Seizure disorders among relatives of Kenyan children with severe falciparum malaria
Dr C. R. J. C. Newton, Centre for Geographic Medicine Research (Coast), Kenya Medical Research Institute, PO Box 230, Kilifi, Kenya. Tel.: +254 125 25043; Fax: +254 125 22390; E-mail: firstname.lastname@example.org
purpose The cause of seizures in children with falciparum malaria is unclear. In malaria endemic areas, children who develop severe falciparum malaria with seizures may have a genetically higher risk of epilepsy or febrile seizures. We used the history of seizures in relatives of children previously admitted with malaria to determine if there is evidence for a familial predisposition of seizures in children admitted with malaria and seizures or cerebral malaria.
methods Family history of seizures were obtained from the parents/guardians of 81 children (35 children previously admitted with severe malaria and 46 children matched for age who had not been admitted with severe malaria). Data were collected on frequency, duration, age of onset, presence of fever and causes of seizures.
results The prevalence of seizures in the relatives of children not admitted with severe malaria was 4.3%, of whom 2.2% had a history of seizures compatible with febrile seizures, and 1.1% with epilepsy. Overall the odds ratio (OR) for relations of children admitted with malaria, to have a seizure disorder was 1.41 [95% confidence interval (CI) 1.06–1.88]. There was a significant risk of the relatives dying if they had epilepsy [relative risk 1.88 (95% CI 1.11–3.19)], but not for other seizure disorders (i.e. febrile, single or unclassifiable seizures).
conclusion Relatives of children admitted with severe falciparum malaria are more likely to have a seizure disorder compared with controls, but it is unclear if this is because of a genetic propensity or caused by exogenous factors such as malaria.
In malaria endemic regions, falciparum malaria is a major cause of seizures in children admitted to hospitals: it was associated with 69% of convulsions in children admitted to a Kenyan district hospital, whilst 31.3% of children admitted with a primary diagnosis of malaria had a history of convulsions (Waruiru et al. 1996). Whether these are a febrile seizure or a seizure associated with an acute encephalopathy is controversial (Newton & Krishna 1998). The incidence of seizures is higher in falciparum malaria than vivax malaria (Wattanagoon et al. 1994). Seizures may be part of the most severe form of neurological involvement – cerebral malaria (CM). More than 80% of children admitted with CM have a history of convulsions and over 50% have convulsions witnessed after admission, although many have non-convulsive seizures (Newton & Krishna 1998). The seizures in falciparum malaria are often complicated (i.e. focal, prolonged or repetitive), and complicated febrile seizures are associated with an increased risk of seizures in the relatives of probands with febrile seizures (Hauser et al. 1985).
Definitions of seizure types should be appropriate for the context in which they are used, but with the current tools it is very difficult to separate febrile from non-febrile seizures in malaria endemic areas. In endemic areas up to 83% of children in the community may have a peripheral parasitaemia (Snow et al. 1997). Infection with Plasmodium falciparum may provoke convulsions in individuals susceptible to febrile seizures and epilepsy, and precipitate admission to hospital. We used family history data to help elucidate the familial propensity of children to develop seizures as a result of falciparum malaria in this community.
Children were recruited from an ongoing study of malaria and epilepsy in a well-defined study area in Kilifi District, Kenya. This area comprises a 40-km stretch of coastline, extending 30 km inland, and is under demographic surveillance. In 2000, the resident population was approximately 74 000 people living in more than 2500 households. More than 75% of the population were Giriama, a subgroup of the Mijikenda ethnic group.
Probands were identified from a group of children previously admitted to hospital with severe falciparum malaria (cases) and children selected from the community (controls). There was no difference in the mean ages of the cases (8.9 ± 0.9 years) and controls (9.3 ± 0.9 years).
Children admitted with severe malaria (cases).
Children who were admitted to Kilifi District Hospital (KDH) with severe malaria in 1993–97 were examined when they were 6–9 years old. Two groups of children were identified:
- • cerebral malaria defined as a child unable to localize a painful stimulus, peripheral parasitaemia and the exclusion of other causes of encephalopathy, in particular, central nervous system infections (lumbar puncture) and hypoglycaemia (WHO 2000) or
- • malaria and complicated seizures (MS), i.e. more than two convulsions within 24 h, focal or prolonged, lasting > 30 min, without impairment of consciousness between seizures.
As it is likely that most (> 90%) (Newton & Krishna 1998), if not all, children with CM have epileptic discharges during their illness, these groups were merged for analysis.
Children recruited from the community (controls).
Children aged 6–9 years were randomly selected from the database of the population living in the study area. Possible subjects were excluded if they had a history of admission to hospital with severe malaria, if there was consanguinity between cases or controls, or if parents refused to be involved in the study. The study was approved by the Kenyan National Ethical Committee, as part of a larger study on the relationship between malaria and epilepsy.
Initially, the mother of each proband was interviewed about the occurrence of seizures in the family by two fieldworkers, both trained in taking family history in the local dialect. If the mother was not available, another close relative, for example, an older sibling or grandmother, was interviewed. The prospective interviewers were identified by a fieldworker at their home and visited by the investigators on the following day. The interviewers did not know to which group the proband belonged. The information was collected using a questionnaire which consisted of four parts: (i) socio-cultural information: interviewee's level of education and knowledge and beliefs about seizures; (ii) detailed family history of living or deceased relatives; (iii) history of seizures in the proband's relatives, including information on the age of onset, frequency, type, and whether it was associated with a febrile illness and (iv) possible precipitating factors, e.g. birth history, or hospital admissions. Seizure disorders were classified according the criteria suggested by the International League Against Epilepsy (ILAE 1993) into:
- • Epilepsy – two or more seizures, in which at least one seizure was not associated with a febrile illness;
- • Febrile seizure (FS) – one or more seizures associated with a febrile illness in children after 1 month of age;
- • Single seizure (SS) – single seizure not fulfilling the criteria for a FS and
- • Unclassifiable seizures which could not be classified into any of the above groups.
Relatives were categorized into first-degree relatives (father, mother and siblings), second-degree relatives (uncles, aunts, grandparents) and third-degree relatives (first cousins). Family members related by marriage only were excluded from analysis.
At the beginning of data collection, a pilot study was conducted to establish the reliability of the questionnaire. Ten probands were selected and their mothers (n = 9), paternal grandmothers (n = 5), maternal grandmothers (n = 3), aunts (n = 3), brother (n = 1) and stepmother (n = 1) were interviewed. The mothers agreed with other relatives about the number of family members in 85% of cases, but about the number of family members with seizures in only 43% of cases. Most disagreement was about deceased family members. In particular, mothers had difficulty talking about their deceased or stillborn children and sometimes did not know whether they or their husbands had had an older sibling who had died at an early age. Other relatives could often fill in these details. These discrepancies prompted us to develop the group interview used in the study, in which the information was checked by interviewing the paternal and, if possible, maternal grandmothers. Information about specific cases of epilepsy was checked through interviews with the affected relatives themselves or their guardians if they were minors. If differences in the history could not be reconciled, the data were not included in the analysis.
The data were double-entered into Microsoft FoxPro (version 3) and statistical analysis was performed using Epi-Info (version 6). The expected number of cases for each seizure disorder was determined from the lifetime prevalence in the relatives of the control children (Schildkraut 1998). The odds ratio (OR) and confidence intervals (CI) for having a relative with seizures were calculated from the ratio of the relatives in the case and control groups.
Of the 81 probands recruited to the study, 35 were children admitted previously to KDH with severe malaria at a median age of 33 months (interquartile range 20.3–37) and 46 were selected from a community database. Information on 4406 relatives was obtained: 46 steprelatives, 64 miscarriages, 57 stillbirths and two children whose fate was unknown, were excluded from further analysis. At the time of interview, 3422 (80.7%) people were alive. Information about the occurrence of seizures was unavailable for eight relatives from the case group and 18 of the controls, and these were excluded from the analysis. Accurate ages could only be determined in 56.3% of the subjects with seizures. The groups were similar in that there was no difference in the ratio of the number in each generation to the proband (Table 1). Also, there was no difference between the ages of the generations of each group, in whom it could be determined.
Table 1. The number of relations with seizures in children admitted with severe malaria (cases) compared with community controls
|Probands||35|| || 31 (88.6)||46|| ||6 (13.0)|| |
|Parents||69||2.0||6 (8.7)||90||2.0||5 (5.6)||1.62 (0.41–6.46)|
|Siblings||176||5.0||28 (15.9)||209||4.5||23 (11.0)||1.53 (0.81–2.88)|
|Grandparents||132||3.8||3 (2.3)||174||3.8||1 (0.06)||4.02 (0.37–101.5)|
|Aunts and uncles||466||13.3||31 (7.0)||542||11.8||28 (5.2)||1.31 (0.75–2.29)|
|Cousins||1023||29.2||43 (4.2)||1245||27.1||40 (3.2)||1.32 (0.83–2.10)|
|Total*||1866|| ||111 (5.9)||2260|| ||97 (4.3)||1.41 (1.06–1.88)|
Overall the OR for relations of the cases to have seizures was 1.41 (95% CI 1.06–1.88). There was no significant risk of seizure disorders in first-degree relatives (OR 1.56; 95% CI 0.89–2.74), second-degree relatives (OR 1.43; 95% CI 0.84–2.44) (Table 1). There was no difference in the prevalence of seizures between males and females in either proband group, or between the maternal and paternal side of the family in the exposed group.
A total of 4.3% of the relatives of the controls had a history of at least one seizure, of whom 2.2% had a history of seizures compatible with FS, and 1.1% with epilepsy. The proportion varied with the generation (Table 2). The prevalence of lifetime epilepsy was 30/1000 in children (probands and siblings) and 12.7/1000 in adults (parents, aunts and uncles). The prevalence of FS was 53.5/1000 in children and 25.3/1000 in adults. There was a significant risk of the relatives dying if they had epilepsy (RR 1.88; 95% CI 1.11–3.19), but not for other seizure disorders (i.e. FS, SS or unclassifiable seizures).
Table 2. Distribution of seizure disorders amongst relatives of children admitted with severe malaria (cases) compared with community controls
|Aunts and uncles||465||13||9||6||3||542||7||15||0||6|
|Total|| ||32||55||9||46|| ||25||50||5||23|
Detailed information on 148 seizures of the relatives of the probands was obtained. The most frequent seizure types were partial becoming generalized and tonic–clonic convulsions (Table 3). There was no difference in proportion of seizure types between relatives of cases and controls. Only 4% of people with epilepsy were on antiepileptic drugs.
Table 3. Distribution of seizure types in relatives of children admitted with severe malaria (cases) compared with community controls
|Simple partial||1||0||1 (0.7)|
|Complex partial||5||6||11 (7.4)|
|Partial becoming generalized||35||34||69 (46.6)|
|Febrile seizure||2||2||4 (2.7)|
Overall, relatives of children admitted with neurological manifestations of severe falciparum malaria are more likely to have seizures than the relatives of the children in the community, but the ratio is small. However, this data needs to be interpreted carefully and does not necessarily support a genetic propensity to developing seizures in response to malaria.
There are a number of pitfalls in determining the familial component of seizures (Annegers et al. 1982). We used standard classifications of seizures and recruited a comparison group of children who were randomly selected from the population, using current census data. But this study needs to be interpreted in the context of recall bias and lack of information about the ages of the subjects. Incomplete recall decreases the ascertainment of seizures. We relied on the recall of convulsions in the family by mothers and other family members. Thus, the low incidence of febrile seizures in the grandparents and the reduction in frequency of seizures with increasing distance of relationship may reflect greater difficulties of recollection, rather than a reduction in genetic propensity.
Age influences the cumulative incidence rates of seizures (Sander & Shorvon 1996). In this society it is difficult to establish age of a subject reliably, particularly when the subjects are over 20 years of age. However, the relations of the two groups of children had the same ratios of generation to the probands and there was no age difference between those for whom it was known. Thus, the significant difference in the lifetime incidence is not likely to be caused by differences in age.
Although the relatives of children admitted with severe malaria had a significant risk of seizure disorders overall, the OR, an estimate of relative risk was < 2, which does not support a strong genetic component, but does not exclude it either (Farrer & Cupples 1998). Other explanations of the increased incidence include, better recall of seizures by families who had a child admitted to a research unit; increase in the number of other family members who had an episode of severe falciparum malaria or suffer from brain damage as a result of malaria; and/or the inheritance of other conditions such as learning difficulty, which is a risk factor for a high rate of seizures. We have assumed that all relatives in this malaria endemic region are likely to have similar exposures to malaria, as nearly all the inhabitants develop immunity to severe disease by the age of 10 years (Snow et al. 1997).
These data provide an estimate of the minimum prevalence of seizures in this community. The higher prevalence of lifetime epilepsy (12.7/1000 in adults) we found compared with that of an earlier study in the same area (4/1000) (Snow et al. 1994) probably reflects a difference in methodology rather than an increase in lifetime prevalence of epilepsy in the general population. The latter study relied on key informants who identified individuals with generalized tonic–clonic convulsions, known in the vernacular as kifafa or vitsala. Our study asked detailed questions about each member of the family and used at least two members of the family as sources of information. The lifetime prevalence in this study is higher than the average from a number of studies across the world (Sander & Shorvon 1996). The higher prevalence of febrile seizures (53.5/1000) in children compared with Western countries (32/1000) (Hauser & Kurland 1975), may reflect the greater exposure of these children to infections, including malaria, compared with other areas. Most of the seizures were tonic–clonic or partial becoming generalized. The lack of absences and other types of partial seizures may reflect difficulty in recognizing of these seizure types in poor rural communities (Newton & Gero 1984).
The increased mortality of people with seizures is well documented, and our data suggest that the risk is further increased in Africa. The increase in mortality may have further contributed to reduction of seizures reported in the older age groups, although poor recall is also likely. Mortality may be reduced with treatment, education about the risks of epilepsy.
In conclusion, we found an increased frequency of seizures in relatives of children admitted with severe falciparum malaria in a community with a high prevalence of epilepsy and febrile seizures. The latter may contribute to the increase incidence of seizures in falciparum malaria, but whether this increase is caused by genetic or environmental factors is unclear. Our study highlights the methodological problems of using seizure definitions, developed in settings other than tropical Africa. This requires further investigations, possibly by a long-term follow-up a cohort, examining the impact of an intervention against malaria and more detailed genetic studies.
This study was supported by grants from the Dutch National Epilepsy Fund, the Spinoza Fund and the Wellcome Trust. Dr C.R.J.C. Newton holds a Wellcome Trust Career Post in Tropical Medicine (050533) and J. Carter, a Wellcome Trust Prize Studentship (No. 059336). We are grateful to L. Mitsanze (KEMRI) for fieldwork, R. Odhiambo (KEMRI) for data-processing, V. Odera Mung'ala (KEMRI) for demographic support and Dr C. Bartels (Kenyan Association for the Welfare of Epileptics, Nairobi) for her advice on the questionnaire. We thank Dr A. Scott and Amanda Ross for advice on the analysis, and Professor J.A.W. Sande for helpful comments on the manuscript. This work is published with the permission of the Director of KEMRI.