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West syndrome: the Philippine experience
Brain & Development 23 (2001) 616–623 www.elsevier.com/locate/braindev
Original article
West syndrome: the Philippine experience Aida M. Salonga a,*, Marissa B. Lukban a, Marilyn H. Ortiz b, Bernadette Balatero-Terencio a, Ana Marissa Lagman a a
Department of Pediatrics, University of the Philippines-Philippine General Hospital, Taft Avenue, Manila, Philippines b Child Neuroscience Division, Philippine Children’s Medical Center, Quezon City, Philippines Received 16 March 2001; received in revised form 1 June 2001; accepted 4 June 2001
Abstract Aim: To provide information on the current status of West syndrome (WS) in the Philippines. Methods: This is a retrospective review of WS cases from January 1997 to December 1999 from two largest referral government institutions. A questionnaire interview survey on anticonvulsant usage was also conducted among practicing child neurologists. Results: Twelve patients diagnosed to have infantile spasms at 2–15 months were included, with a male:female ratio of 1:1. The proportion of WS cases among epileptic children under age 3 was 3.18%. The etiologies were idiopathic/cryptogenic in four (33%) and symptomatic in eight (66%). Symptomatic cases include hypoxic-ischemic encephalopathy, neonatal sepsis, bacterial meningitis, inborn error of metabolism, congenital brain anomaly and intracranial hemorrhage. Phenobarbital was the first line drug in 75% of cases. Other drugs used were valproic acid, clonazepam and pyridoxine. With a follow-up duration of 1–40 months, only three patients became seizure free and most had poor neurodevelopmental outcome. Among practicing child neurologists, the preferred ideal drug was adrenocorticotrophic hormone (ACTH) and valproic acid for idiopathic and symptomatic cases, respectively. However, in actual clinical practice valproic acid or prednisone was the initial drug used. Pyridoxine was usually added on. Conclusions: The proportion of WS in our patient population may not reflect the true prevalence in our country since our data came from a biased population, i.e. referral centers. A national statistics is currently not available. ACTH, which was perceived by most child neurologists as the ideal first line drug was not used primarily because it is unavailable and unaffordable. The poor seizure control and developmental outcome may be due to the treatment given or directly related to the etiology of WS. q 2001 Published by Elsevier Science B.V. Keywords: Infantile spasm; West syndrome
1. Introduction The Philippines is a tropical country with 7100 islands lying in the Pacific Ocean and off the coast of Southeast Asia. It has an estimated population of about 72 million in 2000 and the average population density is 243 per square kilometer. Presently, there are 26 certified child neurologists and about 140 certified adult neurologists serving the country with more than 50% based in the national capital region, giving us a neurologist to population ratio of about 1/ 700,000. There are at present three training institutions for child neurology with an average output of two to three child neurologists per year. The University of the PhilippinesPhilippine General Hospital Medical Center (UPPGH), a general hospital with 1500 bed capacity and Philippine Chil-
* Corresponding author. Tel.: 163-2-524-0892; fax: 163-2-526-0150. E-mail address: [email protected] (A.M. Salonga). 0387-7604/01/$ - see front matter q 2001 Published by Elsevier Science B.V. PII: S03 87- 7604(01)0029 7-2
dren’s Medical Center (PCMC), a 200 bed children’s hospital are the two major government referral centers for children, serving the less privileged sector of the country. From 1997 to 1999 there were 5985 and 4584 outpatient consults related to childhood seizure and epilepsy at the UPPGH and PCMC, respectively. In the Philippines, there are no available statistics on West syndrome (WS) and other related epileptic syndromes. We are still in the planning stage for setting up a National Epilepsy Registry. Our data on the epilepsies, in general, are primarily hospital based. Antiepileptic drugs (AED) used are also varied among practicing child neurologists. The success in controlling infantile spasms (IS), however, has not been evaluated. This study aims to provide information concerning the current status of WS in the Philippines and share the current practice of Filipino child neurologists in the management of IS.
A.M. Salonga et al. / Brain & Development 23 (2001) 616–623
2. Methodology The study was prepared in two parts. Part I describes a hospital based survey of WS in two major pediatric centers, UPPGH and PCMC. Part II describes the current practice of pediatric neurologists in the management of IS. Part 1: Medical records of patients 3 years of age or younger who were diagnosed to have epilepsy at UPPGH and PCMC were reviewed. Definite cases of WS from January 1997 to December 1999 were collected and analyzed using formulated questionnaire. The following data were collected: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
Patient’s sex. Age of onset of seizure or spasm. Age of diagnosis of IS. Age at first and last consultation (duration of neurologic follow-up). Clinical features of seizure event, presence or absence of atypical features. Electroencephalographic (EEG) findings. Brain imaging studies. Etiology of IS, if identified. AEDs used. Neurodevelopmental status at first and last consult (using Denver developmental test). Seizure outcome.
2.1. Definition of terms WS is defined as an epilepsy syndrome with the following characteristics [1]: 1. Seizures presenting as IS. 2. Presence or development of psychomotor retardation. 3. EEG features showing hypsarrhythmia.
617
Etiology [2] Cryptogenic: those patients in whom no etiologic cause can be identified or those who in addition have normal development before the onset of spasms. Symptomatic: those patients with definite etiologic factors identified and having abnormal mental and/or neurodevelopmental development prior to onset of spasms. Part II: A questionnaire survey was presented to practicing pediatric neurologists in the country. Responses were gathered by either actual or telephone interviews (Appendix A). Twenty-one out of the 26 board certified child neurologists responded. 3. Results 3.1. Part I During the study period (1997–1999), there were 154 and 223 new cases of childhood epilepsy in children under 3 years of age from UPPGH and PCMC, respectively. Twelve definite cases of WS were identified, four from UPPGH and eight from PCMC. The proportion of WS cases among our total epileptic children under age 3 is thus 3.18%. 3.2. Clinical features (Table 1) The ages of first consult ranged from 2 to 15 months with a male to female ratio of 1:1. Total duration of follow-up was 1–40 months. Four children (33%) had onset of IS before 3 months of age. The youngest case (Case No. 4) reported clusters of spasms at 3 weeks of age but was diagnosed to have WS only at 4 months. Five children (42%) had onset of seizures between 3 and 7 months of age, which is the maximum incidence of IS reported. The remaining three children (25%) had onset of spasms at 8 months of age.
Table 1 Clinical features of WS cases a Patient No.
Etiology
Onset of spasms (months)
1 2 3 4 5 6
Cryptogenic HIE HIE Cryptogenic HIE Inborn metabolic disorder Intracranial hemorrhage Neonatal sepsis Congenital brain malformation Bacterial meningitis Cryptogenic Cryptogenic
3 4 3 0.75 7 1.5
7 8 9 10 11 12 a
Diagnosis of IS (months)
Duration of follow-up (months)
EEG (typical/atypical)
Brain imaging CUS/CT/MRI
5 4 5 4 7 4
1 40 6 8 30 1
T T T T T T
Normal Brain atrophy Normal Normal Encephalomalacic changes Brain atrophy
8 2 2
8 2 2
12 40 11
A T T
Encephalomalacic changes Brain atrophy Pachygyria
8 8 6
8 8 15
7 15 22
T T T
Brain atrophy Normal Not done
HIE, hypoxic–ischemic encephalopathy; CUS, cranial ultrasound.
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A.M. Salonga et al. / Brain & Development 23 (2001) 616–623
The diagnosis of IS was made during the first consultation after the onset of the seizures in seven cases (58%). For the remaining five cases (42%) the consultation and diagnosis were delayed for 2–9 months. 3.3. Etiology of WS There were no identified etiologies in four cases (33%). Three of these cases were reported to have normal development prior to the onset of IS. The other patient (Case No. 4) was the infant with reported spasms in the neonatal period. This patient was noted to be developmentally delayed during her initial consultation at 4 months of age. Apart from a cranial ultrasound which was normal, this patient, however, did not benefit from further work-up. Among the eight symptomatic cases (66%), three had hypoxic-ischemic encephalopathy (HIE) secondary to severe perinatal asphyxia at birth and one had a history of sepsis and hyperbilirubinemia during the first week of life. Three of these children with perinatal neurologic insults had onset of spasms between 2 and 4 months of age. One patient had intracranial hemorrhage at 3 months of age secondary to acquired prothrombin complex deficiency (APCD) and one infant had bacterial meningitis also at 3 months of age. Both children had onset of IS at 8 months of age or 5 months after the neurologic insult. One patient had multiple dysmorphic features and was found to have pachygyria on computerized tomography (CT) scan. The other patient (Case No. 6) had abnormal urine metabolic screen although the exact metabolic disorder was not identified. His IS started at 1.5 months of age but diagnosis was delayed at 4 months. Brain atrophy was seen on magnetic resonance imaging (MRI). 3.4. Neurodiagnostic tests Cranial ultrasound was performed in eight cases. There were four normal studies and three of the four patients with normal cranial ultrasounds were classified as idiopathic/ cryptogenic cases. The other child with a normal ultrasound had a history of perinatal asphyxia (Case No. 3). Four cases showed abnormal cranial ultrasound studies. Two of the abnormal cranial ultrasounds showed cerebral atrophy (Case Nos. 2 and 8). The other two cases showed encephalomalacic changes. This included one child with history of perinatal asphyxia (Case No. 5) and the other child had postnatal subdural hematoma due to APCD (Case No. 7). CT scan was performed in two children, one with pachygyria and the other with brain atrophy. The child with suspected inborn error of metabolism showed cerebral atrophy on MRI. One child diagnosed to have cryptogenic WS had no brain imaging study performed. EEG showed typical hypsarrhythmia in 11 cases (92%). The child diagnosed to have intracranial hemorrhage due to APCD (Case No. 7) showed significant asymmetry with
voltage attenuation and epileptiform discharges predominantly on the side of the previous hematoma. 3.5. AED usage The initial AED used was phenobarbital in nine patients (75%), valproic acid in two cases (17%) and clonazepam in one patient (8%). Clonazepam was added on in five patients who did not respond to phenobarbital. There was no improvement of spasms with this combination. Two cases classified as cryptogenic had control of spasms at 6 and 19 months, respectively (Case Nos. 11 and 12). Both were on a combination of phenobarbital and valproic acid. The other child who had control of spasms after 30 months, classified as symptomatic, was on a combination of phenobarbital, valproic acid and clonazepam. Pyridoxine was added in the latter part of the follow-up in two patients (17%). 3.6. Seizure and neurodevelopmental outcome (Table 2) Two patients (Case Nos. 1 and 6) had only one outpatient follow-up within a month after diagnosis and thus observation for seizure and neurodevelopmental outcome is inadequate. Both had no change in the seizure type and frequency. These children were classified as cryptogenic cases. The other two remaining cryptogenic cases had control of spasms at 6 and 19 months, respectively. Both were developmentally normal at the onset of seizures and at last consultation (15–22 months follow-up), both were able to walk independently but had language and cognitive difficulties. All the eight (66%) patients classified as symptomatic cases were neurodevelopmentally delayed at first consultation. Seven of the eight cases had severe global developmental delay from the first to the last consultation. The only child with mild delay was the child who had intracranial hematoma due to APCD at 3 months of age (Case No. 4). He had residual hemiplegia and thus delayed motor development prior to the onset of spasms at 8 months. His spasms persisted but decreased in frequency during the 12 months follow-up. At 1 year of age he remains unable to stand independently but has social play and utters monosyllable words. The other seven symptomatic cases remained severely developmentally delayed, most without visual eye contact and no language development. Only one child in the symptomatic group became seizure free at 30 months of age (Case No. 8). The spasms persisted but decreased in frequency in three cases (Case Nos. 7, 9 and 10). One child (Case No. 2) reverted to Lennox Gastaut syndrome after 1 year. 3.7. Part II There were 21 respondents, with areas of practice in Metro Manila (76%), Luzon Province (14%) and Visayas Province (10%). Ten respondents (48%) have been practi-
A.M. Salonga et al. / Brain & Development 23 (2001) 616–623
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Table 2 Seizure and developmental outcome a Patient No.
1 2 3 4 5 6 7 8 9 10 11 12 a
Etiology
Onset of spasms (months)
Cryptogenic HIE HIE Cryptogenic HIE Inborn metabolic disorder Intracranial hemorrhage Neonatal sepsis Congenital brain malformation Bacterial meningitis Cryptogenic Cryptogenic
3 4 3 0.75 7 1.5 8 2 2 8 8 6
AED
PB CZP PB PB PB PB VPA PB PB PB VPA PB
Developmental status
Seizure outcome
First consult
Last consult
Normal Severe delay Severe delay Severe delay Severe delay Severe delay Mild delay Severe delay Severe delay Severe delay Normal Normal
? Severe delay Severe delay Severe delay Severe delay ? Mild delay Severe delay Severe delay Severe delay Mild delay Mild delay
? Changed to mixed type Persisting unchanged Persisting unchanged Persisting unchanged ? Persisting less severe Controlled at 30 months Persisting less severe Persisting less severe Controlled at 6 months Controlled at 19 months
AED, antiepileptic drug; HIE, hypoxic-ischemic encephalopathy; CZP, clonazepam; PB, phenobarbital; VPA, valproic acid.
cing child neurology for 5–10 years. Eight neurologists (38%) have been practicing for more than 10 years and three (14%) for less than 5 years.
3.8. Drugs of choice for the treatment of idiopathic/ cryptogenic IS (Tables 3 and 4) Most of the respondents believe that ACTH/prednisone (71%) followed by valproic acid (14%) ideally was the drug of first choice for IS. Valproic acid (43%) followed by clonazepam (28%) was the second choice for most respondents. Valproic acid (28%) followed by topiramate (14%) and vigabatrin (14%) was the third choice for most child neurologists. In actual practice, prednisone (38%) and valproic acid (38%) were equally used as first line drug. As second most commonly used drug, clonazepam (33%), valproic acid (28%) and prednisone (24%) were used. Phenobarbital is the third drug added on after prednisone, valproic acid and clonazepam have been started. A number of respondents have subsequently used vigabatrin and topiramate as alternative drugs for resistant cases.
3.9. Drugs of choice for the treatment of symptomatic IS (Tables 5 and 6) In the treatment of symptomatic cases, most of the respondents believe that valproic acid (43%) followed by ACTH (38%) ideally was the drug of first choice. Clonazepam (38%) followed by valproic acid (28%) was the second choice for most respondents. ACTH and valproic acid (24% each) followed by clonazepam (19%) was the third choice for most child neurologists. Topiramate (28%) followed by phenobarbital (14%) and vigabatrin (14%) was believed to be an alternative ideal drug for resistant cases. In actual practice, similar to the adhered ideal choices, valproic acid (57%) followed by prednisone (19%) was used as first line drug. As second most commonly used drug, clonazepam (48%) followed by valproic acid (19%) was used. For those who have not started either valproic acid or prednisone as first and second drugs used, these two drugs are added on as a third drug. Clonazepam was a third choice. Twenty-eight percent have used topiramate as the last choice after the other conventional drugs have been tried. Phenobarbital and vigabatrin (14% each) are also last choices as add on treatment for resistant cases.
Table 3 Ideal drugs of choice for idiopathic/cryptogenic IS Drugs
First choice # (%)
Second choice # (%)
Third choice # (%)
Fourth choice # (%)
ACTH/prednisone Phenobarbital Valproic acid Clonazepam Carbamazepine Phenytoin Topiramate Lamotrigine Gabapentin Vigabatrin Total
15 (71) 2 (10) 3 (14) 0 0 0 0 0 0 1 (5) 21 (100)
3 (14) 0 9 (43) 6 (28) 0 0 0 0 1 (5) 2 (10) 21
2 (10) 2 (10) 6 (28) 3 (14) 0 0 3 (14) 1 (5) 0 3 (14) 20 (95)
1 (5) 1 (5) 2 (10) 4 (19) 0 0 5 (24) 1 (5) 0 3 (14) 17 (81)
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Table 4 Actual drugs used of choice for treatment of idiopathic/cryptogenic IS Drugs ACTH/prednisone Phenobarbital Valproic acid Clonazepam Carbamazepine Phenytoin Topiramate Lamotrigine Gabapentin Vigabatrin Total
First choice # (%) 8 (38) 2 (10) 8 (38) 1 (5) 0 0 0 1 (5) 0 0 20 (95)
Second choice # (%)
Third choice # (%)
Fourth choice # (%)
5 1 6 7 0 0 1 0 0 1 21
4 (19) 3 (14) 3 (14) 4 (19) 0 0 1 (5) 1 (5) 0 3 (14) 21 (100)
1 1 3 4 0 0 6 1 0 0 16
(24) (5) (28) (33)
(5)
(5) (100)
3.10. Use of pyridoxine in IS Regarding the use of pyridoxine, eight out of 21 (38%) child neurologists gave the drug before starting other anticonvulsants. Six out of eight (75%) used pyridoxine initially for both idiopathic and symptomatic cases. Two out of eight (25%) tried pyridoxine for idiopathic cases only and only one believed it achieved at least 50% control of seizures. Thirteen out of 21 (62%) used pyridoxine as add on drug together with other anticonvulsants. Of the 13 who used pyridoxine as add on drug, nine (69%) reported no added benefit of the addition of pyridoxine in the control of seizures.
4. Discussion The proportion of WS in our patient population may not reflect the true prevalence in our country since our data came from a biased population, i.e. referral centers. In addition, our centers are both government funded institutions serving the indigent members of the society, mostly children with unemployed parents. This may in part explain the etiologies of our symptomatic cases. Four cases are due to poor neonatal care presenting with perinatal asphyxia and neonatal sepsis. The other two cases, bacterial meningitis and
(5) (5) (14) (19)
(28) (5)
(76)
postnatal intracranial hemorrhage due to acquired prothrombin deficiency reflects inadequate infant care as these cases are preventable with immunization and vitamin K supplementation, respectively. As seen in reported literature [1], majority of our cases had onset of spasms at age 4–7 months. However, our data also presented a significant number (33%) of IS occurring before the fourth month of life, mostly symptomatic cases. One child in our series of studies reported clusters of spasms at 3 weeks of age and persisted until age 4 months when the diagnosis of IS was given. This child is severely developmentally delayed at the onset and although he was classified as cryptogenic because of the absence of a definite etiology, we surmise that if given more opportunities for extensive work-up an etiology might be discovered. According to Aicardi [1], cases with neonatal onset are on record but unusual. We also observed that the cases with delayed onset of spasms (8 months) were seen in two cases with neurologic insults occurring at a much later age of 3 months. EEG showed typical hypsarrhythmia in the majority of cases. It is noteworthy that the only child with atypical EEG pattern because of a significant voltage attenuation and asymmetrical frequency of epileptiform discharges showed a history of a focal destructive lesion due to intracranial hemorrhage prior to the onset of IS. Cranial ultrasound has been a useful armamentarium for
Table 5 Ideal drugs of choice for symptomatic IS Drugs ACTH/prednisone Phenobarbital Valproic acid Clonazepam Carbamazepine Phenytoin Topiramate Lamotrigine Gabapentin Vigabatrin Total
First choice # (%) 8 (38) 2 (10) 9 (43) 1 (5) 0 0 0 1 (5) 0 0 21 (100)
Second choice # (%)
Third choice # (%)
Fourth choice # (%)
2 0 6 8 0 0 3 0 1 1 21
5 (24) 1 (5) 5 (24) 4 (19) 0 0 1 (5) 1 (5) 0 2 (10) 19 (92)
0 3 0 2 0 0 6 1 0 3 15
(10) (28) (38)
(14) (5) (5) (100)
(14) (10)
(28) (5) (14) (71)
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Table 6 Actual drugs used for treatment of symptomatic IS Drugs
First choice # (%)
Second choice # (%)
Third choice # (%)
Fourth choice # (%)
ACTH/Prednisone Phenobarbital Valproic acid Clonazepam Carbamazepine Phenytoin Topiramate Lamotrigine Gabapentin Vigabatrin Total
4 (19) 3 (14) 12 (57) 1 (5) 0 0 0 1 (5) 0 0 21 (100)
3 (14) 1 (5) 4 (19) 10 (48) 0 0 2 (10) 0 0 1 (5) 21
4 (19) 3 (14) 4(19) 1 (5) 0 0 2 (10) 2 (10) 0 2 (10) 20 (95)
0 1 (5) 1 (5) 2 (10) 0 0 6 (28) 2 (10) 0 3 (14) 15 (71)
child neurologists in our country to screen and image the infant brain. It is easily accessible and inexpensive and in UPPGH and PCMC it is performed by child neurologists themselves. The pattern of the AED usage in government institutions is reflective of two factors. Phenobarbital and clonazepam are the cheapest AEDs available in the local market. Considering that our population of patients is predominantly indigent, and that in the Philippines, patients barely get support for their own medications, these two drugs were the most frequently used. ACTH was not used in any of these patients primarily because of the unavailability of the drug in our country and its cost. The use of prednisone has been abandoned for several years in most centers because of its side effects; this population of children is at high risk for infection. However, for most practicing child neurologists in the Philippines, majority still believe that ACTH is the ideal drug of choice for idiopathic IS. Because of its unavailability, in private practice, most would use prednisone as an alternate first drug or start with valproic acid instead. Valproic acid and clonazepam are the second and third ideal choices given. For symptomatic cases, however, valproic acid was the preferred ideal drug of choice and the actual first line drug used. There is no disagreement in the ideal choice of treatment given and the actual use of these drugs. In the United States, ACTH is also the first choice drug for IS [3]. Vigabatrin which is the preferred first line drug in the United Kingdom is only considered as a last choice for resistant cases because it is also not available locally [4]. It is interesting to note, however, that topiramate is emerging as an alternative choice in our country. On the other hand, compared to the Japanese practice, pyridoxine is used as an add on drug rather than first line drug for IS [5,6]. However, its benefit for control of spasms is still in question even to those who use it. It is, however, becoming part of the armamentarium of drugs among the child neurologists in the Philippines. The neurodevelopmental outcome as well as seizure control is poor in our series of studies. We surmise that this is partly due to the greater number of symptomatic
cases in our series of studies as well as to the AED used. Two cases with cryptogenic etiology became seizure free after 6 and 19 months with phenobarbital and valproic acid. The same combination in five symptomatic cases did not eliminate the spasms although it reduced the frequency of attacks in two of them. None of the patients had drug level assays. The duration of treatment and neurologic follow-up did not appear to influence their clinical course. 5. Summary and conclusions Twelve cases of WS were identified in two of our country’s major referral centers for the less privileged children over the past 3 years (1997–1999), giving us a proportion of 3.18% among the total number of new cases of epileptics under 3 years of age. Sixty six (66%) percent of our patients have symptomatic etiologies, i.e. mostly secondary to HIE. Only three of our patients became seizure-free. Whether this is related to the fact that majority of our cases are symptomatic or related to our anticonvulsant usage is difficult to answer at this time. Additional data will be necessary. Among practicing pediatric neurologists, the ideal first line drug for idiopathic/cryptogenic IS is ACTH and for symptomatic cases, valproic acid. In actual practice, the most commonly used first line drug is valproic acid. Pyridoxine is usually added on as an adjunct treatment but majority of those who use pyridoxine feel that its addition did not improve seizure control. The significantly poor neurodevelopmental outcome among our population of patients may also be secondary to the treatment given or directly related to the etiology. Acknowledgements We wish to acknowledge the participation of the staff of the pediatric neurology sections of the University of the Philippines-Philippine General Hospital and Philippine Children’s Medical Center as well as the members of the Child Neurology Society Philippines, Inc.
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Appendix A
A.M. Salonga et al. / Brain & Development 23 (2001) 616–623
A.M. Salonga et al. / Brain & Development 23 (2001) 616–623
References [1] Aicardi J. Epilepsy in children. 2nd ed.. New York, NY: Raven Press, 1994. [2] Browne TR, Feldman RG, editors. Epilepsy diagnosis and management Boston, MA: Little, Brown and Co, 1983. [3] Bobele GB, Bodensteiner JB. The treatment of infantile spasms by child neurologists. J Child Neurol 1994;9:432–435.
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[4] Appleton RE. The treatment of infantile spasms by paediatric neurologists in United Kingdom and Ireland. Dev Med Child Neurol 1996;38:278–279. [5] Watanabe K. Medical treatment of West syndrome in Japan. J Child Neurol 1995;10:143–147. [6] Ito M. Current therapy for West syndrome in Japan. J Child Neurol 2000;5:424–428.
Original article
West syndrome: the Philippine experience Aida M. Salonga a,*, Marissa B. Lukban a, Marilyn H. Ortiz b, Bernadette Balatero-Terencio a, Ana Marissa Lagman a a
Department of Pediatrics, University of the Philippines-Philippine General Hospital, Taft Avenue, Manila, Philippines b Child Neuroscience Division, Philippine Children’s Medical Center, Quezon City, Philippines Received 16 March 2001; received in revised form 1 June 2001; accepted 4 June 2001
Abstract Aim: To provide information on the current status of West syndrome (WS) in the Philippines. Methods: This is a retrospective review of WS cases from January 1997 to December 1999 from two largest referral government institutions. A questionnaire interview survey on anticonvulsant usage was also conducted among practicing child neurologists. Results: Twelve patients diagnosed to have infantile spasms at 2–15 months were included, with a male:female ratio of 1:1. The proportion of WS cases among epileptic children under age 3 was 3.18%. The etiologies were idiopathic/cryptogenic in four (33%) and symptomatic in eight (66%). Symptomatic cases include hypoxic-ischemic encephalopathy, neonatal sepsis, bacterial meningitis, inborn error of metabolism, congenital brain anomaly and intracranial hemorrhage. Phenobarbital was the first line drug in 75% of cases. Other drugs used were valproic acid, clonazepam and pyridoxine. With a follow-up duration of 1–40 months, only three patients became seizure free and most had poor neurodevelopmental outcome. Among practicing child neurologists, the preferred ideal drug was adrenocorticotrophic hormone (ACTH) and valproic acid for idiopathic and symptomatic cases, respectively. However, in actual clinical practice valproic acid or prednisone was the initial drug used. Pyridoxine was usually added on. Conclusions: The proportion of WS in our patient population may not reflect the true prevalence in our country since our data came from a biased population, i.e. referral centers. A national statistics is currently not available. ACTH, which was perceived by most child neurologists as the ideal first line drug was not used primarily because it is unavailable and unaffordable. The poor seizure control and developmental outcome may be due to the treatment given or directly related to the etiology of WS. q 2001 Published by Elsevier Science B.V. Keywords: Infantile spasm; West syndrome
1. Introduction The Philippines is a tropical country with 7100 islands lying in the Pacific Ocean and off the coast of Southeast Asia. It has an estimated population of about 72 million in 2000 and the average population density is 243 per square kilometer. Presently, there are 26 certified child neurologists and about 140 certified adult neurologists serving the country with more than 50% based in the national capital region, giving us a neurologist to population ratio of about 1/ 700,000. There are at present three training institutions for child neurology with an average output of two to three child neurologists per year. The University of the PhilippinesPhilippine General Hospital Medical Center (UPPGH), a general hospital with 1500 bed capacity and Philippine Chil-
* Corresponding author. Tel.: 163-2-524-0892; fax: 163-2-526-0150. E-mail address: [email protected] (A.M. Salonga). 0387-7604/01/$ - see front matter q 2001 Published by Elsevier Science B.V. PII: S03 87- 7604(01)0029 7-2
dren’s Medical Center (PCMC), a 200 bed children’s hospital are the two major government referral centers for children, serving the less privileged sector of the country. From 1997 to 1999 there were 5985 and 4584 outpatient consults related to childhood seizure and epilepsy at the UPPGH and PCMC, respectively. In the Philippines, there are no available statistics on West syndrome (WS) and other related epileptic syndromes. We are still in the planning stage for setting up a National Epilepsy Registry. Our data on the epilepsies, in general, are primarily hospital based. Antiepileptic drugs (AED) used are also varied among practicing child neurologists. The success in controlling infantile spasms (IS), however, has not been evaluated. This study aims to provide information concerning the current status of WS in the Philippines and share the current practice of Filipino child neurologists in the management of IS.
A.M. Salonga et al. / Brain & Development 23 (2001) 616–623
2. Methodology The study was prepared in two parts. Part I describes a hospital based survey of WS in two major pediatric centers, UPPGH and PCMC. Part II describes the current practice of pediatric neurologists in the management of IS. Part 1: Medical records of patients 3 years of age or younger who were diagnosed to have epilepsy at UPPGH and PCMC were reviewed. Definite cases of WS from January 1997 to December 1999 were collected and analyzed using formulated questionnaire. The following data were collected: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
Patient’s sex. Age of onset of seizure or spasm. Age of diagnosis of IS. Age at first and last consultation (duration of neurologic follow-up). Clinical features of seizure event, presence or absence of atypical features. Electroencephalographic (EEG) findings. Brain imaging studies. Etiology of IS, if identified. AEDs used. Neurodevelopmental status at first and last consult (using Denver developmental test). Seizure outcome.
2.1. Definition of terms WS is defined as an epilepsy syndrome with the following characteristics [1]: 1. Seizures presenting as IS. 2. Presence or development of psychomotor retardation. 3. EEG features showing hypsarrhythmia.
617
Etiology [2] Cryptogenic: those patients in whom no etiologic cause can be identified or those who in addition have normal development before the onset of spasms. Symptomatic: those patients with definite etiologic factors identified and having abnormal mental and/or neurodevelopmental development prior to onset of spasms. Part II: A questionnaire survey was presented to practicing pediatric neurologists in the country. Responses were gathered by either actual or telephone interviews (Appendix A). Twenty-one out of the 26 board certified child neurologists responded. 3. Results 3.1. Part I During the study period (1997–1999), there were 154 and 223 new cases of childhood epilepsy in children under 3 years of age from UPPGH and PCMC, respectively. Twelve definite cases of WS were identified, four from UPPGH and eight from PCMC. The proportion of WS cases among our total epileptic children under age 3 is thus 3.18%. 3.2. Clinical features (Table 1) The ages of first consult ranged from 2 to 15 months with a male to female ratio of 1:1. Total duration of follow-up was 1–40 months. Four children (33%) had onset of IS before 3 months of age. The youngest case (Case No. 4) reported clusters of spasms at 3 weeks of age but was diagnosed to have WS only at 4 months. Five children (42%) had onset of seizures between 3 and 7 months of age, which is the maximum incidence of IS reported. The remaining three children (25%) had onset of spasms at 8 months of age.
Table 1 Clinical features of WS cases a Patient No.
Etiology
Onset of spasms (months)
1 2 3 4 5 6
Cryptogenic HIE HIE Cryptogenic HIE Inborn metabolic disorder Intracranial hemorrhage Neonatal sepsis Congenital brain malformation Bacterial meningitis Cryptogenic Cryptogenic
3 4 3 0.75 7 1.5
7 8 9 10 11 12 a
Diagnosis of IS (months)
Duration of follow-up (months)
EEG (typical/atypical)
Brain imaging CUS/CT/MRI
5 4 5 4 7 4
1 40 6 8 30 1
T T T T T T
Normal Brain atrophy Normal Normal Encephalomalacic changes Brain atrophy
8 2 2
8 2 2
12 40 11
A T T
Encephalomalacic changes Brain atrophy Pachygyria
8 8 6
8 8 15
7 15 22
T T T
Brain atrophy Normal Not done
HIE, hypoxic–ischemic encephalopathy; CUS, cranial ultrasound.
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The diagnosis of IS was made during the first consultation after the onset of the seizures in seven cases (58%). For the remaining five cases (42%) the consultation and diagnosis were delayed for 2–9 months. 3.3. Etiology of WS There were no identified etiologies in four cases (33%). Three of these cases were reported to have normal development prior to the onset of IS. The other patient (Case No. 4) was the infant with reported spasms in the neonatal period. This patient was noted to be developmentally delayed during her initial consultation at 4 months of age. Apart from a cranial ultrasound which was normal, this patient, however, did not benefit from further work-up. Among the eight symptomatic cases (66%), three had hypoxic-ischemic encephalopathy (HIE) secondary to severe perinatal asphyxia at birth and one had a history of sepsis and hyperbilirubinemia during the first week of life. Three of these children with perinatal neurologic insults had onset of spasms between 2 and 4 months of age. One patient had intracranial hemorrhage at 3 months of age secondary to acquired prothrombin complex deficiency (APCD) and one infant had bacterial meningitis also at 3 months of age. Both children had onset of IS at 8 months of age or 5 months after the neurologic insult. One patient had multiple dysmorphic features and was found to have pachygyria on computerized tomography (CT) scan. The other patient (Case No. 6) had abnormal urine metabolic screen although the exact metabolic disorder was not identified. His IS started at 1.5 months of age but diagnosis was delayed at 4 months. Brain atrophy was seen on magnetic resonance imaging (MRI). 3.4. Neurodiagnostic tests Cranial ultrasound was performed in eight cases. There were four normal studies and three of the four patients with normal cranial ultrasounds were classified as idiopathic/ cryptogenic cases. The other child with a normal ultrasound had a history of perinatal asphyxia (Case No. 3). Four cases showed abnormal cranial ultrasound studies. Two of the abnormal cranial ultrasounds showed cerebral atrophy (Case Nos. 2 and 8). The other two cases showed encephalomalacic changes. This included one child with history of perinatal asphyxia (Case No. 5) and the other child had postnatal subdural hematoma due to APCD (Case No. 7). CT scan was performed in two children, one with pachygyria and the other with brain atrophy. The child with suspected inborn error of metabolism showed cerebral atrophy on MRI. One child diagnosed to have cryptogenic WS had no brain imaging study performed. EEG showed typical hypsarrhythmia in 11 cases (92%). The child diagnosed to have intracranial hemorrhage due to APCD (Case No. 7) showed significant asymmetry with
voltage attenuation and epileptiform discharges predominantly on the side of the previous hematoma. 3.5. AED usage The initial AED used was phenobarbital in nine patients (75%), valproic acid in two cases (17%) and clonazepam in one patient (8%). Clonazepam was added on in five patients who did not respond to phenobarbital. There was no improvement of spasms with this combination. Two cases classified as cryptogenic had control of spasms at 6 and 19 months, respectively (Case Nos. 11 and 12). Both were on a combination of phenobarbital and valproic acid. The other child who had control of spasms after 30 months, classified as symptomatic, was on a combination of phenobarbital, valproic acid and clonazepam. Pyridoxine was added in the latter part of the follow-up in two patients (17%). 3.6. Seizure and neurodevelopmental outcome (Table 2) Two patients (Case Nos. 1 and 6) had only one outpatient follow-up within a month after diagnosis and thus observation for seizure and neurodevelopmental outcome is inadequate. Both had no change in the seizure type and frequency. These children were classified as cryptogenic cases. The other two remaining cryptogenic cases had control of spasms at 6 and 19 months, respectively. Both were developmentally normal at the onset of seizures and at last consultation (15–22 months follow-up), both were able to walk independently but had language and cognitive difficulties. All the eight (66%) patients classified as symptomatic cases were neurodevelopmentally delayed at first consultation. Seven of the eight cases had severe global developmental delay from the first to the last consultation. The only child with mild delay was the child who had intracranial hematoma due to APCD at 3 months of age (Case No. 4). He had residual hemiplegia and thus delayed motor development prior to the onset of spasms at 8 months. His spasms persisted but decreased in frequency during the 12 months follow-up. At 1 year of age he remains unable to stand independently but has social play and utters monosyllable words. The other seven symptomatic cases remained severely developmentally delayed, most without visual eye contact and no language development. Only one child in the symptomatic group became seizure free at 30 months of age (Case No. 8). The spasms persisted but decreased in frequency in three cases (Case Nos. 7, 9 and 10). One child (Case No. 2) reverted to Lennox Gastaut syndrome after 1 year. 3.7. Part II There were 21 respondents, with areas of practice in Metro Manila (76%), Luzon Province (14%) and Visayas Province (10%). Ten respondents (48%) have been practi-
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Table 2 Seizure and developmental outcome a Patient No.
1 2 3 4 5 6 7 8 9 10 11 12 a
Etiology
Onset of spasms (months)
Cryptogenic HIE HIE Cryptogenic HIE Inborn metabolic disorder Intracranial hemorrhage Neonatal sepsis Congenital brain malformation Bacterial meningitis Cryptogenic Cryptogenic
3 4 3 0.75 7 1.5 8 2 2 8 8 6
AED
PB CZP PB PB PB PB VPA PB PB PB VPA PB
Developmental status
Seizure outcome
First consult
Last consult
Normal Severe delay Severe delay Severe delay Severe delay Severe delay Mild delay Severe delay Severe delay Severe delay Normal Normal
? Severe delay Severe delay Severe delay Severe delay ? Mild delay Severe delay Severe delay Severe delay Mild delay Mild delay
? Changed to mixed type Persisting unchanged Persisting unchanged Persisting unchanged ? Persisting less severe Controlled at 30 months Persisting less severe Persisting less severe Controlled at 6 months Controlled at 19 months
AED, antiepileptic drug; HIE, hypoxic-ischemic encephalopathy; CZP, clonazepam; PB, phenobarbital; VPA, valproic acid.
cing child neurology for 5–10 years. Eight neurologists (38%) have been practicing for more than 10 years and three (14%) for less than 5 years.
3.8. Drugs of choice for the treatment of idiopathic/ cryptogenic IS (Tables 3 and 4) Most of the respondents believe that ACTH/prednisone (71%) followed by valproic acid (14%) ideally was the drug of first choice for IS. Valproic acid (43%) followed by clonazepam (28%) was the second choice for most respondents. Valproic acid (28%) followed by topiramate (14%) and vigabatrin (14%) was the third choice for most child neurologists. In actual practice, prednisone (38%) and valproic acid (38%) were equally used as first line drug. As second most commonly used drug, clonazepam (33%), valproic acid (28%) and prednisone (24%) were used. Phenobarbital is the third drug added on after prednisone, valproic acid and clonazepam have been started. A number of respondents have subsequently used vigabatrin and topiramate as alternative drugs for resistant cases.
3.9. Drugs of choice for the treatment of symptomatic IS (Tables 5 and 6) In the treatment of symptomatic cases, most of the respondents believe that valproic acid (43%) followed by ACTH (38%) ideally was the drug of first choice. Clonazepam (38%) followed by valproic acid (28%) was the second choice for most respondents. ACTH and valproic acid (24% each) followed by clonazepam (19%) was the third choice for most child neurologists. Topiramate (28%) followed by phenobarbital (14%) and vigabatrin (14%) was believed to be an alternative ideal drug for resistant cases. In actual practice, similar to the adhered ideal choices, valproic acid (57%) followed by prednisone (19%) was used as first line drug. As second most commonly used drug, clonazepam (48%) followed by valproic acid (19%) was used. For those who have not started either valproic acid or prednisone as first and second drugs used, these two drugs are added on as a third drug. Clonazepam was a third choice. Twenty-eight percent have used topiramate as the last choice after the other conventional drugs have been tried. Phenobarbital and vigabatrin (14% each) are also last choices as add on treatment for resistant cases.
Table 3 Ideal drugs of choice for idiopathic/cryptogenic IS Drugs
First choice # (%)
Second choice # (%)
Third choice # (%)
Fourth choice # (%)
ACTH/prednisone Phenobarbital Valproic acid Clonazepam Carbamazepine Phenytoin Topiramate Lamotrigine Gabapentin Vigabatrin Total
15 (71) 2 (10) 3 (14) 0 0 0 0 0 0 1 (5) 21 (100)
3 (14) 0 9 (43) 6 (28) 0 0 0 0 1 (5) 2 (10) 21
2 (10) 2 (10) 6 (28) 3 (14) 0 0 3 (14) 1 (5) 0 3 (14) 20 (95)
1 (5) 1 (5) 2 (10) 4 (19) 0 0 5 (24) 1 (5) 0 3 (14) 17 (81)
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Table 4 Actual drugs used of choice for treatment of idiopathic/cryptogenic IS Drugs ACTH/prednisone Phenobarbital Valproic acid Clonazepam Carbamazepine Phenytoin Topiramate Lamotrigine Gabapentin Vigabatrin Total
First choice # (%) 8 (38) 2 (10) 8 (38) 1 (5) 0 0 0 1 (5) 0 0 20 (95)
Second choice # (%)
Third choice # (%)
Fourth choice # (%)
5 1 6 7 0 0 1 0 0 1 21
4 (19) 3 (14) 3 (14) 4 (19) 0 0 1 (5) 1 (5) 0 3 (14) 21 (100)
1 1 3 4 0 0 6 1 0 0 16
(24) (5) (28) (33)
(5)
(5) (100)
3.10. Use of pyridoxine in IS Regarding the use of pyridoxine, eight out of 21 (38%) child neurologists gave the drug before starting other anticonvulsants. Six out of eight (75%) used pyridoxine initially for both idiopathic and symptomatic cases. Two out of eight (25%) tried pyridoxine for idiopathic cases only and only one believed it achieved at least 50% control of seizures. Thirteen out of 21 (62%) used pyridoxine as add on drug together with other anticonvulsants. Of the 13 who used pyridoxine as add on drug, nine (69%) reported no added benefit of the addition of pyridoxine in the control of seizures.
4. Discussion The proportion of WS in our patient population may not reflect the true prevalence in our country since our data came from a biased population, i.e. referral centers. In addition, our centers are both government funded institutions serving the indigent members of the society, mostly children with unemployed parents. This may in part explain the etiologies of our symptomatic cases. Four cases are due to poor neonatal care presenting with perinatal asphyxia and neonatal sepsis. The other two cases, bacterial meningitis and
(5) (5) (14) (19)
(28) (5)
(76)
postnatal intracranial hemorrhage due to acquired prothrombin deficiency reflects inadequate infant care as these cases are preventable with immunization and vitamin K supplementation, respectively. As seen in reported literature [1], majority of our cases had onset of spasms at age 4–7 months. However, our data also presented a significant number (33%) of IS occurring before the fourth month of life, mostly symptomatic cases. One child in our series of studies reported clusters of spasms at 3 weeks of age and persisted until age 4 months when the diagnosis of IS was given. This child is severely developmentally delayed at the onset and although he was classified as cryptogenic because of the absence of a definite etiology, we surmise that if given more opportunities for extensive work-up an etiology might be discovered. According to Aicardi [1], cases with neonatal onset are on record but unusual. We also observed that the cases with delayed onset of spasms (8 months) were seen in two cases with neurologic insults occurring at a much later age of 3 months. EEG showed typical hypsarrhythmia in the majority of cases. It is noteworthy that the only child with atypical EEG pattern because of a significant voltage attenuation and asymmetrical frequency of epileptiform discharges showed a history of a focal destructive lesion due to intracranial hemorrhage prior to the onset of IS. Cranial ultrasound has been a useful armamentarium for
Table 5 Ideal drugs of choice for symptomatic IS Drugs ACTH/prednisone Phenobarbital Valproic acid Clonazepam Carbamazepine Phenytoin Topiramate Lamotrigine Gabapentin Vigabatrin Total
First choice # (%) 8 (38) 2 (10) 9 (43) 1 (5) 0 0 0 1 (5) 0 0 21 (100)
Second choice # (%)
Third choice # (%)
Fourth choice # (%)
2 0 6 8 0 0 3 0 1 1 21
5 (24) 1 (5) 5 (24) 4 (19) 0 0 1 (5) 1 (5) 0 2 (10) 19 (92)
0 3 0 2 0 0 6 1 0 3 15
(10) (28) (38)
(14) (5) (5) (100)
(14) (10)
(28) (5) (14) (71)
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Table 6 Actual drugs used for treatment of symptomatic IS Drugs
First choice # (%)
Second choice # (%)
Third choice # (%)
Fourth choice # (%)
ACTH/Prednisone Phenobarbital Valproic acid Clonazepam Carbamazepine Phenytoin Topiramate Lamotrigine Gabapentin Vigabatrin Total
4 (19) 3 (14) 12 (57) 1 (5) 0 0 0 1 (5) 0 0 21 (100)
3 (14) 1 (5) 4 (19) 10 (48) 0 0 2 (10) 0 0 1 (5) 21
4 (19) 3 (14) 4(19) 1 (5) 0 0 2 (10) 2 (10) 0 2 (10) 20 (95)
0 1 (5) 1 (5) 2 (10) 0 0 6 (28) 2 (10) 0 3 (14) 15 (71)
child neurologists in our country to screen and image the infant brain. It is easily accessible and inexpensive and in UPPGH and PCMC it is performed by child neurologists themselves. The pattern of the AED usage in government institutions is reflective of two factors. Phenobarbital and clonazepam are the cheapest AEDs available in the local market. Considering that our population of patients is predominantly indigent, and that in the Philippines, patients barely get support for their own medications, these two drugs were the most frequently used. ACTH was not used in any of these patients primarily because of the unavailability of the drug in our country and its cost. The use of prednisone has been abandoned for several years in most centers because of its side effects; this population of children is at high risk for infection. However, for most practicing child neurologists in the Philippines, majority still believe that ACTH is the ideal drug of choice for idiopathic IS. Because of its unavailability, in private practice, most would use prednisone as an alternate first drug or start with valproic acid instead. Valproic acid and clonazepam are the second and third ideal choices given. For symptomatic cases, however, valproic acid was the preferred ideal drug of choice and the actual first line drug used. There is no disagreement in the ideal choice of treatment given and the actual use of these drugs. In the United States, ACTH is also the first choice drug for IS [3]. Vigabatrin which is the preferred first line drug in the United Kingdom is only considered as a last choice for resistant cases because it is also not available locally [4]. It is interesting to note, however, that topiramate is emerging as an alternative choice in our country. On the other hand, compared to the Japanese practice, pyridoxine is used as an add on drug rather than first line drug for IS [5,6]. However, its benefit for control of spasms is still in question even to those who use it. It is, however, becoming part of the armamentarium of drugs among the child neurologists in the Philippines. The neurodevelopmental outcome as well as seizure control is poor in our series of studies. We surmise that this is partly due to the greater number of symptomatic
cases in our series of studies as well as to the AED used. Two cases with cryptogenic etiology became seizure free after 6 and 19 months with phenobarbital and valproic acid. The same combination in five symptomatic cases did not eliminate the spasms although it reduced the frequency of attacks in two of them. None of the patients had drug level assays. The duration of treatment and neurologic follow-up did not appear to influence their clinical course. 5. Summary and conclusions Twelve cases of WS were identified in two of our country’s major referral centers for the less privileged children over the past 3 years (1997–1999), giving us a proportion of 3.18% among the total number of new cases of epileptics under 3 years of age. Sixty six (66%) percent of our patients have symptomatic etiologies, i.e. mostly secondary to HIE. Only three of our patients became seizure-free. Whether this is related to the fact that majority of our cases are symptomatic or related to our anticonvulsant usage is difficult to answer at this time. Additional data will be necessary. Among practicing pediatric neurologists, the ideal first line drug for idiopathic/cryptogenic IS is ACTH and for symptomatic cases, valproic acid. In actual practice, the most commonly used first line drug is valproic acid. Pyridoxine is usually added on as an adjunct treatment but majority of those who use pyridoxine feel that its addition did not improve seizure control. The significantly poor neurodevelopmental outcome among our population of patients may also be secondary to the treatment given or directly related to the etiology. Acknowledgements We wish to acknowledge the participation of the staff of the pediatric neurology sections of the University of the Philippines-Philippine General Hospital and Philippine Children’s Medical Center as well as the members of the Child Neurology Society Philippines, Inc.
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Appendix A
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References [1] Aicardi J. Epilepsy in children. 2nd ed.. New York, NY: Raven Press, 1994. [2] Browne TR, Feldman RG, editors. Epilepsy diagnosis and management Boston, MA: Little, Brown and Co, 1983. [3] Bobele GB, Bodensteiner JB. The treatment of infantile spasms by child neurologists. J Child Neurol 1994;9:432–435.
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[4] Appleton RE. The treatment of infantile spasms by paediatric neurologists in United Kingdom and Ireland. Dev Med Child Neurol 1996;38:278–279. [5] Watanabe K. Medical treatment of West syndrome in Japan. J Child Neurol 1995;10:143–147. [6] Ito M. Current therapy for West syndrome in Japan. J Child Neurol 2000;5:424–428.