A B S T R A C T Uncomplicated childhood-onset epilepsy is associated with increased brain amyloid... more A B S T R A C T Uncomplicated childhood-onset epilepsy is associated with increased brain amyloid load at late middle age, but its possible association with Alzheimer-type neurodegenerative processes is unclear. After 50-year follow-up, 42 childhood onset epilepsy subjects and 45 matched controls were investigated with [ 18 F]fluorodeoxyglucose PET. There were no significant differences between the subjects and controls, but higher [ 18 F]fluorodeoxyglucose uptake was associated with a higher local amyloid load (as measured with [ 11 C]PIB PET) in the prefrontal cortex, parietal cortex, and posterior cingulate/precuneus in subjects but not in controls. These findings parallel reported observations in cognitively normal individuals with increased brain amyloid accumulation who are at risk for future Alzheimer's disease.
The purpose of this project was to characterize brain structure and organization in persons with ... more The purpose of this project was to characterize brain structure and organization in persons with active and remitted childhood onset epilepsy 50 years after diagnosis compared with healthy controls. Participants from a population-based investigation of uncomplicated childhood onset epilepsy were followed up 5 decades later. Forty-one participants had a history of childhood onset epilepsy (mean age of onset 5 5.2 years, current chronological age 5 56.0 years) and were compared with 48 population-based controls (mean age 5 55.9 years). Of the epilepsy participants, 8 had persisting active epilepsy and in 33 the epilepsy had remitted. All participants underwent 3T MRI with subsequent vertex analysis of cortical volume, thickness, surface area and gyral complexity. In addition, cortical and subcortical volumes, including regions of the frontal, parietal, temporal, and occipital lobes, and subcortical structures including amygdala, thalamus, and hippocampus, were analyzed using graph theory techniques. There were modest group differences in traditional vertex-based analyses of cortical volume, thickness, surface area and gyral index, as well as across volumes of subcortical structures, after correction for multiple comparisons. Graph theory analyses revealed suboptimal topological structural organization with enhanced network segregation and reduced global integration in the Additional Supporting Information may be found in the online
IMPORTANCE The effect of childhood epilepsy on later-life cognitive and brain health is an unclea... more IMPORTANCE The effect of childhood epilepsy on later-life cognitive and brain health is an unclear and little-explored issue. OBJECTIVE To determine whether adults with a history of childhood-onset epilepsy exhibit increased brain amyloid accumulation, possibly predisposing to accelerated cognitive impairment or even frank cognitive disorders in later life. DESIGN, SETTING, AND PARTICIPANTS Forty-one adults from a population-based cohort of individuals with childhood-onset epilepsy in southwestern Finland, together with 46 matched population-based controls, underwent amyloid ligand carbon 11–labeled Pittsburgh Compound B (PiB) positron emission tomography after long-term prospective follow-up. The PiB uptake was quantified as a region to cerebellar cortex ratio. Tracer uptake was evaluated visually and analyzed voxel by voxel over the entire brain to investigate the spatial distribution of amyloid deposition. The study was conducted MAIN OUTCOMES AND MEASURES Brain amyloid accumulation. RESULTS The 41 individuals with epilepsy were originally enrolled in the Turku Adult Childhood Onset Epilepsy study at the mean (SD) age of 5.1 (4.5) years (range, 0-14 years). After a mean 52.5 (4.0) years of follow-up, the participants were evaluated (26 [63%] were women; the mean [SD] age was 56.0 [4.3] years). Nine individuals with childhood-onset epilepsy (22%) and 3 control participants (7%) had a visually abnormal PiB scan showing high cortical uptake in at least 1 of the evaluated brain regions (P = .04). In semiquantitative analyses, there was a significant interaction effect indicating higher prefrontal cortex uptake in apolipoprotein E (APOE) ε4 allele carriers than in noncarriers in participants (mean [SD], 1.66 [0.41] vs 1.43 [0.15]) compared with controls (1.40 [0.26) vs 1.41 [0.12]) (group × APOE interaction, F = 6.8; P = .01). In addition, there was a significant group effect showing higher tracer uptake in participants compared with controls (group effect, F = 8.0; P = .006). CONCLUSIONS AND RELEVANCE Adults with childhood-onset epilepsy, particularly APOE ε4 carriers, have an increased brain amyloid load at late middle age. Thus, epilepsy is linked with a biomarker that might be related to accelerated brain aging and can be considered a neurobiological predisposition to later-life cognitive disorders.
This study investigated the short-term response to a standardized hormonal therapy protocol for t... more This study investigated the short-term response to a standardized hormonal therapy protocol for treatment of infantile spasms. Twenty-seven children with video electroencephalography (EEG)-confirmed infantile spasms received very high dose (8 mg/kg/day, max 60 mg/day) oral prednisolone for 2 weeks. Response (absence of both hypsarrhythmia and spasms) to prednisolone was ascertained by repeat overnight video-EEG. Responders were tapered over 2 weeks and nonresponders were immediately transitioned to high dose (150 IU/m(2)/day) intramuscular adrenocorticotropic hormone (ACTH) for two additional weeks. Response was again determined by overnight video-EEG after ACTH therapy. Sixty-three percent (17/27) of patients responded completely to prednisolone. Subsequently, 40% (4/10) of prednisolone nonresponders exhibited a complete response after an additional 2-week course with ACTH. Among 27 subjects with median follow-up of 13.5 months (interquartile range [IQR] 4.8-25.9), 12% (2/17) of prednisolone responders and 50% (2/4) of ACTH responders experienced a relapse between 2 and 9 months after initial response. Very high dose prednisolone demonstrated significantly higher efficacy than previously reported for lower doses in prior studies. High dose ACTH may be superior to very high dose prednisolone, and in lieu of a definitive clinical trial, the choice between prednisolone and ACTH for initial treatment of infantile spasms remains controversial.
I n a prospective study, antiepileptic drugs were discontinued in 264 children with epilepsy afte... more I n a prospective study, antiepileptic drugs were discontinued in 264 children with epilepsy after a mean seizure-free interval of 2.9 years. They were then followed for a mean of 58 months to ascertain whether seizures recurred. Seizures recurred in 95 (36%) of the children. Etiology was a significant predictor of outcome (relative risk [RRI = 1.81). O n multivariable analysis, significant factors in the idiopathic group included age at onset above 12 years (RR = 5.4), a family history of seizures (RR = 3,1), the presence of slowing on the electroencephalogram prior to medication withdrawal (RR = 2.4), and a history of atypical febrile seizures (RR = 2.8). Specific epileptic syndromes such as juvenile myoclonic epilepsy and benign rolandic epilepsy were also significant predictors of outcome. I n the remote symptomatic group, significant predictors of outcome included age at onset older than 12 years (RR = 3.6), moderate to severe mental retardation (IQ < 50) (RR = 2.8), a history of atypical febrile seizures (RR = 2.0), and a history of absence seizures (RR = 0.4). The majority of children with epilepsy in remission while on antiepileptic drug therapy will remain seizure free when medications are withdrawn. A few readily available parameters distinguish those with a good prognosis from those in whom seizures are likely to recur. These data provide the framework for the clinical decision making for withdrawal of medications in these children. Shinnar S, Berg AT, MoshC SL, Kang H, O'Dell C, Alemany hi, Goldensohn ES, Hauser WA. Discontinuing antiepileptic drugs in children with epilepsy: a prospective study. Ann Neurol 1994;35:514-565
Linkage analysis identified a chromosome 18 locus predisposing to a number of adolescent-onset IG... more Linkage analysis identified a chromosome 18 locus predisposing to a number of adolescent-onset IGEs. We report a single-nucleotide polymorphism (SNP) association analysis of the region around the marker locus with the high LOD score. This analysis, which used both case-control and family-based association methods, yielded strong evidence that malic enzyme 2 (ME2) is the gene predisposing to IGE. We also observed association among subgroups of IGE syndromes. An ME2-centered nine-SNP haplotype, when present homozygously, increases the risk for IGE (odds ratio 6.1; 95% confidence interval 2.9-12.7) compared with any other genotype. Both the linkage analysis and the association analysis support recessive inheritance for the locus, which is compatible with the fact that ME2 is an enzyme. ME2 is a genome-coded mitochondrial enzyme that converts malate to pyruvate and is involved in neuronal synthesis of the neurotransmitter g-aminobutyric acid (GABA). The results suggest that GABA synthesis disruption predisposes to common IGE and that clinical seizures are triggered when mutations at other genes, or perhaps other insults, are present.
Idiopathic generalized epilepsy (IGE) is a common, complex disease with an almost exclusively gen... more Idiopathic generalized epilepsy (IGE) is a common, complex disease with an almost exclusively genetic etiology but with variable phenotypes. Clinically, IGE can be divided into different syndromes. Varying lines of evidence point to the involvement of several interacting genes in the etiology of IGE. We performed a genome scan in 91 families ascertained through a proband with adolescent-onset IGE. The IGEs included juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), and epilepsy with generalized tonic clonic seizures (EGTCS). Our linkage results support an oligogenic model for IGE, with strong evidence for a locus common to most IGEs on chromosome 18 (lod score 4.4/5.2 multipoint/ two-point) and other loci that may influence specific seizure phenotypes for different IGEs: a previously identified locus on chromosome 6 for JME (lod score 2.5/4.2), a locus on chromosome 8 influencing non-JME forms of IGE (lod score 3.8/2.5), and, more tentatively, two newly discovered loci for absence seizures on chromosome 5 (lod scores 3.8/2.8 and 3.4/1.9). Our data also suggest that the genetic classification of different forms of IGE is likely to cut across the clinical classification of these subforms of IGE. We hypothesize that interactions of different combinations of these loci produce the related heterogeneous phenotypes seen in IGE families.
Pediatric experience with gabapentin (GBP), a new antiepileptic drug (AED), is limited. We descri... more Pediatric experience with gabapentin (GBP), a new antiepileptic drug (AED), is limited. We described 3 learning disabled children, 1 aged 7 and 2 aged 10 years, with intractable partial seizures who developed severe behavioral problems while receiving modest doses of GBP. The children became hyperactive and had explosive outburst consisting of aggressive and oppositional behavior. The behavioral problems were sufficiently severe to require discontinuation of GBP despite moderately improved seizure control.
This study assessed the utility of rectal diazepam gel in the home management of prolonged or rep... more This study assessed the utility of rectal diazepam gel in the home management of prolonged or repetitive seizures in children. Thirty-eight children being prescribed rectal diazepam gel by their clinician were prospectively recruited. Seizures, rectal diazepam use, emergency department visits, and quality of life data before and after study entry were recorded. The 38 children included 14 (37%) with complex febrile seizures, and 24 with epilepsy (n = 22) or a single seizure (n = 2). There were 23 (61%) children with prolonged seizures and 15 (39%) with repetitive seizures. During the 6-month follow-up period, 12 children experienced 26 seizures which met the criteria for rectal diazepam administration. Rectal diazepam gel was administered to 8 children on 19 occasions. In 16 (84%) of these episodes, seizures stopped and no emergency department visit was required. Parental stress was decreased between baseline and 6 months in both the overall group and in all the subgroups. Home use of rectal diazepam gel is effective in aborting seizure activity, often avoiding an emergency department visit. Its use reduces morbidity and costs associated with hospital visits and provides parents a treatment option for home management of prolonged or repetitive seizures.
Several loci and candidate genes for epilepsies or epileptic syndromes map or have been suggested... more Several loci and candidate genes for epilepsies or epileptic syndromes map or have been suggested to map to chromosome 8. We investigated families with adolescent-onset idiopathic generalized epilepsy (IGE), for linkage to markers spanning chromosome 8. The IGEs that we studied included juvenile myoclonic epilepsy (JME), epilepsy with only generalized tonic-clonic seizures occurring either randomly during the day (random grand mal) or on awakening (awakening grand mal), and juvenile absence epilepsy (JAE). We looked for a gene common to all these IGEs, but we also investigated linkage to specific subforms of IGE. We found evidence for linkage to chromosome 8 in adolescent-onset IGE families in which JME was not present. The maximum multipoint LOD score was 3.24 when family members with IGE or generalized spike-and-waves (SW) were considered affected. The LOD score remained very similar (3.18) when clinically normal family members with SW were not considered to be affected. Families with either pure grand mal epilepsy or absence epilepsy contributed equally to the positive LOD score. The area where the LOD score reaches the maximum encompasses the location of the gene for the b3-subunit of the nicotinic acetylcholine receptor (CHRNB3), thus making this gene a possible candidate for these specific forms of adolescent-onset IGE. The data excluded linkage of JME to this region. These results indicate genetic heterogeneity within IGE and provide no evidence, on chromosome 8, for a gene common to all IGEs.
Adrenocorticotropic hormone (ACTH) in gel form is increasingly being used in the treatment of a v... more Adrenocorticotropic hormone (ACTH) in gel form is increasingly being used in the treatment of a variety of childhood seizure disorders. The therapy involves intramuscular injections and can be associated with significant morbidity. A teaching/learning plan for parents or caregivers based on Knowles&amp;amp;#39; theory of adult learning was developed and incorporated into the ACTH protocol presented here. Twenty-nine families completed this protocol. Despite a wide range of educational levels and support systems, all caregivers proved capable of administering the medication. Few complications were encountered. In interviews with the caregivers regarding the teaching-learning process, caregivers believed it contributed to their ability to complete the therapeutic program.
We examined EEG findings from an ongoing study of 347 children with a first unprovoked seizure. E... more We examined EEG findings from an ongoing study of 347 children with a first unprovoked seizure. EEGs were available in 321 (93%), and 135 (42%) had an abnormal EEG. EEG abnormalities included focal spikes (n = 77), generalized spike and wave discharges (n = 28), slowing (n = 43), and nonspecific abnormalities (n = 7). Abnormal EEGs were more common in children with remote symptomatic seizures (60%) than in those with idiopathic seizures (38%) (p < 0.003), more common in partial seizures (56%) than in generalized seizures (35%) (p < 0.001), and more common in children age >3 years (52%) than in younger children (12%) (p < 0.001).
Juvenile myoclonic epilepsy (JME) is a distinct epileptic syndrome with a complex mode of inherit... more Juvenile myoclonic epilepsy (JME) is a distinct epileptic syndrome with a complex mode of inheritance. Several studies found evidence for a locus involved in JME on chromosome 6 near the HLA region. Recently, Elmslie et al. [1997] reported evidence of linkage in JME to chromosome 15q14 assuming a recessive mode of inheritance with 50% penetrance and 65% linked families. The area on chromosome 15q14 encompasses the location of the gene for the alpha-7 subunit of the nicotinic acetylcholine receptor. This could fit the hypothesis that there are two interacting loci, one on chromosome 6 and on chromosome 15 or that there is genetic heterogeneity in JME. In an independent dataset of JME families, we tested for linkage to chromosome 15 but found little evidence for linkage. Moreover, families with more than one family member affected with JME provide a lodscore of 3.4 for the HLA-DR/DQ haplotype on chromosome 6. The lodscore for these same families on chromosome 15q14 is &amp;amp;amp;amp;lt;-2 assuming homogeneity and the maximum lodscore is 0.2 assuming alpha =.25. Only one of these families has a negative lodscore on chromosome 6 and a positive lodscore of 0.5 on chromosome 15q14. Our results indicate that this possible gene on chromosome 15 plays at most a minor role in our JME families. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:49-52, 2000.
Evidence for genetic influences in epilepsy is strong, but reports identifying specific chromosom... more Evidence for genetic influences in epilepsy is strong, but reports identifying specific chromosomal origins of those influences conflict. One early study reported that human leukocyte antigen (HLA) markers were genetically linked to juvenile myoclonic epilepsy (JME); this was confirmed in a later study. Other reports did not find linkage to HLA markers. One found evidence of linkage to markers on chromosome 15, another to markers on chromosome 6, centromeric to HLA. We identified families through a patient with JME and genotyped markers throughout chromosome 6. Linkage analysis assuming equal malefemale recombination probabilities showed evidence for linkage (LOD score 2.5), but at a high recombination fraction (v), suggesting heterogeneity. When linkage analysis was redone to allow independent male-female vs, the LOD score was significantly higher (4.2) at a male-female v of .5, .01. Although the overall pattern of LOD scores with respect to male-female v could not be explained solely by heterogeneity, the presence of heterogeneity and predominantly maternal inheritance of JME might explain it. By analyzing loci between HLA-DP and HLA-DR and stratifying the families on the basis of evidence for or against linkage, we were able to show evidence of heterogeneity within JME and to propose a marker associated with the linked form. These data also suggest that JME may be predominantly maternally inherited and that the HLA-linked form is more likely to occur in families of European origin.
A B S T R A C T Uncomplicated childhood-onset epilepsy is associated with increased brain amyloid... more A B S T R A C T Uncomplicated childhood-onset epilepsy is associated with increased brain amyloid load at late middle age, but its possible association with Alzheimer-type neurodegenerative processes is unclear. After 50-year follow-up, 42 childhood onset epilepsy subjects and 45 matched controls were investigated with [ 18 F]fluorodeoxyglucose PET. There were no significant differences between the subjects and controls, but higher [ 18 F]fluorodeoxyglucose uptake was associated with a higher local amyloid load (as measured with [ 11 C]PIB PET) in the prefrontal cortex, parietal cortex, and posterior cingulate/precuneus in subjects but not in controls. These findings parallel reported observations in cognitively normal individuals with increased brain amyloid accumulation who are at risk for future Alzheimer's disease.
The purpose of this project was to characterize brain structure and organization in persons with ... more The purpose of this project was to characterize brain structure and organization in persons with active and remitted childhood onset epilepsy 50 years after diagnosis compared with healthy controls. Participants from a population-based investigation of uncomplicated childhood onset epilepsy were followed up 5 decades later. Forty-one participants had a history of childhood onset epilepsy (mean age of onset 5 5.2 years, current chronological age 5 56.0 years) and were compared with 48 population-based controls (mean age 5 55.9 years). Of the epilepsy participants, 8 had persisting active epilepsy and in 33 the epilepsy had remitted. All participants underwent 3T MRI with subsequent vertex analysis of cortical volume, thickness, surface area and gyral complexity. In addition, cortical and subcortical volumes, including regions of the frontal, parietal, temporal, and occipital lobes, and subcortical structures including amygdala, thalamus, and hippocampus, were analyzed using graph theory techniques. There were modest group differences in traditional vertex-based analyses of cortical volume, thickness, surface area and gyral index, as well as across volumes of subcortical structures, after correction for multiple comparisons. Graph theory analyses revealed suboptimal topological structural organization with enhanced network segregation and reduced global integration in the Additional Supporting Information may be found in the online
IMPORTANCE The effect of childhood epilepsy on later-life cognitive and brain health is an unclea... more IMPORTANCE The effect of childhood epilepsy on later-life cognitive and brain health is an unclear and little-explored issue. OBJECTIVE To determine whether adults with a history of childhood-onset epilepsy exhibit increased brain amyloid accumulation, possibly predisposing to accelerated cognitive impairment or even frank cognitive disorders in later life. DESIGN, SETTING, AND PARTICIPANTS Forty-one adults from a population-based cohort of individuals with childhood-onset epilepsy in southwestern Finland, together with 46 matched population-based controls, underwent amyloid ligand carbon 11–labeled Pittsburgh Compound B (PiB) positron emission tomography after long-term prospective follow-up. The PiB uptake was quantified as a region to cerebellar cortex ratio. Tracer uptake was evaluated visually and analyzed voxel by voxel over the entire brain to investigate the spatial distribution of amyloid deposition. The study was conducted MAIN OUTCOMES AND MEASURES Brain amyloid accumulation. RESULTS The 41 individuals with epilepsy were originally enrolled in the Turku Adult Childhood Onset Epilepsy study at the mean (SD) age of 5.1 (4.5) years (range, 0-14 years). After a mean 52.5 (4.0) years of follow-up, the participants were evaluated (26 [63%] were women; the mean [SD] age was 56.0 [4.3] years). Nine individuals with childhood-onset epilepsy (22%) and 3 control participants (7%) had a visually abnormal PiB scan showing high cortical uptake in at least 1 of the evaluated brain regions (P = .04). In semiquantitative analyses, there was a significant interaction effect indicating higher prefrontal cortex uptake in apolipoprotein E (APOE) ε4 allele carriers than in noncarriers in participants (mean [SD], 1.66 [0.41] vs 1.43 [0.15]) compared with controls (1.40 [0.26) vs 1.41 [0.12]) (group × APOE interaction, F = 6.8; P = .01). In addition, there was a significant group effect showing higher tracer uptake in participants compared with controls (group effect, F = 8.0; P = .006). CONCLUSIONS AND RELEVANCE Adults with childhood-onset epilepsy, particularly APOE ε4 carriers, have an increased brain amyloid load at late middle age. Thus, epilepsy is linked with a biomarker that might be related to accelerated brain aging and can be considered a neurobiological predisposition to later-life cognitive disorders.
This study investigated the short-term response to a standardized hormonal therapy protocol for t... more This study investigated the short-term response to a standardized hormonal therapy protocol for treatment of infantile spasms. Twenty-seven children with video electroencephalography (EEG)-confirmed infantile spasms received very high dose (8 mg/kg/day, max 60 mg/day) oral prednisolone for 2 weeks. Response (absence of both hypsarrhythmia and spasms) to prednisolone was ascertained by repeat overnight video-EEG. Responders were tapered over 2 weeks and nonresponders were immediately transitioned to high dose (150 IU/m(2)/day) intramuscular adrenocorticotropic hormone (ACTH) for two additional weeks. Response was again determined by overnight video-EEG after ACTH therapy. Sixty-three percent (17/27) of patients responded completely to prednisolone. Subsequently, 40% (4/10) of prednisolone nonresponders exhibited a complete response after an additional 2-week course with ACTH. Among 27 subjects with median follow-up of 13.5 months (interquartile range [IQR] 4.8-25.9), 12% (2/17) of prednisolone responders and 50% (2/4) of ACTH responders experienced a relapse between 2 and 9 months after initial response. Very high dose prednisolone demonstrated significantly higher efficacy than previously reported for lower doses in prior studies. High dose ACTH may be superior to very high dose prednisolone, and in lieu of a definitive clinical trial, the choice between prednisolone and ACTH for initial treatment of infantile spasms remains controversial.
I n a prospective study, antiepileptic drugs were discontinued in 264 children with epilepsy afte... more I n a prospective study, antiepileptic drugs were discontinued in 264 children with epilepsy after a mean seizure-free interval of 2.9 years. They were then followed for a mean of 58 months to ascertain whether seizures recurred. Seizures recurred in 95 (36%) of the children. Etiology was a significant predictor of outcome (relative risk [RRI = 1.81). O n multivariable analysis, significant factors in the idiopathic group included age at onset above 12 years (RR = 5.4), a family history of seizures (RR = 3,1), the presence of slowing on the electroencephalogram prior to medication withdrawal (RR = 2.4), and a history of atypical febrile seizures (RR = 2.8). Specific epileptic syndromes such as juvenile myoclonic epilepsy and benign rolandic epilepsy were also significant predictors of outcome. I n the remote symptomatic group, significant predictors of outcome included age at onset older than 12 years (RR = 3.6), moderate to severe mental retardation (IQ < 50) (RR = 2.8), a history of atypical febrile seizures (RR = 2.0), and a history of absence seizures (RR = 0.4). The majority of children with epilepsy in remission while on antiepileptic drug therapy will remain seizure free when medications are withdrawn. A few readily available parameters distinguish those with a good prognosis from those in whom seizures are likely to recur. These data provide the framework for the clinical decision making for withdrawal of medications in these children. Shinnar S, Berg AT, MoshC SL, Kang H, O'Dell C, Alemany hi, Goldensohn ES, Hauser WA. Discontinuing antiepileptic drugs in children with epilepsy: a prospective study. Ann Neurol 1994;35:514-565
Linkage analysis identified a chromosome 18 locus predisposing to a number of adolescent-onset IG... more Linkage analysis identified a chromosome 18 locus predisposing to a number of adolescent-onset IGEs. We report a single-nucleotide polymorphism (SNP) association analysis of the region around the marker locus with the high LOD score. This analysis, which used both case-control and family-based association methods, yielded strong evidence that malic enzyme 2 (ME2) is the gene predisposing to IGE. We also observed association among subgroups of IGE syndromes. An ME2-centered nine-SNP haplotype, when present homozygously, increases the risk for IGE (odds ratio 6.1; 95% confidence interval 2.9-12.7) compared with any other genotype. Both the linkage analysis and the association analysis support recessive inheritance for the locus, which is compatible with the fact that ME2 is an enzyme. ME2 is a genome-coded mitochondrial enzyme that converts malate to pyruvate and is involved in neuronal synthesis of the neurotransmitter g-aminobutyric acid (GABA). The results suggest that GABA synthesis disruption predisposes to common IGE and that clinical seizures are triggered when mutations at other genes, or perhaps other insults, are present.
Idiopathic generalized epilepsy (IGE) is a common, complex disease with an almost exclusively gen... more Idiopathic generalized epilepsy (IGE) is a common, complex disease with an almost exclusively genetic etiology but with variable phenotypes. Clinically, IGE can be divided into different syndromes. Varying lines of evidence point to the involvement of several interacting genes in the etiology of IGE. We performed a genome scan in 91 families ascertained through a proband with adolescent-onset IGE. The IGEs included juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), and epilepsy with generalized tonic clonic seizures (EGTCS). Our linkage results support an oligogenic model for IGE, with strong evidence for a locus common to most IGEs on chromosome 18 (lod score 4.4/5.2 multipoint/ two-point) and other loci that may influence specific seizure phenotypes for different IGEs: a previously identified locus on chromosome 6 for JME (lod score 2.5/4.2), a locus on chromosome 8 influencing non-JME forms of IGE (lod score 3.8/2.5), and, more tentatively, two newly discovered loci for absence seizures on chromosome 5 (lod scores 3.8/2.8 and 3.4/1.9). Our data also suggest that the genetic classification of different forms of IGE is likely to cut across the clinical classification of these subforms of IGE. We hypothesize that interactions of different combinations of these loci produce the related heterogeneous phenotypes seen in IGE families.
Pediatric experience with gabapentin (GBP), a new antiepileptic drug (AED), is limited. We descri... more Pediatric experience with gabapentin (GBP), a new antiepileptic drug (AED), is limited. We described 3 learning disabled children, 1 aged 7 and 2 aged 10 years, with intractable partial seizures who developed severe behavioral problems while receiving modest doses of GBP. The children became hyperactive and had explosive outburst consisting of aggressive and oppositional behavior. The behavioral problems were sufficiently severe to require discontinuation of GBP despite moderately improved seizure control.
This study assessed the utility of rectal diazepam gel in the home management of prolonged or rep... more This study assessed the utility of rectal diazepam gel in the home management of prolonged or repetitive seizures in children. Thirty-eight children being prescribed rectal diazepam gel by their clinician were prospectively recruited. Seizures, rectal diazepam use, emergency department visits, and quality of life data before and after study entry were recorded. The 38 children included 14 (37%) with complex febrile seizures, and 24 with epilepsy (n = 22) or a single seizure (n = 2). There were 23 (61%) children with prolonged seizures and 15 (39%) with repetitive seizures. During the 6-month follow-up period, 12 children experienced 26 seizures which met the criteria for rectal diazepam administration. Rectal diazepam gel was administered to 8 children on 19 occasions. In 16 (84%) of these episodes, seizures stopped and no emergency department visit was required. Parental stress was decreased between baseline and 6 months in both the overall group and in all the subgroups. Home use of rectal diazepam gel is effective in aborting seizure activity, often avoiding an emergency department visit. Its use reduces morbidity and costs associated with hospital visits and provides parents a treatment option for home management of prolonged or repetitive seizures.
Several loci and candidate genes for epilepsies or epileptic syndromes map or have been suggested... more Several loci and candidate genes for epilepsies or epileptic syndromes map or have been suggested to map to chromosome 8. We investigated families with adolescent-onset idiopathic generalized epilepsy (IGE), for linkage to markers spanning chromosome 8. The IGEs that we studied included juvenile myoclonic epilepsy (JME), epilepsy with only generalized tonic-clonic seizures occurring either randomly during the day (random grand mal) or on awakening (awakening grand mal), and juvenile absence epilepsy (JAE). We looked for a gene common to all these IGEs, but we also investigated linkage to specific subforms of IGE. We found evidence for linkage to chromosome 8 in adolescent-onset IGE families in which JME was not present. The maximum multipoint LOD score was 3.24 when family members with IGE or generalized spike-and-waves (SW) were considered affected. The LOD score remained very similar (3.18) when clinically normal family members with SW were not considered to be affected. Families with either pure grand mal epilepsy or absence epilepsy contributed equally to the positive LOD score. The area where the LOD score reaches the maximum encompasses the location of the gene for the b3-subunit of the nicotinic acetylcholine receptor (CHRNB3), thus making this gene a possible candidate for these specific forms of adolescent-onset IGE. The data excluded linkage of JME to this region. These results indicate genetic heterogeneity within IGE and provide no evidence, on chromosome 8, for a gene common to all IGEs.
Adrenocorticotropic hormone (ACTH) in gel form is increasingly being used in the treatment of a v... more Adrenocorticotropic hormone (ACTH) in gel form is increasingly being used in the treatment of a variety of childhood seizure disorders. The therapy involves intramuscular injections and can be associated with significant morbidity. A teaching/learning plan for parents or caregivers based on Knowles&amp;amp;#39; theory of adult learning was developed and incorporated into the ACTH protocol presented here. Twenty-nine families completed this protocol. Despite a wide range of educational levels and support systems, all caregivers proved capable of administering the medication. Few complications were encountered. In interviews with the caregivers regarding the teaching-learning process, caregivers believed it contributed to their ability to complete the therapeutic program.
We examined EEG findings from an ongoing study of 347 children with a first unprovoked seizure. E... more We examined EEG findings from an ongoing study of 347 children with a first unprovoked seizure. EEGs were available in 321 (93%), and 135 (42%) had an abnormal EEG. EEG abnormalities included focal spikes (n = 77), generalized spike and wave discharges (n = 28), slowing (n = 43), and nonspecific abnormalities (n = 7). Abnormal EEGs were more common in children with remote symptomatic seizures (60%) than in those with idiopathic seizures (38%) (p < 0.003), more common in partial seizures (56%) than in generalized seizures (35%) (p < 0.001), and more common in children age >3 years (52%) than in younger children (12%) (p < 0.001).
Juvenile myoclonic epilepsy (JME) is a distinct epileptic syndrome with a complex mode of inherit... more Juvenile myoclonic epilepsy (JME) is a distinct epileptic syndrome with a complex mode of inheritance. Several studies found evidence for a locus involved in JME on chromosome 6 near the HLA region. Recently, Elmslie et al. [1997] reported evidence of linkage in JME to chromosome 15q14 assuming a recessive mode of inheritance with 50% penetrance and 65% linked families. The area on chromosome 15q14 encompasses the location of the gene for the alpha-7 subunit of the nicotinic acetylcholine receptor. This could fit the hypothesis that there are two interacting loci, one on chromosome 6 and on chromosome 15 or that there is genetic heterogeneity in JME. In an independent dataset of JME families, we tested for linkage to chromosome 15 but found little evidence for linkage. Moreover, families with more than one family member affected with JME provide a lodscore of 3.4 for the HLA-DR/DQ haplotype on chromosome 6. The lodscore for these same families on chromosome 15q14 is &amp;amp;amp;amp;lt;-2 assuming homogeneity and the maximum lodscore is 0.2 assuming alpha =.25. Only one of these families has a negative lodscore on chromosome 6 and a positive lodscore of 0.5 on chromosome 15q14. Our results indicate that this possible gene on chromosome 15 plays at most a minor role in our JME families. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:49-52, 2000.
Evidence for genetic influences in epilepsy is strong, but reports identifying specific chromosom... more Evidence for genetic influences in epilepsy is strong, but reports identifying specific chromosomal origins of those influences conflict. One early study reported that human leukocyte antigen (HLA) markers were genetically linked to juvenile myoclonic epilepsy (JME); this was confirmed in a later study. Other reports did not find linkage to HLA markers. One found evidence of linkage to markers on chromosome 15, another to markers on chromosome 6, centromeric to HLA. We identified families through a patient with JME and genotyped markers throughout chromosome 6. Linkage analysis assuming equal malefemale recombination probabilities showed evidence for linkage (LOD score 2.5), but at a high recombination fraction (v), suggesting heterogeneity. When linkage analysis was redone to allow independent male-female vs, the LOD score was significantly higher (4.2) at a male-female v of .5, .01. Although the overall pattern of LOD scores with respect to male-female v could not be explained solely by heterogeneity, the presence of heterogeneity and predominantly maternal inheritance of JME might explain it. By analyzing loci between HLA-DP and HLA-DR and stratifying the families on the basis of evidence for or against linkage, we were able to show evidence of heterogeneity within JME and to propose a marker associated with the linked form. These data also suggest that JME may be predominantly maternally inherited and that the HLA-linked form is more likely to occur in families of European origin.
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Papers by Shlomo Shinnar