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Familial genetic predisposition, epilepsy localization and antecedent febrile seizures
Epilepsy Research (2007) 73, 104—110
journal homepage: www.elsevier.com/locate/epilepsyres
Familial genetic predisposition, epilepsy localization and antecedent febrile seizures B. Abou-Khalil a,∗, L. Krei a, B. Lazenby a, P.A. Harris b,c, J.L. Haines d, P. Hedera a a
Department of Neurology, United States General Clinical Research Center, United States c Department of Biomedical Informatics, United States d Center for Human Genetics Research, United States b
Received 16 July 2005; received in revised form 17 August 2006; accepted 22 August 2006 Available online 13 October 2006
KEYWORDS Epilepsy; Febrile seizures; Family history; Localization
∗
Summary Purpose: The magnitude of genetic influence in epilepsy may vary in relation to epilepsy classification and localization and factors such as antecedent febrile seizures. We assessed this genetic influence in a large epilepsy population. Methods: Patients with established epilepsy diagnosis evaluated in the Vanderbilt Epilepsy Program were systematically questioned about family history of epilepsy and febrile seizures, prior febrile seizures and other risk factors for epilepsy. Results: A total of 1994 patients with epilepsy and reliable family history were identified. Patients with prior febrile seizures (FS) were more likely to have a family history of febrile seizures than those without prior FS (p < 0.000001) and also had a greater proportion of relatives with febrile seizures. The groups did not differ with respect to family history of epilepsy. Patients with generalized epilepsy were more likely to have first and second degree relatives with epilepsy than those with partial epilepsy (40.2% versus 31.2%, p = 0.001), and also had a greater proportion of affected first degree relatives (p < 0.000001). The proportion of first degree relatives affected with epilepsy was higher than local published prevalence, for both groups. Conclusion: Susceptibility for febrile seizures with subsequent epilepsy may be genetically distinct from susceptibility for afebrile seizures alone. Although family history of epilepsy was more likely with generalized epilepsy, a familial tendency was considerable in partial epilepsy. © 2006 Elsevier B.V. All rights reserved.
Corresponding author at: 2311 Pierce Avenue, Room 2224, Nashville, TN 37232, United States. Tel.: +1 615 936 2591; fax: +1 615 936 0223. E-mail address: [email protected] (B. Abou-Khalil).
Introduction There is evidence that several forms of epilepsy have a genetic component (Berkovic and Scheffer, 1999; Scheffer and Berkovic, 2003). Traditionally, generalized epilepsy was
0920-1211/$ — see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.eplepsyres.2006.08.005
Genetic predisposition, epilepsy localization and antecedent febrile seizures believed to have a strong genetic component, while partial epilepsy has been considered an acquired condition, with few recognized genetic syndromes (Anon., 1989). However, a number of genetically determined partial epileptic syndromes have been described in the past decade (Berkovic et al., 1996; Cendes et al., 1998; Scheffer et al., 1995, 1998; Winawer et al., 2000). In addition, partial epilepsy is often preceded by febrile seizures, which are felt to have a major genetic component (Hirose et al., 2003). It has been debated whether febrile seizures are mostly a non-specific marker of a seizure tendency or whether they have a specific association with particular epilepsy syndromes. It is not clear whether the febrile seizures preceding epilepsy reflect an independent genetic predisposition for febrile seizures, or only the genetic tendency of the afebrile epileptic syndrome. If febrile seizures have an independent genetic predisposition, this could be important in the analysis of families with both epilepsy and febrile seizures. We anticipated that through analysis of family history we could determine whether epilepsy with antecedent febrile seizures has a family history profile distinct from epilepsy without antecedent febrile seizures. We sought to assess the genetic predisposition in partial and generalized epilepsy, with and without antecedent febrile seizures in a large consecutively ascertained epilepsy patient group. We tested the following hypotheses: A. Both generalized and partial epilepsy have a strong genetic component. B. Different localizations in partial epilepsy are differently influenced by genetic tendency for febrile seizures and for epilepsy. C. Genetic predisposition to febrile seizures is independent from predisposition to epilepsy, and this dichotomy is more pronounced in partial than generalized epilepsy. D. The genetic predisposition is no different in patients with prior complex febrile seizures than in patients with prior simple febrile seizures.
Methods Subjects The study population included consecutively ascertained patients with an established epilepsy diagnosis seen in the clinic of the first author. The basis for a diagnosis of epilepsy was a thorough history obtained from the patient and family members or others who have observed attacks. This diagnosis was supported by EEG and neuro-imaging with MRI (or occasionally CT), prolonged EEG-video monitoring (>20% of patients) or full presurgical evaluation (>11%). Patients with single unprovoked seizures and those who only had clearly provoked seizures were excluded. Individuals with pure nonepileptic seizures were excluded (including patients with recorded non-epileptic events, those with atypical seizure descriptions and negative evaluation that failed to provide objective evidence of epilepsy). Patients carrying a diagnosis of both epileptic seizures and non-epileptic events were included. These individuals had to have strong evidence supporting the presence of epilepsy and had to have a clear delineation between epileptic seizures and nonepileptic spells.
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Febrile seizures and other risk factors for epilepsy As part of the detailed history, all patients were systematically questioned about risk factors for epilepsy, including febrile seizures (FS). Risk factors were disregarded if they followed the onset of seizures, unless there was a change in either the character or frequency in the patient’s attacks following the risk factor. We specifically inquired about prenatal and perinatal complications/unusual events, prematurity, perinatal hypoxia, birth trauma, neonatal seizures, delayed developmental milestones, central nervous system infections, traumatic brain injuries, brain tumors, cerebral vascular malformations, cortical developmental malformations, strokes, brain surgery and degenerative disease. Febrile seizures (preceding the onset of epilepsy) received special attention, if present. We asked about age at first febrile seizure, FS duration, number of FS in a single day or with a single illness, presence of any focal ictal or postictal features, total number of FS and age at FS remission. Details were sought from parents or older siblings, whenever they were available or could be reached. We also tried to retrieve old records from hospitalization for severe febrile seizures and other significant childhood illnesses. Febrile seizures were classified as complex if they lasted longer than 15 min, had focal ictal or postictal features or occurred more than once in the same day.
Family history We obtained a detailed family history from all patients. We requested the total number of first and second degree relatives, as well as first cousins. We then obtained the number of relatives with a history of epilepsy, febrile convulsions or both. For first degree relatives, information was obtained on the patient’s mother, father, brothers, sisters and children; for second degree relatives, the patient was asked about grandparents, grandchildren, nieces, nephews, aunts and uncles. We also sought history of epilepsy or FS in maternal and paternal first cousins, but this information was often deficient or unreliable and hence was not included in our final analysis. We attempted to obtain information on the seizure types and epilepsy syndromes of affected individuals, but this was usually difficult to obtain and considered unreliable for the final analysis.
Seizure type and epileptic syndrome identification We obtained information regarding seizure manifestations from patients as well as observers. We reviewed available seizure recordings and report descriptions, as well as EEG and imaging data. Based on the combined results, each patient’s epilepsy was characterized, and whenever possible, classified and localized. In most individuals, seizure classification and epilepsy classification and localization were possible based on the combination of clinical, EEG and imaging data. Whenever conflicting or incongruent data were present the diagnosis/localization that was supported by the preponderance of information available or by the most reliable tests was recorded. We did not try to force a classification or localization when these were not possible. As a result, we ended with a substantial number of patients who had unclassifiable epilepsy or unlocalizable partial epilepsy. The localization was most certain in those patients who became seizure-free following focal resection, but such patients constituted a minority of patient in this inclusive group.
Data storage and analysis All results were entered into a relational database (Microsoft Access, Redmond, WA, USA). Identified subgroups included different epilepsy classifications, different epileptic syndromes, as well as different localizations. Queries were run on the database
106
B. Abou-Khalil et al.
to divide the study population into groups based on the classification and localization of epileptic syndrome, as well as the presence or absence of febrile seizures, family history of febrile seizures and family history of epilepsy. We also identified the proportion of first and second degree relatives affected with epilepsy or febrile seizures. To determine if the prevalence of epilepsy in family members was more than expected, we compared this prevalence to that from a published survey of epilepsy in Tennessee and Georgia (Kobau et al., 2004). Statistical analyses were performed using the R Statistical Computing Language and Environment, Version 1.9.1 (www.R-project.org). Chi-square and Fisher’s Exact tests were used to determine statistical significance in group frequency comparisons. Independent samples t-test and Mann—Whitney Utest results were used to compare mean age at onset between groups. After correction for multiple comparisons using the Bonferroni method, a p-value of 0.001 was considered statistically significant.
Results Patients There were 2288 patients with documented epilepsy (Fig. 1). Family history data was incomplete or missing in 294 patients who were excluded from further analysis. The remaining 1994 patients had complete family history data, including 1108 female and 886 male subjects with ages ranging from 2 months to 86 years (mean 33.8 and median 32.1). This was a predominantly adult and adolescent population (<5 years, N = 30; <10 years, N = 83). The epilepsy classification was partial epilepsy in 1534 patients and generalized epilepsy in 358 patients. The remaining 102 patients could not be classified as having either partial or generalized epilepsy, usually because there was not enough data, but occasionally because both partial and generalized onset seizures were noted.
Figure 1
Classification—localization in relation to prior FS Among the total patient group, 319 patients (16.0%) had antecedent FS (Fig. 1). FS were elicited from 16.9% of patients with partial epilepsy and 15.1% of patients with generalized epilepsy. The difference between the two groups was not statistically significant. When the partial epilepsy group was subdivided into localization subgroups, antecedent FS were found to be more likely in patients with temporal lobe epilepsy (24.3%) than in those with extratemporal epilepsy (10.1%) (p < 0.000001) or those with generalized epilepsy (15.1%) (p = 0.0006).
Family history in relation to seizure classification and localization Of the study population of 1994 epilepsy patients, 773 (38.8%) patients had first or second degree relatives with epilepsy, febrile seizures or both epilepsy and febrile seizures. Family history of epilepsy was present in 655 (32.8%) patients and a family history of FS was present in 247 (12.4%) patients (Table 1). Patients with generalized epilepsy were more likely to have a family history of epilepsy than those with partial epilepsy. However, the groups did not differ with respect to family history of FS. When we analyzed the proportion of first degree relatives with epilepsy, this was 3.47% for partial epilepsy and 17.6% for generalized epilepsy (p < 0.000001). Both percentages were higher than the reported 2.1% incidence of epilepsy in Tennessee based on a telephone survey (p < 0.000001 for both) (Kobau et al., 2004). The proportion of first degree relatives with febrile seizures was identical between the two groups at 1.85%. Patients with temporal lobe epilepsy (TLE) and those with extratemporal epilepsy (ETE) differed significantly in
Classification and localization of epilepsy group.
Genetic predisposition, epilepsy localization and antecedent febrile seizures Table 1
107
Family history of epilepsy and FS in relation to localization
Classification/localization, total number
Number (%) with first or second degree relative or epilepsy
Number (%) with first or second degree relative with FS
Number (%) with first or second degree relative with epilepsy or FS
Partial, 1534 Temporal, 773 Frontal, 230 Parietal, 86 Occipital, 51 All extratemporal, 367 Generalized, 358 Idiopathic, 248 JME, 121
479 239 73 23 17 113 144 106 54
186 (12.1) 101 (13.1) 13 (5.6) 10 (11.6) 3 (5.9) 26 (7.1) 49 (13.7) 36 (14.5) 16 (13.2)
556 287 78 29 18 125 170 124 61
(31.2) (30.9) (31.6) (26.7) (33.3) (30.7) (40.2) (42.6) (44.6)
proportion of relatives affected with febrile seizures (0.82% versus 0.49%, p < 0.005), but not proportion of relatives with epilepsy (2.01% versus 2.35%). In parallel with that, patients with TLE were more likely than those with ETE to have a family history of febrile convulsions, but not a family history of epilepsy.
Family history in relation to prior FS As a primary measure, we analyzed the number of relatives affected with epilepsy and with febrile seizures in patients with epilepsy preceded by febrile seizures and in those without antecedent febrile seizures. There was a significant difference between these groups, most prominent for first degree relatives (Table 2). For example, in temporal lobe epilepsy patients, the proportion of first degree relatives with febrile seizures was almost five times higher in patients with antecedent febrile seizures (Table 2). Among the 319 patients with antecedent FS, 35.4% had first or second degree relatives with epilepsy and 23.2% had first or second degree relatives with FS as compared to
Table 2
(36.2) (37.1) (33.8) (33.7) (35.3) (34.0) (47.5) (49.8) (50.4)
32.3 and 10.4%, respectively, for patients without prior FS (Table 3). There was no significant difference between the groups with respect to family history of epilepsy in first or second degree relatives. However, there was a highly statistically significant difference with respect to family history of FS (p < 0.00001). Similar results were found for the partial epilepsy group, but temporal lobe epilepsy patients were responsible for that difference (a difference was not seen in patients with extratemporal epilepsy). Most patients with a family history of febrile seizures also had family history of epilepsy. Less than one-half had family history of febrile seizures but not epilepsy (Table 3).
Simple FS versus complex FS A total of 265 patients with antecedent FS were classified with either complex or simple FS while those patients with unknown complex features were excluded from further analysis. We compared patients with classified FS to explore the possibility that complex FS are less associated with positive family history than simple FS. We
Number of affected relatives (percentage between parentheses)
Classification
Epilepsy
Partial With FS Without FS Temporal With FS Without FS Generalized With FS Without FS * p < 0.000001
Total
First degree
Second degree
First degree
Second degree
First degree
Second degree
80 (4.8) 378 (3.8)
110 (2.2)§ 452 (1.7)
83 (5.0)* 143 (1.4)
35 (0.69)† 75 (0.28)
1669 9902
5051 26470
65 (4.7)‡ 254 (3.2)
87 (2.1)‡ 313 (1.5)
70 (5.2)* 112 (1.4)
27 (0.64)† 50 (0.24)
1338 7830
4185 20853
48 (4.6)§ 109 (3.0)
52 (1.7) 140 (1.5)
60 (5.7)* 43 (1.2)
17 (0.56)‡ 23 (0.24)
1049 3639
3013 9638
14 (5.4) 99 (6.5)
23 (2.9) 108 (2.6)
12 (4.6)‡ 21 (1.4)
7 (0.88) 20 (0.48)
259 1520
793 4171
All epilepsy With FS Without FS
FS
in comparison with patients without FS, † p < 0.0001.
No longer significant with Bonferroni correction: ‡ p < 0.01,
§ p < 0.05.
108 Table 3
B. Abou-Khalil et al. Family history of febrile seizures and epilepsy by FS category
Classification
Number (%) with affected relatives
p-Value
With antecedent FS
Without antecedent FS
Total (1994) First or second degree with epilepsy First or second degree with FS First or second degree with FS, but not epilepsy
319 113 (34.3) 74 (23.2) 30 (9.4)
1668 539 (32.3) 173 (10.4) 88 (5.3)
0.311753, NS <0.000001 0.006404, NS
Partial (1534) First or second degree with epilepsy First or second degree with FS First or second degree with FS, but not epilepsy
259 90 (34.7) 58 (22.4) 23 (8.9)
1268 386 (30.4) 128 (10.1) 64 (5.0)
0.196996, NS <0.000001 0.022727, NS
Temporal (773) First or second degree with epilepsy First or second degree with FS First or second degree with FS, but not epilepsy
188 63 (33.5) 46 (24.5) 21 (11.2)
582 175 (30.1) 55 (9.5) 27 (4.6)
0.425400, NS <0.000001 0.002314, NS
Extratemporal (367) First or second degree with epilepsy First or second degree with FS First or second degree with FS, but not epilepsy
37 15 (40.5) 3 (8.1) 0
330 98 (29.7) 23 (7.0) 0
0.243163, NS 0.934698, NS —
Generalized (358) First or second degree with epilepsy First or second degree with FS First or second degree with FS, but not epilepsy
54 22 (40.7) 14 (25.9) 6 (11.1)
304 122 (40.1) 35 (11.5) 20 (6.6)
0.947, NS 0.0087, NS 0.2534, NS
Idiopathic generalized (248) First or second degree with epilepsy First or second degree with FS First or second degree with FS, but not epilepsy
29 13 (44.8) 9 (31.0) 3 (10.3)
219 93 (42.5) 27 (12.3) 15 (6.8)
0.966596, NS 0.02021, NS 0.4508, NS
FS history was unknown for some patients. Values in parentheses are given in percentage.
TLE than in patients with generalized epilepsy (Table 4). This relationship persisted when examining patients with family history of epilepsy or patients with a family history of FS.
found no difference between the two groups in proportion of patients with first or second degree relatives affected with epilepsy or FS, or in proportion of affected relatives (Table 4). Complex FS were more likely in patients with
Table 4
Family history in relation to category of febrile seizure Simple FS
All epilepsy Number of first or second degree relatives with epilepsy (percentage of total) Number of first or second degree relatives with FS (percentage of total) Number of first or second degree relatives with either epilepsy or FS (percentage of total) Number of patients who have first or second degree relatives with epilepsy (percentage of patients) Number of patients who have first or second degree relatives with FS (percentage of patients) Number of patients who have first or second degree relatives with epilepsy or FS (percentage of patients) TLE Generalized epilepsy Values in parentheses are given in percentage.
Complex FS
p-Value
70 44 (3.36)
195 106 (2.51)
NS
30 (2.29)
73 (1.73)
NS
68 (5.19)
153 (3.62)
27 (38.6)
64 (32.8)
NS after Bonferroni correction, p = 0.014 NS
16 (22.9)
47 (24.1)
NS
33 (47.1)
85 (43.6)
NS
22 26
138 15
<0.000001 for TLE vs. GE
Genetic predisposition, epilepsy localization and antecedent febrile seizures
Discussion The key findings of this study are that family history of epilepsy and family history of febrile seizures seem to be independently influenced. Family history of epilepsy was not significantly different in patients with and without febrile seizures, but family history of febrile seizures was elicited significantly more often in patients who themselves had febrile seizures than those who did not. The same findings were replicated with an analysis of percentage of affected relatives. This suggests that at least for some groups of epilepsy patients the inherited tendency for febrile seizures is different from and usually independent of inherited afebrile seizure tendency. This provides further support that febrile seizures are not a non-specific marker of seizure tendency. Over the past decade, multiple new genetic mutations have been identified in association with various epileptic syndromes (Berkovic and Scheffer, 1998; Scheffer and Berkovic, 2003). Mutations associated with epileptic syndromes that include antecedent febrile seizures have typically been different from mutations with epileptic syndromes not including antecedent febrile seizures (Baulac et al., 2001a,b; Berkovic and Scheffer, 1998; Escayg et al., 2000; Hedera et al., 2004; Ottman et al., 1995, 2004; Steinlein et al., 1995; Wallace et al., 1998). The mutations identified were from rare large families, typically with autosomal dominant transmission. These families are not representative of the general epilepsy population, where environmental and genetic factors interact and complex polygenic inheritance is suspected. Therefore, the relevance of the identified mutations to the general population is unknown. The current study suggests that even in the general epilepsy clinic population, epilepsy preceded by febrile seizures is frequently genetically distinct from epilepsy not preceded by febrile seizures. Our family history findings are in agreement with prior studies of patients with epilepsy and febrile seizures. In one study, febrile seizures but not epilepsy, were more likely in first and second degree relatives of children with antecedent febrile seizures (Berg et al., 1999). In another study investigating a group with prior febrile seizures, patient with TLE and hippocampal sclerosis were a subgroup particularly more likely to have a family history of febrile seizures (Saltik et al., 2003). Antecedent febrile seizures were more common in temporal lobe epilepsy than in extratemporal epilepsy and even more common than in generalized epilepsy. This finding was previously demonstrated in a smaller subgroup of the current patient population (Hamati-Haddad and Abou-Khalil, 1998). The finding that family history of febrile seizures was more likely in temporal lobe epilepsy than in extratemporal epilepsy is an expected consequence of the greater association of febrile seizures with temporal lobe epilepsy. Patients with generalized epilepsy were more likely to have a family history of epilepsy than those with partial epilepsy, in agreement with prior studies (Ottman et al., 1998). This is to be expected, as generalized epilepsy is usually assumed to have a greater genetic basis. Nevertheless, patients with generalized epilepsy were not more likely to have a family history of febrile seizures. Our patient population showed a prominent genetic influence in patients with partial epilepsy, as 36.2% of these patients had a first
109
or second degree relative with epilepsy or febrile seizures, and the prevalence of epilepsy was significantly greater in first degree relatives of patients than the published prevalence for the region (Kobau et al., 2004). Some authors have suggested that complex febrile seizures may be different from simple febrile seizures in that their severity may reflect preexisting pathology (AlEissa et al., 1992; Annegers et al., 1987; Shinnar, 1998). To investigate whether epilepsy with complex febrile seizures is less likely to have a genetic component, we compared patients with simple and those with complex febrile seizures for family history of epilepsy and febrile seizures. The two groups did not differ. This suggested that a genetic influence is not less likely in patients with complex FS. This was not surprising, as we previously found that FS were usually complex in one large family with GEFS plus and a sodium channelopathy (Abou-Khalil et al., 2001). We confirmed our previous finding that a history of complex febrile seizures is more likely in patients with TLE, whereas antecedent simple febrile seizures are more likely with generalized epilepsy (Hamati-Haddad and Abou-Khalil, 1998). In addition, we demonstrated that this relationship remained when considering only patients with positive family history of epilepsy or of febrile seizures. This study has some limitations. It is based on patients seen in a referral center, and is not community based. On the other hand we included all referred patients, not just those with refractory epilepsy or those considered for epilepsy surgery. Patient and family recall of epilepsy and particularly FS history carries an inherent risk of incompleteness or inaccuracy. We excluded from analysis 294 patients in whom family history was incomplete, such as those who were adopted or had no contact with their families. Whenever possible, hospital records and confirmatory histories from other family members were obtained. The first degree relative information proved reliable, as previously suggested (Ottman et al., 1993). Information regarding second degree relatives may have been less reliable, but was nevertheless provided in the vast majority of patients. An effort was made to include family history from living mothers, as this was shown to increase the validity of the family history (Ottman et al., 1993). We initially included first cousins in the family history, but eventually decided to exclude these, as patients frequently had little contact with their cousins. Our study also has strengths. We analyzed a large number of consecutive patients, without selection, except for those without an obtainable family history. We collected family history and febrile seizure data systematically and prospectively on all patients, and managed to classify and localize the epilepsy in the majority of patients. In addition to evaluating percentage of patients with family history, we were able to calculate the proportion of affected first and second degree relatives in each patient group. We found highly significant differences that were preserved with Bonferroni corrections. One of the major difficulties in genetic studies of complex diseases such as epilepsy is distinguishing the phenotypic variability. Phenotypic subtypes of epilepsy may define genetically more homogeneous subtypes as well. Most of the known epilepsy genes have in fact been identified in phenotypic subsets, whether or not those subsets were originally used to identify the subset of patients being examined.
110 Thus, the results of this study suggest that having prior FS and a family history of FS may be one of these phenotypic subsets. It will be important in the future to record and consider not only the patients’ history of febrile seizures, but also the family history of febrile seizures. This may ease the search for specific susceptibility genes related to the FSepilepsy subtype and thus help clarify the role of genes in epilepsy. This study suggests that in epilepsy families where some affected individuals have FS, the possibility should be considered that different susceptibility genes might be playing a role than in those without FS. Future studies should separate epilepsy families based on the presence or absence of FS.
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B. Abou-Khalil et al. SCN1A, encoding a neuronal sodium channel, in two families with GEFS + 2. Nat. Genet. 24, 343—345. Hamati-Haddad, A., Abou-Khalil, B., 1998. Epilepsy diagnosis and localization in patients with antecedent childhood febrile convulsions. Neurology 50, 917—922. Hedera, P., Abou-Khalil, B., Crunk, A.E., Taylor, K.A., Haines, J.L., Sutcliffe, J.S., 2004. Autosomal dominant lateral temporal epilepsy: two families with novel mutations in the LGI1 gene. Epilepsia 45, 218—222. Hirose, S., Mohney, R.P., Okada, M., Kaneko, S., Mitsudome, A., 2003. The genetics of febrile seizures and related epilepsy syndromes. Brain Dev. 25, 304—312. Kobau, R., DiIorio, C.A., Price, P.H., Thurman, D.J., Martin, L.M., Ridings, D.L., Henry, T.R., 2004. Prevalence of epilepsy and health status of adults with epilepsy in Georgia and Tennessee: Behavioral Risk Factor Surveillance System, 2002. Epilepsy Behav. 5, 358—366. Ottman, R., Hauser, W.A., Susser, M., 1993. Validity of family history data on seizure disorders. Epilepsia 34, 469—475. Ottman, R., Risch, N., Hauser, W.A., Pedley, T.A., Lee, J.H., BarkerCummings, C., Lustenberger, A., Nagle, K.J., Lee, K.S., Scheuer, M.L., et al., 1995. Localization of a gene for partial epilepsy to chromosome 10q. Nat. Genet. 10, 56—60. Ottman, R., Lee, J.H., Hauser, W.A., Risch, N., 1998. Are generalized and localization-related epilepsies genetically distinct? Arch. Neurol. 55, 339—344. Ottman, R., Winawer, M.R., Kalachikov, S., Barker-Cummings, C., Gilliam, T.C., Pedley, T.A., Hauser, W.A., 2004. LGI1 mutations in autosomal dominant partial epilepsy with auditory features. Neurology 62, 1120—1126. Saltik, S., Angay, A., Ozkara, C., Demirbilek, V., Dervant, A., 2003. A retrospective analysis of patients with febrile seizures followed by epilepsy. Seizure 12, 211—216. Scheffer, I.E., Bhatia, K.P., Lopes-Cendes, I., Fish, D.R., Marsden, C.D., Andermann, E., Andermann, F., Desbiens, R., Keene, D., Cendes, F., et al., 1995. Autosomal dominant nocturnal frontal lobe epilepsy. A distinctive clinical disorder. Brain 118 (Pt 1), 61—73. Scheffer, I.E., Phillips, H.A., O’Brien, C.E., Saling, M.M., Wrennall, J.A., Wallace, R.H., Mulley, J.C., Berkovic, S.F., 1998. Familial partial epilepsy with variable foci: a new partial epilepsy syndrome with suggestion of linkage to chromosome 2. Ann. Neurol. 44, 890—899. Scheffer, I.E., Berkovic, S.F., 2003. The genetics of human epilepsy. Trends Pharmacol. Sci. 24, 428—433. Shinnar, S., 1998. Prolonged febrile seizures and mesial temporal sclerosis. Ann. Neurol. 43, 411—412. Steinlein, O.K., Mulley, J.C., Propping, P., Wallace, R.H., Phillips, H.A., Sutherland, G.R., Scheffer, I.E., Berkovic, S.F., 1995. A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat. Genet. 11, 201—203. Wallace, R.H., Wang, D.W., Singh, R., Scheffer, I.E., George Jr., A.L., Phillips, H.A., Saar, K., Reis, A., Johnson, E.W., Sutherland, G.R., Berkovic, S.F., Mulley, J.C., 1998. Febrile seizures and generalized epilepsy associated with a mutation in the Na+channel beta1 subunit gene SCN1B. Nat. Genet. 19, 366—370. Winawer, M.R., Ottman, R., Hauser, W.A., Pedley, T.A., 2000. Autosomal dominant partial epilepsy with auditory features: defining the phenotype. Neurology 54, 2173—2176.
journal homepage: www.elsevier.com/locate/epilepsyres
Familial genetic predisposition, epilepsy localization and antecedent febrile seizures B. Abou-Khalil a,∗, L. Krei a, B. Lazenby a, P.A. Harris b,c, J.L. Haines d, P. Hedera a a
Department of Neurology, United States General Clinical Research Center, United States c Department of Biomedical Informatics, United States d Center for Human Genetics Research, United States b
Received 16 July 2005; received in revised form 17 August 2006; accepted 22 August 2006 Available online 13 October 2006
KEYWORDS Epilepsy; Febrile seizures; Family history; Localization
∗
Summary Purpose: The magnitude of genetic influence in epilepsy may vary in relation to epilepsy classification and localization and factors such as antecedent febrile seizures. We assessed this genetic influence in a large epilepsy population. Methods: Patients with established epilepsy diagnosis evaluated in the Vanderbilt Epilepsy Program were systematically questioned about family history of epilepsy and febrile seizures, prior febrile seizures and other risk factors for epilepsy. Results: A total of 1994 patients with epilepsy and reliable family history were identified. Patients with prior febrile seizures (FS) were more likely to have a family history of febrile seizures than those without prior FS (p < 0.000001) and also had a greater proportion of relatives with febrile seizures. The groups did not differ with respect to family history of epilepsy. Patients with generalized epilepsy were more likely to have first and second degree relatives with epilepsy than those with partial epilepsy (40.2% versus 31.2%, p = 0.001), and also had a greater proportion of affected first degree relatives (p < 0.000001). The proportion of first degree relatives affected with epilepsy was higher than local published prevalence, for both groups. Conclusion: Susceptibility for febrile seizures with subsequent epilepsy may be genetically distinct from susceptibility for afebrile seizures alone. Although family history of epilepsy was more likely with generalized epilepsy, a familial tendency was considerable in partial epilepsy. © 2006 Elsevier B.V. All rights reserved.
Corresponding author at: 2311 Pierce Avenue, Room 2224, Nashville, TN 37232, United States. Tel.: +1 615 936 2591; fax: +1 615 936 0223. E-mail address: [email protected] (B. Abou-Khalil).
Introduction There is evidence that several forms of epilepsy have a genetic component (Berkovic and Scheffer, 1999; Scheffer and Berkovic, 2003). Traditionally, generalized epilepsy was
0920-1211/$ — see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.eplepsyres.2006.08.005
Genetic predisposition, epilepsy localization and antecedent febrile seizures believed to have a strong genetic component, while partial epilepsy has been considered an acquired condition, with few recognized genetic syndromes (Anon., 1989). However, a number of genetically determined partial epileptic syndromes have been described in the past decade (Berkovic et al., 1996; Cendes et al., 1998; Scheffer et al., 1995, 1998; Winawer et al., 2000). In addition, partial epilepsy is often preceded by febrile seizures, which are felt to have a major genetic component (Hirose et al., 2003). It has been debated whether febrile seizures are mostly a non-specific marker of a seizure tendency or whether they have a specific association with particular epilepsy syndromes. It is not clear whether the febrile seizures preceding epilepsy reflect an independent genetic predisposition for febrile seizures, or only the genetic tendency of the afebrile epileptic syndrome. If febrile seizures have an independent genetic predisposition, this could be important in the analysis of families with both epilepsy and febrile seizures. We anticipated that through analysis of family history we could determine whether epilepsy with antecedent febrile seizures has a family history profile distinct from epilepsy without antecedent febrile seizures. We sought to assess the genetic predisposition in partial and generalized epilepsy, with and without antecedent febrile seizures in a large consecutively ascertained epilepsy patient group. We tested the following hypotheses: A. Both generalized and partial epilepsy have a strong genetic component. B. Different localizations in partial epilepsy are differently influenced by genetic tendency for febrile seizures and for epilepsy. C. Genetic predisposition to febrile seizures is independent from predisposition to epilepsy, and this dichotomy is more pronounced in partial than generalized epilepsy. D. The genetic predisposition is no different in patients with prior complex febrile seizures than in patients with prior simple febrile seizures.
Methods Subjects The study population included consecutively ascertained patients with an established epilepsy diagnosis seen in the clinic of the first author. The basis for a diagnosis of epilepsy was a thorough history obtained from the patient and family members or others who have observed attacks. This diagnosis was supported by EEG and neuro-imaging with MRI (or occasionally CT), prolonged EEG-video monitoring (>20% of patients) or full presurgical evaluation (>11%). Patients with single unprovoked seizures and those who only had clearly provoked seizures were excluded. Individuals with pure nonepileptic seizures were excluded (including patients with recorded non-epileptic events, those with atypical seizure descriptions and negative evaluation that failed to provide objective evidence of epilepsy). Patients carrying a diagnosis of both epileptic seizures and non-epileptic events were included. These individuals had to have strong evidence supporting the presence of epilepsy and had to have a clear delineation between epileptic seizures and nonepileptic spells.
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Febrile seizures and other risk factors for epilepsy As part of the detailed history, all patients were systematically questioned about risk factors for epilepsy, including febrile seizures (FS). Risk factors were disregarded if they followed the onset of seizures, unless there was a change in either the character or frequency in the patient’s attacks following the risk factor. We specifically inquired about prenatal and perinatal complications/unusual events, prematurity, perinatal hypoxia, birth trauma, neonatal seizures, delayed developmental milestones, central nervous system infections, traumatic brain injuries, brain tumors, cerebral vascular malformations, cortical developmental malformations, strokes, brain surgery and degenerative disease. Febrile seizures (preceding the onset of epilepsy) received special attention, if present. We asked about age at first febrile seizure, FS duration, number of FS in a single day or with a single illness, presence of any focal ictal or postictal features, total number of FS and age at FS remission. Details were sought from parents or older siblings, whenever they were available or could be reached. We also tried to retrieve old records from hospitalization for severe febrile seizures and other significant childhood illnesses. Febrile seizures were classified as complex if they lasted longer than 15 min, had focal ictal or postictal features or occurred more than once in the same day.
Family history We obtained a detailed family history from all patients. We requested the total number of first and second degree relatives, as well as first cousins. We then obtained the number of relatives with a history of epilepsy, febrile convulsions or both. For first degree relatives, information was obtained on the patient’s mother, father, brothers, sisters and children; for second degree relatives, the patient was asked about grandparents, grandchildren, nieces, nephews, aunts and uncles. We also sought history of epilepsy or FS in maternal and paternal first cousins, but this information was often deficient or unreliable and hence was not included in our final analysis. We attempted to obtain information on the seizure types and epilepsy syndromes of affected individuals, but this was usually difficult to obtain and considered unreliable for the final analysis.
Seizure type and epileptic syndrome identification We obtained information regarding seizure manifestations from patients as well as observers. We reviewed available seizure recordings and report descriptions, as well as EEG and imaging data. Based on the combined results, each patient’s epilepsy was characterized, and whenever possible, classified and localized. In most individuals, seizure classification and epilepsy classification and localization were possible based on the combination of clinical, EEG and imaging data. Whenever conflicting or incongruent data were present the diagnosis/localization that was supported by the preponderance of information available or by the most reliable tests was recorded. We did not try to force a classification or localization when these were not possible. As a result, we ended with a substantial number of patients who had unclassifiable epilepsy or unlocalizable partial epilepsy. The localization was most certain in those patients who became seizure-free following focal resection, but such patients constituted a minority of patient in this inclusive group.
Data storage and analysis All results were entered into a relational database (Microsoft Access, Redmond, WA, USA). Identified subgroups included different epilepsy classifications, different epileptic syndromes, as well as different localizations. Queries were run on the database
106
B. Abou-Khalil et al.
to divide the study population into groups based on the classification and localization of epileptic syndrome, as well as the presence or absence of febrile seizures, family history of febrile seizures and family history of epilepsy. We also identified the proportion of first and second degree relatives affected with epilepsy or febrile seizures. To determine if the prevalence of epilepsy in family members was more than expected, we compared this prevalence to that from a published survey of epilepsy in Tennessee and Georgia (Kobau et al., 2004). Statistical analyses were performed using the R Statistical Computing Language and Environment, Version 1.9.1 (www.R-project.org). Chi-square and Fisher’s Exact tests were used to determine statistical significance in group frequency comparisons. Independent samples t-test and Mann—Whitney Utest results were used to compare mean age at onset between groups. After correction for multiple comparisons using the Bonferroni method, a p-value of 0.001 was considered statistically significant.
Results Patients There were 2288 patients with documented epilepsy (Fig. 1). Family history data was incomplete or missing in 294 patients who were excluded from further analysis. The remaining 1994 patients had complete family history data, including 1108 female and 886 male subjects with ages ranging from 2 months to 86 years (mean 33.8 and median 32.1). This was a predominantly adult and adolescent population (<5 years, N = 30; <10 years, N = 83). The epilepsy classification was partial epilepsy in 1534 patients and generalized epilepsy in 358 patients. The remaining 102 patients could not be classified as having either partial or generalized epilepsy, usually because there was not enough data, but occasionally because both partial and generalized onset seizures were noted.
Figure 1
Classification—localization in relation to prior FS Among the total patient group, 319 patients (16.0%) had antecedent FS (Fig. 1). FS were elicited from 16.9% of patients with partial epilepsy and 15.1% of patients with generalized epilepsy. The difference between the two groups was not statistically significant. When the partial epilepsy group was subdivided into localization subgroups, antecedent FS were found to be more likely in patients with temporal lobe epilepsy (24.3%) than in those with extratemporal epilepsy (10.1%) (p < 0.000001) or those with generalized epilepsy (15.1%) (p = 0.0006).
Family history in relation to seizure classification and localization Of the study population of 1994 epilepsy patients, 773 (38.8%) patients had first or second degree relatives with epilepsy, febrile seizures or both epilepsy and febrile seizures. Family history of epilepsy was present in 655 (32.8%) patients and a family history of FS was present in 247 (12.4%) patients (Table 1). Patients with generalized epilepsy were more likely to have a family history of epilepsy than those with partial epilepsy. However, the groups did not differ with respect to family history of FS. When we analyzed the proportion of first degree relatives with epilepsy, this was 3.47% for partial epilepsy and 17.6% for generalized epilepsy (p < 0.000001). Both percentages were higher than the reported 2.1% incidence of epilepsy in Tennessee based on a telephone survey (p < 0.000001 for both) (Kobau et al., 2004). The proportion of first degree relatives with febrile seizures was identical between the two groups at 1.85%. Patients with temporal lobe epilepsy (TLE) and those with extratemporal epilepsy (ETE) differed significantly in
Classification and localization of epilepsy group.
Genetic predisposition, epilepsy localization and antecedent febrile seizures Table 1
107
Family history of epilepsy and FS in relation to localization
Classification/localization, total number
Number (%) with first or second degree relative or epilepsy
Number (%) with first or second degree relative with FS
Number (%) with first or second degree relative with epilepsy or FS
Partial, 1534 Temporal, 773 Frontal, 230 Parietal, 86 Occipital, 51 All extratemporal, 367 Generalized, 358 Idiopathic, 248 JME, 121
479 239 73 23 17 113 144 106 54
186 (12.1) 101 (13.1) 13 (5.6) 10 (11.6) 3 (5.9) 26 (7.1) 49 (13.7) 36 (14.5) 16 (13.2)
556 287 78 29 18 125 170 124 61
(31.2) (30.9) (31.6) (26.7) (33.3) (30.7) (40.2) (42.6) (44.6)
proportion of relatives affected with febrile seizures (0.82% versus 0.49%, p < 0.005), but not proportion of relatives with epilepsy (2.01% versus 2.35%). In parallel with that, patients with TLE were more likely than those with ETE to have a family history of febrile convulsions, but not a family history of epilepsy.
Family history in relation to prior FS As a primary measure, we analyzed the number of relatives affected with epilepsy and with febrile seizures in patients with epilepsy preceded by febrile seizures and in those without antecedent febrile seizures. There was a significant difference between these groups, most prominent for first degree relatives (Table 2). For example, in temporal lobe epilepsy patients, the proportion of first degree relatives with febrile seizures was almost five times higher in patients with antecedent febrile seizures (Table 2). Among the 319 patients with antecedent FS, 35.4% had first or second degree relatives with epilepsy and 23.2% had first or second degree relatives with FS as compared to
Table 2
(36.2) (37.1) (33.8) (33.7) (35.3) (34.0) (47.5) (49.8) (50.4)
32.3 and 10.4%, respectively, for patients without prior FS (Table 3). There was no significant difference between the groups with respect to family history of epilepsy in first or second degree relatives. However, there was a highly statistically significant difference with respect to family history of FS (p < 0.00001). Similar results were found for the partial epilepsy group, but temporal lobe epilepsy patients were responsible for that difference (a difference was not seen in patients with extratemporal epilepsy). Most patients with a family history of febrile seizures also had family history of epilepsy. Less than one-half had family history of febrile seizures but not epilepsy (Table 3).
Simple FS versus complex FS A total of 265 patients with antecedent FS were classified with either complex or simple FS while those patients with unknown complex features were excluded from further analysis. We compared patients with classified FS to explore the possibility that complex FS are less associated with positive family history than simple FS. We
Number of affected relatives (percentage between parentheses)
Classification
Epilepsy
Partial With FS Without FS Temporal With FS Without FS Generalized With FS Without FS * p < 0.000001
Total
First degree
Second degree
First degree
Second degree
First degree
Second degree
80 (4.8) 378 (3.8)
110 (2.2)§ 452 (1.7)
83 (5.0)* 143 (1.4)
35 (0.69)† 75 (0.28)
1669 9902
5051 26470
65 (4.7)‡ 254 (3.2)
87 (2.1)‡ 313 (1.5)
70 (5.2)* 112 (1.4)
27 (0.64)† 50 (0.24)
1338 7830
4185 20853
48 (4.6)§ 109 (3.0)
52 (1.7) 140 (1.5)
60 (5.7)* 43 (1.2)
17 (0.56)‡ 23 (0.24)
1049 3639
3013 9638
14 (5.4) 99 (6.5)
23 (2.9) 108 (2.6)
12 (4.6)‡ 21 (1.4)
7 (0.88) 20 (0.48)
259 1520
793 4171
All epilepsy With FS Without FS
FS
in comparison with patients without FS, † p < 0.0001.
No longer significant with Bonferroni correction: ‡ p < 0.01,
§ p < 0.05.
108 Table 3
B. Abou-Khalil et al. Family history of febrile seizures and epilepsy by FS category
Classification
Number (%) with affected relatives
p-Value
With antecedent FS
Without antecedent FS
Total (1994) First or second degree with epilepsy First or second degree with FS First or second degree with FS, but not epilepsy
319 113 (34.3) 74 (23.2) 30 (9.4)
1668 539 (32.3) 173 (10.4) 88 (5.3)
0.311753, NS <0.000001 0.006404, NS
Partial (1534) First or second degree with epilepsy First or second degree with FS First or second degree with FS, but not epilepsy
259 90 (34.7) 58 (22.4) 23 (8.9)
1268 386 (30.4) 128 (10.1) 64 (5.0)
0.196996, NS <0.000001 0.022727, NS
Temporal (773) First or second degree with epilepsy First or second degree with FS First or second degree with FS, but not epilepsy
188 63 (33.5) 46 (24.5) 21 (11.2)
582 175 (30.1) 55 (9.5) 27 (4.6)
0.425400, NS <0.000001 0.002314, NS
Extratemporal (367) First or second degree with epilepsy First or second degree with FS First or second degree with FS, but not epilepsy
37 15 (40.5) 3 (8.1) 0
330 98 (29.7) 23 (7.0) 0
0.243163, NS 0.934698, NS —
Generalized (358) First or second degree with epilepsy First or second degree with FS First or second degree with FS, but not epilepsy
54 22 (40.7) 14 (25.9) 6 (11.1)
304 122 (40.1) 35 (11.5) 20 (6.6)
0.947, NS 0.0087, NS 0.2534, NS
Idiopathic generalized (248) First or second degree with epilepsy First or second degree with FS First or second degree with FS, but not epilepsy
29 13 (44.8) 9 (31.0) 3 (10.3)
219 93 (42.5) 27 (12.3) 15 (6.8)
0.966596, NS 0.02021, NS 0.4508, NS
FS history was unknown for some patients. Values in parentheses are given in percentage.
TLE than in patients with generalized epilepsy (Table 4). This relationship persisted when examining patients with family history of epilepsy or patients with a family history of FS.
found no difference between the two groups in proportion of patients with first or second degree relatives affected with epilepsy or FS, or in proportion of affected relatives (Table 4). Complex FS were more likely in patients with
Table 4
Family history in relation to category of febrile seizure Simple FS
All epilepsy Number of first or second degree relatives with epilepsy (percentage of total) Number of first or second degree relatives with FS (percentage of total) Number of first or second degree relatives with either epilepsy or FS (percentage of total) Number of patients who have first or second degree relatives with epilepsy (percentage of patients) Number of patients who have first or second degree relatives with FS (percentage of patients) Number of patients who have first or second degree relatives with epilepsy or FS (percentage of patients) TLE Generalized epilepsy Values in parentheses are given in percentage.
Complex FS
p-Value
70 44 (3.36)
195 106 (2.51)
NS
30 (2.29)
73 (1.73)
NS
68 (5.19)
153 (3.62)
27 (38.6)
64 (32.8)
NS after Bonferroni correction, p = 0.014 NS
16 (22.9)
47 (24.1)
NS
33 (47.1)
85 (43.6)
NS
22 26
138 15
<0.000001 for TLE vs. GE
Genetic predisposition, epilepsy localization and antecedent febrile seizures
Discussion The key findings of this study are that family history of epilepsy and family history of febrile seizures seem to be independently influenced. Family history of epilepsy was not significantly different in patients with and without febrile seizures, but family history of febrile seizures was elicited significantly more often in patients who themselves had febrile seizures than those who did not. The same findings were replicated with an analysis of percentage of affected relatives. This suggests that at least for some groups of epilepsy patients the inherited tendency for febrile seizures is different from and usually independent of inherited afebrile seizure tendency. This provides further support that febrile seizures are not a non-specific marker of seizure tendency. Over the past decade, multiple new genetic mutations have been identified in association with various epileptic syndromes (Berkovic and Scheffer, 1998; Scheffer and Berkovic, 2003). Mutations associated with epileptic syndromes that include antecedent febrile seizures have typically been different from mutations with epileptic syndromes not including antecedent febrile seizures (Baulac et al., 2001a,b; Berkovic and Scheffer, 1998; Escayg et al., 2000; Hedera et al., 2004; Ottman et al., 1995, 2004; Steinlein et al., 1995; Wallace et al., 1998). The mutations identified were from rare large families, typically with autosomal dominant transmission. These families are not representative of the general epilepsy population, where environmental and genetic factors interact and complex polygenic inheritance is suspected. Therefore, the relevance of the identified mutations to the general population is unknown. The current study suggests that even in the general epilepsy clinic population, epilepsy preceded by febrile seizures is frequently genetically distinct from epilepsy not preceded by febrile seizures. Our family history findings are in agreement with prior studies of patients with epilepsy and febrile seizures. In one study, febrile seizures but not epilepsy, were more likely in first and second degree relatives of children with antecedent febrile seizures (Berg et al., 1999). In another study investigating a group with prior febrile seizures, patient with TLE and hippocampal sclerosis were a subgroup particularly more likely to have a family history of febrile seizures (Saltik et al., 2003). Antecedent febrile seizures were more common in temporal lobe epilepsy than in extratemporal epilepsy and even more common than in generalized epilepsy. This finding was previously demonstrated in a smaller subgroup of the current patient population (Hamati-Haddad and Abou-Khalil, 1998). The finding that family history of febrile seizures was more likely in temporal lobe epilepsy than in extratemporal epilepsy is an expected consequence of the greater association of febrile seizures with temporal lobe epilepsy. Patients with generalized epilepsy were more likely to have a family history of epilepsy than those with partial epilepsy, in agreement with prior studies (Ottman et al., 1998). This is to be expected, as generalized epilepsy is usually assumed to have a greater genetic basis. Nevertheless, patients with generalized epilepsy were not more likely to have a family history of febrile seizures. Our patient population showed a prominent genetic influence in patients with partial epilepsy, as 36.2% of these patients had a first
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or second degree relative with epilepsy or febrile seizures, and the prevalence of epilepsy was significantly greater in first degree relatives of patients than the published prevalence for the region (Kobau et al., 2004). Some authors have suggested that complex febrile seizures may be different from simple febrile seizures in that their severity may reflect preexisting pathology (AlEissa et al., 1992; Annegers et al., 1987; Shinnar, 1998). To investigate whether epilepsy with complex febrile seizures is less likely to have a genetic component, we compared patients with simple and those with complex febrile seizures for family history of epilepsy and febrile seizures. The two groups did not differ. This suggested that a genetic influence is not less likely in patients with complex FS. This was not surprising, as we previously found that FS were usually complex in one large family with GEFS plus and a sodium channelopathy (Abou-Khalil et al., 2001). We confirmed our previous finding that a history of complex febrile seizures is more likely in patients with TLE, whereas antecedent simple febrile seizures are more likely with generalized epilepsy (Hamati-Haddad and Abou-Khalil, 1998). In addition, we demonstrated that this relationship remained when considering only patients with positive family history of epilepsy or of febrile seizures. This study has some limitations. It is based on patients seen in a referral center, and is not community based. On the other hand we included all referred patients, not just those with refractory epilepsy or those considered for epilepsy surgery. Patient and family recall of epilepsy and particularly FS history carries an inherent risk of incompleteness or inaccuracy. We excluded from analysis 294 patients in whom family history was incomplete, such as those who were adopted or had no contact with their families. Whenever possible, hospital records and confirmatory histories from other family members were obtained. The first degree relative information proved reliable, as previously suggested (Ottman et al., 1993). Information regarding second degree relatives may have been less reliable, but was nevertheless provided in the vast majority of patients. An effort was made to include family history from living mothers, as this was shown to increase the validity of the family history (Ottman et al., 1993). We initially included first cousins in the family history, but eventually decided to exclude these, as patients frequently had little contact with their cousins. Our study also has strengths. We analyzed a large number of consecutive patients, without selection, except for those without an obtainable family history. We collected family history and febrile seizure data systematically and prospectively on all patients, and managed to classify and localize the epilepsy in the majority of patients. In addition to evaluating percentage of patients with family history, we were able to calculate the proportion of affected first and second degree relatives in each patient group. We found highly significant differences that were preserved with Bonferroni corrections. One of the major difficulties in genetic studies of complex diseases such as epilepsy is distinguishing the phenotypic variability. Phenotypic subtypes of epilepsy may define genetically more homogeneous subtypes as well. Most of the known epilepsy genes have in fact been identified in phenotypic subsets, whether or not those subsets were originally used to identify the subset of patients being examined.
110 Thus, the results of this study suggest that having prior FS and a family history of FS may be one of these phenotypic subsets. It will be important in the future to record and consider not only the patients’ history of febrile seizures, but also the family history of febrile seizures. This may ease the search for specific susceptibility genes related to the FSepilepsy subtype and thus help clarify the role of genes in epilepsy. This study suggests that in epilepsy families where some affected individuals have FS, the possibility should be considered that different susceptibility genes might be playing a role than in those without FS. Future studies should separate epilepsy families based on the presence or absence of FS.
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