of seizure and delayed development. Therefore, the prognosis of WS relies heavily on whether a patient is cryptogenic or symptomatic but not on whether or not he/she was treated with ACTH. The survey by the Taiwan Child Neurology Society in 1998 and 1999 reached the same conclusion [5]. Other factors that frequently reported to influence the long-term outcome favorably are good response to therapy and short treatment lag [7,10]. However, there have been controversies concerning whether they are useful predictors. Some investigators have reported that a higher percentage of patients responding to hormonal therapy show normal intelligence, whereas others have found no differences in long-term outcome between responders and non-responders [13,15]. In this study, good response to ACTH indeed associates with a better developmental outcome when cryptogenic and symptomatic patients were considered altogether. But, it was not true if the symptomatic group was considered alone. Several investigators also reported no difference in developmental outcome between treated and untreated symptomatic patients [13,20,21]. On the other hand, strong evidence suggests that ACTH does alter the prognosis of cryptogenic cases [10]. The favorable outcome of ACTH responders in our study might be attributed to the confounding effect of cryptogenic patients who had a better developmental outcome with treatment. From the point of developmental outcome, it would suggest that ACTH therapy is not justified for symptomatic patients but valuable in cryptogenic patients. As far as treatment lag was concerned, most investigators agreed that ACTH treatment within the first month of disease onset produced favorable long-term prognosis, compared to treatment started after spasms had persisted for more than a month [8,16]. It was especially true in cryptogenic cases. [7,10]. Scientists believe that as long as the hypsarrhythmia exists, the brain cannot process information normally, and that if this abnormal activity persists for a long time, it can lead to retardation. However, some other studies showed that in the symptomatic cases delay in treatment does not affect seizure remission, mental development or educational level at follow-up [13,15,16]. Our study did not show short treatment lag (less than one month) could improve long-term prognosis of West syndrome, probably because most of our cases were symptomatic, and as we mentioned above, treatment or not does not affect the outcome of symptomatic patients.
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Subsequent chronic epilepsy is present in 50–75% of patients if left untreated whether they belonged to symptomatic or cryptogenic group [10,12,15]. In our study, 83.3% of the non-responders had intractable residual seizures, including 80% of symptomatic non-responders and all of crytogenic ones. Seizure outcomes were significantly unfavorable if ACTH therapy failed. Considering the symptomatic group, over half of the responders remained free of seizure during the follow-up period; on the contrary, only 10% of unsuccessfully treated patients remained seizure free. From this point of view, it is justifiable to control the spasms for symptomatic patients with ACTH therapy even though their development outcomes could not be better. At higher doses, ACTH therapy is associated with 15– 25% of severe infection and short-term mortality could be as high as 5–11% [22,23]. While in lower dose between 0.6 and 1.6 IU/kg/day, severe side effects were seldom encountered without decreasing therapeutic efficacy [24,25]. Since, our protocol adopted a medium dosage and a high percentage of our patients suffered severe side effects, future studies in Taiwan may be aimed at finding a lowest dose with the same therapeutic efficacy as the present study when ACTH is considered for treating WS. For symptomatic cases, ACTH should be used more carefully, or other treatments can be tried before ACTH therapy is prescribed. For such a severe epileptic syndrome with poor prognosis as WS, family of patients should be well informed about the choices of treatments, their efficacy, and possible side effects associated with each regimen. A treatment should be started only after thorough discussion between doctors and family and a consensus is made.
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[5] Young C. Taiwan child neurology society. National survey of west syndrome in Taiwan. Brain Dev 2001;23:570–4. [6] Wang MC, Mak SC, Chi CS, Chen CH, Shian WJ. A long-term follow-up study of West syndrome. Zhonghua Yi Xue Za Zi 1994;53: 158–62. [7] Koo B, Hwang PA, Logan WJ. Infantile spasms: outcome and prognostic factors of cryptogenic and symptomatic groups. Neurology 1993;43:2322–7. [8] Riikonen R. Infantile spasms: modern practical aspects. Acta Pediatr Scand 1984;73:1–12. [9] Hrachovy RA, Glaze DG, Frost Jr JD. A retrospective study of spontaneous remission and long-term outcome in patients with infantile spasms. Epilepsia 1991;32:212–4. [10] Lombroso CT. A prospective study of infantile spasms: clinical and therapeutic correlations. Epilepsia 1983;24:135–58. [11] Hrachovy RA, Frost Jr JD. Infantile spasms. Pediatr Clin North Am 1989;36:311–29. [12] Mikati MA, Lepejian GA, Holmes GL. Medical treatment of patients with infantile spasms. Clin Neuropharmacol 2002;25:61–70. [13] Hrachovy RA, Frost Jr JD, Kellaway P, Zion TE. Double-blind study of ACTH vs prednisone therapy in infantile spasms. J Pediatr 1983; 103:641–5. [14] Singer WD, Rabe EF, Haller JS. The effect of ACTH therapy upon infantile spasms. J Pediatr 1980;96:485–9. [15] Glaze DG, Hrachovy RA, Frost Jr JD, Kellaway P, Zion TE. Prospective study of outcome of infants with infantile spasms treated during controlled studies of ACTH and prednisone. J Pediatr 1988; 112:389–96. [16] Fois A, Malandrini F, Balestri P, Giorgi D. Infantile spasms- longterm results of ACTH treatment. Eur J Pediatr 1984;142:51–5. [17] Bobele GB, Bodensteiner JB. The treatment of infantile spasms by child neurologists. J Child Neurol 1994;9:432–5. [18] Ito M. Extremely low-dose ACTH therapy for west syndrome in Japan. Brain Dev 2001;23:635–41. [19] Mackay MT, Weiss SK, Adams-Webber T, Ashwal S, Stephens D, Ballaban-Gill K, et al. Practice parameter: medical treatment of infantile spasms. Neurology 2004;62:1668–81. [20] Jeavons PM, Bower BD, Dimitrakoudi M. Long-term prognosis of 150 cases of ‘ West syndrome’. Epilepsia 1973;14:153–64. [21] Kurokawa T, Goya N, Fukuyama Y, Suzuki M, Seki T, Ohtahara S. West syndrome and Lennox-Gaustaut syndrome: a survey of natural history. Pediatrics 1980;65:81–8. [22] Riikonen R, Donner M. ACTH therapy in infantile spasm: side effects. Arch Dis Child 1980;55:664–72. [23] Shamir R, Garty BZ, Rachmel A, Kivity S, Alpert G. Risk of infection during adrenocorticotropic hormone treatment in infants with infantile spasms. Pediatr Infect Dis J 1993;12:913–6. [24] Yanagaki S, Oguni H, Hayashi K, Imai K, Funatuka M, Tanaka T, et al. A comparative study of high-dose and low-dose ACTH therapy for west syndrome. Brain Dev 1999;21:461–7. [25] Ito M, Okuno T, Fujii T, Mutoh K, Oguro K, Shiraishi H, et al. ACTH therapy in infantile spasms: relationship between dose of ACTH and initial effect or long-term prognosis. Pediatr Neurol 1990;6:240–4.
Original article
ACTH therapy for Taiwanese children with West syndrome—efficacy and impact on long-term prognosis Haung-Chi Lina,*, Chainllie Youngb,d, Pen-Jung Wangc, Wang-Tso Leed, Yu-Zen Shend a
Department of Pediatrics, En Chu Kong Hospital, 399, Fuhsing Road, San-Shia Town, Taipei County, Taiwan, ROC b Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA c Department of Pediatrics, Buddhist Tzu Chi University Hospital, Hua-Lien, Taiwan, ROC d Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan, ROC Received 21 January 2005; received in revised form 28 June 2005; accepted 22 July 2005
Abstract To study the efficacy of adrenocorticotrophic hormone (ACTH) in treating Taiwanese children with West syndrome (WS) and the impact on long-term prognosis, 66 patients with WS (54 symptomatic and 12 cryptogenic) were collected from 1987 to 1998 in a medical center in Taiwan. A total of 53 patients were enrolled in this study and treated with ACTH at the dosage of 2.5 IU/kg daily for 2 weeks with gradual tapering in subsequent 6 weeks. Immediate responses, side effects of ACTH and long-term outcomes of the patients including seizure and developmental status were evaluated during the average follow-up period of 35.6 months. The spasm-free percentage after one or two courses of ACTH treatment was 77.4%. Nine (17%) patients encountered severe side effects such as major infections, which prompted us to stop ACTH. At the end of follow-up, 22 (41.5%) patients had intractable seizures but 25 (47.2%) patients remained seizure free with or without anticonvulsants. The ACTH-responders had a better chance of remaining seizure free (P!0.05). Regarding the long-term developmental outcome, 12 (22.6%) patients had normal or borderline development; two thirds of them belonged to the crytpogenic group. Six (11.3%) patients expired and 24 (45.3%) were severely retarded; all but one of them belonged to the symptomatic group. The prognosis of WS heavily relies on whether a patient is cryptogenic or symptomatic (P!0.001). Good response to therapy or short treatment lag did not favorably affect the developmental outcomes of the symptomatic cases. We conclude that the long-term outcomes of WS in Taiwan were generally poor despite of treatment. Only cryptogenic patients had favorable prognosis. For symptomatic patients, ACTH therapy may be used to control the spasms and decrease the incidence of subsequent epilepsy, but it will not improve developmental outcome. Considering a high percentage of severe side effects in our study, a lower dosage of ACTH with adequate therapeutic efficacy but less side effects should be considered for treating Taiwanese children with WS. q 2005 Published by Elsevier B.V. Keywords: Infantile spasms; Adrenocorticotropic hormone; Long-term outcome; Prognosis
1. Introduction West syndrome (WS) is a severe epileptic syndrome during infancy with distinctive clinical and electroencephalographic (EEG) features. Most WS is refractory to conventional anticonvulsant therapy and the reported long-term outcome is generally poor. In 1958, Sorel and
* Corresponding author. Tel.: C886 2 26723456x6957; fax: C886 2 86710550. E-mail address: [email protected] (H.-C. Lin).
0387-7604/$ - see front matter q 2005 Published by Elsevier B.V. doi:10.1016/j.braindev.2005.07.002
Dusaucy-Bauloye [1] reported that adrenocorticotropic hormone (ACTH) successfully stopped the spasms of patients with WS and improved their EEGs. Until the end of 20th century, ACTH has since remained the treatment of choice in many countries despite its significant adverse effects. As new anticonvulsants effective in treating WS become available, the optimal approach in treating patients of West syndrome raises debate. Evidence and data regarding the efficacy of ACTH and its impact on longterm outcome of patients with West syndrome should be revised. Most reports regarding the efficacy of ACTH in WS or the prognosis of WS, however, were from Western countries and Japan. Data from non-Japanese Asian children with WS are quite limited. In this study, we examined
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the efficacy of ACTH in treating Taiwanese children with WS in the past decade and studied their long-term outcomes.
2. Patients and methods Children diagnosed as West syndrome or Infantile spasms (IS) at National Taiwan University Hospital between 1987 and 1998 were enrolled for this study if they met the following criteria: (1) clinical diagnosis by experienced child neurologists of WS or IS with compatible EEG pattern, including hypsarrythmia or modified hypsarrhythmia; (2) never been treated with ACTH or corticosteroids for WS before; (3) availability of follow-up information, including developmental status and EEGs. Every patient received a three-day trial of pyridoxine (30–50 mg/kg/day) before ACTH was administered. If the patients responded to pyridoxine, there was no need for ACTH therapy. The interval between the onset of spasms and the initiation of ACTH treatment was termed as treatment lag. Treatment lag was regarded as short if it was less than one month, and long if more than 1 month. According to the classification of Epilepsy and Epileptic Syndromes of the International League Against Epilepsy (ILAE) [2], patients were classified into symptomatic and cryptogenic groups. For etiological investigation, every patient received thorough clinical history evaluation, developmental and neurological assessments, neuroimage studies such as computed tomography (CT) or magnetic resonance image (MRI) of the head, chromosomal studies, and metabolic studies including serum amino acids and urine organic acids. Cryptogenic group was defined as (1) normal pregnancy and birth, (2) normal development before the onset of spasms and absence of neurological abnormalities at the onset of spasms, (3) absence of any other types of seizure before the onset of spasms, and (4) negative laboratory and neuroimage findings after adequate investigation [3]. When the criteria for cryptogenic group were not fulfilled, the patient was classified as symptomatic group.
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treatment. Patients were examined for evidence of infection daily during hospital stay. Blood pressure elevations were treated with fluid restriction and/or antihypertensive drugs such as nifedipine and hydralazine if necessary. In case of severe side effects such as serious infection or lifethreatening bleeding, ACTH therapy was stopped immediately. Patients with cessations of spasms and disappearance of hypsarrhythmia at the end of treatment were considered as responders. Those patients whose spasms persisted after 2 weeks of ACTH were non-responders and ACTH was discontinued. If spasms stopped in the first two weeks but relapsed during tapering period or in the follow-up period, a second course of ACTH or oral prednisolone (1– 2 mg/kg/day) was given. 2.2. Assessment of long-term outcomes The patients were followed up at the pediatric neurologic clinic regularly. Seizure outcomes were categorized as seizure free, rare seizure or intractable seizure. Intractable seizure was defined as residual seizure with the mean frequency of at least once per month. Developmental outcomes were presented as degrees of developmental delay or retardation. A ‘developmental age’ was assessed according to the Chinese Child Developmental Inventory and Early Inventory Developmental Profile [4]. A patient was considered severely retarded if the developmental age was less than 35% of the chronological age; 35–49%, moderately delayed; 50–69%, mildly delayed; 70–84%, borderline development; and R85%, normal development. 2.3. Statistics Data were presented as meanGSEM. For statistical analysis, we used Statistical Analysis System (SAS) Version 8.2. A P value %0.05 was considered significant.
3. Results 2.1. Treatment protocol 3.1. Demographic characteristics of patients Synthetic ACTH (Cortrosyn, N.V. Organon) was injected intramuscularly at a dose of 2.5 IU (0.025 mg)/kg daily for the first two weeks. If the spasms stopped, the dosing frequency was tapered to once every other day for the next 2 weeks, then twice weekly for another 2 weeks and finally once weekly for 2 weeks. The total dosage was 67.5 IU/kg in a span of 8 weeks. The patient stayed at the pediatric ward in the hospital during the first 2 weeks of treatment for close observation and evaluation. Before ACTH treatment, each patient was examined to exclude concurrent infections, renal, hepatic or immune dysfunction. Body weight, blood pressure, fluid intake, serum electrolyte, urinalysis, urine sugar, and stool occult blood were closely monitored throughout the course of ACTH
Sixty-six WS patients were diagnosed at National Taiwan University Hospital between 1987 and 1998, including 33 males and 33 females. Fifty-four patients (81.8%) were classified as symptomatic and 12 patients (18.2%), cryptogenic. In the symptomatic group, prenatal etiology could be traced in 30 patients (55.6%) while 10 patients (18.5%) were associated with perinatal factors and 11 (20.3%) with postnatal factors. The underlying diseases of the symptomatic cases were listed in Table 1. Of the 66 patients diagnosed as WS, seven did not receive ACTH and were excluded from the study. Among them, one responded to pyridoxine and the other six refused ACTH therapy for fear of the side effects or because of
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Table 1 Underlying conditions of symptomatic type West syndrome Underlying disease
Patient number
%
Neurocutaneous syndromes Tuberous sclerosis Hypomelanosis of Ito Brain malformation Neuronal migration disorder Co-morbid with systemic anomaly Other brain dysgenesis Chromosome anomaly Down syndrome Co-morbid with brain malformation Miller-Dieker syndrome 8p deletion with holoprosencephaly 9q deletion with colpocephaly Asphyxia Prematurity Neurodegenerative diseases Pelizaeus-Merzbacher disease Others Infection Bacterial meningitis Congenital Traumatic brain injury Pyridoxine dependence Hypoxic-ischemic encephalopathy, postnatal Unknown causes Co-morbid with cerebral palsy Co-morbid with early infantile epileptic Encephalopathy Total
9 8 1 6 3
16.7
2 1 4 1 3
11.1
3.2. Response and side effects of ACTH treatment 7.4
1 1 1 8 6 5 1 4 4 3 1 4 1 1
6 2 2 54
and 7 months after ACTH therapy. The average follow-up period was 35.6G3.6 months. The mean age at the time of the last follow-up was 47.8G3.9 months. Demographic characteristics including gender, age of disease onset, treatment lag, and age at initiation of ACTH therapy did not differ between the symptomatic and cryptogenic groups (PO0.05; c2-test or Wilcoxon rank sum test).
14.8 11.1 9.3
7.4
7.4 1.9 1.9
11.1
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the grave prognosis associated with their underlying diseases (1 with Pelizaes-Merzbacher disease, 2 with lissencephaly, 1 evolving from early myoclonic encephalopathy, 1 with Ebstein anomaly and 1 with tuberous sclerosis). Six patients were lost of follow-up after ACTH treatment despite our vigorous effort of trying to contact them, but the medical information about their treatment responses and long-term outcomes or even the reason of lost of follow-up could not be obtained, so they were excluded from the analysis. A total of 53 patients, 41 symptomatic and 12 cryptogenic, were thus available for analysis. They consisted of 25 males and 28 females. The average age of disease onset was 8.2G1.2 months. The average age when ACTH treatment was started was 11.1G1.4 months. About half were treated within 1 month of spasm onset and the other half, more than 1 month after spasm onset. The average treatment lag was 2.9G0.6 months. All of the 53 patients were followed for at least 1 year to evaluate longterm outcomes, except three patients who expired between 5
Among a total of 53 patients, 46 patients responded to the first course of ACTH therapy and 35 of them remained spasm-free thereafter. The average duration needed for spasms to disappear was 7.1G0.6 days after ACTH therapy started. Among the 46 responders, 11 (20.8%) had relapse of spasms. The mean time before relapse was 4.6G1.8 months. Eight out of these 11 whose spasms relapsed received a second course of ACTH or oral steroid and six of them achieved complete remission. The overall responding rate with spasms free after one or two courses of ACTH was 77.4% (41/53). Whether the patient was classified as symptomatic or cryptogenic did not affect clinical efficacy of ACTH. Eighty-three percent (10/12) of the cryptogenic patients stopped having spasms after ACTH, while 75.6% (31/41) of the symptomatic patients were responders (PO0.05; Fisher’s exact test). Gender, age of disease onset, treatment lag, or age at the time of ACTH therapy, none of them affected the efficacy of ACTH therapy. Most of the patients tolerated well with ACTH treatment. Nine (17%) patients, however, encountered severe side effects, which prompted us to stop ACTH. Six patients had pneumonia; two had Staphylococcus sepsis; and one had a urinary tract infection with Klebsiela and Pseudomonas. No patient expired during or shortly after ACTH therapy. 3.3. Long-term outcomes 3.3.1. Part I, seizure status During the follow-up period of 35.6G3.6 months, 22 (41.5%) patients had intractable seizures other than IS despite vigorous effort of antiepileptic drug therapy. Twenty-five patients (47.2%), all of whom were responders, remained seizure free with or without antiepileptic drugs. Thus, the responders to ACTH had a better chance of remaining seizure free, considering all cases together (P! 0.01) or within the symptomatic group (P!0.05; Fisher’s exact test). Statistical analysis for the cryptogenic group was not applicable due to small sample size. Seizure outcome was not affected by gender (c2-test), etiological classification, age of disease onset, short or long treatment lag, or age when ACTH therapy was started (Fisher’s exact test). Seizure outcomes in relation to the responses of ACTH were shown in Table 2.
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Table 2 Seizure outcomes in relation to the responses of ACTH
All cases (NZ53)
Responder, first course Responders, second course Non-responders Subtotal (% of total) Responder, first course Responder, second course Non-responders Subtotal (% of total) Responder, first course Responder, second course Non-responders Subtotal (% of total)
Symptomatic (NZ41)
Cryptogenic (NZ12)
Seizure free
Rare seizure
Intractable seizure
20 4 1 25 (47.2%) 13 3 1 17(41.5%) 7 1 0 8(66.7%)
3 2 1 6 (11.3%) 2 2 1 5(12.2%) 1 0 0 1(8.3%)
12 0 10 22 (41.5%) 11 0 8 19(46.3%) 1 0 2 3(25.0%)
P*
0.003 0.019
N/A
*Fisher’s exact test; N/A: not applicable due to small sample size.
3.4. Long-term outcomes 3.4.1. Part II, developmental status At the end of the follow-up period, 12 (22.6%) patients had normal or borderline development; two thirds of them belonged to the crytpogenic group. Twenty-four patients (45.3%) were severely retarded; all but one of them belonged to the symptomatic group. Six patients (11.3%) expired from causes not related to ACTH therapy; all of them belonged to the symptomatic group. Thus, the symptomatic group had graver developmental outcomes than the cryptogenic group (P!0.001; Fisher’s exact test). Developmental outcomes in relation to the responses of ACTH were shown in Table 3. All of the 12 patients with normal or borderline development were those who responded to the first course of ACTH without relapse; they consisted of eight cryptogenic and four symptomatic cases. Developmental outcomes were favorable for the responders to first course of ACTH without relapse when WS patients were considered altogether (P!0.05; Fisher’s exact test). However, treatment responses did not favorably predict the developmental outcomes when the patients were symptomatic (PZ0.336; Fisher’s exact test). Statistical
analysis for the cryptogenic group was not applicable due to small sample size. Again, developmental outcome was not affected by gender, age of disease onset, short or long treatment lag, or age when the ACTH therapy was started. There was a correlation between seizure outcome and developmental outcome (P!0.01).
4. Discussion Although ACTH has remained the treatment of choice in many countries for four decades, few patients with WS in Taiwan were treated with ACTH before 1980s. The necessity of hospitalization and the risks of serious side effects made it unpopular. Only two studies so far have been published to address the efficacy of ACTH treatment and the outcomes of the patients with WS in Taiwan [5,6]. The present study contained the largest number of patients and included the longest period of time among all the studies of WS in Taiwan. Symptomatic patients composed 81.8% of our cases diagnosed in the past 10 years. A retrospective national survey by the Taiwan Child Neurology Society, which evaluated West syndrome that occurred in 1998 and 1999 in
Table 3 Developmental outcomes in relation to the responses of ACTH
All cases (NZ53)
Symptomatic (NZ41)
Cryptogenic (NZ12)
Responder, first course Responder, second course Non-responder Subtotal (% of total) Responder, first course Responder, second course Non-responder Subtotal (% of total) Responder, first course Responder, second course Non-responder Subtotal (% of total)
Normal or borderline
Mild or moderate delay
Severely retarded or death
P*
12 0 0 12(22.6%) 4 0 0 4(9.8%) 8 0 0 8(66.7%)
5 3 3 11(20.8%) 5 2 1 8(19.5%) 0 1 2 3(25.0%)
18 3 9 30(56.6%) 17 3 9 29(70.7%) 1 0 0 1(8.3%)
0.034
*Fisher’s exact test; N/A: not applicable due to small sample size.
0.336
N/A
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Taiwan, revealed a similar percentage (77%) [5]. The percentage thus does not seem to change over time. In Western and Japanese studies, 70–90% of West syndrome was symptomatic and 10–30%, cryptogenic [7,8]. In terms of the underlying diseases, a large proportion of our symptomatic patients had asphyxia, which is usually the most common cause reported in other studies [9]. However, asphyxia was outnumbered in this study by brain malformations including neurocutaneous syndrome. This might reflect a higher detection rate of brain malformation and neurocutaneous syndrome by MRI in our series than in other earlier studies. Tuberous sclerosis (14.8%) was the most common single etiology in this study, which is similar to Lombroso’s study [10]. Before vigabatrin was available, hormonal therapy with ACTH and/or prednisolone remains to be the most effective treatment [8,11]. In our study, 77.4% of our WS patients became free of IS after one or two courses of ACTH. The response of Taiwanese patients to ACTH therapy is thus similar to Western or Japanese patients whose response rates are around 60–80% [8,12]. Our study also confirmed the efficacy of a second course of ACTH therapy when IS relapsed. About 75% of the patients with relapse responded and similar experience was found in other studies [8,13]. The choices for the dosage of ACTH and duration of treatment varied among different countries and medical centers. Most of earlier Western studies have used natural ACTH, at higher dosage of ACTH (40–160 units/day) and for a longer duration (3–12 months) [14,15]. When synthetic ACTH became available, it apparently had more adverse effects than natural ACTH and had been used at relatively lower dosage and for a shorter duration. In the study of Fois et al. [16], the therapeutic schedule consisted of daily administration of 2 IU/kg of corticotropin for 10 days with tapering for another 3 weeks. In a survey that investigated the treatment of WS by pediatric neurologists in the United States in 1991, most commonly used dosage of ACTH was 40 IU/day [17]. In Japan, ACTH was used in a dosage as small as 0.4–0.59 IU/kg/day, about 3.8–5.7 IU/day [18]. Our protocol is actually using a medium dose. Since, our medium dosage produced similar efficacy to Japanese protocol but higher incidence of side effects, we should consider changing our protocol to use a lower dosage to minimize the risks of side effects. Until now, there is insufficient evidence to recommend the optimum dosage and duration of treatment with ACTH for WS [19]. The outcomes of WS patients in our study were poor even though they were treated with ACTH. This is probably because most of the patients in this series are symptomatic and have congenital anomalies. Only 12 patients had normal or borderline development and 24 patients were severely retarded. Jeavons et al. [20] reported that in either steroidtreated or untreated patients, the percentage of patients with borderline to normal mentality was about 26%, and the percentage of severe retardation for both groups were both about 50%. They concluded that there was no significant
difference in long-term prognosis whether the patients were treated with steroid or not. The results of long-term prognosis in our study were similar. The overall developmental prognosis for West syndrome remains poor despite of treatment. However, when the patients were divided into symptomatic or cryptogenic groups, there was a difference in longterm prognosis. About 67% of the crytpogenic patients achieved normal or borderline development and remained seizure-free throughout the follow-up period, in contrast to 9.8% of symptomatic patients free of seizure and delayed development. Therefore, the prognosis of WS relies heavily on whether a patient is cryptogenic or symptomatic but not on whether or not he/she was treated with ACTH. The survey by the Taiwan Child Neurology Society in 1998 and 1999 reached the same conclusion [5]. Other factors that frequently reported to influence the long-term outcome favorably are good response to therapy and short treatment lag [7,10]. However, there have been controversies concerning whether they are useful predictors. Some investigators have reported that a higher percentage of patients responding to hormonal therapy show normal intelligence, whereas others have found no differences in long-term outcome between responders and non-responders [13,15]. In this study, good response to ACTH indeed associates with a better developmental outcome when cryptogenic and symptomatic patients were considered altogether. But, it was not true if the symptomatic group was considered alone. Several investigators also reported no difference in developmental outcome between treated and untreated symptomatic patients [13,20,21]. On the other hand, strong evidence suggests that ACTH does alter the prognosis of cryptogenic cases [10]. The favorable outcome of ACTH responders in our study might be attributed to the confounding effect of cryptogenic patients who had a better developmental outcome with treatment. From the point of developmental outcome, it would suggest that ACTH therapy is not justified for symptomatic patients but valuable in cryptogenic patients. As far as treatment lag was concerned, most investigators agreed that ACTH treatment within the first month of disease onset produced favorable long-term prognosis, compared to treatment started after spasms had persisted for more than a month [8,16]. It was especially true in cryptogenic cases. [7,10]. Scientists believe that as long as the hypsarrhythmia exists, the brain cannot process information normally, and that if this abnormal activity persists for a long time, it can lead to retardation. However, some other studies showed that in the symptomatic cases delay in treatment does not affect seizure remission, mental development or educational level at follow-up [13,15,16]. Our study did not show short treatment lag (less than one month) could improve long-term prognosis of West syndrome, probably because most of our cases were symptomatic, and as we mentioned above, treatment or not does not affect the outcome of symptomatic patients.
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Subsequent chronic epilepsy is present in 50–75% of patients if left untreated whether they belonged to symptomatic or cryptogenic group [10,12,15]. In our study, 83.3% of the non-responders had intractable residual seizures, including 80% of symptomatic non-responders and all of crytogenic ones. Seizure outcomes were significantly unfavorable if ACTH therapy failed. Considering the symptomatic group, over half of the responders remained free of seizure during the follow-up period; on the contrary, only 10% of unsuccessfully treated patients remained seizure free. From this point of view, it is justifiable to control the spasms for symptomatic patients with ACTH therapy even though their development outcomes could not be better. At higher doses, ACTH therapy is associated with 15– 25% of severe infection and short-term mortality could be as high as 5–11% [22,23]. While in lower dose between 0.6 and 1.6 IU/kg/day, severe side effects were seldom encountered without decreasing therapeutic efficacy [24,25]. Since, our protocol adopted a medium dosage and a high percentage of our patients suffered severe side effects, future studies in Taiwan may be aimed at finding a lowest dose with the same therapeutic efficacy as the present study when ACTH is considered for treating WS. For symptomatic cases, ACTH should be used more carefully, or other treatments can be tried before ACTH therapy is prescribed. For such a severe epileptic syndrome with poor prognosis as WS, family of patients should be well informed about the choices of treatments, their efficacy, and possible side effects associated with each regimen. A treatment should be started only after thorough discussion between doctors and family and a consensus is made.
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