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Etiology, clinical course and outcome of infant epilepsy: Experience of a tertiary center in Thailand
Journal of Clinical Neuroscience xxx (2018) xxx–xxx
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Clinical study
Etiology, clinical course and outcome of infant epilepsy: Experience of a tertiary center in Thailand Thitiporn Fangsaad a,⇑, Siriluk Assawabumrungkul a, Ponghatai Damrongphol b,c, Tayard Desudchit d a
Department of Pediatrics, Bhumibol Adulyadej Hospital, Bangkok, Thailand Center of Excellence for Medical Genetics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand c Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand d Division of Pediatric Neurology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand b
a r t i c l e
i n f o
Article history: Received 10 June 2018 Accepted 27 October 2018 Available online xxxx Keywords: Infant epilepsy Under 1 year of age Etiology Outcome Intractable seizure Developmental delay
a b s t r a c t Purpose: Explore etiology, clinical course and outcome of infant epilepsy in Bhumibol Adulyadej Hospital. Method: Retrospective and prospective descriptive analysis of infants 1 month to 1 year diagnosed with epilepsy between January 1, 2012, and April 30, 2018. Results: Total 57 infants. Average age of seizure onset was 4.7 months. Follow-up period averaged 34.2 months. Prenatal risk factors were found in 28.1 percent (16/57). Of these, 50 percent (8/16) had seizure in neonatal period. An additional 6 infants without any prenatal risk factor had seizure in the neonatal period, bringing the total newborn with seizure to 24.6 percent (14/57). Family history of seizure was positive in only 15.8 percent (9/57). Neuroimaging was done 68.4 percent (39/57) and electroencephalogram 50.9 percent (29/57). The etiology was mostly structural 38.6 percent (22/57), followed by unknown 35.1 percent (20/57), genetics 14 percent (8/57), infection 10.5 percent (6/57) and metabolic 1.8 percent (1/57). Status epilepticus was found 21.1 percent of the times (12/57). Antiepileptic drugs were discontinued 19.3 percent (11/57). Intractable seizure was found 29.8 percent (17/57) and developmental delay 56.1 percent (32/57). By multivariate logistic regression analysis, status epilepticus and developmental delay predicted intractable seizure, whereas, abnormal neurological examination and abnormal neuroimaging predicted developmental delay. Mortality rate was 3.5 percent. Conclusion: The study shows that early onset of epilepsy in children under a year is similar to that found in children less than 2–3 years as found in prior studies. High percentages of intractable seizure and developmental delay were found. Ó 2018 Published by Elsevier Ltd.
1. Introduction Epilepsy is a common neurological disease especially in infancy and old age with highest incidence in the first year of life with rate 102.4 per 100,000 [1,2]. It has been reported that childhood epilepsy with proper and adequate treatment achieved remission 60–70% of the time and nearly half were able to discontinue antiepileptic medication [3–6]. However, epilepsy in early childhood may have less favorable outcome including intractable seizure, severe neurodevelopmental delay, intellectual disability and high mortality rate [7,8]. Etiology and electroclinical syndrome in this age group are the important predictor outcomes. Etiology including cortical dysplasia and other structural abnormalities [9], neurometabolic disorder and perinatal brain injury and severe
⇑ Corresponding author. E-mail address: [email protected] (T. Fangsaad).
epileptic encephalopathies including West, Dravet and Lennox Gastaut syndrome are highly correlated with intractability [10]. There is also evidence that poorly controlled seizures in the developing brain negatively impact intellectual functioning [8]. In addition, there are 2 studies showing that, in symptomatic generalized epilepsy, nearly one quarter died and most survivors had mental retardation and were highly dependent [7,11]. These studies suggest the important of early diagnosis and effective treatment in early childhood epilepsy. The International League Against Epilepsy (ILAE) classification has been updated in 2017. The new classification incorporates etiology at each step of diagnosis. Etiology is broken into six subgroups, structural, genetic, infectious, metabolic, immune and unknown. The etiology may belong to more than one subgroup. The subgroups differ in their potential therapeutic consequences [12]. Structural etiology refers to visible structural abnormalities, as shown by neuroimaging, together with electroclinical assessment, which are the likely cause of the seizure. Genetic etiology
https://doi.org/10.1016/j.jocn.2018.10.117 0967-5868/Ó 2018 Published by Elsevier Ltd.
Please cite this article in press as: Fangsaad T et al. Etiology, clinical course and outcome of infant epilepsy: Experience of a tertiary center in Thailand. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.10.117
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T. Fangsaad et al. / Journal of Clinical Neuroscience xxx (2018) xxx–xxx
is shown by family history of an autosomal dominant disorder or by molecular genetics. Infectious etiology refers to a patient with epilepsy directly resulting from a known infection or postinfectious development of epilepsy, but not from a seizure occurring during meningitis or encephalitis. Metabolic etiology refers to epilepsy resulting from metabolic defect or biochemical changes. Early identification of etiology will assist the diagnosis and appropriate management and potential prevention of intellectual impairment [12]. Intractable epilepsy is defined as the failure of two or more antiepileptic drugs to control seizure either after epilepsy surgery or seizure frequency of more than one every 6 months in the year immediately prior to the final follow-up [13,14]. Risk factors for intractable epilepsy from previous studies are epilepsy onset under age of one, abnormal EEG findings and neurological deficit at the time of diagnosis, symptomatic seizures, high frequency of seizures, and non-response to the first AED [13–17]. Long term outcome studied on infants with epilepsy onset less than 3 year [8] demonstrated children with symptomatic epilepsy or epileptic encephalopathy syndromes impaired adaptive behavior at the time of initial diagnosis and declined over time even after controlling for symptomatic etiology and poor seizure control. This study was confirmed later [18]. The earlier age of seizure onset, the poorer the epilepsy outcome. This study aims to explore etiology, clinical course and outcome of infants diagnosed with epilepsy from 1 month to 1 year old in Bhumibol Adulyadej Hospital.
acid. If metabolic tests were negative, whole exome genome sequencing was offered to the parents. If the parents agree to do the test and enter the research project with the affiliate institute, the test was run. Intractable epilepsy was defined using the ILAE definition as the failure of two or more anti-epileptic drugs to control seizure either after epilepsy surgery or seizure frequency of more than one every 6 months in the year immediately prior to the final follow-up [13,14]. The development was determined at final follow-up or at least 1 month after the diagnosis of epilepsy. Developmental milestones were used to classify development as normal or delayed. Medical records were reviewed to collect data of sex, age onset at first seizure, perinatal risk factors, neonatal seizure, neurological examination at the first presentation, seizure type, EEG, neuroimaging, history of status epilepticus, family history, etiology, antiepileptic drugs (AEDs), follow-up, intractable epilepsy, and development delay. Univariate analyses between each categorical variable with the outcome (intractable epilepsy and developmental delay) were performed using chi-squared test. Multiple logistic regression analyses were then adjusted for all potential risk factors. The level of significance was set at p < 0.05. All statistical analyses were performed with SPSS Statistic 19. This study was reviewed and approved by the Bhumibol Adulyadej Hospital Ethics Committee.
3. Results 2. Methods 3.1. Clinical characteristics A retrospective and prospective descriptive analysis study was conducted in infants aged 1 month to 1 year who were diagnosed with epilepsy from January 1, 2012 through April 30, 2018. The cases were identified by ICD 10 coding G400-409. This study used the definitions of seizure and epilepsy as defined by the ILAE. Seizure is defined as ‘‘a transient occurrence of sign and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain” [19]. Epilepsy is diagnosed when an individual has: 1) at least 2 unprovoked or reflex seizures more than 24 h apart, 2) one provoked or reflex seizure and a probability of having another seizure similar to the general recurrence risk after two provoked seizures (more than 60%) over the next 10 years, or 3) an epileptic syndrome [20]. Patients with an abnormal neurodevelopmental examination, focal abnormality on brain imaging and abnormal EEG findings are considered at having a higher risk of recurrence. The infants who presented with a provoked seizure alone were excluded, defined as ‘‘seizures at the time of a systemic insult or in close temporal association with an acute neurological insult” [21]. Similarly, vaccine-associated and non-vaccine associated febrile seizures were excluded. Seizure type and etiology were classified using the 2017 ILAE protocols [12]. Seizures were classified into focal onset, generalized onset, and unknown onset based upon medical records, EEG and neuroimaging finding. Etiology was divided into structural, genetic, infectious, metabolic, immune and unknown category. The ILAE protocol provided the importance given to a patient’s etiology group may depend on the circumstances [12]. Due to limited resources, the etiology was diagnosed by history and physical examination. If initial work up, consisting of electrolyte, blood glucose, EEG and/or neuroimaging, was consistent with the history and physical examination, the investigation was stopped. In cases of unknown etiology and uncontrolled seizure, metabolic etiology was tested, consisting of chromosome, serum lactate and serum ammonia, plasma amino acid and urine organic
The subject population consists of a total 57 infants who were diagnosed with epilepsy at between 1 month and 1 year of age during the approximately 6-year period of study. The clinical characteristics of 57 infants are summarized in Table 1. The 31 subjects (54.4%) were male. The averaged follow-up period was 34.2 months (ranging from 1.7 to 75.6 months). The average age of seizure onset was 4.7 months (ranged 1 day to 11.2 months). Prenatal risk factors (preterm, IUGR, HIE, meningitis) were found in 28.1 percent of the cases (16/57). Of these, 50 percent (8/16)
Table 1 Clinical characteristics of 57 subjects. Characteristics
Number (%)
Male gender Average age at first seizure Prenatal risk factors (total): -Preterm -Hypoxic ischemic encephalopathy -Infection -Others (e.g. IUGR, dysmorphic features, chromosome abnormality) Neonatal seizure Family history of seizure Abnormal neuro examination at first presentation Type of seizure: -Focal -Generalized Status epilepticus Neuroimaging (total): -Ultrasound -CT -MRI -CT and MRI EEG (total) -Epileptiform discharges -Background slowing/chaotic
31 (54.4) 4.7 months 16 (28.1) 9 (15.8) 7 (12.3) 4 (7) 4 (7) 14 (24.6) 9 (15.8) 22 (38.6) 16 (28.1) 41 (71.9) 12 (21.1) 39 (68.4) 5 (8.8) 19 (33.3) 6 (10.5) 9 (15.8) 29 (50.9) 17 (29.8) 15 (26.3)
Please cite this article in press as: Fangsaad T et al. Etiology, clinical course and outcome of infant epilepsy: Experience of a tertiary center in Thailand. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.10.117
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had seizure in the neonatal period (less than 1 month). An additional 6 infants without any prenatal risk factor had seizure in that neonatal period, bringing the total newborn with seizure to 24.6 percent (14/57). Family history of seizure was positive in only 15.8 percent (9/57). Seizure type was divided into focal 28.1 percent (16/57) and generalized 71.9 percent (41/57). Status epilepticus was found 21.1 percent of the time (12/57). Neuroimaging was done in 68.4 percent of the total case (39/57) and electroencephalogram in 50.9 percent (29/57).
4. Discussion There are only a few publications studying infants under 2– 3 years of age with epilepsy. These publications included studied of drug-resistant or intractable epilepsy [10,22] and long-term outcome of epilepsy [8,18]. Other publications found the incidence of epilepsy in children less than 2 years is approximately 70 per 100,000 whereas the incidence of epilepsy in children less than one year is 102.4 per 100,000, the highest rate of all [1,2]. In instant study, the subject population was limited to children under 1 year of age. The sample size of this study was 57 subjects, making it was comparable to the sample sizes in the above publications. Each study made its own decision regarding of categorization of etiology. Etiology is capable of being divided into 3 groups, structural/metabolic, genetic and unknown [10,18], or into 2 groups, cryptogenic/idiopathic and remote symptomatic [8] or into 5 groups [22], according the ILAE 2017 classification. In the ILAE 2017 classification technically, there are 6 groups, but in this age group being study, immune etiology is rarely found, so it dropped category. Following the ILAE 2017 classification and Yildiz, the present study would utilize 5 categories of the etiology. Similar to the findings to previous studies, the most commonly found etiology in our study in this age group was structural [10,18,22] while the other etiologies were found varied extent. However, in the present study, consistent with the prior studies, etiology was identifiable only in a total of 64.9 percent of the cases. Therefore, unknown etiology accounted for 35.1 percent of the cases [8,10,18,22]. The unknown etiology in the present study consisted of two groups. The first group consisted of patients who epilepsy was controlled and who showed normal development without family history of epilepsy. This group would get an initial investigation that included laboratory testing with or without CT scan. The second group consisted of patients with intractable epilepsy and/or developmental delay. In this group, if all laboratory testing and MRI results were negative, would be sent for genetic testing, up on the consent of the parents. The patients who had genetic testing, consisting of whole exome genome sequencing, accounted for a total of 35.3 percent (6/17) of this second group. The genetic testing revealed a positive result for 83.3 percent (5/6) consisting of 1 of tuberous sclerosis, 2 of Dravet syndrome, 1 of early infantile epileptic encephalopathy 41, 1 of Menke syndrome and 1 of unidentified pathological gene. Unfortunately, due to limit resources or lack of parental consent, not all infants in the second group of unknown etiology were able to had genetic testing. But this circumstance does not distract from the usefulness of the tool. The etiology discovered upon the genetic testing highly beneficial for the individual infant who was able to receive this testing. Previous studies found intractable epilepsy in 35 percent of the under 2–3 year age group [10,22]. The risk factors for intractable epilepsy in children from the previous studies [4,5,9,10,13,15–17, 23,24,27,28] consisted of history of status epilepticus, epilepsy onset under age of one, abnormal EEG findings and neurological
3.2. Etiology, clinical course and outcome The details of etiology, clinical course and outcome are shown in Table 2. The etiology was mostly structural 38.6 percent (22/57), followed by unknown 35.1 percent (20/57), genetics 14 percent (8/57), infection 10.5 percent (6/57) and metabolic 1.8 percent (1/57). Structural etiology was divided into congenital brain anomaly 42.9 percent (9/21), hypoxic ischemic change 38.1 percent (8/21) and traumatic brain injury 19 percent (4/21). In those with congenital brain anomaly was lissencephaly (1/9), focal cortical dysplasia (1/9), sturge weber (1/9) and structural brain anomaly (6/9). Genetic etiology was tuberous sclerosis (1/8), Dravet syndrome (2/8), EIEE 41 (1/8), and benign familial infantile epilepsy (4/8), which was diagnosed by multiple family members having similar clinical course. The 1 patient in the metabolic category was diagnosed with Menkes disease. Antiepileptic drugs were discontinued only 19.3 percent (11/57) over the study period. Intractable epilepsy was found in 29.8 percent (17/57) and developmental delay was found 56.1 percent (32/57). Almost 10 percent (5/57) were referred for further treatment consisting of surgery (2/5) and continued local services (3/5). Only 3.5 (2/57) percent died over the course of study, from infection. 3.3. Potential risk factors for intractable epilepsy and developmental delay From univariate analysis, potential risk factors for intractable epilepsy were status epilepticus (p = 0.029) and developmental delay (p < 0.000). All variables in this univariate analysis were used in logistic regression model. Multivariate logistic regression analysis also showed status epilepticus (p = 0.046) and developmental delay (p = 0.004) predicted intractable seizure. By contrast, from univariate analysis, potential risk factors for developmental delay were abnormal neurological examination (P < 0.000), abnormal neuroimaging (P = 0.001), epileptogenic discharges (P = 0.044) and EEG background abnormality (P = 0.030). Again, all variables in this univariate analysis were used in logistic regression model. Multivariate logistic regression analysis showed that only abnormal neurological examination (p = 0.029) and abnormal neuroimaging (p = 0.010) predicted developmental delay. The multivariate analysis details are shown in Table 3.
Table 2 Clinical course and outcome of 57 patients depending on the etiology. Course/outcome Total No. (%)
AEDs -discontinue -1–2 ->2 Intractable seizure Developmental delay Death
Etiology No. (%) Structure 22 (38.6)
Genetic 8 (14)
Infection 6 (10.5)
Metabolic 1 (1.8)
Unknown 20 (35.1)
Total 57 (100)
3 (13.6) 13 (59.1) 6 (27.3) 8 (38.1) 18 (81.8) 2 (9.5)
2 3 3 3 4 0
2 3 1 1 2 0
0 0 1 1 1 0
4 (20) 12 (60) 4 (20) 4 (19) 7 (35) 0 (0)
11 (19.3) 31 (54.4) 15 (26.3) 17 (29.8) 32 (56.1) 2 (3.5)
(25) (37.5) (37.5) (37.5) (50) (0)
(33.3) (50) (16.7) (16.7) (33.3) (0)
(0) (0) (100) (100) (100) (0)
Please cite this article in press as: Fangsaad T et al. Etiology, clinical course and outcome of infant epilepsy: Experience of a tertiary center in Thailand. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.10.117
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T. Fangsaad et al. / Journal of Clinical Neuroscience xxx (2018) xxx–xxx
Table 3 Multivariate analysis for potential risk factors of intractable epilepsy and developmental delay. Variables (No.)
Intractable epilepsy No. (%)
Adjusted Odd ratio (95%CI)
P
Develop mental delay No. (%)
Adjusted Odd ratio (95%CI)
P
Male gender (31)
11 (35.5)
0.06
17 (54.8)
10 (29.4)
0.506
16 (47.1)
0.20
11 (68.8)
Preterm (10)
2 (20)
0.79
7 (70)
Neonatal seizure (14)
4 (28.6)
0.76
9 (64.9)
Family history (9)
3 (33.3)
0.39
3 (33.3)
Abnormal neuro exam (22)
9 (40.9)
0.56
19 (36.4)
Focal seizure (16)
3 (18.8)
0.74
7 (43.8)
Status epilepticus (12)
7 (58.3)
0.046
9 (75)
Abnormal neuroimaging (14)
6 (42.8)
0.15
13 (92.7)
8.67 (0.76–98.70) 43.47 (0.96–1996.54) 105.90 (0.07–1612.38) 0.00 (0.00–3.80) 0.34 (0.00–12.67) 0.69 (0.03–15.67) 0.003 (0.00–0.54) 25.1 (0.57–1109.99) 0.10 (0.00–2.38) 0.001 (0.00–0.17)
0.08
Age at onset -Less than 6 mo (34) Perinatal risk factor (16)
0.10 (0.00–1.34) 0.50 (0.06–3.90) 10.10 (0.30–341.9) 0.66 (0.03–13.76) 0.68 (0.06–7.24) 0.26 (0.01–5.40) 0.52 (0.06–4.66) 1.46 (0.15–13.73) 0.10 (0.01–0.96) 5.98 (0.54–66.61)
Abnormal EEG (29) -Epileptogenic discharges (17)
8 (47.1)
0.60
13 (76.5)
-Background slowing (15)
6 (40.0)
Developmental delay (32)
4 (25)
16 (50)
0.53 (0.05–5.79) 1.89 (0.15–13.55) 0.003 (0.00–0.16)
deficit at the time of diagnosis, symptomatic seizures, high frequency of seizures, non-responsiveness to the first AED, abnormal neuroimaging and focal slowing on initial EEG associated with intractable epilepsy. However, in the present study, intractable seizure was found in less than one-third (29.8 percent) of infants with epilepsy under 1 year of age. Furthermore, in the present study, there were only 2 factors associated with intractable epilepsy, status epilepticus and developmental delay. The present study was both retrospective and prospective study, therefore, intractable seizure might not be identified, because it may be delayed, especially in focal epilepsy and in cases of unpredictable variation in time of onset, course and duration [27,29]. A study [18] of patients who had epilepsy onset less than 3 year of age, showed a link between early age of epilepsy onset and intellectual disability in multiple regression analysis. In the present study, long-term outcome was evaluated by milestone at 1 month or at last follow-up and mortality rate. Developmental delay was found in more than half (56.1 percent) cases. Univariate analysis, the four independent risk factors for developmental delay consisted of abnormal neurological examination, abnormal neuroimaging, epileptogenic discharges, and abnormal electrographic background. However, multivariate analysis showed developmental delay related only to abnormal neurological examination and abnormal neuroimaging. Previous reports [18,25,26] of the percentage (2.1–3.8 percent) and cause of death were similar to those found here. Mortality rate in the present study was 3.5 percent over 6 years. The cause of death was unrelated to the seizure resulting from neurological disability. This study had limitations. First, our center had limit resources for conducting investigations where etiology was unknown. However, the incidence of unknown etiology in our study was not higher than those found in previous publications. In any research project, resources for further investigation are not unlimited. Insofar as possible, we try to make a decision about further investigation based on clinical considerations. Second, the risk factors for intractable epilepsy and developmental delay studied here were
0.62 0.004
12 (80.0) –
0.05 (0.00–1.03) 0.51 (0.02–13.32 –
0.05 0.21 0.11 0.56 0.82 0.029 0.10 0.15 0.01
0.052 0.69 –
the same as those in the previous publications. However, we modified some risk factors because they were not relevant to infants under the age of 1 who were the subjects of the study, such as febrile seizure, and frequency of seizures before the diagnosis [10]. We did that because some infants may not have febrile seizure before 1 year of age. In addition, some patients may be diagnosed with epilepsy at age more than 1 year in cases of Dravet syndrome, so we used age at first seizure instead. However, as a consequence, there might be residual confounding risk factors not adjusted for multivariate analysis. Third and finally, the total number of infant subjects was small, so we are not able to find a statistically significant correlation between the outcome and the etiology. We choose here to refine our population and include only those infants under 1 year old. In the future, a study of a larger group for a longer period of time should be conducted. 5. Conclusion The study shows that early onset of epilepsy in children under a year is similar to that found in children less than 2–3 years as found in prior studies. Structural defect was the most commonly found. High percentages of intractable seizure and developmental delay were found in the subject infants. Genetic testing was helpful in diagnosis, treatment and predicting outcome. Acknowledgements The authors would like to express our sincere gratitude to Gp. Capt. Napaporn Jiraphongsa M.D., M.Sc. Utcharee Intusoma, M.D. Ph.D., Master Sanpath Sunggad, and Ms. Suwittra Huanraluck for their help and advice on statistical analysis of the data; to Wg. CDR. M.L. Nattawadee Jaroonrojana, Sqn.LDR. Surawadee Singhanat and Miss Wilaiwan Arun for their assistance in EEG recording; and to Ms. Christine Gordon for English editing of the manuscript. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Please cite this article in press as: Fangsaad T et al. Etiology, clinical course and outcome of infant epilepsy: Experience of a tertiary center in Thailand. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.10.117
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References [1] Camfield CS, Camfield PR, Gordon K, Wirrell E, Dooley JM. Incidence of epilepsy in childhood and adolescence: a population-based study in Nova Scotia from 1977 to 1985. Epilepsia 1996;37:19–23. [2] Wirrell EC, Grossardt BR, Wong-Kisiel LC, Nickels KC. Incidence and classification of new-onset epilepsy and epilepsy syndromes in children in Olmsted Country, Minnesota from 1980 to 2004: a population-based study. Epilepsy Res 2011;95:110–8. [3] Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342:314–9. [4] Brorson LO, Wranne L. Long-term prognosis in childhood epilepsy: survival and seizure prognosis. Epilepsia 1987;28:324–30. [5] Camfield P, Camfield C. Childhood epilepsy: what is the evidence for what we think and wat we do? J Child Neuro 2003;18:272–87. [6] Sillanpaa M, Schmidt D. Natural history of treated childhood-onset epilepsy: prospective, long-term population-based study. Brain 2006;129:617–24. [7] Camfield C, Camfield P. Twenty years after childhood-onset symptomatic generalized epilepsy the social outcome is usually dependency or death: a population-based study. Dev Med Child Neurol 2008;50:859–63. [8] Berg AT, Smith SN, Frobish D, Beckerman B, Levy SR, Testa FM, et al. Longitudinal assessment of adaptive behavior in infants and young children with newly diagnosed epilepsy: influence of etiology, syndrome, and seizure control. Pediatrics 2004;114:645–50. [9] Semah F, Picot MC, Adam C, Brogllin D, Arzimanoglou A, Bazin B, et al. Is the underlying cause of epilepsy a major prognosis factor for recurrence? Neurology 1998;51:1256–62. [10] Wirrell E, Wong-Kisiel L, Mandrekar J, Nickels K. Predictors and course of medically intractable epilepsy in young children presenting before 36 months of age: a retrospective, population-based study. Epilepsia 2012;53 (9):1563–9. [11] Camfield C, Camfield P. Long-term prognosis for symptomatic (secondarily) generalized epilepsies: a population-based study. Epilepsia 2007;48:1128–32. [12] Scheffer IE, Berkovic S, Capovilla G, Connolly MB, et al. ILAE classification of the epilepsies: position paper of the ILAE commission for classification and terminology. Epilepsia 2017;58(4):512–21. [13] Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2008;51:1069–77.
5
[14] Wirrell EC. Predicting pharmacoresistance in pediatric epilepsy. J Pediatr 2013;54(s2):19–22. [15] Shahar E, Genizi J. Predictive factors of seizure control in childhood onset epilepsy. J Pediatr Neuroscience 2008;3:117–20. [16] Sillanpaa M, Schmidt D. Early seizure frequency and aetiology predict longterm medical outcome in childhood-onset epilepsy. Brain 2009;132:989–98. [17] Camfield C, Camfield P, Gordon K, Smith B, Dooley J. Outcome of childhood epilepsy: a population-based study with a simple predictive scoring system for those treated with medication. J Pediatr 1993;122:861–8. [18] Vignoli A, Peron A, Turner K, Scornavacca GF, Briola FL, Chiesa V, et al. Longterm outcome of epilepsy with onset in the first three years of life: Findings from a large cohort of patients. Eur J Pediatric Neurol 2016;20:566–72. [19] Fisher RS, Cross JH, French JA, et al. Operational classification of seizure types by the International League Against Epilepsy: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017;58:522–30. [20] Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical point clinical definition of epilepsy. Epilepsia 2014;55:475–82. [21] Beghi E, Carpio A, Forsgren L, Hesdorffer DC, Malmgren K, Sander JW, et al. Recommendation for a definition of acute symptomatic seizure. Epilepsia 2010;51:671–5. [22] Yildiz EP, Gunes D, Bektas G, Uzunhan TA, Tatli B, Caliskan M, et al. Predictive factors of drug-resistant epilepsy in children present under 2 years of age: experience of a tertiary center in Turkey. Acta Neurol Belg 2017. [23] Ko TS, Holmes GL. EEG and clinical predictors of medically intractable childhood epilepsy. Clin Neurophysiol 1999;110:1245–51. [24] Sillanpaa M, Camfield P, Canfield C. Predicting long-term outcome of childhood epilepsy in Nova Scotia, Canada, and Turku, Finland. Validation of a simple scoring system. Arch Neurol 1995;52:589–92. [25] Berg AT, Shinnar S, Testa FM, Levy SR, Smith SN, Beckerman B. Mortality in childhood-onset epilepsy. Arch Pediatr Adolesc Med 2004;158:1147–52. [26] Camfield CS, Camfield PR, Veugelers PJ. Death in children with epilepsy: a population-based study. Lancet 2002;359:1891–5. [27] Berg AT, Vickrey BG, Testa FM, Levy SR, Shinnar S, DiMario F, et al. How long does it take for epilepsy to become intractable childhood epilepsy? A prospective investigation. Ann Neurol 2006;60:73–9. [28] Seker Yilmaz B, Okuyaz C, Komur M. Predictors of intractable childhood epilepsy. Pediatr Neurol 2013;48:52–5. [29] Geerts A, Brouwer O, Stroink H, van Donselaar C, Peters B, Peeters E, et al. Onset of intractractability and its course over time: the Dutch study of epilepsy in childhood. Epilepsia 2012;53(4):741–51.
Please cite this article in press as: Fangsaad T et al. Etiology, clinical course and outcome of infant epilepsy: Experience of a tertiary center in Thailand. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.10.117
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Clinical study
Etiology, clinical course and outcome of infant epilepsy: Experience of a tertiary center in Thailand Thitiporn Fangsaad a,⇑, Siriluk Assawabumrungkul a, Ponghatai Damrongphol b,c, Tayard Desudchit d a
Department of Pediatrics, Bhumibol Adulyadej Hospital, Bangkok, Thailand Center of Excellence for Medical Genetics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand c Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand d Division of Pediatric Neurology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand b
a r t i c l e
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Article history: Received 10 June 2018 Accepted 27 October 2018 Available online xxxx Keywords: Infant epilepsy Under 1 year of age Etiology Outcome Intractable seizure Developmental delay
a b s t r a c t Purpose: Explore etiology, clinical course and outcome of infant epilepsy in Bhumibol Adulyadej Hospital. Method: Retrospective and prospective descriptive analysis of infants 1 month to 1 year diagnosed with epilepsy between January 1, 2012, and April 30, 2018. Results: Total 57 infants. Average age of seizure onset was 4.7 months. Follow-up period averaged 34.2 months. Prenatal risk factors were found in 28.1 percent (16/57). Of these, 50 percent (8/16) had seizure in neonatal period. An additional 6 infants without any prenatal risk factor had seizure in the neonatal period, bringing the total newborn with seizure to 24.6 percent (14/57). Family history of seizure was positive in only 15.8 percent (9/57). Neuroimaging was done 68.4 percent (39/57) and electroencephalogram 50.9 percent (29/57). The etiology was mostly structural 38.6 percent (22/57), followed by unknown 35.1 percent (20/57), genetics 14 percent (8/57), infection 10.5 percent (6/57) and metabolic 1.8 percent (1/57). Status epilepticus was found 21.1 percent of the times (12/57). Antiepileptic drugs were discontinued 19.3 percent (11/57). Intractable seizure was found 29.8 percent (17/57) and developmental delay 56.1 percent (32/57). By multivariate logistic regression analysis, status epilepticus and developmental delay predicted intractable seizure, whereas, abnormal neurological examination and abnormal neuroimaging predicted developmental delay. Mortality rate was 3.5 percent. Conclusion: The study shows that early onset of epilepsy in children under a year is similar to that found in children less than 2–3 years as found in prior studies. High percentages of intractable seizure and developmental delay were found. Ó 2018 Published by Elsevier Ltd.
1. Introduction Epilepsy is a common neurological disease especially in infancy and old age with highest incidence in the first year of life with rate 102.4 per 100,000 [1,2]. It has been reported that childhood epilepsy with proper and adequate treatment achieved remission 60–70% of the time and nearly half were able to discontinue antiepileptic medication [3–6]. However, epilepsy in early childhood may have less favorable outcome including intractable seizure, severe neurodevelopmental delay, intellectual disability and high mortality rate [7,8]. Etiology and electroclinical syndrome in this age group are the important predictor outcomes. Etiology including cortical dysplasia and other structural abnormalities [9], neurometabolic disorder and perinatal brain injury and severe
⇑ Corresponding author. E-mail address: [email protected] (T. Fangsaad).
epileptic encephalopathies including West, Dravet and Lennox Gastaut syndrome are highly correlated with intractability [10]. There is also evidence that poorly controlled seizures in the developing brain negatively impact intellectual functioning [8]. In addition, there are 2 studies showing that, in symptomatic generalized epilepsy, nearly one quarter died and most survivors had mental retardation and were highly dependent [7,11]. These studies suggest the important of early diagnosis and effective treatment in early childhood epilepsy. The International League Against Epilepsy (ILAE) classification has been updated in 2017. The new classification incorporates etiology at each step of diagnosis. Etiology is broken into six subgroups, structural, genetic, infectious, metabolic, immune and unknown. The etiology may belong to more than one subgroup. The subgroups differ in their potential therapeutic consequences [12]. Structural etiology refers to visible structural abnormalities, as shown by neuroimaging, together with electroclinical assessment, which are the likely cause of the seizure. Genetic etiology
https://doi.org/10.1016/j.jocn.2018.10.117 0967-5868/Ó 2018 Published by Elsevier Ltd.
Please cite this article in press as: Fangsaad T et al. Etiology, clinical course and outcome of infant epilepsy: Experience of a tertiary center in Thailand. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.10.117
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T. Fangsaad et al. / Journal of Clinical Neuroscience xxx (2018) xxx–xxx
is shown by family history of an autosomal dominant disorder or by molecular genetics. Infectious etiology refers to a patient with epilepsy directly resulting from a known infection or postinfectious development of epilepsy, but not from a seizure occurring during meningitis or encephalitis. Metabolic etiology refers to epilepsy resulting from metabolic defect or biochemical changes. Early identification of etiology will assist the diagnosis and appropriate management and potential prevention of intellectual impairment [12]. Intractable epilepsy is defined as the failure of two or more antiepileptic drugs to control seizure either after epilepsy surgery or seizure frequency of more than one every 6 months in the year immediately prior to the final follow-up [13,14]. Risk factors for intractable epilepsy from previous studies are epilepsy onset under age of one, abnormal EEG findings and neurological deficit at the time of diagnosis, symptomatic seizures, high frequency of seizures, and non-response to the first AED [13–17]. Long term outcome studied on infants with epilepsy onset less than 3 year [8] demonstrated children with symptomatic epilepsy or epileptic encephalopathy syndromes impaired adaptive behavior at the time of initial diagnosis and declined over time even after controlling for symptomatic etiology and poor seizure control. This study was confirmed later [18]. The earlier age of seizure onset, the poorer the epilepsy outcome. This study aims to explore etiology, clinical course and outcome of infants diagnosed with epilepsy from 1 month to 1 year old in Bhumibol Adulyadej Hospital.
acid. If metabolic tests were negative, whole exome genome sequencing was offered to the parents. If the parents agree to do the test and enter the research project with the affiliate institute, the test was run. Intractable epilepsy was defined using the ILAE definition as the failure of two or more anti-epileptic drugs to control seizure either after epilepsy surgery or seizure frequency of more than one every 6 months in the year immediately prior to the final follow-up [13,14]. The development was determined at final follow-up or at least 1 month after the diagnosis of epilepsy. Developmental milestones were used to classify development as normal or delayed. Medical records were reviewed to collect data of sex, age onset at first seizure, perinatal risk factors, neonatal seizure, neurological examination at the first presentation, seizure type, EEG, neuroimaging, history of status epilepticus, family history, etiology, antiepileptic drugs (AEDs), follow-up, intractable epilepsy, and development delay. Univariate analyses between each categorical variable with the outcome (intractable epilepsy and developmental delay) were performed using chi-squared test. Multiple logistic regression analyses were then adjusted for all potential risk factors. The level of significance was set at p < 0.05. All statistical analyses were performed with SPSS Statistic 19. This study was reviewed and approved by the Bhumibol Adulyadej Hospital Ethics Committee.
3. Results 2. Methods 3.1. Clinical characteristics A retrospective and prospective descriptive analysis study was conducted in infants aged 1 month to 1 year who were diagnosed with epilepsy from January 1, 2012 through April 30, 2018. The cases were identified by ICD 10 coding G400-409. This study used the definitions of seizure and epilepsy as defined by the ILAE. Seizure is defined as ‘‘a transient occurrence of sign and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain” [19]. Epilepsy is diagnosed when an individual has: 1) at least 2 unprovoked or reflex seizures more than 24 h apart, 2) one provoked or reflex seizure and a probability of having another seizure similar to the general recurrence risk after two provoked seizures (more than 60%) over the next 10 years, or 3) an epileptic syndrome [20]. Patients with an abnormal neurodevelopmental examination, focal abnormality on brain imaging and abnormal EEG findings are considered at having a higher risk of recurrence. The infants who presented with a provoked seizure alone were excluded, defined as ‘‘seizures at the time of a systemic insult or in close temporal association with an acute neurological insult” [21]. Similarly, vaccine-associated and non-vaccine associated febrile seizures were excluded. Seizure type and etiology were classified using the 2017 ILAE protocols [12]. Seizures were classified into focal onset, generalized onset, and unknown onset based upon medical records, EEG and neuroimaging finding. Etiology was divided into structural, genetic, infectious, metabolic, immune and unknown category. The ILAE protocol provided the importance given to a patient’s etiology group may depend on the circumstances [12]. Due to limited resources, the etiology was diagnosed by history and physical examination. If initial work up, consisting of electrolyte, blood glucose, EEG and/or neuroimaging, was consistent with the history and physical examination, the investigation was stopped. In cases of unknown etiology and uncontrolled seizure, metabolic etiology was tested, consisting of chromosome, serum lactate and serum ammonia, plasma amino acid and urine organic
The subject population consists of a total 57 infants who were diagnosed with epilepsy at between 1 month and 1 year of age during the approximately 6-year period of study. The clinical characteristics of 57 infants are summarized in Table 1. The 31 subjects (54.4%) were male. The averaged follow-up period was 34.2 months (ranging from 1.7 to 75.6 months). The average age of seizure onset was 4.7 months (ranged 1 day to 11.2 months). Prenatal risk factors (preterm, IUGR, HIE, meningitis) were found in 28.1 percent of the cases (16/57). Of these, 50 percent (8/16)
Table 1 Clinical characteristics of 57 subjects. Characteristics
Number (%)
Male gender Average age at first seizure Prenatal risk factors (total): -Preterm -Hypoxic ischemic encephalopathy -Infection -Others (e.g. IUGR, dysmorphic features, chromosome abnormality) Neonatal seizure Family history of seizure Abnormal neuro examination at first presentation Type of seizure: -Focal -Generalized Status epilepticus Neuroimaging (total): -Ultrasound -CT -MRI -CT and MRI EEG (total) -Epileptiform discharges -Background slowing/chaotic
31 (54.4) 4.7 months 16 (28.1) 9 (15.8) 7 (12.3) 4 (7) 4 (7) 14 (24.6) 9 (15.8) 22 (38.6) 16 (28.1) 41 (71.9) 12 (21.1) 39 (68.4) 5 (8.8) 19 (33.3) 6 (10.5) 9 (15.8) 29 (50.9) 17 (29.8) 15 (26.3)
Please cite this article in press as: Fangsaad T et al. Etiology, clinical course and outcome of infant epilepsy: Experience of a tertiary center in Thailand. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.10.117
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had seizure in the neonatal period (less than 1 month). An additional 6 infants without any prenatal risk factor had seizure in that neonatal period, bringing the total newborn with seizure to 24.6 percent (14/57). Family history of seizure was positive in only 15.8 percent (9/57). Seizure type was divided into focal 28.1 percent (16/57) and generalized 71.9 percent (41/57). Status epilepticus was found 21.1 percent of the time (12/57). Neuroimaging was done in 68.4 percent of the total case (39/57) and electroencephalogram in 50.9 percent (29/57).
4. Discussion There are only a few publications studying infants under 2– 3 years of age with epilepsy. These publications included studied of drug-resistant or intractable epilepsy [10,22] and long-term outcome of epilepsy [8,18]. Other publications found the incidence of epilepsy in children less than 2 years is approximately 70 per 100,000 whereas the incidence of epilepsy in children less than one year is 102.4 per 100,000, the highest rate of all [1,2]. In instant study, the subject population was limited to children under 1 year of age. The sample size of this study was 57 subjects, making it was comparable to the sample sizes in the above publications. Each study made its own decision regarding of categorization of etiology. Etiology is capable of being divided into 3 groups, structural/metabolic, genetic and unknown [10,18], or into 2 groups, cryptogenic/idiopathic and remote symptomatic [8] or into 5 groups [22], according the ILAE 2017 classification. In the ILAE 2017 classification technically, there are 6 groups, but in this age group being study, immune etiology is rarely found, so it dropped category. Following the ILAE 2017 classification and Yildiz, the present study would utilize 5 categories of the etiology. Similar to the findings to previous studies, the most commonly found etiology in our study in this age group was structural [10,18,22] while the other etiologies were found varied extent. However, in the present study, consistent with the prior studies, etiology was identifiable only in a total of 64.9 percent of the cases. Therefore, unknown etiology accounted for 35.1 percent of the cases [8,10,18,22]. The unknown etiology in the present study consisted of two groups. The first group consisted of patients who epilepsy was controlled and who showed normal development without family history of epilepsy. This group would get an initial investigation that included laboratory testing with or without CT scan. The second group consisted of patients with intractable epilepsy and/or developmental delay. In this group, if all laboratory testing and MRI results were negative, would be sent for genetic testing, up on the consent of the parents. The patients who had genetic testing, consisting of whole exome genome sequencing, accounted for a total of 35.3 percent (6/17) of this second group. The genetic testing revealed a positive result for 83.3 percent (5/6) consisting of 1 of tuberous sclerosis, 2 of Dravet syndrome, 1 of early infantile epileptic encephalopathy 41, 1 of Menke syndrome and 1 of unidentified pathological gene. Unfortunately, due to limit resources or lack of parental consent, not all infants in the second group of unknown etiology were able to had genetic testing. But this circumstance does not distract from the usefulness of the tool. The etiology discovered upon the genetic testing highly beneficial for the individual infant who was able to receive this testing. Previous studies found intractable epilepsy in 35 percent of the under 2–3 year age group [10,22]. The risk factors for intractable epilepsy in children from the previous studies [4,5,9,10,13,15–17, 23,24,27,28] consisted of history of status epilepticus, epilepsy onset under age of one, abnormal EEG findings and neurological
3.2. Etiology, clinical course and outcome The details of etiology, clinical course and outcome are shown in Table 2. The etiology was mostly structural 38.6 percent (22/57), followed by unknown 35.1 percent (20/57), genetics 14 percent (8/57), infection 10.5 percent (6/57) and metabolic 1.8 percent (1/57). Structural etiology was divided into congenital brain anomaly 42.9 percent (9/21), hypoxic ischemic change 38.1 percent (8/21) and traumatic brain injury 19 percent (4/21). In those with congenital brain anomaly was lissencephaly (1/9), focal cortical dysplasia (1/9), sturge weber (1/9) and structural brain anomaly (6/9). Genetic etiology was tuberous sclerosis (1/8), Dravet syndrome (2/8), EIEE 41 (1/8), and benign familial infantile epilepsy (4/8), which was diagnosed by multiple family members having similar clinical course. The 1 patient in the metabolic category was diagnosed with Menkes disease. Antiepileptic drugs were discontinued only 19.3 percent (11/57) over the study period. Intractable epilepsy was found in 29.8 percent (17/57) and developmental delay was found 56.1 percent (32/57). Almost 10 percent (5/57) were referred for further treatment consisting of surgery (2/5) and continued local services (3/5). Only 3.5 (2/57) percent died over the course of study, from infection. 3.3. Potential risk factors for intractable epilepsy and developmental delay From univariate analysis, potential risk factors for intractable epilepsy were status epilepticus (p = 0.029) and developmental delay (p < 0.000). All variables in this univariate analysis were used in logistic regression model. Multivariate logistic regression analysis also showed status epilepticus (p = 0.046) and developmental delay (p = 0.004) predicted intractable seizure. By contrast, from univariate analysis, potential risk factors for developmental delay were abnormal neurological examination (P < 0.000), abnormal neuroimaging (P = 0.001), epileptogenic discharges (P = 0.044) and EEG background abnormality (P = 0.030). Again, all variables in this univariate analysis were used in logistic regression model. Multivariate logistic regression analysis showed that only abnormal neurological examination (p = 0.029) and abnormal neuroimaging (p = 0.010) predicted developmental delay. The multivariate analysis details are shown in Table 3.
Table 2 Clinical course and outcome of 57 patients depending on the etiology. Course/outcome Total No. (%)
AEDs -discontinue -1–2 ->2 Intractable seizure Developmental delay Death
Etiology No. (%) Structure 22 (38.6)
Genetic 8 (14)
Infection 6 (10.5)
Metabolic 1 (1.8)
Unknown 20 (35.1)
Total 57 (100)
3 (13.6) 13 (59.1) 6 (27.3) 8 (38.1) 18 (81.8) 2 (9.5)
2 3 3 3 4 0
2 3 1 1 2 0
0 0 1 1 1 0
4 (20) 12 (60) 4 (20) 4 (19) 7 (35) 0 (0)
11 (19.3) 31 (54.4) 15 (26.3) 17 (29.8) 32 (56.1) 2 (3.5)
(25) (37.5) (37.5) (37.5) (50) (0)
(33.3) (50) (16.7) (16.7) (33.3) (0)
(0) (0) (100) (100) (100) (0)
Please cite this article in press as: Fangsaad T et al. Etiology, clinical course and outcome of infant epilepsy: Experience of a tertiary center in Thailand. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.10.117
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T. Fangsaad et al. / Journal of Clinical Neuroscience xxx (2018) xxx–xxx
Table 3 Multivariate analysis for potential risk factors of intractable epilepsy and developmental delay. Variables (No.)
Intractable epilepsy No. (%)
Adjusted Odd ratio (95%CI)
P
Develop mental delay No. (%)
Adjusted Odd ratio (95%CI)
P
Male gender (31)
11 (35.5)
0.06
17 (54.8)
10 (29.4)
0.506
16 (47.1)
0.20
11 (68.8)
Preterm (10)
2 (20)
0.79
7 (70)
Neonatal seizure (14)
4 (28.6)
0.76
9 (64.9)
Family history (9)
3 (33.3)
0.39
3 (33.3)
Abnormal neuro exam (22)
9 (40.9)
0.56
19 (36.4)
Focal seizure (16)
3 (18.8)
0.74
7 (43.8)
Status epilepticus (12)
7 (58.3)
0.046
9 (75)
Abnormal neuroimaging (14)
6 (42.8)
0.15
13 (92.7)
8.67 (0.76–98.70) 43.47 (0.96–1996.54) 105.90 (0.07–1612.38) 0.00 (0.00–3.80) 0.34 (0.00–12.67) 0.69 (0.03–15.67) 0.003 (0.00–0.54) 25.1 (0.57–1109.99) 0.10 (0.00–2.38) 0.001 (0.00–0.17)
0.08
Age at onset -Less than 6 mo (34) Perinatal risk factor (16)
0.10 (0.00–1.34) 0.50 (0.06–3.90) 10.10 (0.30–341.9) 0.66 (0.03–13.76) 0.68 (0.06–7.24) 0.26 (0.01–5.40) 0.52 (0.06–4.66) 1.46 (0.15–13.73) 0.10 (0.01–0.96) 5.98 (0.54–66.61)
Abnormal EEG (29) -Epileptogenic discharges (17)
8 (47.1)
0.60
13 (76.5)
-Background slowing (15)
6 (40.0)
Developmental delay (32)
4 (25)
16 (50)
0.53 (0.05–5.79) 1.89 (0.15–13.55) 0.003 (0.00–0.16)
deficit at the time of diagnosis, symptomatic seizures, high frequency of seizures, non-responsiveness to the first AED, abnormal neuroimaging and focal slowing on initial EEG associated with intractable epilepsy. However, in the present study, intractable seizure was found in less than one-third (29.8 percent) of infants with epilepsy under 1 year of age. Furthermore, in the present study, there were only 2 factors associated with intractable epilepsy, status epilepticus and developmental delay. The present study was both retrospective and prospective study, therefore, intractable seizure might not be identified, because it may be delayed, especially in focal epilepsy and in cases of unpredictable variation in time of onset, course and duration [27,29]. A study [18] of patients who had epilepsy onset less than 3 year of age, showed a link between early age of epilepsy onset and intellectual disability in multiple regression analysis. In the present study, long-term outcome was evaluated by milestone at 1 month or at last follow-up and mortality rate. Developmental delay was found in more than half (56.1 percent) cases. Univariate analysis, the four independent risk factors for developmental delay consisted of abnormal neurological examination, abnormal neuroimaging, epileptogenic discharges, and abnormal electrographic background. However, multivariate analysis showed developmental delay related only to abnormal neurological examination and abnormal neuroimaging. Previous reports [18,25,26] of the percentage (2.1–3.8 percent) and cause of death were similar to those found here. Mortality rate in the present study was 3.5 percent over 6 years. The cause of death was unrelated to the seizure resulting from neurological disability. This study had limitations. First, our center had limit resources for conducting investigations where etiology was unknown. However, the incidence of unknown etiology in our study was not higher than those found in previous publications. In any research project, resources for further investigation are not unlimited. Insofar as possible, we try to make a decision about further investigation based on clinical considerations. Second, the risk factors for intractable epilepsy and developmental delay studied here were
0.62 0.004
12 (80.0) –
0.05 (0.00–1.03) 0.51 (0.02–13.32 –
0.05 0.21 0.11 0.56 0.82 0.029 0.10 0.15 0.01
0.052 0.69 –
the same as those in the previous publications. However, we modified some risk factors because they were not relevant to infants under the age of 1 who were the subjects of the study, such as febrile seizure, and frequency of seizures before the diagnosis [10]. We did that because some infants may not have febrile seizure before 1 year of age. In addition, some patients may be diagnosed with epilepsy at age more than 1 year in cases of Dravet syndrome, so we used age at first seizure instead. However, as a consequence, there might be residual confounding risk factors not adjusted for multivariate analysis. Third and finally, the total number of infant subjects was small, so we are not able to find a statistically significant correlation between the outcome and the etiology. We choose here to refine our population and include only those infants under 1 year old. In the future, a study of a larger group for a longer period of time should be conducted. 5. Conclusion The study shows that early onset of epilepsy in children under a year is similar to that found in children less than 2–3 years as found in prior studies. Structural defect was the most commonly found. High percentages of intractable seizure and developmental delay were found in the subject infants. Genetic testing was helpful in diagnosis, treatment and predicting outcome. Acknowledgements The authors would like to express our sincere gratitude to Gp. Capt. Napaporn Jiraphongsa M.D., M.Sc. Utcharee Intusoma, M.D. Ph.D., Master Sanpath Sunggad, and Ms. Suwittra Huanraluck for their help and advice on statistical analysis of the data; to Wg. CDR. M.L. Nattawadee Jaroonrojana, Sqn.LDR. Surawadee Singhanat and Miss Wilaiwan Arun for their assistance in EEG recording; and to Ms. Christine Gordon for English editing of the manuscript. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Please cite this article in press as: Fangsaad T et al. Etiology, clinical course and outcome of infant epilepsy: Experience of a tertiary center in Thailand. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.10.117
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References [1] Camfield CS, Camfield PR, Gordon K, Wirrell E, Dooley JM. Incidence of epilepsy in childhood and adolescence: a population-based study in Nova Scotia from 1977 to 1985. Epilepsia 1996;37:19–23. [2] Wirrell EC, Grossardt BR, Wong-Kisiel LC, Nickels KC. Incidence and classification of new-onset epilepsy and epilepsy syndromes in children in Olmsted Country, Minnesota from 1980 to 2004: a population-based study. Epilepsy Res 2011;95:110–8. [3] Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342:314–9. [4] Brorson LO, Wranne L. Long-term prognosis in childhood epilepsy: survival and seizure prognosis. Epilepsia 1987;28:324–30. [5] Camfield P, Camfield C. Childhood epilepsy: what is the evidence for what we think and wat we do? J Child Neuro 2003;18:272–87. [6] Sillanpaa M, Schmidt D. Natural history of treated childhood-onset epilepsy: prospective, long-term population-based study. Brain 2006;129:617–24. [7] Camfield C, Camfield P. Twenty years after childhood-onset symptomatic generalized epilepsy the social outcome is usually dependency or death: a population-based study. Dev Med Child Neurol 2008;50:859–63. [8] Berg AT, Smith SN, Frobish D, Beckerman B, Levy SR, Testa FM, et al. Longitudinal assessment of adaptive behavior in infants and young children with newly diagnosed epilepsy: influence of etiology, syndrome, and seizure control. Pediatrics 2004;114:645–50. [9] Semah F, Picot MC, Adam C, Brogllin D, Arzimanoglou A, Bazin B, et al. Is the underlying cause of epilepsy a major prognosis factor for recurrence? Neurology 1998;51:1256–62. [10] Wirrell E, Wong-Kisiel L, Mandrekar J, Nickels K. Predictors and course of medically intractable epilepsy in young children presenting before 36 months of age: a retrospective, population-based study. Epilepsia 2012;53 (9):1563–9. [11] Camfield C, Camfield P. Long-term prognosis for symptomatic (secondarily) generalized epilepsies: a population-based study. Epilepsia 2007;48:1128–32. [12] Scheffer IE, Berkovic S, Capovilla G, Connolly MB, et al. ILAE classification of the epilepsies: position paper of the ILAE commission for classification and terminology. Epilepsia 2017;58(4):512–21. [13] Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2008;51:1069–77.
5
[14] Wirrell EC. Predicting pharmacoresistance in pediatric epilepsy. J Pediatr 2013;54(s2):19–22. [15] Shahar E, Genizi J. Predictive factors of seizure control in childhood onset epilepsy. J Pediatr Neuroscience 2008;3:117–20. [16] Sillanpaa M, Schmidt D. Early seizure frequency and aetiology predict longterm medical outcome in childhood-onset epilepsy. Brain 2009;132:989–98. [17] Camfield C, Camfield P, Gordon K, Smith B, Dooley J. Outcome of childhood epilepsy: a population-based study with a simple predictive scoring system for those treated with medication. J Pediatr 1993;122:861–8. [18] Vignoli A, Peron A, Turner K, Scornavacca GF, Briola FL, Chiesa V, et al. Longterm outcome of epilepsy with onset in the first three years of life: Findings from a large cohort of patients. Eur J Pediatric Neurol 2016;20:566–72. [19] Fisher RS, Cross JH, French JA, et al. Operational classification of seizure types by the International League Against Epilepsy: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017;58:522–30. [20] Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical point clinical definition of epilepsy. Epilepsia 2014;55:475–82. [21] Beghi E, Carpio A, Forsgren L, Hesdorffer DC, Malmgren K, Sander JW, et al. Recommendation for a definition of acute symptomatic seizure. Epilepsia 2010;51:671–5. [22] Yildiz EP, Gunes D, Bektas G, Uzunhan TA, Tatli B, Caliskan M, et al. Predictive factors of drug-resistant epilepsy in children present under 2 years of age: experience of a tertiary center in Turkey. Acta Neurol Belg 2017. [23] Ko TS, Holmes GL. EEG and clinical predictors of medically intractable childhood epilepsy. Clin Neurophysiol 1999;110:1245–51. [24] Sillanpaa M, Camfield P, Canfield C. Predicting long-term outcome of childhood epilepsy in Nova Scotia, Canada, and Turku, Finland. Validation of a simple scoring system. Arch Neurol 1995;52:589–92. [25] Berg AT, Shinnar S, Testa FM, Levy SR, Smith SN, Beckerman B. Mortality in childhood-onset epilepsy. Arch Pediatr Adolesc Med 2004;158:1147–52. [26] Camfield CS, Camfield PR, Veugelers PJ. Death in children with epilepsy: a population-based study. Lancet 2002;359:1891–5. [27] Berg AT, Vickrey BG, Testa FM, Levy SR, Shinnar S, DiMario F, et al. How long does it take for epilepsy to become intractable childhood epilepsy? A prospective investigation. Ann Neurol 2006;60:73–9. [28] Seker Yilmaz B, Okuyaz C, Komur M. Predictors of intractable childhood epilepsy. Pediatr Neurol 2013;48:52–5. [29] Geerts A, Brouwer O, Stroink H, van Donselaar C, Peters B, Peeters E, et al. Onset of intractractability and its course over time: the Dutch study of epilepsy in childhood. Epilepsia 2012;53(4):741–51.
Please cite this article in press as: Fangsaad T et al. Etiology, clinical course and outcome of infant epilepsy: Experience of a tertiary center in Thailand. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.10.117