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Prevalence and neuro-psychiatric comorbidities of pediatric epilepsy in Taiwan: A national population-based study
Epilepsy Research (2014) 108, 1451—1460
journal homepage: www.elsevier.com/locate/epilepsyres
Prevalence and neuro-psychiatric comorbidities of pediatric epilepsy in Taiwan: A national population-based study Kuo-Liang Chiang a, Chen-Yang Cheng b,∗ a
Department of Pediatric Neurology, Kuang-Tien General Hospital, No. 117, Shatian Road Shalu District, Taichung City 433, Taiwan ROC b Program of Health Administration, Tunghai University, No. 181, Section 3, Taichung Harbor Road, Taichung, 407-04, Taiwan ROC Received 6 March 2014; received in revised form 27 June 2014; accepted 14 July 2014 Available online 23 July 2014
KEYWORDS Pediatric epilepsy; Prevalence; Comorbidity; Urbanization; Taiwan; National Health Insurance
Abstract Objective: Children with epilepsy may have comorbidities that result in significant disability. Epidemiological information for pediatric patients with epilepsy in Taiwan is scant. This research estimates the prevalence and common neuro-psychiatric comorbidities of children with epilepsy in Taiwan. Methods: Patients aged less than 20 years old who had received a diagnosis of epilepsy and suffered from epileptic seizures in 2005 were identified in the NHIRD based on ICD-9-CM and prescription records for the use of at least one AED. We used cases of epileptic seizure to survey outpatient service data, and identify common neuro-psychiatric comorbidities. The crude prevalence rate and the age- and sex-specific prevalence were estimated. We also examined the effects of urbanization. Results: The estimated prevalence of epilepsy was 0.33% in the pediatric population, with 0.29% for girls and 0.36% for boys. The most common neuropsychiatric comorbidities were learning disability and developmental delay, cerebral palsy, and mental retardation. Epilepsy was more prevalent in boys than in girls, especially among infants, preschool children, and those living in rural areas. In addition, boys with epilepsy had a higher rate of neurological comorbidities. The prevalence of psychiatric comorbidities was lower than that reported in previous studies performed in other countries, especially among children with epilepsy living in rural areas.
Abbreviations: NHIRD, National Health Insurance Research Database; ICD-9-CM, the diagnostic criteria of the International Classification of Diseases, Ninth Revision, Clinical Modification; NHRI, National Health Research Institute; AED, anti-epileptic drug; OR, odds ratio; CI, confidence interval; LDDD, learning disability and developmental delay; ADHD, attention-deficit hyperactivity disorder. ∗ Corresponding author. Tel.: +886 4 23594319 140; fax: +886 4 2359 1756. E-mail addresses: [email protected] (K.-L. Chiang), [email protected] (C.-Y. Cheng). http://dx.doi.org/10.1016/j.eplepsyres.2014.07.004 0920-1211/© 2014 Elsevier B.V. All rights reserved.
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K.-L. Chiang, C.-Y. Cheng Conclusion: This research provides the largest nationwide, population-based study of childhood epilepsy to estimate the prevalence and the associated neuropsychiatric comorbidities of pediatric epilepsy in Taiwan. Potential rural—urban disparity basing on prevalence and associated neuropsychiatric comorbidities cannot be ignored in Taiwan. © 2014 Elsevier B.V. All rights reserved.
Introduction Epilepsy, a neurological condition characterized by recurrent seizures, is one of the most highly prevalent pediatric neurological disorders and also a costly and complicated major public health problem (England et al., 2012). The epilepsy of a child influences the whole family system and leads to different burdens for the family members especially the parents. Studies reported increased stress and burden for families are particularly to be expected if the child shows additional emotional respectively behavioral problems or other comorbid conditions (Dehn et al., 2012; Hamiwka and Wirrell, 2009). Comorbidities refer to the co-occurrence of more than one condition in the same person. Generally, comorbidities are associated with poor health outcomes. It is now widely appreciated that comorbidities impact the quality of life in pediatric epilepsy and are evident at or prior to the onset of epilepsy (Lin et al., 2012). Pediatric epilepsy patients have the greatest long-term morbidity, despite accounting for only approximately 20% of all patients newly diagnosed with a seizure disorder (Hauser, 1994). For healthcare providers, understanding the epidemiology and comorbidities of epilepsy in pediatric patients could help improve diagnosis, understand patient’s prognosis, and widen insight of pathogenesis by revealing shared neurological mechanisms underlying multiple disorders that lead to contribution of information regarding available treatment choices. In highly developed countries, prevalence estimations are relayed on available medical records and health care database. On the other hand, challenges in most developing countries are lack of national health care systems. Population-based studies with direct personal interviews through door-to-door or face-to-face survey remains the main tool for epidemiological studies (El-Tallawy et al., 2013; Ray et al., 2002; Shehata and Mahran, 2011; Snape et al., 2009). According to our survey, the prevalence of epilepsy has been conducted in local areas in Taiwan using door to door survey, however, both of them have focused mainly on adults (Chen et al., 2006a; Su et al., 1998). Population-based studies dealing specifically with children are few and suffer from difficulties with definitions and differences in methodology (Hauser, 1994; Hauser and Banerjee, 2008). The National Health Insurance (NHI) program was implemented in Taiwan in 1995, and provides equitable, affordable, and universal health-care coverage to more than 98% of the 23 million residents of Taiwan (Chien et al., 2004, 2012). With such high cover rate, the claims data is suitable for epidemiology study. Currently, there are two studies, that using NHIRD for the prevalence and incidence of epilepsy. Hsieh et al. conducted a study using antiepileptic drug prescription data of NHIRD, and the prevalence of
adult population in Taiwan of this study was 0.42% (Hsieh and Huang, 2008). However, the study excluded patients younger than 25 years old, that the results could not deliver any information for children. Another study had only one group of 0—19 subgroup and did not provide a detailed analysis for children and adolescents (Chen et al., 2012). Hence, epidemiological information regarding pediatric patients with epilepsy and the related comorbidities in Taiwan is scant. In current research, we used NHI claims data from 2005 to determine the prevalence of epileptic seizures and epilepsy among children and adolescents. We also examined the rates of neuro-psychiatric comorbidities of the target subjects considering the effects of age, sex, and urbanization.
Materials and methods Data source and sampling We obtained the data for our study from the National Health Insurance Research Database (NHIRD), which is a subset of randomly selected NHI claims records. According to the National Health Research Institute (NHRI), which prepared and manages the NHIRD, the sampling randomization for the NHIRD used the linear congruential random number generation function of the Sun Work Shop C 5.0 (Chen et al., 2006b). The NHRI has reported no statistically significant difference in age, sex, or average household income exists between the NHIRD and the combined records of all NHI enrollees. The NHI Bureau has approved the following 14 antiepileptic drugs (AEDs) for use by epilepsy patients in Taiwan: carbamazepine, phenytoin, gabapentin, clonazepam, clobazam, levetiracetam, oxcarbazepine, lamotrigine, primidone, tiagabine, topiramate, sodium valproate (valporic acid), vigabatrin, and phenobarbital. These AEDs were available in a total of 151 commercial forms in 2005. Our study used 10 cohort datasets from the NHIRD. Each cohort included 40, 000 patients randomly sampled from all NHI beneficiaries in 2005. A total of 102,081 patients aged 20 years and younger were included in our analysis as of December 31, 2005, among whom 48,800 (47.8%) were females and 53,241 (52.3%) were males. Our study was approved by the Institutional Review Board of Kuang-Tien General Hospital.
Definition of epilepsy For the purposes of our study, epileptic seizure was defined according to the diagnostic criteria of the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) as ICD-9-CM 345.xx for epilepsy and ICD-9-CM 780.3 and 790.39 for convulsion (Fisher et al., 2005; McAfee
Prevalence and neuro-psychiatric comorbidities of pediatric epilepsy in Taiwan
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0.36 0.32 0.31 0.31 0.33 0.45 0.36 0.31 0.35 0.36 0.26 0.29 0.31 0.28 0.29 72 85 88 88 333 47 49 46 51 193 0.78 0.53 0.42 0.41 0.52 0.92 0.58 0.42 0.46 0.57 0.63 0.48 0.42 0.36 0.46 155 139 118 116 528 96 79 62 67 304 59 60 56 49 224 19,849 26,181 28,066 27,985 102,081 10,412 13,654 14,621 14,554 53,241 9437 12,527 13,445 13,431 48,840 0—4 5—9 10—14 15—19 All
All Male Female Male
All
Male
All
Prevalence (95% CI)
(0.66—0.90) (0.44—0.62) (0.34—0.50) (0.36—0.48) (0.48—0.56)
25 36 42 37 140
All Male Male Female Female Female
Epilepsy Epileptic seizures
The SQL Server 2012 database software (Microsoft, Redmond, WA, USA) was used to link data from order forms and prescriptions to the registry of beneficiaries. The Microsoft Excel 2003 and SPSS, Version 17.0, (IBM, Armonk, NY, USA) computer software packages were used for all data processing, including data selection, data merging, data aggregation, and calculations. The chi-squared test was used for our stratified analyses of the prevalence of epilepsy based on age, sex, and urbanization level. We compared the data for the epileptic and non-epileptic cohorts to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for the comorbidities and the urbanization levels. A two-tailed
Inhabitants
Data analysis
Age
We also stratified our analysis of pediatric epilepsy and epileptic seizures in children based on urbanization level to examine differences between children with epilepsy living in urban areas and those living in rural areas. We used the criteria for urbanization defined by the NHRI Information regarding the township in which each beneficiary resides is available (Liu et al., 2006). All 359 townships in Taiwan have been classified by the NHRI into seven clusters. Based on these criteria, the townships were categorized as rural (Levels 5—7), suburban (Levels 3 and 4), or urban (Levels 1 and 2), as described previously (Lin et al., 2013).
Age and gender-specific prevalence of epileptic seizures and epilepsy in 2005 in Taiwan of current study.
Urbanization
Table 1
Comorbidity in epilepsy is defined as other conditions may precede, co-occur with, or follow the diagnosis of epilepsy (Gaitatzis et al., 2004). Because each record for a medical claim in the NHIRD may contain up to three ICD-9-CM codes, we used the unique identification number for each patient to survey all their outpatient service data in 2005 to identify common neurological and psychiatric comorbidities (McAfee et al., 2007). The comorbidities include brain tumor, schizophrenia, affective psychoses, autism/autistic spectrum disorder, Tourette syndrome/tics, sleep disorder, depression disorder, acquired hydrocephalus, ADHD, learning disability and developmental delay, mental retardation/intellectual disability, CNS infection, multiple sclerosis, cerebral palsy, migraine, cerebral vascular disorder, congenital brain anomaly and head injury. The comorbidities were selected on the basis of prior researches (Baca et al., 2011; Cortesi et al., 1999; Gaitatzis et al., 2004; Jones et al., 2008; Kelley et al., 2012; Lin et al., 2012; Russ et al., 2012; Stores et al., 1998; Suren et al., 2012). The ICD9-CM codes for the neuropsychiatric comorbidities included in our analysis are listed in supporting Table 1.
All
Definition of the comorbidities
Female
Prevalence (95% CI)
(0.28—0.44) (0.25—0.39) (0.25—0.38) (0.24—0.38) (0.29—0.36)
et al., 2007; Schiariti et al., 2009). We excluded febrile seizures (ICD-9-CM 780.31 and 780.32), and certain ICD-9-CM codes, including those for myoclonic and neonatal seizures. We defined epilepsy as the use of at least one of the NHIapproved AEDs by a patient who had received a diagnosis of epileptic seizures (Pugh et al., 2005).
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K.-L. Chiang, C.-Y. Cheng
Figure 1
Age-specific prevalence rate in current study.
P value < 0.05 was considered to indicate a statistically significant difference.
Results Prevalence of pediatric epileptic seizures and epilepsy A total of 528 patients diagnosed with epileptic seizure in 2005 were identified in the NHIRD, among whom 224 (42.4%) were females and 304 (57.6%) were males. The crude prevalence of epileptic seizure was 0.46% for females and 0.57% for males, yielding a combined crude prevalence of epileptic seizure in the general population of 0.52%. At least one AED was prescribed to 140 (45.8%) females and 193 (54.2%) males. The crude prevalence of epilepsy was 0.29% for females and 0.36% for males, yielding a combined crude prevalence of 3.3 per 1000 population in 2005. The age- and sex-specific prevalence of epileptic seizure and epilepsy is shown in Table 1, respectively.
Age- and sex-specific prevalence of epileptic seizures and epilepsy The age-specific prevalence of epileptic seizure and epilepsy are graphically depicted in Figure 1. The prevalence of epileptic seizure was significantly higher (P < 0.05) in children aged ≤4 years, although the difference was not statistically significant, the prevalence of epilepsy was slightly higher in children aged ≤4 years. Significant sex-specific differences in the prevalence of epileptic seizure and epilepsy were observed. Both epileptic seizure (P < 0.01) and epilepsy (P < 0.05) were significantly more prevalent in males than in females. The prevalence of epilepsy in females was fairly constant from birth to early adulthood. The prevalence of epilepsy was significantly higher (P < 0.05) in boys aged ≤4 years, and decreased from birth to early adolescence, increasing slightly in late adolescence. The prevalence of both epilepsy (P < 0.05) and epileptic seizures (P < 0.01) among boys aged
≤4 years was significantly higher than that for girls, as shown in Figure 2.
Neuropsychiatric comorbidities Comorbidity prevalence Among the 528 patients identified with epilepsy, 206 patients (39.0%) had neuropsychiatric comorbidities, of whom 76 patients (33.9%) were female and 130 (42.8%) were male. The prevalence rates and ORs of the comorbidities analyzed are shown in Table A2. We categorized the comorbidities identified as psychiatric comorbidities and neurological comorbidities. Psychiatric and neurological comorbidities were present in 24.6% and 24.8%, respectively, among the patients with epilepsy. The prevalence of neuropsychiatric comorbidities in patients with epilepsy was higher (P < 0.05) among males than in females. The prevalence of neurological comorbidities was 28.6% among males and 19.6% among females (P < 0.01). No significant sex-specific differences existed in the psychiatric comorbidities identified between males and females (Table A3). The most common psychiatric comorbidities in patients with epilepsy were learning disability and developmental delay (LDDD; 13.1%), mental retardation (7.8%), attentiondeficit hyperactivity disorder (ADHD; 5.9%), and sleep disorders (3.4%). No epilepsy patient was diagnosed with major depressive disorder, and one patient was diagnosed with affective psychosis. The most common neurological comorbidities were cerebral palsy (10.4%), head injury (6.1%), congenital brain anomaly (3.6%), and cerebral vascular disorder (2.8%). Odds ratios of common comorbidities The ORs for mental retardation, schizophrenia and organic psychosis, and ADHD were 32.3, 24, and 25.8, respectively. Although LDDD was the most prevalent comorbidity, the OR of LDDD (18.4) was only the fourth highest among the conditions analyzed. Among the neurological comorbidities, the ORs for cerebral palsy, congenital brain anomaly, and cerebral vascular disorder were 91.4, 68.9, and 45.7, respectively. Among the neuropsychiatric comorbidities analyzed, cerebral palsy had the highest OR, as shown in Table 2.
Prevalence and neuro-psychiatric comorbidities of pediatric epilepsy in Taiwan
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1 0.92 0.9
**
0.8
0.7 0.63 0.6
0.58
0.5
0.48
0.45
*
Epilepc seizures female 0.46 0.42
0.4
0.36
0.36
0.3
0.35 0.31
0.29
0.26
Epilepc seizures male Epilepsy female Epilepsy male
0.28
0.2
0.1
0
0-4
5-9
10-14
15-19
Figure 2 Prevalence of epileptic seizures and epilepsy in the function of age and sex categories in 2005 in our study. **p < 0.01 (epileptic seizure: male vs female in 0—4 group); *p < 0.05 (epilepsy: male vs female in 0—4 group).
Table 2
Common comorbidities found in current study.
Psychiatric comorbidities
Neurological comorbidities
Disease
Mean age
M/F
Co-morbidity rate%
Odds ratio
Learning disability and developmetal delay Mental retardation ADHD Sleep disorders Autistic spectrum disorder Neurotic-anxiety disorder Schizophrenia and organic psychosis Cerebral palsy Head injury with skull fracture Congenital brain anomaly Cerebral vascular disorder Tourett or tics Migraine CNS infection Acquired hydrocephalus
6.2±4.2
1.56
13.1
18.4
10.2±4.5 8.4±3.1 14.2±4.6 7.6±3.5
1.93 2.1 0.64 3.25
7.8 5.9 3.4 3.2
32.3 9.3 6.1 25.8
15.3±4
1
1.9
3.3
16.0±3.2
2.5
1.3
24
8.2±5.3 9.2±6.15
1.39 1.67
10.4 6.1
91.4 5.1
7.9±5.4
2.17
3.6
68.9
9.4±7.27
1.14
2.8
45.7
9.4±4.9 11.8±3.9 8.2±5.6 6.3±3.5
3.67 1.8 4 0.5
2.7 2.7 1 0.58
22.3 12 17.6 36.3
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K.-L. Chiang, C.-Y. Cheng
Figure 3
Prevalence rate of epilepsy and epileptic seizure divided in urbanization level.
Influence of urbanization on pediatric epilepsy and the comorbidities The prevalence of pediatric epileptic seizures in urban, suburban, and rural townships was 5.0, 5.4, and 6.4 per 1000, respectively, and the prevalence of pediatric epilepsy in urban, suburban, and rural townships was 3.1, 3.5, and 3.9 per 1000, respectively. Epilepsy and epileptic seizures were most prevalent among children living in rural areas (OR, 1.28; 95% CI, 0.97—1.69). Although the effect of urbanization was not statistically significant, a gradual trend toward an increasing prevalence of pediatric epilepsy was observed from urban to rural areas (Figure 3). The overall prevalence of the psychiatric comorbidities was lower among children with epilepsy in rural townships than that of those living in suburban or urban areas, and stratification based on urbanization revealed no significant difference in the overall prevalence of neurological comorbidities among pediatric epilepsy patients (Figure 4).
Figure 4
Discussion This study discusses the rates of neuro-psychiatric comorbidities, the prevalence of pediatric epilepsy, and the epilepsy-related rural-urban disparity based on NHIRD. The result indicates comorbidities are identified in 39.0% in children younger than 20 year old with epilepsy. The most common neuropsychiatric comorbidities are developmental delay, cerebral palsy, and mental retardation. The prevalence of psychiatric comorbidities is lower than previously reported, especially in rural areas. In addition, prevalence of neuropsychiatric comorbidities is significantly higher among boys. The prevalence of epileptic seizures is 0.52%, and the prevalence of epilepsy is 0.33%. The prevalence of pediatric epilepsy is higher in rural areas, and in boys younger than 4 years old. The following sections are explained these results. The comparison of our study and previous studies of epilepsy comorbidities is presented in Table 3. The
Comorbidity rate of epileptic seizure with urban stratification.
Prevalence and neuro-psychiatric comorbidities of pediatric epilepsy in Taiwan Table 3
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Comparison of common comorbidities prevalence rate of our study and previous literatures..
Comorbidities
Previous literature
Our current study
Intellectual disabilities Cerebral palsy Learning disabilities and developmental delay Migraine Sleep disorder ADHD Autistic spectrum disorders Depressive disorder Anxiety disorder
10—25% (Lin et al., 2012; Russ et al., 2012) 12—15% (Suren et al., 2012) 40—50% (Baca et al., 2011; Russ et al., 2012) 25% (Kelley et al., 2012) Unknown (Cortesi et al., 1999; Stores et al., 1998) 15—40% (Jones et al., 2008) 6% (Suren et al., 2012) 10—30% (Jones et al., 2008) 13—49% (Jones et al., 2008)
7.8% 10.4% 13.1% 2.7%* 3.4% 5.9% 3.2% No patient** 1.90%**
Our study vs. previous studies to the lower limit of literature, * p < 0.01,
prevalence rates of the most common neuropsychiatric comorbidities are similar to those reported in previous studies except for a lower prevalence of depression and anxiety (Jones et al., 2008, 2007). Study reported children with either previously or current epilepsy/seizure disorder were more likely to experience mental health and developmental comorbidities (Russ et al., 2012). Cognitive, motor, and/or psychiatric comorbidities occur in 25—45% of children with epilepsy (Cowan, 2002, 1989; Schiariti et al., 2009). Our analysis reveals similar results. Previous studies have also reported higher prevalence of neuropsychiatric comorbidities in children, including cerebral palsy (10—15%) (Suren et al., 2012), LDDD (40—50%) (Baca et al., 2011; Russ et al., 2012), mental retardation (10%), and IQ below 70 or 80 (25%) (Lin et al., 2012; Russ et al., 2012).Other neurological comorbidities include migraine (25%) (Kelley et al., 2012) and sleep disorders (Cortesi et al., 1999; Stores et al., 1998), and the prevalence of depressive disorder (10—30%), anxiety disorder (13—49%), ADHD (15—40%), and autistic spectrum disorder in pediatric patients (6%) (Jones et al., 2008, 2007). It is noteworthy that no patient with major depressive disorder is identified, and that psychiatric comorbidities including autism, anxiety, and schizophrenia, are relatively rare in our study. We speculate that these diseases are likely under-recognized and under-treated in epileptic children in Taiwan. Psychiatric comorbidities are considered a stigma in Taiwanese culture. Physicians may be apprehensive about coding such as diagnoses if they determine that medical treatment is unnecessary. However, untreated depression and other psychiatric problems are more likely to become chronic as children grow into adults, and these problems can have a greater effect on a patient’s quality of life than epilepsy (Jones et al., 2007). Physicians should always consider neuropsychiatric assessment and treatment to protect the quality of life of children with epilepsy. Neurological conditions, including cerebral palsy, congenital brain anomaly, cerebral vascular disorder, and migraine were common among the children with epilepsy in our study. Due to sharing a common etiology or risk factor, such findings might be expected to cause epileptic seizures or associate with epilepsy (Gaitatzis et al., 2012). With the prevalence of epilepsy, our finding in Taiwan is consistent with those of studies in Singapore, Tokyo, and Hong Kong, which reported prevalence of 3.6; 2.8—3.2;
**
p < 0.05.
and 1.52 per 1000 population, respectively (Hauser, 1994; Hauser and Banerjee, 2008; Kwong et al., 2001; Lee et al., 1997; Schiariti et al., 2009; Tsuboi, 1984). Wide variations occur in the prevalence of childhood epilepsy worldwide, ranging between 3 and 22.2 per 1000 population. The prevalence of pediatric epilepsy in European and North American countries have consistently reported a prevalence of approximately 5 per 1000 population, whereas higher prevalence have been reported in less developing countries (Hauser, 1994; Hauser and Banerjee, 2008). Higher prevalence has also been reported in South American countries. Most studies of sex-specific differences among children with epilepsy have shown a higher incidence in boys than that in girls, which is consistent with the findings of our study. Our analysis reveals a significantly higher prevalence of epileptic seizure in children ≤4 years of age (P < 0.05). A study in Canada also revealed similar results (Schiariti et al., 2009). Our findings of the effects of age and sex on the prevalence of epilepsy are also consistent with those of series studies in Japan (Tsuboi, 1984, 1986, 1988). In addition, we calculated the mortality rate of target subjects. The results was 7.6/1000 (95% CI, 0.2—15.0) which was similar to previous study in adult Taiwanese patients (Tsai, 2005). We found no significant urbanization-related effect on the prevalence of neurological comorbidities in our epilepsy cohort. However, the prevalence of the psychiatric comorbidities is lower among children living in rural areas than in urban areas. A study showed that the prevalence and incidence of ADHD was significant lower in rural areas, which is consistent with our findings (Chien et al., 2012). Two possible causes of this finding. Medical resources for the diagnosis of pediatric psychiatric problems are relatively poor in rural areas. Urban—rural health-care disparities in Taiwan are apparently (Lin et al., 2007; Lin et al., 2013; Wang et al., 2013). Study proved neurologists are better at diagnosing epilepsy than non-specialists with misdiagnosis rate 5.6% versus 18.9% (Leach et al., 2005). Pediatric epilepsy and related neuropsychological comorbidities are majorly diagnosed and treated by pediatric neurologists and pediatric psychiatrists in Taiwan. The density of two specialists presents the prominent urban—rural disparity, that possible under-recognized and under-treated of the psychiatric comorbidities would be serious in rural areas (Figure 5). Besides, epilepsy is still misunderstood in Taiwan culture
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Figure 5 *Lasted available density of pediatric neurologists and psychiatrists (total number per 100,000 population by urbanization stratification, age below 20 years old). *Reference: (1) Official website of Taiwan Child Neurology Society. (2) Official website of Taiwanese Society of Child and Adolescent Psychiatry. (3) Population data from National health insurance research database 2011.
(Kuan et al., 2011). Low education level among people living in rural areas may lead to negative attitude in families regarding psychiatric illnesses that cause parents to be apprehensive in diagnosis and treatment of their epileptic children. Before implanting national health insurance in Taiwan, a questionnaire survey concern about the public awareness, understanding, and attitudes toward epilepsy was conducted. It showed obviously more negative than that in Western societies (Chung et al., 1995). Comparing to other countries, epilepsy is still a stigmatizing disorder in most developing countries. Uncorrected knowledge, deep influence of traditional briefs, and negative attitudes toward patients with epilepsy flaws the wide treatment gap. A study reported Egypt school students have a vague knowledge about the etiology of epilepsy, misconceptions, and negative attitudes (Shehata and Mahran, 2011). The situation is more worsening in rural areas, including Egypt, India, and China (El-Tallawy et al., 2013; Ray et al., 2002; Snape et al., 2009). On the other hand, studies have suggested that the prevalence of epilepsy is higher in populations in rural areas (Baumann et al., 1977; Hauser et al., 1990), which is similar to the result of our study. A recent study showed that patients with epilepsy were more likely to reside or work in less urbanized areas (Chang et al., 2011). A Egypt study reported higher prevalence of epilepsy among rural inhabitants in New Valley, and suggests possible due to higher rate of consanguinity in rural than urban communities and thus higher rate of idiopathic epilepsy (El-Tallawy et al., 2013), similar results reported in China (Snape et al., 2009). Thus, the effects of urban—rural disparities on the prevalence of pediatric epilepsy and related comorbidities in Taiwan should not be ignored. To our knowledge, our study is the first to use a population-based dataset to determine the neuropsychiatric comorbidities and prevalence in pediatric epileptic patients in Taiwan, and also the first study to discuss the urbanization effect on the neuropsychiatric comorbidities in the world. The prevalence of psychiatric comorbidities is significantly lower than previously reported, especially epileptic children living in rural areas. These diseases might be under-recognized and under-treated due to inaccurate and
K.-L. Chiang, C.-Y. Cheng inappropriate public perceptions about epilepsy and related psychiatric comorbidities, and poor medical resource for the diagnosis of pediatric psychiatric problems. We therefore suggest that further research is desirable to find out the cause, influence as well as more resolution for the urban—rural disparity in pediatric epilepsy with psychiatric comorbidities. Certain limitations to our findings should be considered. First, because the diagnoses analyzed came from administrative claims, some may represent a tentative, rather than a final diagnosis. Second, we did not differentiate between the subtypes, or stratify our analysis based on the severity of epilepsy. Neither did we include incidence information in our analysis. Third, the reliability and validity of the secondary data in the NHIRD could not be verified. However, the NHI Bureau had a medical review system to avoid the fake or tentative diagnoses. Fourth, certain sociodemographic characteristics, such as race and socioeconomic status, were not available in the NHIRD.
Conclusions This research provides the largest nationwide, populationbased study of childhood epilepsy in Taiwan. The prevalence of psychiatric comorbidities is lower than previously reported, especially in rural areas. Although NHI program has successfully provided universal and quality healthcare to all citizens in Taiwan since 1995, potential rural-urban disparity based on the prevalence and associated neuropsychiatric comorbidities cannot be ignored. Such disparity should be addressed by the agencies responsible for ensuring equitable public health care for all the citizens of Taiwan, and it is also noteworthy worldwide in making future public health policy.
Acknowledgments We thank the National Health Research Institute and the Bureau of National Health Insurance for supplying the data.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.eplepsyres.2014.07.004.
References Baca, C.B., Vickrey, B.G., Caplan, R., Vassar, S.D., Berg, A.T., 2011. Psychiatric and medical comorbidity and quality of life outcomes in childhood-onset epilepsy. Pediatrics 128, e1532—e1543. Baumann, R.J., Marx, M.B., Leonidakis, M.G., 1977. An estimate of the prevalence of epilepsy in a rural Appalachian population. Am. J. Epidemiol. 106, 42—52. Chang, Y.T., Chen, P.C., Tsai, I.J., Sung, F.C., Chin, Z.N., Kuo, H.T., Tsai, C.H., Chou, I.C., 2011. Bidirectional relation between schizophrenia and epilepsy: a population-based retrospective cohort study. Epilepsia 52, 2036—2042. Chen, C.C., Chen, L.S., Yen, M.F., Chen, H.H., Liou, H.H., 2012. Geographic variation in the age- and gender-specific prevalence
Prevalence and neuro-psychiatric comorbidities of pediatric epilepsy in Taiwan and incidence of epilepsy: analysis of Taiwanese National Health Insurance-based data. Epilepsia 53, 283—290. Chen, C.C., Chen, T.F., Hwang, Y.C., Wen, Y.R., Chiu, Y.H., Wu, C.Y., Chen, R.C., Chen, T.H., Liou, H.H., 2006a. Populationbased survey on prevalence of adult patients with epilepsy in Taiwan (Keelung community-based integrated screening no. 12). Epilepsy Res. 72, 67—74. Chen, T.J., Chou, L.F., Hwang, S.J., 2006b. Patterns of ambulatory care utilization in Taiwan. BMC Health Serv. Res. 6, 54. Chien, I.C., Chou, Y.J., Lin, C.H., Bih, S.H., Chou, P., 2004. Prevalence of psychiatric disorders among National Health Insurance enrollees in Taiwan. Psychiatr. Serv. 55, 691—697. Chien, I.C., Lin, C.H., Chou, Y.J., Chou, P., 2012. Prevalence, incidence, and stimulant use of attention-deficit hyperactivity disorder in Taiwan, 1996—2005: a national population-based study. Psychiatry Psychiatr. Epidemiol. 47, 1885—1990. Chung, M.Y., Chang, Y.C., Lai, Y.H., Lai, C.W., 1995. Survey of public awareness, understanding, and attitudes toward epilepsy in Taiwan. Epilepsia 36, 488—493. Cortesi, F., Giannotti, F., Ottaviano, S., 1999. Sleep problems and daytime behavior in childhood idiopathic epilepsy. Epilepsia 40, 1557—1565. Cowan, L.D., 2002. The epidemiology of the epilepsies in children. Ment. Retard. Dev. Disabil. Res. Rev. 8, 171—181. Cowan, L.D., Bodensteiner, J.B., Leviton, A., Doherty, L., 1989. Prevalence of the epilepsies in children and adolescents. Epilepsia 30, 94—106. Dehn, L., Korn-Merker, E., Pfäfflin, M., Fischbach, H., Frantz, M., Hauser, A., May, T., 2012. Burdens of parents with epileptic children—–results of a study using a short-form of the German version of the Impact-on-Family-Scale. Neuropediatrics 43, PS19 07. El-Tallawy, H.N., Farghaly, W.M., Shehata, G.A., Abdel-Hakeem, N.M., Rageh, T.A., Abo-Elftoh, N.A., Hegazy, A., Badry, R., 2013. Epidemiology of epilepsy in New Valley Governorate, Al Kharga District, Egypt. Epilepsy Res. 104, 167—174. England, M.J., Liverman, C.T., Schultz, A.M., Strawbridge, L.M., 2012. Epilepsy across the spectrum: promoting health and understanding. A summary of the Institute of Medicine report. Epilepsy Behav.: E&B 25, 266—276. Fisher, R.S., van Emde Boas, W., Blume, W., Elger, C., Genton, P., Lee, P., Engel Jr., J., 2005. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 46, 470—472. Gaitatzis, A., Carroll, K., Majeed, A., J., W.S., 2004. The epidemiology of the comorbidity of epilepsy in the general population. Epilepsia 45, 1613—1622. Gaitatzis, A., Sisodiya, S.M., Sander, J.W., 2012. The somatic comorbidity of epilepsy: a weighty but often unrecognized burden. Epilepsia 53, 1282—1293. Hamiwka, L.D., Wirrell, E.C., 2009. Comorbidities in pediatric epilepsy: beyond just treating the seizures. J. Child Neurol. 24, 734—742. Hauser, W.A., 1994. The prevalence and incidence of convulsive disorders in children. Epilepsia 35 (Suppl. 2), S1—S6. Hauser, W.A., Banerjee, P.N., 2008. Epidemiology of epilepsy in children. In: Pellock, J.M., Dodson, W.E., Bourgeois, B.F. (Eds.), Pediatric Epilepsy: Diagnosis and Therapy. , third edition. Demos Medical Publishing, LLC, New York, pp. 147—164. Hauser, W.A., Ortega, R., Zarelli, M., 1990. The prevalence of epilepsy in a rural Mexican village. Epilepsia 31, 604. Hsieh, L.P., Huang, C.Y., 2008. Prevalence of treated epilepsy in western medicine among the adult population in Taiwan: a study conducted using antiepileptic drug prescription data. Epilepsy Res. 80, 114—118.
1459
Jones, J.E., Austin, J.K., Caplan, R., Dunn, D., Plioplys, S., Salpekar, J.A., 2008. Psychiatric disorders in children and adolescents who have epilepsy. Pediatr. Rev./Am. Acad. Pediatr. 29, e9—e14. Jones, J.E., Watson, R., Sheth, R., Caplan, R., Koehn, M., Seidenberg, M., Hermann, B., 2007. Psychiatric comorbidity in children with new onset epilepsy. Dev. Med. Child Neurol. 49, 493—497. Kelley, S.A., Hartman, A.L., Kossoff, E.H., 2012. Comorbidity of migraine in children presenting with epilepsy to a tertiary care center. Neurology 79, 468—473. Kuan, Y.C., Yen, D.J., Yiu, C.H., Lin, Y.Y., Kwan, S.Y., Chen, C., Chou, C.C., Yu, H.Y., 2011. Treatment-seeking behavior of people with epilepsy in Taiwan: a preliminary study. Epilepsy Behav.: E&B 22, 308—312. Kwong, K.L., Chak, W.K., Wong, S.N., So, K.T., 2001. Epidemiology of childhood epilepsy in a cohort of 309 Chinese children. Pediatr. Neurol. 24, 276—282. Leach, J.P., Lauder, R., Nicolson, A., Smith, D.F., 2005. Epilepsy in the UK: misdiagnosis, mistreatment, and undertreatment? The Wrexham area epilepsy project. Seizure: J. Br. Epilepsy Assoc. 14, 514—520. Lee, W.L., LOW, P.S., Murugasu, B., Rajan, U., 1997. Epidemiology of epilepsy in Singapore children. Neurol. J. Southeast Asia 2, 31—35. Lin, H.C., Lin, Y.J., Liu, T.C., Chen, C.S., Chiu, W.T., 2007. Urbanization and stroke prevalence in Taiwan: analysis of a nationwide survey. J. Urban Health: Bull. N. Y. Acad. Med. 84, 604—614. Lin, J.J., Mula, M., Hermann, B.P., 2012. Uncovering the neurobehavioural comorbidities of epilepsy over the lifespan. Lancet 380, 1180—1192. Lin, Y.H., Tseng, Y.H., Chen, Y.C., Lin, M.H., Chou, L.F., Chen, T.J., Hwang, S.J., 2013. The rural—urban divide in ambulatory care of gastrointestinal diseases in Taiwan. BMC Int. Health Hum. Rights 13, 15. Liu, C.Y., Hung, Y.T., Chuang, Y.L., Chen, Y.J., Weng, W.S., Liu, J.S., Liang, K.Y., 2006. Incorporating development stratification of Taiwan townships into sampling design of large scale health interview survey. J. Health Manag. 4, 1—22. McAfee, A.T., Chilcott, K.E., Johannes, C.B., Hornbuckle, K., Hauser, W.A., Walker, A.M., 2007. The incidence of first provoked and unprovoked seizure in pediatric patients with and without psychiatric diagnoses. Epilepsia 48, 1075—1082. Pugh, M.J., Copeland, L.A., Zeber, J.E., Cramer, J.A., Amuan, M.E., Cavazos, J.E., Kazis, L.E., 2005. The impact of epilepsy on health status among younger and older adults. Epilepsia 46, 1820—1827. Ray, B.K., Bhattacharya, S., Kundu, T.N., Saha, S.P., Das, S.K., 2002. Epidemiology of epilepsy—–Indian perspective. J. Indian Med. Assoc. 100, 322—326. Russ, S.A., Larson, K., Halfon, N., 2012. A national profile of childhood epilepsy and seizure disorder. Pediatrics 129, 256—264. Schiariti, V., Farrell, K., Hoube, J.S., Lisonkova, S., 2009. Period prevalence of epilepsy in children in BC: a population-based study. Can. J. Neurol. Sci. J. Can. Sci. Neurol. 36, 36—41. Shehata, G.A., Mahran, D.G., 2011. Knowledge and attitude of epilepsy among secondary schools students (epileptic and nonepileptic) in Assiut city Egypt. Epilepsy Res. 95, 130—135. Snape, D., Wang, W., Wu, J., Jacoby, A., Baker, G.A., 2009. Knowledge gaps and uncertainties about epilepsy: findings from an ethnographic study in China. Epilepsy Behav.: E&B 14, 172—178. Stores, G., Wiggs, L., Campling, G., 1998. Sleep disorders and their relationship to psychological disturbance in children with epilepsy. Child: Care Health Dev. 24, 5—19. Su, C.L., Chang, S.F., Chen, Z.Y., Lee, C.S., Chen, R.C., 1998. Neuroepidemiological survey in Ilan, Taiwan (NESIT): (4) prevalence of epilepsy. Acta Neurol. Taiwan. 7, 75—84.
1460 Suren, P., Bakken, I.J., Aase, H., Chin, R., Gunnes, N., Lie, K.K., Magnus, P., Reichborn-Kjennerud, T., Schjolberg, S., Oyen, A.S., Stoltenberg, C., 2012. Autism spectrum disorder, ADHD, epilepsy, and cerebral palsy in Norwegian children. Pediatrics 130, e152—e158. Tsai, J.J., 2005. Mortality of epilepsy from national vital statistics and University epilepsy clinic in Taiwan. Epilepsia 46 (Suppl. 11), S8—S10. Tsuboi, T., 1984. Epidemiology of febrile and afebrile convulsions in children in Japan. Neurology 34, 175—181.
K.-L. Chiang, C.-Y. Cheng Tsuboi, T., 1986. Seizures of childhood. A population-based and clinic-based study. Acta Neurol. Scand. Supplementum 110, 1—237. Tsuboi, T., 1988. Prevalence and incidence of epilepsy in Tokyo. Epilepsia 29, 103—110. Wang, J.H., Wu, M.C., Chang, H.H., 2013. Urban-rural disparity in physical fitness of elementary schoolchildren in Taiwan. Pediatr. Int.: Off. J. Jpn. Pediatr. Soc. 55, 346—354.
journal homepage: www.elsevier.com/locate/epilepsyres
Prevalence and neuro-psychiatric comorbidities of pediatric epilepsy in Taiwan: A national population-based study Kuo-Liang Chiang a, Chen-Yang Cheng b,∗ a
Department of Pediatric Neurology, Kuang-Tien General Hospital, No. 117, Shatian Road Shalu District, Taichung City 433, Taiwan ROC b Program of Health Administration, Tunghai University, No. 181, Section 3, Taichung Harbor Road, Taichung, 407-04, Taiwan ROC Received 6 March 2014; received in revised form 27 June 2014; accepted 14 July 2014 Available online 23 July 2014
KEYWORDS Pediatric epilepsy; Prevalence; Comorbidity; Urbanization; Taiwan; National Health Insurance
Abstract Objective: Children with epilepsy may have comorbidities that result in significant disability. Epidemiological information for pediatric patients with epilepsy in Taiwan is scant. This research estimates the prevalence and common neuro-psychiatric comorbidities of children with epilepsy in Taiwan. Methods: Patients aged less than 20 years old who had received a diagnosis of epilepsy and suffered from epileptic seizures in 2005 were identified in the NHIRD based on ICD-9-CM and prescription records for the use of at least one AED. We used cases of epileptic seizure to survey outpatient service data, and identify common neuro-psychiatric comorbidities. The crude prevalence rate and the age- and sex-specific prevalence were estimated. We also examined the effects of urbanization. Results: The estimated prevalence of epilepsy was 0.33% in the pediatric population, with 0.29% for girls and 0.36% for boys. The most common neuropsychiatric comorbidities were learning disability and developmental delay, cerebral palsy, and mental retardation. Epilepsy was more prevalent in boys than in girls, especially among infants, preschool children, and those living in rural areas. In addition, boys with epilepsy had a higher rate of neurological comorbidities. The prevalence of psychiatric comorbidities was lower than that reported in previous studies performed in other countries, especially among children with epilepsy living in rural areas.
Abbreviations: NHIRD, National Health Insurance Research Database; ICD-9-CM, the diagnostic criteria of the International Classification of Diseases, Ninth Revision, Clinical Modification; NHRI, National Health Research Institute; AED, anti-epileptic drug; OR, odds ratio; CI, confidence interval; LDDD, learning disability and developmental delay; ADHD, attention-deficit hyperactivity disorder. ∗ Corresponding author. Tel.: +886 4 23594319 140; fax: +886 4 2359 1756. E-mail addresses: [email protected] (K.-L. Chiang), [email protected] (C.-Y. Cheng). http://dx.doi.org/10.1016/j.eplepsyres.2014.07.004 0920-1211/© 2014 Elsevier B.V. All rights reserved.
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K.-L. Chiang, C.-Y. Cheng Conclusion: This research provides the largest nationwide, population-based study of childhood epilepsy to estimate the prevalence and the associated neuropsychiatric comorbidities of pediatric epilepsy in Taiwan. Potential rural—urban disparity basing on prevalence and associated neuropsychiatric comorbidities cannot be ignored in Taiwan. © 2014 Elsevier B.V. All rights reserved.
Introduction Epilepsy, a neurological condition characterized by recurrent seizures, is one of the most highly prevalent pediatric neurological disorders and also a costly and complicated major public health problem (England et al., 2012). The epilepsy of a child influences the whole family system and leads to different burdens for the family members especially the parents. Studies reported increased stress and burden for families are particularly to be expected if the child shows additional emotional respectively behavioral problems or other comorbid conditions (Dehn et al., 2012; Hamiwka and Wirrell, 2009). Comorbidities refer to the co-occurrence of more than one condition in the same person. Generally, comorbidities are associated with poor health outcomes. It is now widely appreciated that comorbidities impact the quality of life in pediatric epilepsy and are evident at or prior to the onset of epilepsy (Lin et al., 2012). Pediatric epilepsy patients have the greatest long-term morbidity, despite accounting for only approximately 20% of all patients newly diagnosed with a seizure disorder (Hauser, 1994). For healthcare providers, understanding the epidemiology and comorbidities of epilepsy in pediatric patients could help improve diagnosis, understand patient’s prognosis, and widen insight of pathogenesis by revealing shared neurological mechanisms underlying multiple disorders that lead to contribution of information regarding available treatment choices. In highly developed countries, prevalence estimations are relayed on available medical records and health care database. On the other hand, challenges in most developing countries are lack of national health care systems. Population-based studies with direct personal interviews through door-to-door or face-to-face survey remains the main tool for epidemiological studies (El-Tallawy et al., 2013; Ray et al., 2002; Shehata and Mahran, 2011; Snape et al., 2009). According to our survey, the prevalence of epilepsy has been conducted in local areas in Taiwan using door to door survey, however, both of them have focused mainly on adults (Chen et al., 2006a; Su et al., 1998). Population-based studies dealing specifically with children are few and suffer from difficulties with definitions and differences in methodology (Hauser, 1994; Hauser and Banerjee, 2008). The National Health Insurance (NHI) program was implemented in Taiwan in 1995, and provides equitable, affordable, and universal health-care coverage to more than 98% of the 23 million residents of Taiwan (Chien et al., 2004, 2012). With such high cover rate, the claims data is suitable for epidemiology study. Currently, there are two studies, that using NHIRD for the prevalence and incidence of epilepsy. Hsieh et al. conducted a study using antiepileptic drug prescription data of NHIRD, and the prevalence of
adult population in Taiwan of this study was 0.42% (Hsieh and Huang, 2008). However, the study excluded patients younger than 25 years old, that the results could not deliver any information for children. Another study had only one group of 0—19 subgroup and did not provide a detailed analysis for children and adolescents (Chen et al., 2012). Hence, epidemiological information regarding pediatric patients with epilepsy and the related comorbidities in Taiwan is scant. In current research, we used NHI claims data from 2005 to determine the prevalence of epileptic seizures and epilepsy among children and adolescents. We also examined the rates of neuro-psychiatric comorbidities of the target subjects considering the effects of age, sex, and urbanization.
Materials and methods Data source and sampling We obtained the data for our study from the National Health Insurance Research Database (NHIRD), which is a subset of randomly selected NHI claims records. According to the National Health Research Institute (NHRI), which prepared and manages the NHIRD, the sampling randomization for the NHIRD used the linear congruential random number generation function of the Sun Work Shop C 5.0 (Chen et al., 2006b). The NHRI has reported no statistically significant difference in age, sex, or average household income exists between the NHIRD and the combined records of all NHI enrollees. The NHI Bureau has approved the following 14 antiepileptic drugs (AEDs) for use by epilepsy patients in Taiwan: carbamazepine, phenytoin, gabapentin, clonazepam, clobazam, levetiracetam, oxcarbazepine, lamotrigine, primidone, tiagabine, topiramate, sodium valproate (valporic acid), vigabatrin, and phenobarbital. These AEDs were available in a total of 151 commercial forms in 2005. Our study used 10 cohort datasets from the NHIRD. Each cohort included 40, 000 patients randomly sampled from all NHI beneficiaries in 2005. A total of 102,081 patients aged 20 years and younger were included in our analysis as of December 31, 2005, among whom 48,800 (47.8%) were females and 53,241 (52.3%) were males. Our study was approved by the Institutional Review Board of Kuang-Tien General Hospital.
Definition of epilepsy For the purposes of our study, epileptic seizure was defined according to the diagnostic criteria of the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) as ICD-9-CM 345.xx for epilepsy and ICD-9-CM 780.3 and 790.39 for convulsion (Fisher et al., 2005; McAfee
Prevalence and neuro-psychiatric comorbidities of pediatric epilepsy in Taiwan
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0.36 0.32 0.31 0.31 0.33 0.45 0.36 0.31 0.35 0.36 0.26 0.29 0.31 0.28 0.29 72 85 88 88 333 47 49 46 51 193 0.78 0.53 0.42 0.41 0.52 0.92 0.58 0.42 0.46 0.57 0.63 0.48 0.42 0.36 0.46 155 139 118 116 528 96 79 62 67 304 59 60 56 49 224 19,849 26,181 28,066 27,985 102,081 10,412 13,654 14,621 14,554 53,241 9437 12,527 13,445 13,431 48,840 0—4 5—9 10—14 15—19 All
All Male Female Male
All
Male
All
Prevalence (95% CI)
(0.66—0.90) (0.44—0.62) (0.34—0.50) (0.36—0.48) (0.48—0.56)
25 36 42 37 140
All Male Male Female Female Female
Epilepsy Epileptic seizures
The SQL Server 2012 database software (Microsoft, Redmond, WA, USA) was used to link data from order forms and prescriptions to the registry of beneficiaries. The Microsoft Excel 2003 and SPSS, Version 17.0, (IBM, Armonk, NY, USA) computer software packages were used for all data processing, including data selection, data merging, data aggregation, and calculations. The chi-squared test was used for our stratified analyses of the prevalence of epilepsy based on age, sex, and urbanization level. We compared the data for the epileptic and non-epileptic cohorts to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for the comorbidities and the urbanization levels. A two-tailed
Inhabitants
Data analysis
Age
We also stratified our analysis of pediatric epilepsy and epileptic seizures in children based on urbanization level to examine differences between children with epilepsy living in urban areas and those living in rural areas. We used the criteria for urbanization defined by the NHRI Information regarding the township in which each beneficiary resides is available (Liu et al., 2006). All 359 townships in Taiwan have been classified by the NHRI into seven clusters. Based on these criteria, the townships were categorized as rural (Levels 5—7), suburban (Levels 3 and 4), or urban (Levels 1 and 2), as described previously (Lin et al., 2013).
Age and gender-specific prevalence of epileptic seizures and epilepsy in 2005 in Taiwan of current study.
Urbanization
Table 1
Comorbidity in epilepsy is defined as other conditions may precede, co-occur with, or follow the diagnosis of epilepsy (Gaitatzis et al., 2004). Because each record for a medical claim in the NHIRD may contain up to three ICD-9-CM codes, we used the unique identification number for each patient to survey all their outpatient service data in 2005 to identify common neurological and psychiatric comorbidities (McAfee et al., 2007). The comorbidities include brain tumor, schizophrenia, affective psychoses, autism/autistic spectrum disorder, Tourette syndrome/tics, sleep disorder, depression disorder, acquired hydrocephalus, ADHD, learning disability and developmental delay, mental retardation/intellectual disability, CNS infection, multiple sclerosis, cerebral palsy, migraine, cerebral vascular disorder, congenital brain anomaly and head injury. The comorbidities were selected on the basis of prior researches (Baca et al., 2011; Cortesi et al., 1999; Gaitatzis et al., 2004; Jones et al., 2008; Kelley et al., 2012; Lin et al., 2012; Russ et al., 2012; Stores et al., 1998; Suren et al., 2012). The ICD9-CM codes for the neuropsychiatric comorbidities included in our analysis are listed in supporting Table 1.
All
Definition of the comorbidities
Female
Prevalence (95% CI)
(0.28—0.44) (0.25—0.39) (0.25—0.38) (0.24—0.38) (0.29—0.36)
et al., 2007; Schiariti et al., 2009). We excluded febrile seizures (ICD-9-CM 780.31 and 780.32), and certain ICD-9-CM codes, including those for myoclonic and neonatal seizures. We defined epilepsy as the use of at least one of the NHIapproved AEDs by a patient who had received a diagnosis of epileptic seizures (Pugh et al., 2005).
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Figure 1
Age-specific prevalence rate in current study.
P value < 0.05 was considered to indicate a statistically significant difference.
Results Prevalence of pediatric epileptic seizures and epilepsy A total of 528 patients diagnosed with epileptic seizure in 2005 were identified in the NHIRD, among whom 224 (42.4%) were females and 304 (57.6%) were males. The crude prevalence of epileptic seizure was 0.46% for females and 0.57% for males, yielding a combined crude prevalence of epileptic seizure in the general population of 0.52%. At least one AED was prescribed to 140 (45.8%) females and 193 (54.2%) males. The crude prevalence of epilepsy was 0.29% for females and 0.36% for males, yielding a combined crude prevalence of 3.3 per 1000 population in 2005. The age- and sex-specific prevalence of epileptic seizure and epilepsy is shown in Table 1, respectively.
Age- and sex-specific prevalence of epileptic seizures and epilepsy The age-specific prevalence of epileptic seizure and epilepsy are graphically depicted in Figure 1. The prevalence of epileptic seizure was significantly higher (P < 0.05) in children aged ≤4 years, although the difference was not statistically significant, the prevalence of epilepsy was slightly higher in children aged ≤4 years. Significant sex-specific differences in the prevalence of epileptic seizure and epilepsy were observed. Both epileptic seizure (P < 0.01) and epilepsy (P < 0.05) were significantly more prevalent in males than in females. The prevalence of epilepsy in females was fairly constant from birth to early adulthood. The prevalence of epilepsy was significantly higher (P < 0.05) in boys aged ≤4 years, and decreased from birth to early adolescence, increasing slightly in late adolescence. The prevalence of both epilepsy (P < 0.05) and epileptic seizures (P < 0.01) among boys aged
≤4 years was significantly higher than that for girls, as shown in Figure 2.
Neuropsychiatric comorbidities Comorbidity prevalence Among the 528 patients identified with epilepsy, 206 patients (39.0%) had neuropsychiatric comorbidities, of whom 76 patients (33.9%) were female and 130 (42.8%) were male. The prevalence rates and ORs of the comorbidities analyzed are shown in Table A2. We categorized the comorbidities identified as psychiatric comorbidities and neurological comorbidities. Psychiatric and neurological comorbidities were present in 24.6% and 24.8%, respectively, among the patients with epilepsy. The prevalence of neuropsychiatric comorbidities in patients with epilepsy was higher (P < 0.05) among males than in females. The prevalence of neurological comorbidities was 28.6% among males and 19.6% among females (P < 0.01). No significant sex-specific differences existed in the psychiatric comorbidities identified between males and females (Table A3). The most common psychiatric comorbidities in patients with epilepsy were learning disability and developmental delay (LDDD; 13.1%), mental retardation (7.8%), attentiondeficit hyperactivity disorder (ADHD; 5.9%), and sleep disorders (3.4%). No epilepsy patient was diagnosed with major depressive disorder, and one patient was diagnosed with affective psychosis. The most common neurological comorbidities were cerebral palsy (10.4%), head injury (6.1%), congenital brain anomaly (3.6%), and cerebral vascular disorder (2.8%). Odds ratios of common comorbidities The ORs for mental retardation, schizophrenia and organic psychosis, and ADHD were 32.3, 24, and 25.8, respectively. Although LDDD was the most prevalent comorbidity, the OR of LDDD (18.4) was only the fourth highest among the conditions analyzed. Among the neurological comorbidities, the ORs for cerebral palsy, congenital brain anomaly, and cerebral vascular disorder were 91.4, 68.9, and 45.7, respectively. Among the neuropsychiatric comorbidities analyzed, cerebral palsy had the highest OR, as shown in Table 2.
Prevalence and neuro-psychiatric comorbidities of pediatric epilepsy in Taiwan
1455
1 0.92 0.9
**
0.8
0.7 0.63 0.6
0.58
0.5
0.48
0.45
*
Epilepc seizures female 0.46 0.42
0.4
0.36
0.36
0.3
0.35 0.31
0.29
0.26
Epilepc seizures male Epilepsy female Epilepsy male
0.28
0.2
0.1
0
0-4
5-9
10-14
15-19
Figure 2 Prevalence of epileptic seizures and epilepsy in the function of age and sex categories in 2005 in our study. **p < 0.01 (epileptic seizure: male vs female in 0—4 group); *p < 0.05 (epilepsy: male vs female in 0—4 group).
Table 2
Common comorbidities found in current study.
Psychiatric comorbidities
Neurological comorbidities
Disease
Mean age
M/F
Co-morbidity rate%
Odds ratio
Learning disability and developmetal delay Mental retardation ADHD Sleep disorders Autistic spectrum disorder Neurotic-anxiety disorder Schizophrenia and organic psychosis Cerebral palsy Head injury with skull fracture Congenital brain anomaly Cerebral vascular disorder Tourett or tics Migraine CNS infection Acquired hydrocephalus
6.2±4.2
1.56
13.1
18.4
10.2±4.5 8.4±3.1 14.2±4.6 7.6±3.5
1.93 2.1 0.64 3.25
7.8 5.9 3.4 3.2
32.3 9.3 6.1 25.8
15.3±4
1
1.9
3.3
16.0±3.2
2.5
1.3
24
8.2±5.3 9.2±6.15
1.39 1.67
10.4 6.1
91.4 5.1
7.9±5.4
2.17
3.6
68.9
9.4±7.27
1.14
2.8
45.7
9.4±4.9 11.8±3.9 8.2±5.6 6.3±3.5
3.67 1.8 4 0.5
2.7 2.7 1 0.58
22.3 12 17.6 36.3
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Figure 3
Prevalence rate of epilepsy and epileptic seizure divided in urbanization level.
Influence of urbanization on pediatric epilepsy and the comorbidities The prevalence of pediatric epileptic seizures in urban, suburban, and rural townships was 5.0, 5.4, and 6.4 per 1000, respectively, and the prevalence of pediatric epilepsy in urban, suburban, and rural townships was 3.1, 3.5, and 3.9 per 1000, respectively. Epilepsy and epileptic seizures were most prevalent among children living in rural areas (OR, 1.28; 95% CI, 0.97—1.69). Although the effect of urbanization was not statistically significant, a gradual trend toward an increasing prevalence of pediatric epilepsy was observed from urban to rural areas (Figure 3). The overall prevalence of the psychiatric comorbidities was lower among children with epilepsy in rural townships than that of those living in suburban or urban areas, and stratification based on urbanization revealed no significant difference in the overall prevalence of neurological comorbidities among pediatric epilepsy patients (Figure 4).
Figure 4
Discussion This study discusses the rates of neuro-psychiatric comorbidities, the prevalence of pediatric epilepsy, and the epilepsy-related rural-urban disparity based on NHIRD. The result indicates comorbidities are identified in 39.0% in children younger than 20 year old with epilepsy. The most common neuropsychiatric comorbidities are developmental delay, cerebral palsy, and mental retardation. The prevalence of psychiatric comorbidities is lower than previously reported, especially in rural areas. In addition, prevalence of neuropsychiatric comorbidities is significantly higher among boys. The prevalence of epileptic seizures is 0.52%, and the prevalence of epilepsy is 0.33%. The prevalence of pediatric epilepsy is higher in rural areas, and in boys younger than 4 years old. The following sections are explained these results. The comparison of our study and previous studies of epilepsy comorbidities is presented in Table 3. The
Comorbidity rate of epileptic seizure with urban stratification.
Prevalence and neuro-psychiatric comorbidities of pediatric epilepsy in Taiwan Table 3
1457
Comparison of common comorbidities prevalence rate of our study and previous literatures..
Comorbidities
Previous literature
Our current study
Intellectual disabilities Cerebral palsy Learning disabilities and developmental delay Migraine Sleep disorder ADHD Autistic spectrum disorders Depressive disorder Anxiety disorder
10—25% (Lin et al., 2012; Russ et al., 2012) 12—15% (Suren et al., 2012) 40—50% (Baca et al., 2011; Russ et al., 2012) 25% (Kelley et al., 2012) Unknown (Cortesi et al., 1999; Stores et al., 1998) 15—40% (Jones et al., 2008) 6% (Suren et al., 2012) 10—30% (Jones et al., 2008) 13—49% (Jones et al., 2008)
7.8% 10.4% 13.1% 2.7%* 3.4% 5.9% 3.2% No patient** 1.90%**
Our study vs. previous studies to the lower limit of literature, * p < 0.01,
prevalence rates of the most common neuropsychiatric comorbidities are similar to those reported in previous studies except for a lower prevalence of depression and anxiety (Jones et al., 2008, 2007). Study reported children with either previously or current epilepsy/seizure disorder were more likely to experience mental health and developmental comorbidities (Russ et al., 2012). Cognitive, motor, and/or psychiatric comorbidities occur in 25—45% of children with epilepsy (Cowan, 2002, 1989; Schiariti et al., 2009). Our analysis reveals similar results. Previous studies have also reported higher prevalence of neuropsychiatric comorbidities in children, including cerebral palsy (10—15%) (Suren et al., 2012), LDDD (40—50%) (Baca et al., 2011; Russ et al., 2012), mental retardation (10%), and IQ below 70 or 80 (25%) (Lin et al., 2012; Russ et al., 2012).Other neurological comorbidities include migraine (25%) (Kelley et al., 2012) and sleep disorders (Cortesi et al., 1999; Stores et al., 1998), and the prevalence of depressive disorder (10—30%), anxiety disorder (13—49%), ADHD (15—40%), and autistic spectrum disorder in pediatric patients (6%) (Jones et al., 2008, 2007). It is noteworthy that no patient with major depressive disorder is identified, and that psychiatric comorbidities including autism, anxiety, and schizophrenia, are relatively rare in our study. We speculate that these diseases are likely under-recognized and under-treated in epileptic children in Taiwan. Psychiatric comorbidities are considered a stigma in Taiwanese culture. Physicians may be apprehensive about coding such as diagnoses if they determine that medical treatment is unnecessary. However, untreated depression and other psychiatric problems are more likely to become chronic as children grow into adults, and these problems can have a greater effect on a patient’s quality of life than epilepsy (Jones et al., 2007). Physicians should always consider neuropsychiatric assessment and treatment to protect the quality of life of children with epilepsy. Neurological conditions, including cerebral palsy, congenital brain anomaly, cerebral vascular disorder, and migraine were common among the children with epilepsy in our study. Due to sharing a common etiology or risk factor, such findings might be expected to cause epileptic seizures or associate with epilepsy (Gaitatzis et al., 2012). With the prevalence of epilepsy, our finding in Taiwan is consistent with those of studies in Singapore, Tokyo, and Hong Kong, which reported prevalence of 3.6; 2.8—3.2;
**
p < 0.05.
and 1.52 per 1000 population, respectively (Hauser, 1994; Hauser and Banerjee, 2008; Kwong et al., 2001; Lee et al., 1997; Schiariti et al., 2009; Tsuboi, 1984). Wide variations occur in the prevalence of childhood epilepsy worldwide, ranging between 3 and 22.2 per 1000 population. The prevalence of pediatric epilepsy in European and North American countries have consistently reported a prevalence of approximately 5 per 1000 population, whereas higher prevalence have been reported in less developing countries (Hauser, 1994; Hauser and Banerjee, 2008). Higher prevalence has also been reported in South American countries. Most studies of sex-specific differences among children with epilepsy have shown a higher incidence in boys than that in girls, which is consistent with the findings of our study. Our analysis reveals a significantly higher prevalence of epileptic seizure in children ≤4 years of age (P < 0.05). A study in Canada also revealed similar results (Schiariti et al., 2009). Our findings of the effects of age and sex on the prevalence of epilepsy are also consistent with those of series studies in Japan (Tsuboi, 1984, 1986, 1988). In addition, we calculated the mortality rate of target subjects. The results was 7.6/1000 (95% CI, 0.2—15.0) which was similar to previous study in adult Taiwanese patients (Tsai, 2005). We found no significant urbanization-related effect on the prevalence of neurological comorbidities in our epilepsy cohort. However, the prevalence of the psychiatric comorbidities is lower among children living in rural areas than in urban areas. A study showed that the prevalence and incidence of ADHD was significant lower in rural areas, which is consistent with our findings (Chien et al., 2012). Two possible causes of this finding. Medical resources for the diagnosis of pediatric psychiatric problems are relatively poor in rural areas. Urban—rural health-care disparities in Taiwan are apparently (Lin et al., 2007; Lin et al., 2013; Wang et al., 2013). Study proved neurologists are better at diagnosing epilepsy than non-specialists with misdiagnosis rate 5.6% versus 18.9% (Leach et al., 2005). Pediatric epilepsy and related neuropsychological comorbidities are majorly diagnosed and treated by pediatric neurologists and pediatric psychiatrists in Taiwan. The density of two specialists presents the prominent urban—rural disparity, that possible under-recognized and under-treated of the psychiatric comorbidities would be serious in rural areas (Figure 5). Besides, epilepsy is still misunderstood in Taiwan culture
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Figure 5 *Lasted available density of pediatric neurologists and psychiatrists (total number per 100,000 population by urbanization stratification, age below 20 years old). *Reference: (1) Official website of Taiwan Child Neurology Society. (2) Official website of Taiwanese Society of Child and Adolescent Psychiatry. (3) Population data from National health insurance research database 2011.
(Kuan et al., 2011). Low education level among people living in rural areas may lead to negative attitude in families regarding psychiatric illnesses that cause parents to be apprehensive in diagnosis and treatment of their epileptic children. Before implanting national health insurance in Taiwan, a questionnaire survey concern about the public awareness, understanding, and attitudes toward epilepsy was conducted. It showed obviously more negative than that in Western societies (Chung et al., 1995). Comparing to other countries, epilepsy is still a stigmatizing disorder in most developing countries. Uncorrected knowledge, deep influence of traditional briefs, and negative attitudes toward patients with epilepsy flaws the wide treatment gap. A study reported Egypt school students have a vague knowledge about the etiology of epilepsy, misconceptions, and negative attitudes (Shehata and Mahran, 2011). The situation is more worsening in rural areas, including Egypt, India, and China (El-Tallawy et al., 2013; Ray et al., 2002; Snape et al., 2009). On the other hand, studies have suggested that the prevalence of epilepsy is higher in populations in rural areas (Baumann et al., 1977; Hauser et al., 1990), which is similar to the result of our study. A recent study showed that patients with epilepsy were more likely to reside or work in less urbanized areas (Chang et al., 2011). A Egypt study reported higher prevalence of epilepsy among rural inhabitants in New Valley, and suggests possible due to higher rate of consanguinity in rural than urban communities and thus higher rate of idiopathic epilepsy (El-Tallawy et al., 2013), similar results reported in China (Snape et al., 2009). Thus, the effects of urban—rural disparities on the prevalence of pediatric epilepsy and related comorbidities in Taiwan should not be ignored. To our knowledge, our study is the first to use a population-based dataset to determine the neuropsychiatric comorbidities and prevalence in pediatric epileptic patients in Taiwan, and also the first study to discuss the urbanization effect on the neuropsychiatric comorbidities in the world. The prevalence of psychiatric comorbidities is significantly lower than previously reported, especially epileptic children living in rural areas. These diseases might be under-recognized and under-treated due to inaccurate and
K.-L. Chiang, C.-Y. Cheng inappropriate public perceptions about epilepsy and related psychiatric comorbidities, and poor medical resource for the diagnosis of pediatric psychiatric problems. We therefore suggest that further research is desirable to find out the cause, influence as well as more resolution for the urban—rural disparity in pediatric epilepsy with psychiatric comorbidities. Certain limitations to our findings should be considered. First, because the diagnoses analyzed came from administrative claims, some may represent a tentative, rather than a final diagnosis. Second, we did not differentiate between the subtypes, or stratify our analysis based on the severity of epilepsy. Neither did we include incidence information in our analysis. Third, the reliability and validity of the secondary data in the NHIRD could not be verified. However, the NHI Bureau had a medical review system to avoid the fake or tentative diagnoses. Fourth, certain sociodemographic characteristics, such as race and socioeconomic status, were not available in the NHIRD.
Conclusions This research provides the largest nationwide, populationbased study of childhood epilepsy in Taiwan. The prevalence of psychiatric comorbidities is lower than previously reported, especially in rural areas. Although NHI program has successfully provided universal and quality healthcare to all citizens in Taiwan since 1995, potential rural-urban disparity based on the prevalence and associated neuropsychiatric comorbidities cannot be ignored. Such disparity should be addressed by the agencies responsible for ensuring equitable public health care for all the citizens of Taiwan, and it is also noteworthy worldwide in making future public health policy.
Acknowledgments We thank the National Health Research Institute and the Bureau of National Health Insurance for supplying the data.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.eplepsyres.2014.07.004.
References Baca, C.B., Vickrey, B.G., Caplan, R., Vassar, S.D., Berg, A.T., 2011. Psychiatric and medical comorbidity and quality of life outcomes in childhood-onset epilepsy. Pediatrics 128, e1532—e1543. Baumann, R.J., Marx, M.B., Leonidakis, M.G., 1977. An estimate of the prevalence of epilepsy in a rural Appalachian population. Am. J. Epidemiol. 106, 42—52. Chang, Y.T., Chen, P.C., Tsai, I.J., Sung, F.C., Chin, Z.N., Kuo, H.T., Tsai, C.H., Chou, I.C., 2011. Bidirectional relation between schizophrenia and epilepsy: a population-based retrospective cohort study. Epilepsia 52, 2036—2042. Chen, C.C., Chen, L.S., Yen, M.F., Chen, H.H., Liou, H.H., 2012. Geographic variation in the age- and gender-specific prevalence
Prevalence and neuro-psychiatric comorbidities of pediatric epilepsy in Taiwan and incidence of epilepsy: analysis of Taiwanese National Health Insurance-based data. Epilepsia 53, 283—290. Chen, C.C., Chen, T.F., Hwang, Y.C., Wen, Y.R., Chiu, Y.H., Wu, C.Y., Chen, R.C., Chen, T.H., Liou, H.H., 2006a. Populationbased survey on prevalence of adult patients with epilepsy in Taiwan (Keelung community-based integrated screening no. 12). Epilepsy Res. 72, 67—74. Chen, T.J., Chou, L.F., Hwang, S.J., 2006b. Patterns of ambulatory care utilization in Taiwan. BMC Health Serv. Res. 6, 54. Chien, I.C., Chou, Y.J., Lin, C.H., Bih, S.H., Chou, P., 2004. Prevalence of psychiatric disorders among National Health Insurance enrollees in Taiwan. Psychiatr. Serv. 55, 691—697. Chien, I.C., Lin, C.H., Chou, Y.J., Chou, P., 2012. Prevalence, incidence, and stimulant use of attention-deficit hyperactivity disorder in Taiwan, 1996—2005: a national population-based study. Psychiatry Psychiatr. Epidemiol. 47, 1885—1990. Chung, M.Y., Chang, Y.C., Lai, Y.H., Lai, C.W., 1995. Survey of public awareness, understanding, and attitudes toward epilepsy in Taiwan. Epilepsia 36, 488—493. Cortesi, F., Giannotti, F., Ottaviano, S., 1999. Sleep problems and daytime behavior in childhood idiopathic epilepsy. Epilepsia 40, 1557—1565. Cowan, L.D., 2002. The epidemiology of the epilepsies in children. Ment. Retard. Dev. Disabil. Res. Rev. 8, 171—181. Cowan, L.D., Bodensteiner, J.B., Leviton, A., Doherty, L., 1989. Prevalence of the epilepsies in children and adolescents. Epilepsia 30, 94—106. Dehn, L., Korn-Merker, E., Pfäfflin, M., Fischbach, H., Frantz, M., Hauser, A., May, T., 2012. Burdens of parents with epileptic children—–results of a study using a short-form of the German version of the Impact-on-Family-Scale. Neuropediatrics 43, PS19 07. El-Tallawy, H.N., Farghaly, W.M., Shehata, G.A., Abdel-Hakeem, N.M., Rageh, T.A., Abo-Elftoh, N.A., Hegazy, A., Badry, R., 2013. Epidemiology of epilepsy in New Valley Governorate, Al Kharga District, Egypt. Epilepsy Res. 104, 167—174. England, M.J., Liverman, C.T., Schultz, A.M., Strawbridge, L.M., 2012. Epilepsy across the spectrum: promoting health and understanding. A summary of the Institute of Medicine report. Epilepsy Behav.: E&B 25, 266—276. Fisher, R.S., van Emde Boas, W., Blume, W., Elger, C., Genton, P., Lee, P., Engel Jr., J., 2005. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 46, 470—472. Gaitatzis, A., Carroll, K., Majeed, A., J., W.S., 2004. The epidemiology of the comorbidity of epilepsy in the general population. Epilepsia 45, 1613—1622. Gaitatzis, A., Sisodiya, S.M., Sander, J.W., 2012. The somatic comorbidity of epilepsy: a weighty but often unrecognized burden. Epilepsia 53, 1282—1293. Hamiwka, L.D., Wirrell, E.C., 2009. Comorbidities in pediatric epilepsy: beyond just treating the seizures. J. Child Neurol. 24, 734—742. Hauser, W.A., 1994. The prevalence and incidence of convulsive disorders in children. Epilepsia 35 (Suppl. 2), S1—S6. Hauser, W.A., Banerjee, P.N., 2008. Epidemiology of epilepsy in children. In: Pellock, J.M., Dodson, W.E., Bourgeois, B.F. (Eds.), Pediatric Epilepsy: Diagnosis and Therapy. , third edition. Demos Medical Publishing, LLC, New York, pp. 147—164. Hauser, W.A., Ortega, R., Zarelli, M., 1990. The prevalence of epilepsy in a rural Mexican village. Epilepsia 31, 604. Hsieh, L.P., Huang, C.Y., 2008. Prevalence of treated epilepsy in western medicine among the adult population in Taiwan: a study conducted using antiepileptic drug prescription data. Epilepsy Res. 80, 114—118.
1459
Jones, J.E., Austin, J.K., Caplan, R., Dunn, D., Plioplys, S., Salpekar, J.A., 2008. Psychiatric disorders in children and adolescents who have epilepsy. Pediatr. Rev./Am. Acad. Pediatr. 29, e9—e14. Jones, J.E., Watson, R., Sheth, R., Caplan, R., Koehn, M., Seidenberg, M., Hermann, B., 2007. Psychiatric comorbidity in children with new onset epilepsy. Dev. Med. Child Neurol. 49, 493—497. Kelley, S.A., Hartman, A.L., Kossoff, E.H., 2012. Comorbidity of migraine in children presenting with epilepsy to a tertiary care center. Neurology 79, 468—473. Kuan, Y.C., Yen, D.J., Yiu, C.H., Lin, Y.Y., Kwan, S.Y., Chen, C., Chou, C.C., Yu, H.Y., 2011. Treatment-seeking behavior of people with epilepsy in Taiwan: a preliminary study. Epilepsy Behav.: E&B 22, 308—312. Kwong, K.L., Chak, W.K., Wong, S.N., So, K.T., 2001. Epidemiology of childhood epilepsy in a cohort of 309 Chinese children. Pediatr. Neurol. 24, 276—282. Leach, J.P., Lauder, R., Nicolson, A., Smith, D.F., 2005. Epilepsy in the UK: misdiagnosis, mistreatment, and undertreatment? The Wrexham area epilepsy project. Seizure: J. Br. Epilepsy Assoc. 14, 514—520. Lee, W.L., LOW, P.S., Murugasu, B., Rajan, U., 1997. Epidemiology of epilepsy in Singapore children. Neurol. J. Southeast Asia 2, 31—35. Lin, H.C., Lin, Y.J., Liu, T.C., Chen, C.S., Chiu, W.T., 2007. Urbanization and stroke prevalence in Taiwan: analysis of a nationwide survey. J. Urban Health: Bull. N. Y. Acad. Med. 84, 604—614. Lin, J.J., Mula, M., Hermann, B.P., 2012. Uncovering the neurobehavioural comorbidities of epilepsy over the lifespan. Lancet 380, 1180—1192. Lin, Y.H., Tseng, Y.H., Chen, Y.C., Lin, M.H., Chou, L.F., Chen, T.J., Hwang, S.J., 2013. The rural—urban divide in ambulatory care of gastrointestinal diseases in Taiwan. BMC Int. Health Hum. Rights 13, 15. Liu, C.Y., Hung, Y.T., Chuang, Y.L., Chen, Y.J., Weng, W.S., Liu, J.S., Liang, K.Y., 2006. Incorporating development stratification of Taiwan townships into sampling design of large scale health interview survey. J. Health Manag. 4, 1—22. McAfee, A.T., Chilcott, K.E., Johannes, C.B., Hornbuckle, K., Hauser, W.A., Walker, A.M., 2007. The incidence of first provoked and unprovoked seizure in pediatric patients with and without psychiatric diagnoses. Epilepsia 48, 1075—1082. Pugh, M.J., Copeland, L.A., Zeber, J.E., Cramer, J.A., Amuan, M.E., Cavazos, J.E., Kazis, L.E., 2005. The impact of epilepsy on health status among younger and older adults. Epilepsia 46, 1820—1827. Ray, B.K., Bhattacharya, S., Kundu, T.N., Saha, S.P., Das, S.K., 2002. Epidemiology of epilepsy—–Indian perspective. J. Indian Med. Assoc. 100, 322—326. Russ, S.A., Larson, K., Halfon, N., 2012. A national profile of childhood epilepsy and seizure disorder. Pediatrics 129, 256—264. Schiariti, V., Farrell, K., Hoube, J.S., Lisonkova, S., 2009. Period prevalence of epilepsy in children in BC: a population-based study. Can. J. Neurol. Sci. J. Can. Sci. Neurol. 36, 36—41. Shehata, G.A., Mahran, D.G., 2011. Knowledge and attitude of epilepsy among secondary schools students (epileptic and nonepileptic) in Assiut city Egypt. Epilepsy Res. 95, 130—135. Snape, D., Wang, W., Wu, J., Jacoby, A., Baker, G.A., 2009. Knowledge gaps and uncertainties about epilepsy: findings from an ethnographic study in China. Epilepsy Behav.: E&B 14, 172—178. Stores, G., Wiggs, L., Campling, G., 1998. Sleep disorders and their relationship to psychological disturbance in children with epilepsy. Child: Care Health Dev. 24, 5—19. Su, C.L., Chang, S.F., Chen, Z.Y., Lee, C.S., Chen, R.C., 1998. Neuroepidemiological survey in Ilan, Taiwan (NESIT): (4) prevalence of epilepsy. Acta Neurol. Taiwan. 7, 75—84.
1460 Suren, P., Bakken, I.J., Aase, H., Chin, R., Gunnes, N., Lie, K.K., Magnus, P., Reichborn-Kjennerud, T., Schjolberg, S., Oyen, A.S., Stoltenberg, C., 2012. Autism spectrum disorder, ADHD, epilepsy, and cerebral palsy in Norwegian children. Pediatrics 130, e152—e158. Tsai, J.J., 2005. Mortality of epilepsy from national vital statistics and University epilepsy clinic in Taiwan. Epilepsia 46 (Suppl. 11), S8—S10. Tsuboi, T., 1984. Epidemiology of febrile and afebrile convulsions in children in Japan. Neurology 34, 175—181.
K.-L. Chiang, C.-Y. Cheng Tsuboi, T., 1986. Seizures of childhood. A population-based and clinic-based study. Acta Neurol. Scand. Supplementum 110, 1—237. Tsuboi, T., 1988. Prevalence and incidence of epilepsy in Tokyo. Epilepsia 29, 103—110. Wang, J.H., Wu, M.C., Chang, H.H., 2013. Urban-rural disparity in physical fitness of elementary schoolchildren in Taiwan. Pediatr. Int.: Off. J. Jpn. Pediatr. Soc. 55, 346—354.