Gregory D. Cascino

De novo mutations in epileptic encephalopathies

Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox–Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10−3). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10−10 and P = 7.8 × 10−12, respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10−8), as has been reported previously for autism spectrum disorders.

Incidence and risk factors in sudden unexpected death in epilepsy: A prospective cohort study

Objective: To determine incidence of and risk factors for sudden unexpected death in epilepsy (SUDEP). Methods: Three epilepsy centers enrolled 4,578 patients and prospectively followed these patients for 16,463 patient-years. The cohort was screened for death annually. Deaths were investigated to determine whether SUDEP occurred. Potential risk factors were compared in SUDEP cases and in controls enrolled contemporaneously at the same center. Results: Incidence of SUDEP was 1.21/1,000 patient-years and was higher among women (1.45/1,000) than men (0.98/1,000). SUDEP accounted for 18% of all deaths. Occurrence of tonic-clonic seizures, treatment with more than two anticonvulsant medications, and full-scale IQ less than 70 were independent risk factors for SUDEP. The number of tonic-clonic seizures was a risk factor only in women. The presence of cerebral structural lesions and use of psychotropic drugs at the last visit were not risk factors for SUDEP in this cohort. Subtherapeutic anticonvulsant levels at the last visit were equally common in the two groups. No particular anticonvulsant appeared to be associated with SUDEP. Conclusions: These results support the idea that tonic-clonic seizures are an important proximate cause of SUDEP. This information creates a risk profile for SUDEP that may help direct preventative efforts.

Population-based study of the incidence of sudden unexplained death in epilepsy

Objective: To determine the population-based incidence of sudden unexplained death in epilepsy (SUDEP) and to determine the risk of SUDEP compared with the general population. Background: Prior studies of SUDEP have described a wide range of incidence and have suffered from selection bias and other methodologic limitations. A population-based study of the incidence of SUDEP has never been performed. Furthermore, the risk of sudden death in the epilepsy population has not been compared with that of the general population. Methods: All deaths in persons whose epilepsy was diagnosed between 1935 and 1994 in Rochester, MN, were reviewed. The rate of SUDEP was compared with the expected rate of sudden death in the general population for patients age 20 to 40 years to determine the standardized mortality ratio (SMR). Results: We identified nine cases of SUDEP. SUDEP accounted for 8.6% (7 of 81) of the deaths in persons 15 to 44 years of age. The incidence of SUDEP was 0.35 per 1,000 person-years. SMR for SUDEP was 23.7 (95% confidence interval, 7.7 to 55.0) compared with the general population. Conclusions: The incidence of SUDEP in our study was 0.35 per 1,000 person-years. SUDEP was responsible for 1.7% of deaths in our cohort. SUDEP is a rare cause of death in the epilepsy population but exceeds the expected rate of sudden death in the general population by nearly 24 times.

Incidence of status epilepticus in Rochester, Minnesota, 1965-1984

We determined the incidence of status epilepticus (SE) by ascertaining all first episodes of SE in Rochester, Minnesota through the Rochester Epidemiology Projects records-linkage system between January 1, 1965 and December 31, 1984. Information was collected on age, gender, duration, seizure type, and etiology. The age-adjusted incidence of SE was 18.3 per 100,000 population. SE incidence was U-shaped, peaking under 1 year and over 60 years of age. The incidence of SE was greater for males than for females, for acute symptomatic etiology than any other etiology, and for partial SE that did not generalize than any other seizure type. Status of long duration(at least 2 hours) occurred more frequently among infants and the elderly than among persons aged 1 to 65 years. Cumulative incidence was 4 per 1,000 to age 75 and showed the greatest increase after age 60. Given the aging of the population, SE will become an increasingly important public health problem.

Short-term Mortality after a first episode of status epilepticus

Summary: Purpose: Studies evaluating short‐term mortality among people who experience status epilepticus (SE) have produced conflicting results. Most studies are derived from clinical series with results affected by unspecified follow‐up period and select referral of cases. This study was planned to evaluate short‐term mortality after a first episode of SE.

Gelastic seizures and hypothalamic hamartomas Evaluation of patients undergoing chronic intracranial EEG monitoring and outcome of surgical treatment

We retrospectively studied 12 consecutive patients with gelastic seizures and hypothalamic hamartomas who, because of intractable epilepsy, underwent chronic intracranial EEG monitoring or epilepsy surgery. All patients had medically refractory seizures that included laughter as an ictal behavior (gelastic seizures). The hypothalamic hamartomas were identified with neuroimaging studies (12 of 12) and by pathologic verification (four of 12). Associated clinical features included behavioral disorders (n = 5), developmental delay (n = 4), and precocious puberty (n = 2). Interictal extracranial EEG predominantly showed bihemispheric epileptiform changes suggesting a secondary generalized epileptic disorder. Intracranial EEG recordings, performed in eight patients, indicated the apparent focal onset of seizure activity (anterior temporal lobe [n = 7] and frontal lobe [n = 1]). None of the seven patients who underwent a focal cortical resection, however, experienced a significant reduction in seizure tendency. An anterior corpus callosotomy, performed in two patients with symptomatic generalized epilepsy, resulted in a worthwhile reduction in drop attacks. Results of this study may modify the surgical strategies in patients with gelastic seizures and hypothalamic hamartomas.

Factors predictive of the outcome of frontal lobe epilepsy surgery.

Summary: Purpose: To identify factors that predict the outcome in seizure control after frontal lobe epilepsy surgery (FLES). FLES is the second most frequent type of epilepsy surgery, but the results are generally not as good as those after anterior temporal lobectomy.

Long-term mortality after a first episode of status epilepticus

ObjectiveTo evaluate long-term mortality among people with status epilepticus (SE). MethodsThe authors performed a population-based retrospective cohort study to determine long-term mortality after SE. Between January 1, 1965, and December 31, 1984, all first episodes of SE receiving medical attention were ascertained through the Rochester Epidemiology Project Records-Linkage System. Cases surviving the first 30 days (n = 145) were followed until death or study termination (February 1996). ResultsAt 10 years, cumulative mortality among 30-day survivors was 43%. The standardized mortality ratio (SMR) at 10 years was 2.8 (95% CI, 2.1–3.5). The mortality rate of those with idiopathic/cryptogenic SE was not increased (SMR = 1.1; 95% CI, 0.5–2.3). The following characteristics of SE increased long-term risk for mortality: SE ≥ 24 hours in duration vs SE < 2 hours (relative risk [RR] = 2.3; 95% CI, 1.1–5.1); acute symptomatic etiology vs idiopathic/cryptogenic etiology (RR = 2.2; 95% CI, 1.0–5.1) SE; myoclonic SE vs generalized convulsive SE (RR = 4.0; 95% CI, 1.3–13). ConclusionForty percent of subjects who survived the first 30 days after an incident episode of SE die within the next 10 years. The long-term mortality rate was threefold that of the general population over the same time period. The long-term mortality rate at 10 years was worse for those with myoclonic SE, for those who presented with SE lasting more than 24 hours, and for those with acute symptomatic SE. The long-term mortality rate was not altered in those with idiopathic/cryptogenic SE. We conclude that SE alone does not modify long-term mortality.

Routine EEG and temporal lobe epilepsy: Relation to long-term EEG monitoring, quantitative MRI, and operative outcome

Summary: Purpose: To investigate the relation among routine EEG, long‐term EEG monitoring (LTM), quantitative magnetic resonance imaging (MRI), and surgical outcome in temporal lobe epilepsy (TLE).

Epilepsy and Brain Tumors: Implications for Treatment

Summary: Primary intraparenchymal tumors of the brain are important etiologic factors in partial or focal epilepsy. Indolent low‐grade gliomas may be associated with a long‐standing seizure disorder refractory to medical treatment. Surgical resection of the neoplasm and the epileptogenic area may render patients seizure‐free. Removal of the tumor alone may also be associated with an excellent survival rate and surgical outcome. Conventional neurosurgical procedures are restricted in patients with tumors that are deep‐seated lesions or involve functional cerebral cortex. Computer‐assisted stereotactic surgical procedures have been developed for biopsy and resection of intra‐axial brain‐mass lesions. Stereotactic tumor resection may allow pathological determination of intracranial lesions and produce a worthwhile reduction in seizure activity in some patients with intractable partial epilepsy.