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Objective: To describe the phenotypes and penetrance of paroxysmal kinesigenic dyskinesia (PKD), a movement disorder characterized by attacks of involuntary movements occurring after sudden movements, infantile convulsion and choreoathetosis (ICCA) syndrome, and benign familial infantile convulsions (BFIC), caused by PRRT2 mutations., Methods: We performed clinical and genetic studies in 3 large families with ICCA, 2 smaller families with PKD, and 4 individuals with sporadic PKD. Migraine was also present in several individuals., Results: We detected 3 different PRRT2 heterozygous mutations: the recurrent p.Arg217Profs*8 mutation, previously reported, was identified in 2 families with ICCA, 2 families with PKD, and one individual with sporadic PKD; one novel missense mutation (p.Ser275Phe) was detected in the remaining family with ICCA; and one novel truncating mutation (p.Arg217*) was found in one individual with sporadic PKD. In the 2 remaining individuals with sporadic PKD, PRRT2 mutations were not detected. Importantly, PRRT2 mutations did not cosegregate with febrile convulsions or with migraine. The estimated penetrance of PRRT2 mutations was 61%, if only the PKD phenotype was considered; however, if infantile convulsions were also taken into account, the penetrance was nearly complete. Considering our findings and those reported in literature, 23 PRRT2 mutations explain ∼56% of the families analyzed., Conclusions: PRRT2 mutations are the major cause of PKD or ICCA, but they do not seem to be involved in the etiology of febrile convulsions and migraine. The identification of PRRT2 as a major gene for the PKD-ICCA-BFIC spectrum allows better disease classification, molecular confirmation of the clinical diagnosis, and genetic testing and counseling.

Objective: We report the prospective follow-up of a cohort of people from the onset of febrile seizures for a median of 24 years to estimate the long-term risk of developing epilepsy., Methods: The National General Practice Study of Epilepsy is a large prospective community study of 1,195 people with a first suspected seizure followed from the 1980s, of whom 220 (18%) had febrile seizures. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) for subsequent epilepsy were calculated in 5-year age bands., Results: Follow-up information was obtained for 181 (83%) people with a mean follow-up for the whole cohort of 21.6 (SD 6.0) years. Of these, 175 (97%) were seizure-free in the preceding 5 years, whereas 171 (94%) were seizure-free and off antiepileptic drugs. Six percent developed epilepsy, but the risk of developing epilepsy in the cohort over the whole follow-up period was almost 10 times that of the general population (SIR 9.7, 95% CI 5.7-16.4). The SIR was significantly elevated in the 0- to 14-year age groups but not in the 15- to 19-year age group (SIR 4.5, 95% CI 0.6-32.1)., Conclusion: The risk of developing epilepsy in people who had febrile seizures seems to decrease with time. Further long-term studies are needed to confirm this.

Objective: Most mutations in SCN1A-related epilepsies are novel and when an infant presents with febrile seizures (FS) it is uncertain if they will have simple FS, FS+, or develop a severe epilepsy such as Dravet syndrome. Our objective was to examine whether the nature of a SCN1A mutation affects the epilepsy phenotype., Methods: We retrospectively evaluated clinical and genetic data from 273 individuals with SCN1A mutations identified in our laboratory and reviewed data from 546 published cases. We examined whether the mutation class or distribution or nature of amino acid substitution correlated with the epilepsy phenotype, using the Grantham Score (GS) as a measure of physicochemical difference between amino acids., Results: Compared to missense mutations, truncating mutations were associated with earlier mean onset of prolonged seizures (7.4 vs 8.8 months; p = 0.040), myoclonic seizures (16.4 vs 19.4 months; p = 0.041), and atypical absence seizures (19.1 vs 30.6 months; p = 0.001). The median GS was higher in patients with Dravet syndrome compared to polymorphisms (94 vs 58; p = 0.029) and orthologs (94 vs 45; p < 0.001). A high GS was correlated with early onset of seizures (r(s) = -0.235; p = 0.008). Missense mutations occurred most frequently in the voltage and ion-pore regions where changes in amino acid polarity were greater in the Dravet group compared to the genetic epilepsy with febrile seizures plus group (3.6 vs 2.7; p = 0.031)., Conclusions: These findings help define the clinical significance of specific SCN1A mutations based on mutation class and amino acid property and location.

Objective: Hemiconvulsion-hemiplegia-epilepsy (HHE) syndrome is an uncommon consequence of prolonged febrile convulsive seizures in infancy and early childhood. Delayed epilepsy in HHE syndrome is frequently intractable to medical treatment. The present study evaluated the role and prognosis of surgical treatment in patients with delayed epilepsy of HHE syndrome., Methods: We included 26 consecutive patients who were diagnosed with HHE syndrome and underwent surgical treatment for delayed epilepsy at Seoul National University Hospital. The multidisciplinary presurgical evaluations included brain MRI, video-EEG monitoring, FDG-PET, and ictal SPECT. Anterior temporal lobectomy (ATL), cortical resection, functional hemispherectomy, and callosotomy were performed according to the results of presurgical evaluations., Results: Patients were grouped into either the temporal lobe epilepsy (TLE) group (n = 12) or the neocortical/multifocal epilepsy group (n = 14) according to the results of presurgical evaluations. Patients were included in the TLE group if there was strong evidence that the mesial temporal lobe was the only ictal-onset area. The other patients were included in the neocortical/multifocal group. There were no significant differences in demographic characteristics between the two groups. All patients in the TLE group became seizure-free after ATL, but only four patients became seizure-free, and additional two patients showed improvement after various surgical procedures in the neocortical/multifocal group (p = 0.002)., Conclusion: Surgical intervention may be helpful in patients with delayed epilepsy in hemiconvulsion-hemiplegia-epilepsy (HHE) syndrome, especially if the mesial temporal lobe appears to be the only epileptogenic area, regardless of the presence of additional abnormalities seen with neuroimaging. Therefore, surgical treatment should be considered for selected patients with delayed epilepsy in HHE syndrome.

Objective: To characterize the clinical and radiologic features of hemiparkinsonism-hemiatrophy syndrome (HPHA)., Methods: Medical records of patients with evidence of unilateral parkinsonism and ipsilateral body atrophy, evaluated at the Baylor College of Medicine Movement Disorders Clinic, were reviewed., Results: The mean age at onset of the 30 patients who satisfied the criteria was 44.2 (15 to 63) years with a mean duration of symptoms for 9.7 (2 to 20) years. Half of all patients had dystonia at onset and dystonia was present in 21 (70%) patients during the course of the syndrome. Eleven (37%) also had scoliosis. Brain asymmetry on imaging studies was noted in 9 (30%) patients. Response to levodopa was rated as good in 18, moderate in 6, and poor in 6. Nine of 19 (47%) patients in whom birth history was available had difficult birth or had severe febrile illness in the first few months of life. Overall 10 (33%) patients had difficulty in walking during early childhood., Conclusion: Although the clinical features of hemiparkinsonism-hemiatrophy syndrome are variable, suggesting a heterogeneous pathogenesis, perinatal and early childhood cerebral injury appears to play an important role in about half of the cases.

Background: Generalized epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant syndrome characterized by febrile seizures (FS) and a variety of afebrile generalized seizure types. GEFS+ has previously been linked to mutations in two genes encoding the voltage-gated sodium channel alpha-subunit (SCN1A) and beta1-subunit (SCN1B). We studied a large family with FS and partial as well as generalized seizure types., Methods: All but two living affected family members were interviewed and examined. Information on deceased affected family members was sought. EEG for 11 affected family members and one unaffected family member were obtained. Genetic linkage analysis and mutation screening of SCN1A were performed on blood samples from 16 affected individuals and their first-degree relatives., Results: There were 27 affected family members; 18 were alive at the time of the study. All affected family members had FS; seven had FS only, and 19 also had afebrile seizures. Eleven individuals continued to have FS beyond 6 years of age. FS were complex in 12 family members, usually with prolonged duration. The index patient had right temporal lobe epilepsy and hippocampal sclerosis. Four other patients had strong historical evidence of temporal lobe epilepsy, and three others had nonlocalizing evidence of partial epilepsy. Pedigree analysis indicated autosomal dominant transmission. All affected individuals who were tested and one asymptomatic individual had a sodium channel mutation of SCN1A, an A-->C transversion at nucleotide 3809 resulting in the substitution of lysine 1270 by threonine in the D3/S2 segment (designated as K1270T)., Conclusions: Our findings indicate that partial epilepsy preceded by FS can be associated with sodium channel mutations and may represent a variant of GEFS+.

Objective: To identify characteristics in children with epilepsy that differ between those who did versus did not have a history of preceding febrile seizures., Background: Febrile seizures precede epilepsy in 10 to 15% of children. Little is known about the specific types of epilepsy associated with febrile seizures., Methods: In a community-based, prospectively identified cohort of children, the association between prior febrile seizures and characteristics of the children's epilepsy (seizure type, epilepsy syndrome, age at onset, underlying etiology, family history) were examined for 524 of the children who were aged > or =1 year at onset of epilepsy., Results: Seventy-three (13.9%) had febrile seizures. Children with febrile seizures were more likely to have a first-degree or a second-higher-degree relative with febrile seizures and less likely to have childhood absence epilepsy and absence seizures compared with children without febrile seizures. This was especially true for simple febrile seizures. There was no specific association with localization-related forms of epilepsy. Complex, but not simple, febrile seizures were associated with younger age at onset of epilepsy. There was no evidence that focal or prolonged febrile seizures were associated with localization-related epilepsy or temporal lobe epilepsy per se. Of the three children whose initial MRIs demonstrated hippocampal atrophy, none had a history of febrile seizures., Conclusions: At the time of diagnosis, febrile seizures are not specifically related to temporal lobe epilepsy or localization-related epilepsy in general. A genetic component for febrile seizures is suggested by its positive associations with family history, especially for simple febrile seizures. Complex febrile seizures represent an underlying age-dependent susceptibility.

We reviewed outcome at least 1 year after temporal lobectomy in 44 patients with bitemporal, independent, interictal epileptiform patterns on EEG. All 44 underwent preoperative intracranial monitoring. Twenty-two (50%) were seizure-free, 14 (32%) had at a least 75% reduction in seizures, and eight (18%) had less than a 75% reduction in seizures. We analyzed age of seizure onset, duration of epilepsy, gender, side of operation, history and clinical findings, findings on MRI, results of intracranial EEG-video monitoring, presence or absence of lateralizing neuropsychological deficits, and pathology of resected tissue to identify factors associated with outcome. Three factors emerged as independently associated with a good outcome: concordance of MRI abnormality and side of operation (p = 0.01), history of febrile seizures (p = 0.04), and 100% lateralization of intracranially recorded ictal onsets to the side of operation (p = 0.05). A seizure-free outcome was much more likely to occur if more than one of these factors was present: with at least two factors co-existing, 83% (15/18) of patients were seizure-free, while only 35% (7/20) were seizure-free with a single factor present (p = 0.0009). Of the six patients without any of the three factors, none were seizure-free. We conclude that it is possible to predict reasonably which patients with bitemporal epileptiform abnormalities will have a good outcome after surgery.

We performed a prospective study of neuroimaging studies and temporal lobe pathology in 13 patients with facial asymmetry and intractable partial epilepsy of temporal lobe origin. The 13 patients, derived from 50 consecutive patients with nonlesional medically refractory partial epilepsy, were deemed appropriate candidates for an anterior temporal lobectomy. The facial weakness occurred exclusively, or was most prominent, during emotional expression, ie, spontaneous smiling. The temporal lobe of seizure origin, demonstrated by ictal long-term EEG monitoring, was always contralateral to the side of weakness. All 13 patients had a history of early childhood neurologic disease, eg, complex febrile seizure or bacterial meningitis. Hippocampal formation atrophy was present in all the epileptic temporal lobes by MRI-based volume studies. Twelve of the 13 patients subsequently received an anterior temporal lobectomy, and mesial temporal sclerosis was present in all the surgically excised temporal lobes. Ten of the 12 patients have been seizure-free during short-term follow-up. Facial asymmetry may occur in patients with partial epilepsy related to remote symptomatic seizures and mesial temporal sclerosis.

Knowledge of the recurrence risk following a first unprovoked seizure and the predictors of that risk are necessary for rational treatment decisions. Published estimates of recurrence risk range from 23% to 71%. In a meta-analysis of 16 reports, three methodologic factors explained much of the reported variation: (1) study inclusion criteria, ie, whether patients were enrolled at the time of their first seizure or if patients with prior seizures were included; (2) retrospective versus prospective ascertainment of patients; (3) the interval between the first seizure and the time at which risk was assessed. The average recurrence risk across the 16 studies was 51%. The risk was 40% and 52% in prospective and retrospective studies that employed first-seizure methods and 67% in non-first seizure studies. At or near 2 years following the first seizure, the recurrence risk was 36% and 47% in prospective and retrospective first-seizure studies. The distribution of prognostic factors was also important. Seizure etiology and the EEG were the strongest predictors of recurrence distinguishing between patient subgroups, with recurrence risks as low as 24% and as high as 65%. Partial seizures were associated with an increased recurrence risk, but not consistently. There is considerable agreement among studies concerning the recurrence risk following a first seizure, and much of the discrepancies among studies can be explained by differences in study methods and distributions of important prognostic factors.

Prevalence rates in all 3-year-old children in Fuchu/Tokyo, for a 6-year survey from 1974 to 1980 (total number examined, 17,044), were 8.3% for febrile convulsion and 0.9% for afebrile convulsion. The figures in boys were higher than in girls for febrile convulsion (9.0%:7.5%), but for afebrile convulsion (0.9%:0.9%). Prevalence in a Miyake Island survey for 10 years, from 1973 to 1982 (total number examined, 543) was 9.9% for febrile and 0.4% for afebrile convulsion. Correlations among prevalence of febrile convulsion, epilepsy, and epileptic EEG abnormality in healthy children were inconsistent in geographically isolated villages identified in Miyake Island.

A cohort of 666 children who had convulsions with fever were followed to determine the risks of subsequent epilepsy. High risks were found in children with preexisting cerebral palsy or mental retardation. Other major risk factors were atypical features of the febrile convulsions (such as focal seizures) and duration of febrile seizures for 10 minuts or more. The risk of developing epilepsy by age 20 was about 6 percent for all children who had experienced febrile convulsions. However, this risk figure consisted of a combination of 2.5 percent of children without prior neurologic disorder or atypical or prolonged seizures, and 17 percent of those with such complications.

To our knowledge, this is the first population-based case-control study of risk factors for absence seizures (AS). Diagnosis of AS was based on clinical criteria. The complete medical history of potential cases, available through the records-linkage system for residents of Rochester, MN, was independently reviewed by three neurologists who agreed upon the diagnosis. All AS patients who were residents of Rochester at time of diagnosis between 1935 and 1979, and who were born in this community, were included (N = 30). Two population controls (born in Rochester) were matched to each patient, and for both patients and controls, the records-linkage system was used to obtain information about possible risk factors. The only factor significantly more common in cases than in controls was a history of febrile seizures (odds ratio = 12; p less than 0.01). We suggest that these febrile seizures represent either an early manifestation of the convulsive diathesis or the symptom of a preexisting brain dysfunction. None of the other factors investigated reached statistical significance, including those that have been previously suggested such as twin pregnancy, breech presentation at delivery, being first-born, and perinatal asphyxia. Sample size limitations should be considered in interpreting these findings.

A study was designed to investigate the effects of experimentally produced hyperthermic seizures on the brain of the developing rat. Severty-nine newborn Sprague-Dawley white rats were divided into five groups and exposed to one of the following: Nonseizure-producing hyperthermia at 5 or 15 days (febrile controls), seizure-producing hyperthermia at 5 or 15 days, or no hyperthermia (afebrile controls). As the animals matured, seven developmental reflexes were tested and there were no differences found among the five groups in the ages at which these reflexes were acquired. At age 3 1/2 months, the ability of rats to adapt to a maze, and later to solve 12 maze problems, was studied. Although there was no significant difference in the amount of time required for any of the groups to adapt to the maze, there was a significant difference in the number of maze errors made by the different groups of rats. The mean error score for the control group was 118.5, compared with 183.0 (p less than 0.001), for rats with seizures at 5 days and 161.4 (p less than 0.001), for rats which convulsed at 15 days. It is apparent that experimental induction of a single hyperthermic seizure in the young rat interferes significantly with the animal's maze-solving ability at a later age.