Febrile Seizures in Rural Tanzania: Hospital-based Incidence and Clinical Characteristics

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1 JOURNAL OF TROPICAL PEDIATRICS, VOL. 59, NO. 4, 2013 Febrile Seizures in Rural Tanzania: Hospital-based Incidence and Clinical Characteristics by Andrea S. Winkler, 1,2 Anthony Tluway, 2 and Erich Schmutzhard 3 1 Department of Neurology, Technical University of Munich, Munich, Germany 2 Department of Pediatrics, Haydom Lutheran Hospital, Mbulu, Manyara, Tanzania 3 Department of Neurology, Medical University of Innsbruck, 6020 Innsbruck, Austria Corresponding author: Andrea S. Winkler, Department of Neurology, Klinikum rechts der Isar, Technical University Munich, Ismaninger Strasse 22, Munich, Germany. Tel: þ Fax: þ <drawinkler@yahoo.com.au>. Summary Objective: Febrile seizures may contribute to epilepsy later in life, but data in sub-saharan Africa are scarce. We, therefore, conducted a hospital-based study on clinical characteristics of children with febrile seizures. Methods: Over 2 years, we screened all pediatric admissions of Haydom Lutheran Hospital, northern Tanzania, and recruited 197 children with febrile seizures. Results: The incidence of febrile seizures was 4% of all admitted children aged <10 years, with a mortality of almost 4%. The peak age at the first febrile seizure was 2 years. One of five children experienced repeated episodes, and the majority of children showed features of complex seizures. Approximately 20% of children had a positive family history of febrile seizures or epilepsy. Conclusion: Febrile seizures represent a frequent cause for admission of children, bearing a rather high mortality. Most children exhibit complex febrile seizures, which may contribute to the development of epilepsy later in life. Key words: febrile seizures, complex febrile seizures, hospital incidence, mortality, concomitant disease, lumbar puncture. Introduction Febrile convulsions or rather its complex type has been implicated in the pathogenesis of epilepsy [1]. In sub-saharan Africa, the prevalence of epilepsy seems to be higher compared with high-income countries. A recently conducted community-based study from northern Tanzania (same study area as the present Acknowledgments The authors are very grateful to the patients, staff and all other supporters of Haydom Lutheran Hospital, especially to the late managing medical director Dr Ole Halgrim Evjen Olsen. The authors also are very indebted to all the children and their parents who spared time to answer their lengthy protocol. Funding This work was supported by the Centre for International Migration (CIM), Frankfurt, Germany. The authors have no conflicts of interest. study) shows a point prevalence of epilepsy of 11.2/ 1000 (95% confidence interval: /1000), with an age-adjusted rate of 13.2/1000 [2]. This compares with high-income nations, where the prevalence of epilepsy is estimated to be 4 8/1000 inhabitants [3]. A case control study from southern Tanzania identified four major risk factors for later epilepsy, i.e. a positive family history, neonatal/intrapartum complications, infections of the central nervous system and febrile seizures. The odds ratio of the latter was 2.9 [4]. The risk for febrile seizures to cause epilepsy later in life was even higher in a Nigerian study and a recent Kenyan study, with odds ratios of 11 and 14.6, respectively [5, 6]. However, the relationship between febrile convulsions and later epilepsy is still a matter of debate. Complex febrile seizures may cause epilepsy and have anecdotally been reported to be more common in sub-saharan Africa compared with high-income countries, but studies on the characteristics of febrile seizures in sub-saharan Africa are scarce. The present hospital-based study of northern Tanzania was designed (i) to determine the incidence ß The Author [2013]. Published by Oxford University Press. All rights reserved. For Permissions, please journals.permissions@oup.com 298 doi: /tropej/fmt022 Advance Access published on 24 April 2013

2 and mortality of febrile seizures over a period of almost 2 years, (ii) to describe their clinical characteristics and (iii) to assess associated illnesses and histories of the children suffering from febrile seizures. Methods Research setting The study was conducted at the Haydom Lutheran Hospital, a midsize hospital (350 beds), in the village of Haydom in northern Tanzania, Manyara region, Mbulu district. The total immediate catchment area of the hospital comprises people, and the total greater reference area is extrapolated to people [7]. The population mainly belongs to two tribes, the Iraqw and Datoga people of Cushitic and Nilotic origin, respectively. Most of the Iraqw are subsistence farmers, the staple food being maize, and the Datoga are agropastoralists. The hospital The hospital runs a surgical, medical, tuberculosis, pediatric and maternity ward, and provides an observation intensive care unit. The diagnostic resources of the hospital are limited. The laboratory services include basic tests like hemoglobin, erythrocyte sedimentation rate and blood glucose as well as stool and urine examination. Thick blood films ( blood slides ) are frequently performed in search of malarial parasites. The cerebrospinal fluid (CSF) is examined for cell count, types of cells, sugar and protein. Basic microbiology has recently been established. In terms of imaging, there was only a conventional X-ray machine available at the time of our study. Recruitment of patients The pediatric ward, which allows for 70 children, was visited daily between 4 September 2002 and 25 June 2004 by a clinical officer who preselected the patients and a neurologist who saw all the patients with febrile seizures. A febrile seizure was diagnosed in a child aged 1 month [8] to 7 years [9, 10] who had an epileptic seizure associated with fever without further evidence of intracranial infection. Children with epilepsy, i.e. a medical history of previous non-febrile epileptic seizures, those with previous neurological signs and/or mental retardation and those with previous neonatal seizures (within the first month of life) were excluded, and so were cases of cerebral malaria, i.e. the child had to regain consciousness within 6 h after the epileptic seizure, and those of meningitis (based on clinical examination and CSF results; [11]). Complex febrile seizures were defined as seizures with a long duration (>15 min), focal seizures or those recurring within 24 h [9, 10, 12]. Demographic information, medical history, history of previous febrile seizures, details of the current episode of febrile seizures (number, frequency, duration and semiology), results of physical examination on admission and at regular intervals during the period of admission and laboratory results were documented in an especially designed questionnaire. Ethical clearance Ethical clearance was obtained from the National Institute of Medical Research), and the study was cleared by the Tanzania Commission for Science and Technology. Oral informed consent from the parents to document clinical data of their children was also obtained. Results Hospital incidence and demographic details Two hundred eleven children were originally included into the study. Fourteen children had to be excluded: six children were outside the age limit, two had neonatal seizures, two showed mental handicap and four children died before they could be seen. Therefore, all the results are based on 197 children. The calculated hospital incidence was 9.7/1000 for all patients (number of people admitted to the hospital during the study period: ) and 37.9/1000 for children aged <10 years (number of children admitted: 5200). The mortality was 35.5/1000 (7 of the 197 children died). One child had gastroenteritis, five pneumonia and one gastroenteritis and pneumonia. One hundred ninety children left the hospital without neurological sequelae. The average age of the admitted children was years, with a male to female ratio of 1.3 : 1. The peak age was in the second year of life. Table 1 shows the exact distribution of age. The age at the first febrile seizure (the current episode for 163 children, a previous episode for 34 children) was similar to the average age of the admitted children ( years). Children reached the hospital after h, traveling km. The average hospital stay was days; 47 children (24.0%) were admitted for longer than 1 week. The average costs were US dollars (income per capita per year: US dollars 340 in 2005; [13]). Characteristics of febrile seizures The frequency of febrile seizures of the current episode was known from 183 children and yielded attacks. Seventy percent of children (128/183) had > 1 seizure; three children had > 10 febrile seizures. Referring to 24 h, 65% of children (119/183) had more than one febrile seizure, and therefore had complex febrile seizure. Reliable details regarding duration were available from 154 patients and refer to the first febrile seizure of the present episode only. The average duration was min. Nine children had seizures that Journal of Tropical Pediatrics Vol. 59, No

3 TABLE 1 Age distribution within the study population Age (months) Total (%) Unilateral seizures Female (F; %) 2 98 More than one seizure within 24 h Duration >15 Min FIG. 1. Children with complex febrile seizures. Each of the three subgroups (unilateral seizures, duration of seizures >15 min and repeated seizures within 24 h) is presented separately and in association with the other subgroups. lasted longer than 15 min, of which four children had attacks of 30 min and longer. Regarding focal signs, there was information on 189 children, of which 30 children (15.9%) showed unilateral and therefore complex febrile seizures. Altogether, 135/189 children (71.4%) of whom information was available had signs of complex seizures, as some children had more than one complex feature. For more details, see Fig. 1. Symptoms and signs associated with febrile seizures Complaints on admission consisted mainly of general signs, including fever (28.7%), respiratory symptoms (27.0%), neurological complaints including febrile seizures (24.2%) and gastrointestinal symptoms (20.1%; Table 2). There was an average of days of fever before the first febrile seizure. Three children had fever for 1 week before the first febrile convulsion. In 18 children, fever became evident at the time of the febrile seizure. Actual temperature and speed of increase were not known. On 4 Male (M; %) 3 M/F ratio (15.7) 20 (23.3) 11 (9.9) 0.6: (35.0) 32 (37.2) 37 (33.3) 1.2: (21.8) 16 (18.6) 27 (24.3) 1.7: (13.2) 8 (9.3) 18 (16.2) 2.3: (7.6) 7 (8.1) 8 (7.2) 1.1: (6.6) 3 (3.5) 10 (9.0) 3.3:1 197 (100) 86 (43.7) 111 (56.3) 1.3:1 Symptom/sign TABLE 2 Complaints on admission Frequency (n ¼ 707) Fever 176 General weakness 21 Refuses to eat or suck 4 Rash 2 Cough 104 Cold 58 Dyspnea 26 Coryza 3 Febrile seizures 141 Headache 25 Impairment of 5 consciousness Vomiting 80 Diarrhea 57 Vomiting and diarrhea 5 Grouped symptoms/signs General signs 203 (28.7%) Respiratory symptoms 191 (27.0%) Neurological symptoms 171 (24.2%) Gastrointestinal symptoms 142 (20.1%) examination, which in most cases was performed on the next day, diagnoses mainly pertained to the respiratory and gastrointestinal tract (Table 3). Blood smear for malaria was performed in 184 children (93.4%). Malarial parasites were present in 71 of 184 children (38.6%), Borrelia duttoni in 2 and malarial parasites and B. duttoni in 1. Analysis of CSF was performed in 61 children (31%) and was unremarkable in all of them. Medical and birth history Of 197 children, 34 (17.3%) had previous episode of febrile seizures. On average, there were episodes, with seizures per episode. Of 34 children, 9 (26.5%) had recurrent seizures within 24 h. Unilateral febrile seizures and seizures lasting for longer than 15 min were reported by four children each (11.8%). Altogether, 13 of 34 children (38.2%) had complex febrile seizures in their previous episodes. Information on pregnancy was collected in 133 children. There was pre-eclampsia, severe malaria and hepatitis in one pregnancy each. Information on birth history was present in 140 children. Cesarean section was performed in four women. In two children, birth was precipitated, and in seven, prolonged. Two children were premature. One child was described as floppy, two as blue, who needed oxygen, and two as yellow. There were two twin births. In one pregnancy, the second twin was retained for 24 h, and in the other pregnancy, one twin had an intrauterine infection. Family history Information on family history was collected from 189 of 197 children (95.9%). Thirty-nine children (20.6%) had a history of epileptic seizures within their families. Of those, 22 children (56.4%) had 300 Journal of Tropical Pediatrics Vol. 59, No. 4

4 TABLE 3 Diagnoses on examination Diagnoses Frequency (n ¼ 370) Grouped diagnoses Upper respiratory tract infections 151 Pneumonia 51 Dyspnea (no reason obvious) 11 Respiratory tract 214 (57.8%) Pneumothorax 1 Gastroenteritis % Fever of unknown origin % Malaria 14 Conjunctivitis 3 Varicella 2 Infectious diseases 21 (5.7%) Viral infection 1 Cellulitis 1 Sickle-cell disease 2 Anemia 2 Hematological disorders 4 (1.1%) Impairment of consciousness 2 0.5% Epistaxis 1 0.3% No symptoms at time of examination % TABLE 4 Distribution of epileptic seizures within relatives of affected children Degree of consanguinity Overall epileptic seizures Febrile seizure Epilepsy Epileptic seizure (not further classified) Mother 5 5 Father 2 2 Siblings Grandparents 1 1 Uncle, aunt Half-siblings Total relatives with a history of febrile seizures; one relative reported febrile seizures and epilepsy. Eighteen children (46.2%) had relatives with epilepsy or epileptic seizures. Epileptic seizures had stopped in 14 relatives; four relatives still had epileptic seizures at the time of the interview. For the exact distribution of the epileptic seizures, see Table 4. Discussion The current study conducted in almost 200 children with febrile seizures delivers important clinical data from a low-income country within sub-saharan Africa. The hospital-based incidence of febrile seizures among all patients admitted during the study period was almost 1%. When considering admitted children alone, it was almost 4%. This compares with incidence rates of febrile seizures within neurological inpatient populations of 11.2% (Tanzania, same hospital setting as the present study; [14]) and 26.9% (Zambia; [15]). The incidence of febrile seizures in our population of children may represent an underestimation, as we excluded children with mental handicap and/or focal neurological signs from the study population a priori, despite them having no history of afebrile epileptic seizures. In children with mental handicap, it is difficult to ascertain whether these children suffer from febrile seizures or whether fever has precipitated epileptic seizures caused by structural brain lesions. In our study, children with febrile seizures showed a high mortality of 3.6% owing exclusively to concomitant respiratory and gastrointestinal infections. Nine children had seizures of longer duration (>15 min); none of these children died. This is contrary to high-income countries, where febrile seizures are viewed as a benign condition, with low mortality in most cases [10, 16]. Most children in our study population had their first febrile seizure in their third year of life. This is supported by a prospective cohort study from Denmark, which found a similar age span in children with febrile seizures [17]. We found a preponderance of boys, which was confirmed in another African study [18]. This may be due to sociocultural factors, as results from high-income countries are inconclusive [10, 19, 20], with a clear preponderance of girls in a recent prospective cohort study from Finland [21], a preponderance of boys among black children, but not among white children, in a prospective cohort study from North America [10], a preponderance of boys in a prospective epidemiological study [20] and no preponderance at all in a prospective cohort study from the UK [19]. Journal of Tropical Pediatrics Vol. 59, No

5 The percentage of children with complex febrile seizures in our study population was high. Long-lasting, focal and/or recurrent febrile seizures may lead to structural damage of the brain or point to an insult to the brain that has already taken place. This should not be confused with focal epileptic seizures provoked by fever in children with premorbid brain lesions. Those children were excluded from our study. In the context of complex febrile seizures, there is some evidence that they may be associated with hippocampal sclerosis [22, 23]. Whether febrile seizures may lead to epilepsy later in life is still controversial. Some authors did not find any evidence for a causative relationship between febrile seizures and temporal lobe epilepsy [24, 25], while others did, especially with prolonged and focal febrile conclusions [26]. An evaluation of well-designed largescale studies results indicates that 2 10% of children with febrile seizures will develop unprovoked epileptic seizures later in life. This mainly applies to children with complex febrile seizures, while there only seems to be a small risk of developing epilepsy after simple febrile seizures [1, 9, 27, 28]. Among complex febrile seizures, especially those of the focal type or longer duration and including febrile status seem to bear an increased risk [27, 29]. Referring to the above, a frequency of 70% of complex febrile seizures in our study population seems rather worrying. Although the prevalence of epilepsy in countries of sub-sahara Africa is 2- to 3-fold higher than that in high-income countries (see Introduction section), this does not necessarily imply causality, as causes for epilepsy in sub- Saharan Africa are varied, and besides, febrile seizures include perinatal risk factors, cerebral infection and trauma among others. Interestingly, studies from North America show that there is an increased risk for febrile seizures among black American children [10], but that the development of unprovoked seizures after febrile seizures is independent of race [9, 28]. Also, one has to consider that the result of a high prevalence of complex febrile seizures in our study may represent a bias, as only those children with complex febrile seizures might be brought to the hospital. Compared with a hospital-based study from North America ([30]; 35% complex seizures of the first febrile seizure and 33% of recurrent febrile seizures), the proportion of children with complex seizures in our study seems high. Population-based African studies report a much lower prevalence of complex febrile seizures of 39% in an urban area and 47% in a rural area of Nigeria [31], pointing to some over-reporting of complex febrile seizures in our study population. There is accumulating evidence of a genetic predisposition of children who experience prolonged febrile seizures. Recent data suggest an involvement of interleukin-1 in the genesis of febrile seizures and has linked interleukin-1 gene polymorphism with prolonged febrile seizures and mesial temporal lobe epilepsy [32, 33]. It has been known for some time that a positive family history for febrile seizures represents a risk factor for febrile seizures in the offspring [18, 34, 35]. A recent large-scale study from Denmark has shown that the etiology of febrile seizures depends on a genetic susceptibility that can be transmitted through both parents [17]. In our study, we found that 20% of children with febrile seizures had a positive family history regarding febrile seizures and/or epilepsy. This is in contrast to the low incidence of positive birth and medical histories in the children of our study. Significant medical events rather seem to represent risk factors for later symptomatic focal epilepsies, although some studies have shown prematurity, low birth weight and problems during gestation and delivery to be significant risk factors for febrile seizures [17, 34, 36]. To date, the significance of the actual temperature, the speed of increase of temperature, duration of fever and the pathogens causing the temperature is unclear [12]. Low fever has been associated with complex febrile seizures [30]. We cannot comment on the actual degree of temperature as contributor to complex febrile seizures, as this information was not at hand. Interestingly, in children with febrile seizures, viral infection seems to be of special significance [12, 37, 38]. Specific viruses, such as human herpes virus 6, have been implicated in the genesis of febrile seizures through possible mechanisms of focal cerebral inflammation [39, 40]. In our study area, which is only mesoendemic for malaria, respiratory infections were the most frequent associated disease, followed by gastroenteritis, fever of unknown origin and malaria in that order. Respiratory tract infections seem to be the leading cause for febrile seizures cross-culturally outside malaria holo-/hyperendemic areas [10, 12, 34, 41], where malaria is the leading cause [18]. In our study population, a diagnosis of clinical malaria was made in 14 of 197 patients (11.2%). Seizures in the context of malaria have to be interpreted with care and may represent cerebral malaria, febrile seizures or seizures associated with uncomplicated malaria independent of whether fever is present [42]. Seventeen percent of the children in our study had previous episodes of febrile seizures, with 38% of them having complex seizures. The much lower prevalence of complex seizures during previous episodes compared with the present one may be due to memory waning over time. Throughout high-income countries, the risk of recurrence of febrile seizures is approximately one in three [10, 19, 43] and has been associated with shorter duration and lower temperature before the initial febrile seizure, age <18 months and a positive family history [19, 43]. Recurrent febrile seizures have been implicated as a risk factor for later unprovoked seizures [28]. Whether the occurrence of complex febrile seizures as initial 302 Journal of Tropical Pediatrics Vol. 59, No. 4

6 seizures increase the risk of recurrence is controversial [1, 10, 19, 43] and is not supported by our data. The performance of lumbar puncture has been a much debated issue in children with febrile seizures, and is not recommended as routine procedure but rather reserved for selected cases such as children aged <18 months, those with symptoms and signs suspicious of meningitis, those with a first complex febrile seizure, those with prolonged lethargy and those who have already received antibiotic therapy [41, 44 46]. Following these guidelines, in our study, 31% of children admitted with febrile seizures qualified for lumbar puncture. This is in keeping with results from a prospective cohort in the UK, where 31% of all children with febrile convulsions admitted to hospital underwent lumbar puncture, but 47% of those who presented with complex febrile seizures [19]. However, it has to be considered that in sub- Saharan Africa, with high prevalences of bacterial meningitis, lumbar puncture in all children with fever and convulsions may have a place [47]. It is the author s (A.S.W.) personal experience that in rural areas, the need for lumbar punctures in children with fever and convulsions is met with suspicion based on sociocultural beliefs, and therefore is hardly performed. Instead, these children will routinely be given antimalarial medication and standard antibiotics, which is not in line with good clinical practice. In summary, there is a high incidence of febrile seizures in children admitted to hospital in rural Africa. Compared with high-income countries, it seems not a benign disease, bearing a high mortality and, in the majority of cases, demonstrating complex features, with the implication of development of epilepsy later in life. 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