Published online July 2, 2007
PEDIATRICS
Vol. 120
No. 1
July 2007, pp.
e52-e55
(doi:10.1542/peds.2006-3290)
Preventable and Unpreventable Causes of Childhood-Onset Epilepsy Plus Mental Retardation
Carol Camfield, MD and
Peter Camfield, MD
Department of Pediatrics, Dalhousie University, and the IWK Health Centre, Halifax, Nova Scotia, Canada
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ABSTRACT
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OBJECTIVE. The objective of this study was to determine the causes of childhood epilepsy associated with mental retardation and determine whether these causes are preventable.
METHODS. We selected all patients from the Nova Scotia population-based childhood epilepsy cohort (n = 692) who had mental retardation and had epilepsy onset between 1977 and 1985. Causes and family history were determined by chart review and caregiver interview after 18.8 (SD: ±7) years of follow-up.
RESULTS. Overall, 147 patients had mental retardation and epilepsy (21% of all childhood epilepsy). Standard psychological testing was available for 57%; 38.5% were too impaired for testing, which left 4% with the degree of mental retardation assessed clinically. Severe/profound mental retardation predominated (mild: 24%; moderate: 23%, severe/profound: 53%). Fifty-nine percent had additional severe neurologic deficits, most often associated with severe mental retardation. Epilepsy syndromes were symptomatic generalized (n = 73), partial (n = 58), and other (n = 16). Most had a brain imaging study: 91% had a computed tomography scan, and 12% had an MRI scan. Sixty-three percent had a defined cause; 37% had an unknown cause. A defined cause was more likely in those with severe mental retardation (60 of 78 vs 31 of 65). Identified causes were prenatal or genetic (65%), perinatal (8%), or complications of prematurity (13%). Only 11 (7%) had an acquired cause that was potentially preventable. Many (36%) had a first- or second-degree relative with epilepsy, more often in those without a clear cause (54% vs 30%) and without additional neurologic disability (57% vs 26%).
CONCLUSIONS. Approximately 20% of children with epilepsy have mental retardation. The cause is prenatal or genetic in nearly two thirds, and only 7% have an acquired, preventable cause. Important genetic influences may be present, especially in the absence of a defined cause.
Key Words: epilepsy • children • mental retardation • etiology • epidemiology
Abbreviations: MR—mental retardation
Of people with mental retardation (MR), 15% to 20% have epilepsy, with the risk even higher in those with severe mental disability.1 When children with epilepsy are considered, it has been estimated that 20% to 30% have mental retardation.1–3 When epilepsy is combined with mental retardation, the chance of seizure control and remission is reduced.4,5 Even when the seizures come under control or remit, the MR means a life of dependency. In this article, we define the causes of this distressing combination and consider how often it might be potentially preventable.
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METHODS
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Patients with MR were selected from the Nova Scotia childhood epilepsy study. Details of the methods for this population-based cohort have been published elsewhere.4 In brief, the study used a central electroencephalogram reading facility as an initial case-finding method because it seems that all children with seizures in the Nova Scotia are referred for an electroencephalogram. Detailed case review with physician and hospital chart review and direct patient contact allowed identification of all of the children who developed epilepsy (2 or more unprovoked seizures) in this population between 1977 and 1985. At the time of case ascertainment, the population of Nova Scotia was 
850000. Patients were then followed up in 2003–2005 by chart review, telephone contact with caregivers, and personal contact. For patients who could not be recontacted at that time, we used chart information up to the time of last contact. For patients who died during follow-up, chart information was used up to the time of death supplemented with telephone interviews with caregivers. Patients were excluded when they had progressive neurodegenerative metabolic disorders or brain tumors.
Mild MR was defined as a measured or estimated IQ of 50 to 70, moderate MR as IQ of 35 to 49, and severe/profound MR as IQ of <35. The degree of MR was determined by standard psychological testing or clinical judgment as late in the follow-up as possible. Epilepsy syndromes were defined as per the 1989 International League Against Epilepsy system.6 Cause was defined using the proposed system of the International League Against Epilepsy published in 2000 with some modifications. This classification system groups causes under 12 major categories. We used only 10 of these categories because we excluded patients with progressive metabolic disorders and cerebral neoplasms (Table 1). We acknowledge that some of the categories in this proposed classification are broad and not easily defined (eg, "prenatal suspected"). The cause of the MR/epilepsy combination was based on all of the information that was available up to the time of last contact. When the cause was unclear, both authors reviewed the case and arrived at a consensus. Family history of epilepsy was determined from physician charts but always confirmed directly with the parents for those whom we were able to contact in 2003–2005. The attribute "preventable" was determined by consensus and based on currently available prevention methods, rather than on only those that were available at the time of onset of epilepsy. For example, a child with epilepsy and MR from Haemophilus influenzae meningitis in the prevaccine era was considered to have a preventable cause.
This study was approved by the IWK Health Centre Research Ethics Board. Statistical analysis was performed by using standard 
2 and t tests.
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RESULTS
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Of the 692 children who had epilepsy and make up the entire cohort, 147 (21%) were found to have MR. There were 70 girls and 77 boys with an average age of onset of epilepsy at 38 months (median: 18 months; range: 1–195 months). Forty-four percent had their first seizure in the first year of life. The average follow-up from first seizure to last contact was 18.8 ± 7 SD years. The average age at the end of follow-up was 21 ± 8 years. Twenty-nine children died during follow-up at an average age of 12 years (range: 1.4–30.0 years). The 118 survivors had an average follow-up of 20.6 ± 6 years.
The presence of MR and its degree were established by standard psychological testing in 57%. Thirty-nine percent were too impaired for testing (all severe/profound MR), leaving only 4% with the degree of MR assessed clinically by physicians. The degree of MR was significantly skewed to the more severe: 53% had severe/profound MR, 23% had moderate MR, and 24% had mild MR. In none of the patients was there clear evidence that the seizures caused the MR. Eight were judged clinically to have normal intelligence at onset and later were found to have mild MR by standardized psychological testing; however, 5 of these patients were younger than 2 years at onset, and the remaining 3 were younger than 5 years at onset. Overall, 85 (58%) had additional neurologic deficits that were judged to be severe enough to interfere with activities of daily living. Not surprising, these neurologic deficits were significantly more common in those with the most severe MR. Of those with mild, moderate, and severe/profound MR, 34%, 29%, and 81%, respectively had neurologic deficits (P < .0001; Table 2).
Epilepsy syndromes at onset were symptomatic localization-related (focal or partial) in 58 (39%), symptomatic (secondary) generalized in 81 (55%), and other syndromes in 8 (5%). Nearly (91%) all patients had a brain computed tomography scan, but only 12% had an MRI, reflecting the era when seizures began in this cohort.
Overall, 93 (63%) had a presumed cause, more commonly identified in those with severe/profound MR compared with lesser degrees of MR (P < .001). The coexistence of a severe neurologic disability also was associated with a much higher chance of identifying a cause (64% vs 18%; P < .0001). The cause was considered to be prenatal or genetic in 60 (64.5%), perinatal in a term infant in 7 (7.5%; all with later severe neurologic deficits), and related to complications of prematurity in 12 (12.9%). Overall, 14 (15%) were considered to have a postnatally acquired cause. Specific causes are outlined in Table 1.
A potential genetic influence for the development of epilepsy was apparent in many of these patients (Table 2). Fifty-two (35%) had a first- or second-degree relative with epilepsy, but none of these relatives had a known autosomal dominant disorder that was expressed by the proband. Patients without a defined cause for their epilepsy and MR were significantly more likely to have a positive family history for epilepsy in a first- or second-degree relative than those with a known cause (25 of 54 [46%] vs 27 of 93 [29%]; P = .035). This relationship strengthens when the causes of "primary generalized epilepsy" and "other genetic" are considered as cause unknown (29 of 58 [50%] vs 23 of 89 [26%]; P = .003).
Only 11 (7%) cases were judged to have a potentially preventable cause: 1 maternal midtrimester electrocution, 3 bacterial meningitis, 3 head injury, 1 fetal alcohol syndrome, 1 anoxia after cardiac surgery, 1 anoxia with bronchiolitis, and 1 toxicity from intrathecal methotrexate. There was no statistical relationship between the degree of MR and the presence of a preventable cause.
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DISCUSSION
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There are 3 main findings from our population-based cohort study. First, 20% of children who develop epilepsy will have MR, most often severe/profound. Second, these children have a variety of epilepsy syndromes with a slight predominance of secondary generalized epilepsies. Third, a cause can be ascertained in nearly two thirds, usually a prenatal or genetic cause, but the cause is rarely preventable.
The rate of MR in this study is similar to that noted in the few other published epilepsy incidence studies.1,7 For example, Wakamoto et al2 noted that 49 (32%) of 155 of long-term survivors of childhood epilepsy in 1 rural district in Japan had some degree of MR. In Finland, a 14-year follow-up of all births in 1966 in 2 provinces showed that 21% of those with at least a single unprovoked seizure had MR.3 Prevalence studies tend to find higher rates of MR, reflecting that epilepsy with MR tends to be more resistant to treatment and less likely to remit.8,9
The epilepsy and MR seemed to have the same cause, and we did not encounter children in whom the MR was clearly caused by the epilepsy. For children who were younger than 2 years, physicians have difficulty accurately assessing intelligence, particularly mild MR.10 Because nearly 45% of our patients had the onset of their epilepsy in the first year of life, it is difficult to decide whether the epilepsy exacerbated a preexisting intellectual deficit. For older children, especially with moderate to severe MR, we were unable to exclude a worsening of their MR from seizures because serial standardized psychometric testing was rarely available.
The finding that 36% had no clear cause for their epilepsy–MR may have been influenced by the investigations that were undertaken. Our patients developed epilepsy in an era when MRI scanning had not been developed and even computed tomography scanning was in its early days for routine clinical use. During follow-up, few patients underwent MRI scans, probably because by the time routine MRI was available, the children would have required an anesthetic for the test. In the face of stable MR, there may have been reluctance to subject the child to the risks of an elective anesthesia. The yield for unsuspected significant abnormalities on MRI in children with epilepsy and MR has not been reported; however, 3% to 4% of clinically normal children with epilepsy have been noted to have important, causative MRI findings.11 Nearly all of our patients were cared for at some point by a child neurologist, and the diagnosis was questioned as new information became available; however, some tests with the potential to reveal an unsuspected diagnosis, such as very complex cytogenetic analysis, were not routinely undertaken.12 We conclude that the rate of "no cause" could be reduced further by more extensive investigations.
The cause for the MR/epilepsy combination was prenatal or genetic in 65% of cases. Approximately 36% had no clear cause, especially when the MR was mild. If those with no cause had been further investigated, then we suspect that any additional causes would have fallen into the prenatal or genetic categories. Genetic causes seem particularly likely because those with no clear cause had such a high rate of first- or second-degree relatives with epilepsy (50%). Very few of these patients had a postnatal cause for their neurologic disorder, and only a tiny fraction (7%) had a prenatal or postnatal preventable cause (Table 2).
The distribution of causes for epilepsy and MR is likely in part related to socioeconomic and geographic influences.13 For example, tuberculous meningitis or cerebral malaria are extremely rare in Nova Scotia but common in many countries and may be a major cause of epilepsy and MR. Therefore, from the perspective of the entire world, there may be greater potential for prevention of epilepsy and MR. The perspective of Nova Scotia is that of northern North America and relative affluence. Mandatory seatbelt legislation, helmets for bicycling, high rates of immunizations, universal health care, and low levels of societal violence may have influenced the rate of preventable causes.
It is disappointing that so few cases of MR and epilepsy seem to be amenable to primary prevention. Substantial numbers of families and individuals with this difficult combination of disabilities will continue to require lifelong care.
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FOOTNOTES
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Accepted Dec 12, 2006.
Address correspondence to Peter Camfield, MD, IWK Health Centre, PO Box 9700, 5850 University Ave, Halifax, Nova Scotia, Canada B3K 6R8. E-mail camfield{at}dal.ca
The authors have indicated they have no financial relationships relevant to this article to disclose.
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