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Incidence of early-onset epilepsy: A prospective population-based study
Seizure: European Journal of Epilepsy 75 (2020) 49–54
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Seizure: European Journal of Epilepsy journal homepage: www.elsevier.com/locate/seizure
Incidence of early-onset epilepsy: A prospective population-based study a,
a
a
b
T
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Matthew B. Hunter *, Michael Yoong , Ruth E. Sumpter , Kirsten Verity , Jay Shetty , Ailsa McLellanb, Richard F.M. China,b a b
Muir Maxwell Epilepsy Centre, University of Edinburgh, Edinburgh, UK Department of Paediatric Neurosciences, Royal Hospital for Sick Children, Edinburgh, UK
A R T I C LE I N FO
A B S T R A C T
Keywords: Epidemiology Socioeconomic status Ethnicity West syndrome Infants Children
Purpose: The first five years of life reflect a critical period of development prior to formal education yet few epidemiological studies focus on children with early-onset epilepsy (CWEOE; onset < 60 months). This study aimed to determine early-onset epilepsy incidence using a comprehensive case identification strategy, and examined socioeconomic status (SES) and ethnicity as risk factors. Methods: Through a prospective, population-based study, newly diagnosed CWEOE from Fife and Lothian, Scotland, were identified using multiple-source, active surveillance capture-recapture between May 2013 and June 2015. Crude, ascertainment-adjusted, age-adjusted, age- and gender-specific, and epilepsy-type incidence rates were determined. Risk ratios (RR) were calculated to examine SES and ethnicity as risk factors. Results: 59 (36 Male) CWEOE were identified. Ascertainment was 98% (95% CI 94–103). Crude annual incidence of epilepsy in children 0–59 months was 60.2 (95% CI 44.8–75.5) per 100,000 per year; ascertainmentadjusted annual incidence was 61.7 (95% CI 46.2–77.3) per year. Cumulative incidence of West Syndrome/ Infantile Spasms was 6.7 per 10,000 live births (95% CI 3.6–12.3). Aetiology was unknown in almost two-thirds of CWEOE. Compared to White-British Isles (BI) children, Asian children (RR 2.6 [95% CI 1.2–5.7], p = .02) and White-non-BI children (RR 2.5 [95% CI 1.2–5.2], p = .02) had increased risk. SES was not a risk factor. Conclusion: The high incidence of early-onset epilepsy is similar to previous studies and demonstrates a substantial disease burden. Cause of epilepsy remains unknown in almost two thirds of CWEOE. Ethnicity but not SES affects early-onset epilepsy risk.
1. Introduction
represents a critical time of development prior to formal education. Accordingly, there has been increased interest from policy makers toward improving early development and mental health [9–11] in preschool aged children, in order to improve long-term future development. Incidence data on CWEOE can therefore help inform health and educational policy makers toward early interventions. The incidence of early-onset epilepsy is estimated at 57–130 per 100,000 children aged < 60 months per year (Table 1). Existing data on CWEOE are often based on medical registries [3,12], questionnaires sent to birth cohort members [13], or medical unit surveillance [14,15]. These data have potential for bias due to retrospective study design, miscoding, and variations in self- and clinician-reported response rates. Assessment of potential missing cases is an important feature in incidence studies15] but is rarely carried out. Likewise, validating diagnosis is important due to variation in case identification criteria [3] and high rates of epilepsy misdiagnosis [16], but in some studies epilepsy diagnosis is not validated [13,15]. The role of ethnicity and socioeconomic status (SES) in early-onset
The incidence of childhood epilepsy can vary according to geographic, ethnic and sociodemographic composition [1,2]. It may also vary according to how epilepsy cases are defined and identified [3]. Accurate and contemporary age-related incidence estimates are needed in order to help determine disease burden and appropriate allocation of resources. Epidemiological studies often report age-specific incidence rates for children with epilepsy onset up to five years of age - termed here as children with early-onset epilepsy (CWEOE; onset before the fifth birthday (< 60 months)), but there are few population-based studies that have focussed on the epidemiology of CWEOE and only limited data exist. Epilepsy is most common during these first few years of life compared to later childhood and adolescence [4,5]. It is the period where neurodevelopmental trajectories are particularly at risk [6], where the most severe forms of epilepsy emerge [7], and where neurobehavioural problems are already common [8]. This period also ⁎
Corresponding author at: 9a BioQuarter, Little France Road, Edinburgh, EH16 4UX, Scotland, UK. E-mail address: [email protected] (M.B. Hunter).
https://doi.org/10.1016/j.seizure.2019.12.020 Received 25 January 2019; Received in revised form 5 June 2019; Accepted 17 December 2019 1059-1311/ © 2019 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
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Table 1 Crude annual incidence rates of epilepsy per 100,000 children 0–59 months and < 12 months. Author (year)
Location
Incidence Rate 0-59 months (95% Confidence Interval)
Sillanpää (1973) [36] Blom, Heijbel, and Bergfors (1978) [37] Doose and Sitepu (1983) [38] Granieri et al. (1983) [40] Benna et al. (1984) [39] Joensen (1986) [41] Tsuboi (1988) [42] Hauser, Annegers, and Kurland (1993) [26] Camfield et al. (1996) [43] Olafsson et al. (1996) [44] Kurtz, Tookey, and Ross (1998) [13] Annegers et al. (1999) [17] Beilmann et al. (1999) [32] MacDonald et al. (2000) [14] Freitag et al. (2001) [45] Dura-Trave et al. (2008) [46] Martinez, Sullivan, and Hauser (2009) [12] Wirrell et al. (2011) [47] Casetta et al (2012) [27] Cesnik et al. (2013) [28] Eltze et al. (2013) [15] Meeraus et al. (2013) [3]
SW Finland Västerbotten, Sweden Kiel, Germany Ferrara, Italy Alba-bra, Italy Faroe Islands Fuchu, Tokyo Rochester, USA Nova Scotia, Canada Iceland UK Texas, USA Estonia London, UK Heidelberg/Mannheim, Germany Navarre, Spain UK Rochester, USA Ferrara, Italy Ferrara, Italy London, UK UK
130.9 (84.7 – 202.1)
67.1 (56.6 – 79.7) 112.3 (59.1 – 213.3) 58.2 (43.5 – 77.8) 67.0 (48.8 – 91.9) 76.1 (60.5 – 95.6) 86 76.8 (46.6 – 126.7) 57.0 (43.8 – 74.1) 68.8 (54.8 – 86.3) 63.7 (30.9 – 131.4) 130.1 (122.5 – 138.1)
Incidence Rate < 12 months (95% Confidence Interval) 92.0 (72.6 – 116.6) 95.72 (32.6 – 281.1) 201.6 212.0 (137.3 – 327.3) 211.1 (133.6 – 333.5) 202.9 (124.9 – 329.3) 193.6 (137.9 – 271.8) 86.3 (62.3 – 119.4) 118.1 (98.2 – 142.1) 256.41 (99.8 – 657.5) 90.4 (53.8 – 151.6)
145.9 (62.3 – 341.0) 95.3 (63.0 – 144.3) 84.3 (56.6 – 125.3) 102.4 (77.7 – 135.0) 109.4 (72.9 – 164.1) 82.1 (63.2 – 106.6) 220.2 (201.6 – 240.5)
Note: Crude annual incidence rates and 95% confidence intervals were calculated based on available data.
of age had genetic testing. All other children aged between three years and before their fifth birthday had genetic testing if no structural or metabolic cause was found, or if they had clinical features suggestive of a genetic condition e.g. Rett Syndrome. All children under the age of two, and those older children who had clinical focal seizures, had brain MRI’s. The ILAE definition of epilepsy [23,24] and 2017 ILAE classification of the epilepsies [21] were applied by three child epileptologists (AM, JS, RC) based on all standard clinical investigations including EEG, MRI, and epilepsy gene panel testing. As there is no formal ILAE classification of epilepsy syndromes [21], we adopted the list of electroclinical syndromes and other epilepsies documented in Berg et al. [25] in order to classify epilepsy types. Differences in opinion were resolved by consensus. Age was defined by age at epilepsy diagnosis. That is, the age when a formal diagnosis was recorded in medical notes by a paediatrician with expertise in epilepsy. Population statistics (Table 2), including data on ethnicity (Table 3), were obtained from the 2011 Scottish Census (http://www. scotlandscensus.gov.uk/ods-web/standard-outputs.html). The population of the study region represented 14.6% of the Scottish population, and had a similar proportion of children aged < 60 months (5.9%) as the national structure (5.3%). Ethnic group was self-selected by Census 2011 respondents according to a predefined set of categories. Categories and definitions for all ethnic groups within the Census can be found at https://www.scotlandscensus.gov.uk/variables-classification/ ethnic-group-household-reference-person. In the current study, White British Isles (White-BI) refers to people who identified as Scottish, British, Irish or Gypsy/Traveller, whilst White-non-BI included Polish and ‘other White’. All other census 2011 ethnic categories were grouped into Asian (including Bangladeshi, Chinese, Indian, and Pakistani), African/Caribbean (including other Black), and Other (including Arab) for this study. Ethnic composition of the study region in children < 60 months of age was similar to the national structure of 89.0% White-BI, and 11.0% other ethnicities. Specifically, 83.6% of children < 60 months in the defined region were White-BI, and 16.4% were other ethnicities (6.3% White-non-BI, 5.3% Asian, 1.6% African/Caribbean, and 3.2% Other). Crude annual incidence was calculated as the number of new cases of epilepsy divided by number of person-years using the 2011 Scottish Census as denominator. Ascertainment estimates were applied to crude
epilepsy is unclear. Whilst some studies have proposed a higher incidence in children in non-white populations [15,17] or with lower SES [1], others have found no such association [3,18–20]. Additionally, incidence studies on CWEOE to date have predated the International League Against Epilepsy’s (ILAE’s) definition of epilepsy, and its new classification for seizure types and epilepsy [21]. In consideration of the above, there is a requirement for a contemporary population-based study of CWEOE with a prospective, comprehensive approach to case identification, with validated epilepsy diagnoses, which utilises current ILAE definition and guidelines, and which examines SES and ethnicity as risk factors. The aims of the current study of early-onset epilepsy were to: (1) estimate crude, ascertainment-adjusted, and age-adjusted incidence rates, (2) provide age- and gender-specific incidence rates, (3) calculate specific epilepsy-type incidence rates, and (4) investigate the relative risk of SES and ethnicity. 2. Methods The current study is reported according to STROBE guidelines for observational studies [22]. The study forms part of the wider NEUROdevelopment in PReschool children Of FIfe and Lothian Epilepsy study (NEUROPROFILES), a prospective, population-based study. Details on study population, recruitment strategy, and ascertainment in NEUROPROFILES have been described previously [8]. Restated here in brief, newly diagnosed physician confirmed CWEOE were identified with 98% (95% CI 94–103) ascertainment (see supplemental material) through an active surveillance multi-source capture-recapture system from within a defined geographical area between May 1st 2013 and June 30th 2015. The National Health Service Scotland (NHSS) provides a national free at the point of delivery health care to all patients in Scotland irrespective of age. Thus, patients do not pay for investigations, surgical procedures, in-hospital stay or any treatment provided by NHSS. Children with epilepsy are evaluated following the Scottish Intercollegiate Guidelines Network guideline for management of children with epilepsy. The current study overlapped with a parallel but separate study seeking to identify the genetic and autoimmune causes of epilepsy in children whose epilepsy began before their third birthday. Thus, in our cohort, all children who were under three years 50
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Table 2 Ascertainment-adjusted annual incidence rates per 100,000 children (95% CI). Age (m)
N
Population
Incidence
Gender
N
Population
Incidence
< 12
19
9527
92.3 (50.9-133.8)
12-23
8
9348
44.4 (15.4-73.5)
24-35
4
9174
20.1 (0.4-39.9)
36-47
14
8917
73.5 (35.3-111.8)
48-59
14
8278
87.8 (44.4-131.2)
0-59
59
45244
61.7 (46.2-77.3)
Male Female Male Female Male Female Male Female Male Female Male Female
12 7 4 4 2 2 8 6 10 4 36 23
4856 4671 4775 4573 4605 4569 4604 4313 4232 4046 23072 22172
115.0 (50.2-179.8) 69.2 (17.9-120.4) 39.5 (1.2-77.8) 63.1 (13.6-112.5) 20.1 (-7.7-47.8) 20.2 (-7.8-48.2) 80.6 (24.9-136.3) 66.9 (14.5-119.3) 122.7 (51.0-194.4) 51.3 (3.9-98.8) 73.5 (49.8-97.3) 49.5 (29.6-69.4)
incidence rates to determine ascertainment adjusted figures including age- and gender-specific rates with age- and gender-specific at-risk populations as denominators. An age-adjusted rate directly standardised to the 2011 Scotland population is provided. Data were stored using IBM SPSS Statistics for Windows, Version 22.0.0.1 (Armonk, NY: IBM Corp., Released 2013). Incidence estimates of West Syndrome/Infantile Spasms are typically reported per number of live births (Table 4). In order to facilitate comparison with these previous studies, data on the cumulative incidence of West Syndrome/Infantile Spasms was provided. Cumulative incidence was calculated as the number of new cases divided by the number of live births in the population at risk over the study period. Statistics on live births were accessed from the Information Services Division Scotland (http://www.isdscotland.org/Health-Topics/ Maternity-and-Births/Publications/data-tables.asp). Live birth data were only available for Edinburgh and West Lothian. As the denominator was only available for these regions, the incidence calculation for West Syndrome/Infantile Spasms was restricted to cases resident in Edinburgh and West Lothian only. There were 13,825 live births from 1 st April 2013 to 31 st March 2015 in those regions. Because the present study collected data over a 26-month period (May 2013 – June 2015), the total live births in Edinburgh and West Lothian over the study period was estimated at 14,977. 95% confidence intervals (CI) for incidence rates were calculated using the normal approximation method based on Poisson distributions. The relative risk (RR) of developing early-onset epilepsy was determined for SES and ethnicity as the incidence proportion of one group divided by the incidence proportion of the reference group. The reference group for ethnicity analyses was White-BI, and for SES was high SES. SES was determined by the Scottish Index of Multiple Deprivation (SIMD 2016; https://statistics.gov.scot/home) based on population statistics from the Scottish 2011 Census. SIMD ranks participant home postal codes, from one to five. Quintiles 4–5 were defined as high SES, and 1–3 as low [8].
3. Ethics NEUROPROFILES was approved by the South East Scotland Research Ethics Committee (13/SS/0031), NHS Lothian (2013/0013), and NHS Fife (13-018 NRS13/P61 13/SS/0031). 4. Results 59 (36 Male, 23 Female) children were identified. Median age at first unprovoked seizure was 18 (IQR 6–36), range < 1-55, months, and median age at epilepsy diagnosis was 28 (IQR 9–48), 1–59, months. The median interval from age at first unprovoked seizure to diagnosis was 4 (IQR 1–11), months. Information on aetiology, epilepsy type, and seizure type (onset) are presented in Table 5. The crude annual incidence of epilepsy in children aged 0–59 months in the study region was 60.2 (95% CI 44.8–75.5) per 100,000 children per year. The ascertainment-adjusted annual incidence of epilepsy in children 0–59 months of age was 61.7 (95% CI 46.2–77.3) per 100,000 children per year. Scotland age- and ascertainment-adjusted annual incidence rate for children 0–59 months was 63.4 (95% CI 47.6–79.2) per 100,000 children per year. Age- and gender-specific incidence rates are displayed in Table 2. An electroclinical syndrome was recognised in 57.6% of the CWEOE, whilst 42.4% had no identified syndrome (Table 6). The most common epilepsy types were genetic generalised epilepsy and West Syndrome/ Infantile Spasms. There were 10 (7M:3 F) children who had West Syndrome/Infantile Spasms, all of whom were resident in Edinburgh or West Lothian, giving a cumulative incidence of 6.7 per 10,000 live births (95% CI 3.6–12.3). 36 CWEOE resided in areas of low SES (population 25,762), with 23 from areas of high SES (population 19,576). Relative risk of low SES compared to high SES was 1.19 (95% CI 0.7, 2.0), p = 0.5. Ethnic composition of the CWEOE is presented in Table 3. The RR for all other ethnicities compared to White-BI was 1.89 (95% CI 1.1–3.4), p = .03. In comparisons with ethnic subgroups, the RR for White-non-BI was 2.5 (95% CI 1.2–5.2), p = .02, compared to White-BI. For Asian ethnicity
Table 3 General population data of children aged 0–59 months in Edinburgh, West Lothian, and Fife, and number of CWEOE including age and aetiological data according to ethnic group. General population
CWEOE
Aetiology
Ethnicity
N
N
Age in months Median (range)
Unknown
Structural
Genetic
Structural & Genetic
White-BI All others White-non-BI African/Caribbean Asian Other
27,813 7431 2,863 717 2,411 1,440
43 16 8 1 7 0
18 (1-55)
46.5%
16.3%
34.9%
2.3%
24 (3-46) 3 (NA) 8 (2-45) NA
50.0% 0% 57.1% NA
37.5% 100.0% 14.3% NA
12.5% 0% 14.3% NA
0% 0% 14.3% NA
BI = British Isles. 51
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Table 4 Cumulative Incidence of West Syndrome/Infantile Spasms per 10,000 live births. Author (year)
Location
Incidence (95% CI)
Riikonen and Donner (1979) [48] Lúthvígsson et al. (1994) [49] Sidenvalll and Eeg-Olofsson (1995) [50] Trevathan et al. (1999) [51] Rantala and Putkonen (1999) [52] Riikonen (2001) [35] Brna et al. (2001) [34] Matsuo et al. (2001) [53] Primec et al. (2002) [54] Hino-Fukuyo et al. (2009) [33]
Uusimaa, Finland Iceland Central Sweden Atlanta, USA Oulu, Finland Uusimaa, Finland Nova Scotia/ Prince Edward Island, Canada Nagasaki, Japan Slovenia Miyagi, Japan
4.1 3.0 4.6 2.9 4.1 4.4 3.1 3.2 2.1 4.3
(3.4 (1.8 (3.5 (1.9 (3.0 (3.7 (2.5 (2.4 (1.6 (3.2
– – – – – – – – – –
5.0) 5.2) 5.9) 4.5) 5.7) 5.4) 3.9) 4.2) 2.7) 5.7)
Note: Incidence rates and 95% confidence intervals were calculated based on available data.
the RR was 2.6 (95% CI 1.2–5.7), p = .02, and for African/Caribbean was 1.2 (95% CI 0.2–8.9), p = 0.9, compared to White-BI. It was not possible to carry out a RR for the ‘other’ group as there were no CWEOE in that category.
Table 6 Epilepsy or syndromic classification, with annual incidence rate (AIR) per 100,000 children 0–59 months. Classification (N)
AIR (95% CI)
1. Electroclinical Syndromes Otahara Syndrome (1) Infantile Spasms/West Syndrome (10)a Benign Myoclonic Epilepsy of Infancy (1) Benign Infantile Epilepsy (4) Generalised Epilepsy with Febrile Seizures + (2) Panayiotopoulos Syndrome (1) Childhood Epilepsy with Centrotemporal Spikes (1) Epilepsy with myoclonic atonic seizures (2) Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis (1) Genetic Generalised Epilepsy (11) Childhood Absence Epilepsy (5) GGE with GTCS (1) GGE – other (4) Rett syndrome (1) 2. No Identified Electroclinical Syndrome 2.1 Epilepsies with Known Cause Genetic focal epilepsy due to single gene mutations (3)b Focal epilepsies attributed to structural causes (6)c Neurocutaneous syndromes: Tuberous Sclerosis Complex (1) 2.2 Epilepsies of Unknown Cause Mixed Focal & Generalised Epilepsy of Unknown Origin (3) Generalised Epilepsy of Unknown cause (6) Focal Epilepsy of Unknown Origin (6)
5. Discussion This prospective population-based study with high ascertainment provides contemporary epidemiological data on CWEOE. The main findings are: (1) the incidence of early-onset epilepsy is similar to that of other high income countries, and to those of earlier studies [12,13,17,26–28], (2) the cause of epilepsy remains unknown in almost two-thirds of CWEOE despite developments in routine clinical diagnostics, (3) this study has provided true population-based estimates of early-onset epilepsy syndromes and other epilepsy types, and (4) ethnicity but not SES increases the risk for early-onset epilepsy. Our finding of an annual ascertainment-adjusted incidence in children 0–59 months of age of 61.7 per 100,000 children per year is similar to those of earlier studies in high income countries [12,13,17,26–28], and demonstrates a continued high incidence of epilepsy in the preschool age group. Given that quality of life is negatively impacted in childhood epilepsy [29], and that neurobehavioural problems are already recognisable in CWEOE [8], such a high incidence highlights the substantial burden of epilepsy in this vulnerable age and further supports a case for early psychosocial intervention [30]. Despite improvements in routine clinical diagnostics, the number of children with no known cause for their epilepsy remains high. In the current study almost half of the aetiologies were unknown, with a further 14% of presumed genetic origin (i.e. where a genetic cause is strongly implicated [21]). Combined, this is similar to earlier studies of early and later onset childhood epilepsies, where up to two thirds aetiologies were unknown [15,31]. Although genetic and immunological
1.0 (-1.0, 3.0) 10.2 (3.9, 16.5) 1.0 (-1.0, 3.0) 4.1 (0.1, 8.1) 2.0 (-0.8, 4.9) 1.0 (-1.0, 3.0) 1.0 (-1.0, 3.0) 2.0 (-0.8, 4.9) 1.0 (-1.0, 3.0) 11.2 (4.6, 17.9) 5.1 (0.6, 9.6) 1.0 (-1.0, 3.0) 4.1 (0.1, 8.1) 1.0 (-1.0, 3.0)
3.1 (-0.4, 6.5) 6.1 (1.2, 11.0) 1.0 (-1.0, 3.0) 3.1 (-0.4, 6.5) 6.1 (1.2, 11.0) 6.1 (1.2, 11.0)
a
One child with West Syndrome also had lissencephaly. Genetic causes included PNKP mutation, SLC6A1 mutation, and chromosome 16p11.2 duplication. c Structural causes included cortical dysplasia, traumatic brain injury, lissencephaly, and three other cortical abnormalities. b
Table 5 Seizure type, epilepsy type and aetiology by age at epilepsy diagnosis.
Aetiology
Epilepsy Type
Seizure Type (onset)
Age (months)
0-59 N = 59 n (%)
< 12 n=19 n (%)
12-23 n=8 n (%)
24-35 n=4 n (%)
36-47 n=15 n (%)
48-59 n = 13 n (%)
Structural Known Genetica Structural & Genetica Presumed Genetic Unknown Focal Generalized Combined Generalised Focal Unknown
12 (20.3) 9 (15.3) 2 (3.4) 8 (13.6) 28 (47.5) 21 (35.6) 32 (54.2) 6 (10.2) 33 (55.9) 26 (44.1) 0 (0)
6 (31.6) 1 (5.3) 2 (10.5) 1 (5.3) 9 (47.4) 7 (36.8) 10 (52.6) 2 (10.5)
2 2 0 1 3 3 4 1
0 2 0 0 2 1 3 0
3 3 0 2 7 6 8 1
1 1 0 4 7 4 7 2
(25.0) (25.0) (0) (12.5) (37.5) (37.5) (50.0) (12.5)
(0) (50.0) (0) (0) (50.0) (25.0) (75.0) (0)
(20.0) (20.0) (0) (13.3) (46.7) (40.0) (53.3) (6.7)
(7.7) (7.7) (0) (30.8) (53.8) (30.8) (53.8) (15.4)
a Known genes affected include TSC, SCN1A, PRRT2, LIS1, SLC6A1, & MECP2 mutations, chromosome 16p11.2 & 17q12 duplications, microdeletion of chromosome 16p11.2, & NRXN1 deletion.
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similar to that from other studies across previous decades, highlighting the substantial burden of the disease. Contemporary epilepsy-type incidence data were reported and the findings provide further evidence of global stability in the incidence of West Syndrome/Infantile Spasms. The data here adds to growing evidence that childhood epilepsy is not significantly influenced by SES. In contrast, ethnicity may be an understudied risk factor for early-onset epilepsy.
testing remained ongoing at the time of study end, the 19% with a known genetic cause and 24% with a known structural cause would indicate the benefits of promoting routine genetic testing and brain imaging in this age-group. A U-shaped age-related incidence pattern was observed in the current data. This pattern has also been documented in two previous studies of CWEOE over the first five years of life [13,32] but was not replicated in a recent study by Meeraus and colleagues [3], where a decreasing linear trend was observed. This disparity might be at least partly attributed to natural variations in regional or time point estimates. Case inclusion criteria may be another explanation. The agespecific data reported by Meeraus et al [3] was based on their most highly inclusive case identification criteria (i.e. a diagnostic code for antiepileptic drug prescription, epilepsy diagnosis, or two or more nonfebrile seizures). Although there was validation of epilepsy diagnoses for a random sample of this cohort, it remains possible that some age point specific incidence rates may have been overestimated. Epilepsy syndromes in infancy and childhood are often diagnosed in hospital settings making it difficult to provide true population-based incidence rates. The current study has been able to provide true population-based rates for a number of epilepsy syndromes in infancy and childhood. Such data will be helpful in determining resource allocation or trial study designs for specific epilepsy types. The cumulative incidence of West Syndrome/Infantile Spasms of 6.7 per 10,000 live births found here is higher than those reported previously. However, the 95% confidence intervals overlap with these previous estimates, and therefore, the current finding remains similar to other reports around the world [33–35]. We found that the development of early-onset epilepsy was not associated with SES, supporting similar findings in children with epilepsy up to 16 years of age [19,20]. Thus, there is increasing evidence that although SES plays a role in the risk of epilepsy in adults, this is not the case in childhood epilepsy, including early-onset epilepsy. In our cohort, an increased risk of early-onset epilepsy was observed in children from White-non-BI origins, and those from Asian origin. This is now the second study in the UK to observe a higher incidence of earlyonset epilepsy in those with Asian descent [15], and the third to report ethnic-related differences in CWEOE [15,17]. It is not known why higher incidence rates are reported in these ethnicities, although genetic factors are a potential explanation. It is also plausible that environmental factors, such as cultural differences in child rearing, diet, attitudes to care and medicine, may contribute to risk.
Funding NEUROPROFILES was funded by the Muir Maxwell Trust (charity number SC034364). Declaration of Competing Interest None of the authors have any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.seizure.2019.12.020. References [1] Heaney DC, MacDonald BK, Everitt A, et al. Socioeconomic variation in incidence of epilepsy: prospective community based study in south east England. BMJ 2002;325:1013–6. [2] Ngugi AK, Kariuki SM, Bottomley C, et al. Incidence of epilepsy: a systematic review and meta-analysis. Neurology 2011;77:1005–12. https://doi.org/10.1212/WNL. 0b013e31822cfc90. [3] Meeraus WH, Petersen I, Chin RF, et al. Childhood epilepsy recorded in primary care in the UK. Arch Dis Child 2013;98:195–202. [4] Hauser WA, Annegers JF, Rocca WA. Descriptive epidemiology of epilepsy: contributions of population-based studies from Rochester. Minnesota. Mayo Clin Proc 1996;71:576–86. [5] Christensen J, Vestergaard M, Pedersen MG, et al. Incidence and prevalence of epilepsy in Denmark. Epilepsy Res 2007;76:60–5. [6] Dennis M, Spiegler BJ, Juranek JJ, et al. Age, plasticity, and homeostasis in childhood brain disorders. Neurosci Biobehav Rev 2013;37:2760–73. [7] Neville BGR. Epilepsy in childhood. Br Med J 1997;315:924–30. [8] Hunter MB, Yoong M, Sumpter RE, et al. Neurobehavioral problems in children with early-onset epilepsy: a population-based study. Epilepsy Behav 2019;93:87–93. https://doi.org/10.1016/j.yebeh.2019.1001.1019. [9] Geddes R, Haw S, Frank JW. Interventions for promoting early child development for health: an environmental scan with special reference to Scotland. In: Office SGCSeditor. Early life working group of the Scottish collaboration for public health research and policy: SCPHRP working papers and publications. 2010. [10] NSC. A science-based framework for early childhood policy: using evidence to improve outcomes in learning, behavior, and health for vulnerable children. 2007. [11] Government U. Education Dfeditor. Statutory framework for the early years foundation stage: setting the standards for learning, development and care for children from birth to five. 2017. p. 1–37. [12] Martinez C, Sullivan T, Hauser WA. Prevalence of acute repetitive seizures (ARS) in the United Kingdom. Epilepsy Res 2009;87:137–43. [13] Kurtz Z, Tookey P, Ross E. Epilepsy in young people: 23 year follow up of the British national child development study. Br Med J 1998;316:339–42. [14] MacDonald BK, Cockerell OC, Sander JW, et al. The incidence and lifetime prevalence of neurological disorders in a prospective community-based study in the UK. Brain 2000;123:665–76. [15] Eltze CM, Chong WK, Cox T, et al. A population-based study of newly diagnosed epilepsy in infants. Epilepsia 2013;54:437–45. [16] RCPCH. Epilepsy 12: united Kingdom collaborative clinical audit of health care for children and young people with suspected epileptic seizures. National report. Royal College of Paediatrics and Child Health 2012. [17] Annegers JF, Dubinsky S, Coan SP, et al. The incidence of epilepsy and unprovoked seizures in multiethnic, urban health maintenance organizations. Epilepsia 1999;40:502–6. [18] Banerjee PN, Filippi D, Allen Hauser W. The descriptive epidemiology of epilepsy-a review. Epilepsy Res 2009;85:31–45. [19] Hesdorffer DC, Tian H, Anand K, et al. Socioeconomic status is a risk factor for epilepsy in Icelandic adults but not in children. Epilepsia 2005;46:1297–303. [20] Reading R, Haynes R, Beach R. Deprivation and incidence of epilepsy in children. Seizure 2006;15:190–3. [21] Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies:
6. Limitations Although ascertainment was high, the final sample size was modest. Accordingly, findings drawn from SES and ethnic analyses are limited and would benefit replication in larger populations. The incidence estimates provided here may not have included some children with selflimiting or subtle seizures that had not been recognised by parent or GP, or whom had not been referred to an appropriate paediatrician or EEG department. Aetiological classifications were based upon results available from investigations undertaken as part of the routine clinical diagnostic process during the study period. Accordingly, final aetiological classification may evolve as a matter of course as more clinical details or investigation results become known. The incidence estimates for specific epilepsy types/syndromes need to be considered in this context. Despite these limitations, the major strength of this study was its prospective, multi-source, population-based design with validated epilepsy diagnoses. The findings presented here can therefore be considered more robust to measurement error related to misclassification of cases (e.g. coding errors), and to missing cases. 7. Conclusion A high incidence of early-onset epilepsy was found, which was 53
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Contents lists available at ScienceDirect
Seizure: European Journal of Epilepsy journal homepage: www.elsevier.com/locate/seizure
Incidence of early-onset epilepsy: A prospective population-based study a,
a
a
b
T
b
Matthew B. Hunter *, Michael Yoong , Ruth E. Sumpter , Kirsten Verity , Jay Shetty , Ailsa McLellanb, Richard F.M. China,b a b
Muir Maxwell Epilepsy Centre, University of Edinburgh, Edinburgh, UK Department of Paediatric Neurosciences, Royal Hospital for Sick Children, Edinburgh, UK
A R T I C LE I N FO
A B S T R A C T
Keywords: Epidemiology Socioeconomic status Ethnicity West syndrome Infants Children
Purpose: The first five years of life reflect a critical period of development prior to formal education yet few epidemiological studies focus on children with early-onset epilepsy (CWEOE; onset < 60 months). This study aimed to determine early-onset epilepsy incidence using a comprehensive case identification strategy, and examined socioeconomic status (SES) and ethnicity as risk factors. Methods: Through a prospective, population-based study, newly diagnosed CWEOE from Fife and Lothian, Scotland, were identified using multiple-source, active surveillance capture-recapture between May 2013 and June 2015. Crude, ascertainment-adjusted, age-adjusted, age- and gender-specific, and epilepsy-type incidence rates were determined. Risk ratios (RR) were calculated to examine SES and ethnicity as risk factors. Results: 59 (36 Male) CWEOE were identified. Ascertainment was 98% (95% CI 94–103). Crude annual incidence of epilepsy in children 0–59 months was 60.2 (95% CI 44.8–75.5) per 100,000 per year; ascertainmentadjusted annual incidence was 61.7 (95% CI 46.2–77.3) per year. Cumulative incidence of West Syndrome/ Infantile Spasms was 6.7 per 10,000 live births (95% CI 3.6–12.3). Aetiology was unknown in almost two-thirds of CWEOE. Compared to White-British Isles (BI) children, Asian children (RR 2.6 [95% CI 1.2–5.7], p = .02) and White-non-BI children (RR 2.5 [95% CI 1.2–5.2], p = .02) had increased risk. SES was not a risk factor. Conclusion: The high incidence of early-onset epilepsy is similar to previous studies and demonstrates a substantial disease burden. Cause of epilepsy remains unknown in almost two thirds of CWEOE. Ethnicity but not SES affects early-onset epilepsy risk.
1. Introduction
represents a critical time of development prior to formal education. Accordingly, there has been increased interest from policy makers toward improving early development and mental health [9–11] in preschool aged children, in order to improve long-term future development. Incidence data on CWEOE can therefore help inform health and educational policy makers toward early interventions. The incidence of early-onset epilepsy is estimated at 57–130 per 100,000 children aged < 60 months per year (Table 1). Existing data on CWEOE are often based on medical registries [3,12], questionnaires sent to birth cohort members [13], or medical unit surveillance [14,15]. These data have potential for bias due to retrospective study design, miscoding, and variations in self- and clinician-reported response rates. Assessment of potential missing cases is an important feature in incidence studies15] but is rarely carried out. Likewise, validating diagnosis is important due to variation in case identification criteria [3] and high rates of epilepsy misdiagnosis [16], but in some studies epilepsy diagnosis is not validated [13,15]. The role of ethnicity and socioeconomic status (SES) in early-onset
The incidence of childhood epilepsy can vary according to geographic, ethnic and sociodemographic composition [1,2]. It may also vary according to how epilepsy cases are defined and identified [3]. Accurate and contemporary age-related incidence estimates are needed in order to help determine disease burden and appropriate allocation of resources. Epidemiological studies often report age-specific incidence rates for children with epilepsy onset up to five years of age - termed here as children with early-onset epilepsy (CWEOE; onset before the fifth birthday (< 60 months)), but there are few population-based studies that have focussed on the epidemiology of CWEOE and only limited data exist. Epilepsy is most common during these first few years of life compared to later childhood and adolescence [4,5]. It is the period where neurodevelopmental trajectories are particularly at risk [6], where the most severe forms of epilepsy emerge [7], and where neurobehavioural problems are already common [8]. This period also ⁎
Corresponding author at: 9a BioQuarter, Little France Road, Edinburgh, EH16 4UX, Scotland, UK. E-mail address: [email protected] (M.B. Hunter).
https://doi.org/10.1016/j.seizure.2019.12.020 Received 25 January 2019; Received in revised form 5 June 2019; Accepted 17 December 2019 1059-1311/ © 2019 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
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Table 1 Crude annual incidence rates of epilepsy per 100,000 children 0–59 months and < 12 months. Author (year)
Location
Incidence Rate 0-59 months (95% Confidence Interval)
Sillanpää (1973) [36] Blom, Heijbel, and Bergfors (1978) [37] Doose and Sitepu (1983) [38] Granieri et al. (1983) [40] Benna et al. (1984) [39] Joensen (1986) [41] Tsuboi (1988) [42] Hauser, Annegers, and Kurland (1993) [26] Camfield et al. (1996) [43] Olafsson et al. (1996) [44] Kurtz, Tookey, and Ross (1998) [13] Annegers et al. (1999) [17] Beilmann et al. (1999) [32] MacDonald et al. (2000) [14] Freitag et al. (2001) [45] Dura-Trave et al. (2008) [46] Martinez, Sullivan, and Hauser (2009) [12] Wirrell et al. (2011) [47] Casetta et al (2012) [27] Cesnik et al. (2013) [28] Eltze et al. (2013) [15] Meeraus et al. (2013) [3]
SW Finland Västerbotten, Sweden Kiel, Germany Ferrara, Italy Alba-bra, Italy Faroe Islands Fuchu, Tokyo Rochester, USA Nova Scotia, Canada Iceland UK Texas, USA Estonia London, UK Heidelberg/Mannheim, Germany Navarre, Spain UK Rochester, USA Ferrara, Italy Ferrara, Italy London, UK UK
130.9 (84.7 – 202.1)
67.1 (56.6 – 79.7) 112.3 (59.1 – 213.3) 58.2 (43.5 – 77.8) 67.0 (48.8 – 91.9) 76.1 (60.5 – 95.6) 86 76.8 (46.6 – 126.7) 57.0 (43.8 – 74.1) 68.8 (54.8 – 86.3) 63.7 (30.9 – 131.4) 130.1 (122.5 – 138.1)
Incidence Rate < 12 months (95% Confidence Interval) 92.0 (72.6 – 116.6) 95.72 (32.6 – 281.1) 201.6 212.0 (137.3 – 327.3) 211.1 (133.6 – 333.5) 202.9 (124.9 – 329.3) 193.6 (137.9 – 271.8) 86.3 (62.3 – 119.4) 118.1 (98.2 – 142.1) 256.41 (99.8 – 657.5) 90.4 (53.8 – 151.6)
145.9 (62.3 – 341.0) 95.3 (63.0 – 144.3) 84.3 (56.6 – 125.3) 102.4 (77.7 – 135.0) 109.4 (72.9 – 164.1) 82.1 (63.2 – 106.6) 220.2 (201.6 – 240.5)
Note: Crude annual incidence rates and 95% confidence intervals were calculated based on available data.
of age had genetic testing. All other children aged between three years and before their fifth birthday had genetic testing if no structural or metabolic cause was found, or if they had clinical features suggestive of a genetic condition e.g. Rett Syndrome. All children under the age of two, and those older children who had clinical focal seizures, had brain MRI’s. The ILAE definition of epilepsy [23,24] and 2017 ILAE classification of the epilepsies [21] were applied by three child epileptologists (AM, JS, RC) based on all standard clinical investigations including EEG, MRI, and epilepsy gene panel testing. As there is no formal ILAE classification of epilepsy syndromes [21], we adopted the list of electroclinical syndromes and other epilepsies documented in Berg et al. [25] in order to classify epilepsy types. Differences in opinion were resolved by consensus. Age was defined by age at epilepsy diagnosis. That is, the age when a formal diagnosis was recorded in medical notes by a paediatrician with expertise in epilepsy. Population statistics (Table 2), including data on ethnicity (Table 3), were obtained from the 2011 Scottish Census (http://www. scotlandscensus.gov.uk/ods-web/standard-outputs.html). The population of the study region represented 14.6% of the Scottish population, and had a similar proportion of children aged < 60 months (5.9%) as the national structure (5.3%). Ethnic group was self-selected by Census 2011 respondents according to a predefined set of categories. Categories and definitions for all ethnic groups within the Census can be found at https://www.scotlandscensus.gov.uk/variables-classification/ ethnic-group-household-reference-person. In the current study, White British Isles (White-BI) refers to people who identified as Scottish, British, Irish or Gypsy/Traveller, whilst White-non-BI included Polish and ‘other White’. All other census 2011 ethnic categories were grouped into Asian (including Bangladeshi, Chinese, Indian, and Pakistani), African/Caribbean (including other Black), and Other (including Arab) for this study. Ethnic composition of the study region in children < 60 months of age was similar to the national structure of 89.0% White-BI, and 11.0% other ethnicities. Specifically, 83.6% of children < 60 months in the defined region were White-BI, and 16.4% were other ethnicities (6.3% White-non-BI, 5.3% Asian, 1.6% African/Caribbean, and 3.2% Other). Crude annual incidence was calculated as the number of new cases of epilepsy divided by number of person-years using the 2011 Scottish Census as denominator. Ascertainment estimates were applied to crude
epilepsy is unclear. Whilst some studies have proposed a higher incidence in children in non-white populations [15,17] or with lower SES [1], others have found no such association [3,18–20]. Additionally, incidence studies on CWEOE to date have predated the International League Against Epilepsy’s (ILAE’s) definition of epilepsy, and its new classification for seizure types and epilepsy [21]. In consideration of the above, there is a requirement for a contemporary population-based study of CWEOE with a prospective, comprehensive approach to case identification, with validated epilepsy diagnoses, which utilises current ILAE definition and guidelines, and which examines SES and ethnicity as risk factors. The aims of the current study of early-onset epilepsy were to: (1) estimate crude, ascertainment-adjusted, and age-adjusted incidence rates, (2) provide age- and gender-specific incidence rates, (3) calculate specific epilepsy-type incidence rates, and (4) investigate the relative risk of SES and ethnicity. 2. Methods The current study is reported according to STROBE guidelines for observational studies [22]. The study forms part of the wider NEUROdevelopment in PReschool children Of FIfe and Lothian Epilepsy study (NEUROPROFILES), a prospective, population-based study. Details on study population, recruitment strategy, and ascertainment in NEUROPROFILES have been described previously [8]. Restated here in brief, newly diagnosed physician confirmed CWEOE were identified with 98% (95% CI 94–103) ascertainment (see supplemental material) through an active surveillance multi-source capture-recapture system from within a defined geographical area between May 1st 2013 and June 30th 2015. The National Health Service Scotland (NHSS) provides a national free at the point of delivery health care to all patients in Scotland irrespective of age. Thus, patients do not pay for investigations, surgical procedures, in-hospital stay or any treatment provided by NHSS. Children with epilepsy are evaluated following the Scottish Intercollegiate Guidelines Network guideline for management of children with epilepsy. The current study overlapped with a parallel but separate study seeking to identify the genetic and autoimmune causes of epilepsy in children whose epilepsy began before their third birthday. Thus, in our cohort, all children who were under three years 50
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Table 2 Ascertainment-adjusted annual incidence rates per 100,000 children (95% CI). Age (m)
N
Population
Incidence
Gender
N
Population
Incidence
< 12
19
9527
92.3 (50.9-133.8)
12-23
8
9348
44.4 (15.4-73.5)
24-35
4
9174
20.1 (0.4-39.9)
36-47
14
8917
73.5 (35.3-111.8)
48-59
14
8278
87.8 (44.4-131.2)
0-59
59
45244
61.7 (46.2-77.3)
Male Female Male Female Male Female Male Female Male Female Male Female
12 7 4 4 2 2 8 6 10 4 36 23
4856 4671 4775 4573 4605 4569 4604 4313 4232 4046 23072 22172
115.0 (50.2-179.8) 69.2 (17.9-120.4) 39.5 (1.2-77.8) 63.1 (13.6-112.5) 20.1 (-7.7-47.8) 20.2 (-7.8-48.2) 80.6 (24.9-136.3) 66.9 (14.5-119.3) 122.7 (51.0-194.4) 51.3 (3.9-98.8) 73.5 (49.8-97.3) 49.5 (29.6-69.4)
incidence rates to determine ascertainment adjusted figures including age- and gender-specific rates with age- and gender-specific at-risk populations as denominators. An age-adjusted rate directly standardised to the 2011 Scotland population is provided. Data were stored using IBM SPSS Statistics for Windows, Version 22.0.0.1 (Armonk, NY: IBM Corp., Released 2013). Incidence estimates of West Syndrome/Infantile Spasms are typically reported per number of live births (Table 4). In order to facilitate comparison with these previous studies, data on the cumulative incidence of West Syndrome/Infantile Spasms was provided. Cumulative incidence was calculated as the number of new cases divided by the number of live births in the population at risk over the study period. Statistics on live births were accessed from the Information Services Division Scotland (http://www.isdscotland.org/Health-Topics/ Maternity-and-Births/Publications/data-tables.asp). Live birth data were only available for Edinburgh and West Lothian. As the denominator was only available for these regions, the incidence calculation for West Syndrome/Infantile Spasms was restricted to cases resident in Edinburgh and West Lothian only. There were 13,825 live births from 1 st April 2013 to 31 st March 2015 in those regions. Because the present study collected data over a 26-month period (May 2013 – June 2015), the total live births in Edinburgh and West Lothian over the study period was estimated at 14,977. 95% confidence intervals (CI) for incidence rates were calculated using the normal approximation method based on Poisson distributions. The relative risk (RR) of developing early-onset epilepsy was determined for SES and ethnicity as the incidence proportion of one group divided by the incidence proportion of the reference group. The reference group for ethnicity analyses was White-BI, and for SES was high SES. SES was determined by the Scottish Index of Multiple Deprivation (SIMD 2016; https://statistics.gov.scot/home) based on population statistics from the Scottish 2011 Census. SIMD ranks participant home postal codes, from one to five. Quintiles 4–5 were defined as high SES, and 1–3 as low [8].
3. Ethics NEUROPROFILES was approved by the South East Scotland Research Ethics Committee (13/SS/0031), NHS Lothian (2013/0013), and NHS Fife (13-018 NRS13/P61 13/SS/0031). 4. Results 59 (36 Male, 23 Female) children were identified. Median age at first unprovoked seizure was 18 (IQR 6–36), range < 1-55, months, and median age at epilepsy diagnosis was 28 (IQR 9–48), 1–59, months. The median interval from age at first unprovoked seizure to diagnosis was 4 (IQR 1–11), months. Information on aetiology, epilepsy type, and seizure type (onset) are presented in Table 5. The crude annual incidence of epilepsy in children aged 0–59 months in the study region was 60.2 (95% CI 44.8–75.5) per 100,000 children per year. The ascertainment-adjusted annual incidence of epilepsy in children 0–59 months of age was 61.7 (95% CI 46.2–77.3) per 100,000 children per year. Scotland age- and ascertainment-adjusted annual incidence rate for children 0–59 months was 63.4 (95% CI 47.6–79.2) per 100,000 children per year. Age- and gender-specific incidence rates are displayed in Table 2. An electroclinical syndrome was recognised in 57.6% of the CWEOE, whilst 42.4% had no identified syndrome (Table 6). The most common epilepsy types were genetic generalised epilepsy and West Syndrome/ Infantile Spasms. There were 10 (7M:3 F) children who had West Syndrome/Infantile Spasms, all of whom were resident in Edinburgh or West Lothian, giving a cumulative incidence of 6.7 per 10,000 live births (95% CI 3.6–12.3). 36 CWEOE resided in areas of low SES (population 25,762), with 23 from areas of high SES (population 19,576). Relative risk of low SES compared to high SES was 1.19 (95% CI 0.7, 2.0), p = 0.5. Ethnic composition of the CWEOE is presented in Table 3. The RR for all other ethnicities compared to White-BI was 1.89 (95% CI 1.1–3.4), p = .03. In comparisons with ethnic subgroups, the RR for White-non-BI was 2.5 (95% CI 1.2–5.2), p = .02, compared to White-BI. For Asian ethnicity
Table 3 General population data of children aged 0–59 months in Edinburgh, West Lothian, and Fife, and number of CWEOE including age and aetiological data according to ethnic group. General population
CWEOE
Aetiology
Ethnicity
N
N
Age in months Median (range)
Unknown
Structural
Genetic
Structural & Genetic
White-BI All others White-non-BI African/Caribbean Asian Other
27,813 7431 2,863 717 2,411 1,440
43 16 8 1 7 0
18 (1-55)
46.5%
16.3%
34.9%
2.3%
24 (3-46) 3 (NA) 8 (2-45) NA
50.0% 0% 57.1% NA
37.5% 100.0% 14.3% NA
12.5% 0% 14.3% NA
0% 0% 14.3% NA
BI = British Isles. 51
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Table 4 Cumulative Incidence of West Syndrome/Infantile Spasms per 10,000 live births. Author (year)
Location
Incidence (95% CI)
Riikonen and Donner (1979) [48] Lúthvígsson et al. (1994) [49] Sidenvalll and Eeg-Olofsson (1995) [50] Trevathan et al. (1999) [51] Rantala and Putkonen (1999) [52] Riikonen (2001) [35] Brna et al. (2001) [34] Matsuo et al. (2001) [53] Primec et al. (2002) [54] Hino-Fukuyo et al. (2009) [33]
Uusimaa, Finland Iceland Central Sweden Atlanta, USA Oulu, Finland Uusimaa, Finland Nova Scotia/ Prince Edward Island, Canada Nagasaki, Japan Slovenia Miyagi, Japan
4.1 3.0 4.6 2.9 4.1 4.4 3.1 3.2 2.1 4.3
(3.4 (1.8 (3.5 (1.9 (3.0 (3.7 (2.5 (2.4 (1.6 (3.2
– – – – – – – – – –
5.0) 5.2) 5.9) 4.5) 5.7) 5.4) 3.9) 4.2) 2.7) 5.7)
Note: Incidence rates and 95% confidence intervals were calculated based on available data.
the RR was 2.6 (95% CI 1.2–5.7), p = .02, and for African/Caribbean was 1.2 (95% CI 0.2–8.9), p = 0.9, compared to White-BI. It was not possible to carry out a RR for the ‘other’ group as there were no CWEOE in that category.
Table 6 Epilepsy or syndromic classification, with annual incidence rate (AIR) per 100,000 children 0–59 months. Classification (N)
AIR (95% CI)
1. Electroclinical Syndromes Otahara Syndrome (1) Infantile Spasms/West Syndrome (10)a Benign Myoclonic Epilepsy of Infancy (1) Benign Infantile Epilepsy (4) Generalised Epilepsy with Febrile Seizures + (2) Panayiotopoulos Syndrome (1) Childhood Epilepsy with Centrotemporal Spikes (1) Epilepsy with myoclonic atonic seizures (2) Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis (1) Genetic Generalised Epilepsy (11) Childhood Absence Epilepsy (5) GGE with GTCS (1) GGE – other (4) Rett syndrome (1) 2. No Identified Electroclinical Syndrome 2.1 Epilepsies with Known Cause Genetic focal epilepsy due to single gene mutations (3)b Focal epilepsies attributed to structural causes (6)c Neurocutaneous syndromes: Tuberous Sclerosis Complex (1) 2.2 Epilepsies of Unknown Cause Mixed Focal & Generalised Epilepsy of Unknown Origin (3) Generalised Epilepsy of Unknown cause (6) Focal Epilepsy of Unknown Origin (6)
5. Discussion This prospective population-based study with high ascertainment provides contemporary epidemiological data on CWEOE. The main findings are: (1) the incidence of early-onset epilepsy is similar to that of other high income countries, and to those of earlier studies [12,13,17,26–28], (2) the cause of epilepsy remains unknown in almost two-thirds of CWEOE despite developments in routine clinical diagnostics, (3) this study has provided true population-based estimates of early-onset epilepsy syndromes and other epilepsy types, and (4) ethnicity but not SES increases the risk for early-onset epilepsy. Our finding of an annual ascertainment-adjusted incidence in children 0–59 months of age of 61.7 per 100,000 children per year is similar to those of earlier studies in high income countries [12,13,17,26–28], and demonstrates a continued high incidence of epilepsy in the preschool age group. Given that quality of life is negatively impacted in childhood epilepsy [29], and that neurobehavioural problems are already recognisable in CWEOE [8], such a high incidence highlights the substantial burden of epilepsy in this vulnerable age and further supports a case for early psychosocial intervention [30]. Despite improvements in routine clinical diagnostics, the number of children with no known cause for their epilepsy remains high. In the current study almost half of the aetiologies were unknown, with a further 14% of presumed genetic origin (i.e. where a genetic cause is strongly implicated [21]). Combined, this is similar to earlier studies of early and later onset childhood epilepsies, where up to two thirds aetiologies were unknown [15,31]. Although genetic and immunological
1.0 (-1.0, 3.0) 10.2 (3.9, 16.5) 1.0 (-1.0, 3.0) 4.1 (0.1, 8.1) 2.0 (-0.8, 4.9) 1.0 (-1.0, 3.0) 1.0 (-1.0, 3.0) 2.0 (-0.8, 4.9) 1.0 (-1.0, 3.0) 11.2 (4.6, 17.9) 5.1 (0.6, 9.6) 1.0 (-1.0, 3.0) 4.1 (0.1, 8.1) 1.0 (-1.0, 3.0)
3.1 (-0.4, 6.5) 6.1 (1.2, 11.0) 1.0 (-1.0, 3.0) 3.1 (-0.4, 6.5) 6.1 (1.2, 11.0) 6.1 (1.2, 11.0)
a
One child with West Syndrome also had lissencephaly. Genetic causes included PNKP mutation, SLC6A1 mutation, and chromosome 16p11.2 duplication. c Structural causes included cortical dysplasia, traumatic brain injury, lissencephaly, and three other cortical abnormalities. b
Table 5 Seizure type, epilepsy type and aetiology by age at epilepsy diagnosis.
Aetiology
Epilepsy Type
Seizure Type (onset)
Age (months)
0-59 N = 59 n (%)
< 12 n=19 n (%)
12-23 n=8 n (%)
24-35 n=4 n (%)
36-47 n=15 n (%)
48-59 n = 13 n (%)
Structural Known Genetica Structural & Genetica Presumed Genetic Unknown Focal Generalized Combined Generalised Focal Unknown
12 (20.3) 9 (15.3) 2 (3.4) 8 (13.6) 28 (47.5) 21 (35.6) 32 (54.2) 6 (10.2) 33 (55.9) 26 (44.1) 0 (0)
6 (31.6) 1 (5.3) 2 (10.5) 1 (5.3) 9 (47.4) 7 (36.8) 10 (52.6) 2 (10.5)
2 2 0 1 3 3 4 1
0 2 0 0 2 1 3 0
3 3 0 2 7 6 8 1
1 1 0 4 7 4 7 2
(25.0) (25.0) (0) (12.5) (37.5) (37.5) (50.0) (12.5)
(0) (50.0) (0) (0) (50.0) (25.0) (75.0) (0)
(20.0) (20.0) (0) (13.3) (46.7) (40.0) (53.3) (6.7)
(7.7) (7.7) (0) (30.8) (53.8) (30.8) (53.8) (15.4)
a Known genes affected include TSC, SCN1A, PRRT2, LIS1, SLC6A1, & MECP2 mutations, chromosome 16p11.2 & 17q12 duplications, microdeletion of chromosome 16p11.2, & NRXN1 deletion.
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similar to that from other studies across previous decades, highlighting the substantial burden of the disease. Contemporary epilepsy-type incidence data were reported and the findings provide further evidence of global stability in the incidence of West Syndrome/Infantile Spasms. The data here adds to growing evidence that childhood epilepsy is not significantly influenced by SES. In contrast, ethnicity may be an understudied risk factor for early-onset epilepsy.
testing remained ongoing at the time of study end, the 19% with a known genetic cause and 24% with a known structural cause would indicate the benefits of promoting routine genetic testing and brain imaging in this age-group. A U-shaped age-related incidence pattern was observed in the current data. This pattern has also been documented in two previous studies of CWEOE over the first five years of life [13,32] but was not replicated in a recent study by Meeraus and colleagues [3], where a decreasing linear trend was observed. This disparity might be at least partly attributed to natural variations in regional or time point estimates. Case inclusion criteria may be another explanation. The agespecific data reported by Meeraus et al [3] was based on their most highly inclusive case identification criteria (i.e. a diagnostic code for antiepileptic drug prescription, epilepsy diagnosis, or two or more nonfebrile seizures). Although there was validation of epilepsy diagnoses for a random sample of this cohort, it remains possible that some age point specific incidence rates may have been overestimated. Epilepsy syndromes in infancy and childhood are often diagnosed in hospital settings making it difficult to provide true population-based incidence rates. The current study has been able to provide true population-based rates for a number of epilepsy syndromes in infancy and childhood. Such data will be helpful in determining resource allocation or trial study designs for specific epilepsy types. The cumulative incidence of West Syndrome/Infantile Spasms of 6.7 per 10,000 live births found here is higher than those reported previously. However, the 95% confidence intervals overlap with these previous estimates, and therefore, the current finding remains similar to other reports around the world [33–35]. We found that the development of early-onset epilepsy was not associated with SES, supporting similar findings in children with epilepsy up to 16 years of age [19,20]. Thus, there is increasing evidence that although SES plays a role in the risk of epilepsy in adults, this is not the case in childhood epilepsy, including early-onset epilepsy. In our cohort, an increased risk of early-onset epilepsy was observed in children from White-non-BI origins, and those from Asian origin. This is now the second study in the UK to observe a higher incidence of earlyonset epilepsy in those with Asian descent [15], and the third to report ethnic-related differences in CWEOE [15,17]. It is not known why higher incidence rates are reported in these ethnicities, although genetic factors are a potential explanation. It is also plausible that environmental factors, such as cultural differences in child rearing, diet, attitudes to care and medicine, may contribute to risk.
Funding NEUROPROFILES was funded by the Muir Maxwell Trust (charity number SC034364). Declaration of Competing Interest None of the authors have any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.seizure.2019.12.020. References [1] Heaney DC, MacDonald BK, Everitt A, et al. Socioeconomic variation in incidence of epilepsy: prospective community based study in south east England. BMJ 2002;325:1013–6. [2] Ngugi AK, Kariuki SM, Bottomley C, et al. Incidence of epilepsy: a systematic review and meta-analysis. Neurology 2011;77:1005–12. https://doi.org/10.1212/WNL. 0b013e31822cfc90. [3] Meeraus WH, Petersen I, Chin RF, et al. Childhood epilepsy recorded in primary care in the UK. Arch Dis Child 2013;98:195–202. [4] Hauser WA, Annegers JF, Rocca WA. Descriptive epidemiology of epilepsy: contributions of population-based studies from Rochester. Minnesota. Mayo Clin Proc 1996;71:576–86. [5] Christensen J, Vestergaard M, Pedersen MG, et al. Incidence and prevalence of epilepsy in Denmark. Epilepsy Res 2007;76:60–5. [6] Dennis M, Spiegler BJ, Juranek JJ, et al. Age, plasticity, and homeostasis in childhood brain disorders. Neurosci Biobehav Rev 2013;37:2760–73. [7] Neville BGR. Epilepsy in childhood. Br Med J 1997;315:924–30. [8] Hunter MB, Yoong M, Sumpter RE, et al. Neurobehavioral problems in children with early-onset epilepsy: a population-based study. Epilepsy Behav 2019;93:87–93. https://doi.org/10.1016/j.yebeh.2019.1001.1019. [9] Geddes R, Haw S, Frank JW. Interventions for promoting early child development for health: an environmental scan with special reference to Scotland. In: Office SGCSeditor. Early life working group of the Scottish collaboration for public health research and policy: SCPHRP working papers and publications. 2010. [10] NSC. A science-based framework for early childhood policy: using evidence to improve outcomes in learning, behavior, and health for vulnerable children. 2007. [11] Government U. Education Dfeditor. Statutory framework for the early years foundation stage: setting the standards for learning, development and care for children from birth to five. 2017. p. 1–37. [12] Martinez C, Sullivan T, Hauser WA. Prevalence of acute repetitive seizures (ARS) in the United Kingdom. Epilepsy Res 2009;87:137–43. [13] Kurtz Z, Tookey P, Ross E. Epilepsy in young people: 23 year follow up of the British national child development study. Br Med J 1998;316:339–42. [14] MacDonald BK, Cockerell OC, Sander JW, et al. The incidence and lifetime prevalence of neurological disorders in a prospective community-based study in the UK. Brain 2000;123:665–76. [15] Eltze CM, Chong WK, Cox T, et al. A population-based study of newly diagnosed epilepsy in infants. Epilepsia 2013;54:437–45. [16] RCPCH. Epilepsy 12: united Kingdom collaborative clinical audit of health care for children and young people with suspected epileptic seizures. National report. Royal College of Paediatrics and Child Health 2012. [17] Annegers JF, Dubinsky S, Coan SP, et al. The incidence of epilepsy and unprovoked seizures in multiethnic, urban health maintenance organizations. Epilepsia 1999;40:502–6. [18] Banerjee PN, Filippi D, Allen Hauser W. The descriptive epidemiology of epilepsy-a review. Epilepsy Res 2009;85:31–45. [19] Hesdorffer DC, Tian H, Anand K, et al. Socioeconomic status is a risk factor for epilepsy in Icelandic adults but not in children. Epilepsia 2005;46:1297–303. [20] Reading R, Haynes R, Beach R. Deprivation and incidence of epilepsy in children. Seizure 2006;15:190–3. [21] Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies:
6. Limitations Although ascertainment was high, the final sample size was modest. Accordingly, findings drawn from SES and ethnic analyses are limited and would benefit replication in larger populations. The incidence estimates provided here may not have included some children with selflimiting or subtle seizures that had not been recognised by parent or GP, or whom had not been referred to an appropriate paediatrician or EEG department. Aetiological classifications were based upon results available from investigations undertaken as part of the routine clinical diagnostic process during the study period. Accordingly, final aetiological classification may evolve as a matter of course as more clinical details or investigation results become known. The incidence estimates for specific epilepsy types/syndromes need to be considered in this context. Despite these limitations, the major strength of this study was its prospective, multi-source, population-based design with validated epilepsy diagnoses. The findings presented here can therefore be considered more robust to measurement error related to misclassification of cases (e.g. coding errors), and to missing cases. 7. Conclusion A high incidence of early-onset epilepsy was found, which was 53
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