Rates of twinning before and after fortification of foods in the US with folic acid, Texas, 1996 to 1998.

Several investigators have reported a 40% increase in the prevalence of twinning among women who have taken folic acid or multivitamins containing folic acid at the time of conception. Given that infant morbidity and mortality are greatly increased among twins, such a large increase in twinning could have serious implications. We undertook this study to determine if US fortification of enriched cereal-grain products with folic acid was associated with an unexpected increase in the prevalence of twinning in the state of Texas. We examined 1 003 207 deliveries conceived in Texas, between 1 January 1996 and 31 December 1998. We compared the prevalence of twin deliveries conceived before, during and after fortification with folic acid, mandated to begin on 1 January 1998. Comparing pregnancies conceived in 1997 with those conceived in 1996, we observed a 2.4% yearly increase in twinning, 1.024 [0.98, 1.07]. Comparing pregnancies conceived in 1998 with those conceived in 1997, we observed a 4.6% yearly increase in twinning, 1.046 [1.00, 1.09]. These increases were adjusted for maternal age, race, education, parity and season of conception. The size and pattern of these increases are consistent with the ongoing increase in twinning of 1-4% per year which began in the US prior to fortification.

Long-term mortality after a first episode of status epilepticus.

OBJECTIVE: To evaluate long-term mortality among people with status epilepticus (SE). METHODS: The 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). RESULTS: At 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 > or = 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). CONCLUSION: Forty 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.

Are certain diuretics also anticonvulsants?

A history of diuretic use has been shown to be protective for first unprovoked seizure in adult patients. Recent animal studies suggest that certain diuretics have anticonvulsant activity. We evaluated the potential for the anticonvulsant activity of current diuretic use in a population-based, case-control study in older adults. We also tested chlorthiazide and furosemide for seizure protection in animal models of epilepsy. Concurrent medical prescription of any diuretic was protective for the development of epilepsy [odds ratio (OR) = 0.62, 95% confidence interval (CI) = 0.39-0.99]. A protective effect for current thiazide use was observed (OR = 0.53, CI = 0.31-0.90), and a protective effect for furosemide was suggested (OR = 0.44, CI = 0.1-1.9). In mice, both chlorthiazide and furosemide suppressed the occurrence of maximal electroshock-induced seizures in a dose-dependent manner. Chlorthiazide's toxic dose for 50% of animals tested (TD50) could not be achieved even with dosing as high as 1,500 mg/kg for furosemide; TD50 was 549 mg/kg. Results were similar in rats. Furosemide and chlorthiazide are protective for unprovoked seizures in an epidemiological study and in animal models. Given the potential therapeutic value for seizure control, low toxicity, and low cost, therapeutic efficacy should be explored in clinical studies.

Time trends in incidence, mortality, and case-fatality after first episode of status epilepticus.

PURPOSE: Status epilepticus (SE) is a medical emergency associated with a high mortality. Clinical series have suggested that mortality after SE has decreased. No studies have systematically examined trends in incidence, mortality, and case fatality after SE in a well-defined population. METHODS: All first episodes of SE receiving medical attention between January 1, 1935, and December 31, 1984, were ascertained through the Rochester Epidemiology Project Records-Linkage System and followed up until death or study termination (February 1, 1996). We calculated incidence rates in the 50-year period (1935-1984), while we considered mortality and case-fatality in the last 30-year period (1955-1984). RESULTS: Incidence of SE increased over time to 18.1/100,000 (1975 through 1984). The increase was related to an increased incidence in the elderly and to the advent of myoclonic SE after cardiac arrest, a condition not seen in the early decades. In the last decade, approximately 16% of the incidence was due to myoclonic SE. The mortality rates increased from 3.6 per year in the decade 1955-1965 to 4.0/100,000 per year between 1975 and 1984. The 30-day case-fatality (CF) was unchanged, although a trend toward improvement was shown after excluding myoclonic SE. CONCLUSIONS: Incidence and mortality rates of SE have increased in the last 30 years. Case fatality remained the same. The increased incidence and mortality are due to the occurrence in the last decade of myoclonic SE after cardiac arrest. The mortality in the elderly was twice that of the youngest age group, across all study periods. Changes in the age and cause distribution of SE over time are responsible for the stable survivorship. There is improvement in survivorship in the last decade when myoclonic SE is excluded.

The lifetime cost of bipolar disorder in the US: an estimate for new cases in 1998.

OBJECTIVE: To develop a cost model that estimates the total and per case lifetime cost of bipolar disorder for 1998 incident cases in the US. STUDY DESIGN: Lifetime cost simulation model. PERSPECTIVE: Societal. METHODS: Age- and gender-specific incidence of bipolar disorder in 1998 was estimated by simulation based on existing prevalence data. The course of illness and mental health service cost of 6 clinically defined prognostic groups was estimated based on the research literature and the judgement of panels of experts. Excess cost of general medical care was estimated based on claims data from a large insurer. Indirect cost was projected including excess unemployment and reduced earnings reported in the National Comorbidity Survey. Comorbidity treatment and indirect cost related to alcohol (ethanol) and drug abuse was added based on a National Institute on Drug Abuse study. RESULTS: The present value of the lifetime cost of persons with onset of bipolar disorder in 1998 was estimated at 24 billion US dollars ($US). Average cost per case ranged from $US11,720 for persons with a single manic episode to $US624,785 for persons with nonresponsive/chronic episodes. CONCLUSION: The model indicates the potential cost savings of preventing a case of bipolar disorder and underscores the importance of achieving a stable outcome in new cases to limit the economic consequences of the disorder.

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.

Pregnancy registries in epilepsy.

The risk of major malformations in the offspring of mothers with epilepsy receiving antiepileptic drugs is 4--8% compared to 2--4% in the general population. Risk factors include daily dose and polytherapy. Selected drugs have been found to be associated with a higher risk of specific malformations (congenital heart defects and cleft palate with phenytoin and barbiturates; neural tube defects with valproate and carbamazepine). Although some of these findings are unquestionable, several questions are still unsolved, depending the characteristics of the target populations, the small samples of patients, and the design and limiting factors of the published reports. In the last decade, pregnancy registries have been activated by collaborative groups of physicians in Europe (EURAP), North America (NAREP), Australia and India (the latter two recently merged into EURAP), to enroll a large number of exposed women to be monitored prospectively with standardized methods, and by three pharmaceutical companies marketing lamotrigine, gabapentin and vigabatrin, as part of their post-marketing surveillance. Even though the structure of these registries and the target populations should theoretically result in the identification of a sufficient number of women exposed to different drugs and examined for the occurrence of malformations of any type and severity, the implementation of a common database with information from the existing registries may provide valuable information in a shorter time period. Although differences between some of the registries limit the possibility to pool data, a gradual development of a collaboration is highly desirable to discuss a list of design issues and assess to what extent and how data could be compared and organized.

The risks of epilepsy after traumatic brain injury.

The aim of this study is to present the incidence of traumatic brain injury (TBI) and identify those characteristics of brain injuries that are associated with the development of seizures. We identified 5984 episodes of TBI (loss of consciousness, post-traumatic amnesia, or skull fracture) in Olmsted County, Minnesota, from 1935 to 1984. Of these, 4541 were followed for seizure. Injuries were classified as mild (loss of consciousness or amnesia less than 30 minutes), moderate (loss of consciousness 30 minutes to 1 day or a skull fracture), or severe (loss of consciousness of more than 1 day, subdural hematoma, or brain contusion). The incidence of TBI in the period from 1975 to 84 peaked at 800 per 100 000 in males aged 15-24. The relative risk of seizures was 1.5 (95 percent confidence interval 1.0-2.2) after mild injuries, but with no increase after 5 years; 2.9 (95 percent confidence interval 1.9-4.1) after moderate injuries; and 17.2 (95 percent confidence interval 12.3-23.6) after severe injuries. Significant risk factors were brain contusion with subdural hematoma, skull fracture, loss of consciousness or amnesia of 1 day or more, and age over 65 years. We conclude that TBI is a major public health problem and contributes to the occurrence of seizures and epilepsy.

Epilepsy, vagal nerve stimulation by the NCP system, all-cause mortality, and sudden, unexpected, unexplained death.

PURPOSE: This report concerns the 2-year extension of the study of mortality and sudden, unexpected, unexplained death in epilepsy (SUDEP) in the cohort of patients receiving vagal nerve stimulation by the NCP System for the treatment of epilepsy. METHODS: A cohort of 1,819 individuals was followed 3,176.3 person-years from implantation. The 25 deaths that occurred during NCP System activation were reviewed for SUDEP by a panel. RESULTS: The mortality rates were lower [standardized mortality ratio (SMR = 3.6)] with the extended follow-up compared to the previous finding (SMR = 5.3). The SUDEP rates (4.1 vs. 4.5 per 1,000 person-years) were similar to those in the previous study of this cohort. When the vagal nerve stimulation experience is stratified by duration of use, the rate of SUDEP was 5.5 per 1,000 over the first 2 years, but only 1.7 per 1,000 thereafter. CONCLUSIONS: The mortality and SUDEP rates are similar to those reported from clinical trials of new drugs and cohorts of severe epilepsy. The lower SUDEP rates after 2 years of follow-up are intriguing, but require further investigation.

The cost of epilepsy in the United States: an estimate from population-based clinical and survey data.

PURPOSE: To provide 1995 estimates of the lifetime and annual cost of epilepsy in the United States using data from patients with epilepsy, and adjusting for the effects of comorbidities and socioeconomic conditions. METHODS: Direct treatment-related costs of epilepsy from onset through 6 years were derived from billing and medical chart data for 608 population-based incident cases at two sites in different regions of the country. Indirect productivity-related costs were derived from a survey of 1,168 adult patients visiting regional treatment centers. Direct costs separate the effects of epilepsy and comorbidity conditions. Indirect costs account for the effects of other disabilities and socioeconomic conditions on foregone earnings and household activity. The estimates were applied to 1995 population figures to derive national projections of the lifetime and annual costs of the disorder. RESULTS: The lifetime cost of epilepsy for an estimated 181,000 people with onset in 1995 is projected at $11.1 billion, and the annual cost for the estimated 2.3 million prevalent cases is estimated at $12.5 billion. Indirect costs account for 85% of the total and, with direct costs, are concentrated in people with intractable epilepsy. CONCLUSIONS: Direct costs attributable to epilepsy are below previous estimates. Indirect costs adjusted for the socioeconomic conditions of patients are above previous estimates. Findings indicate that epilepsy is unique in the large proportion of costs that are productivity-related, justifying further investment in the development of effective interventions.

Major depression is a risk factor for seizures in older adults.

We tested the hypothesis that major depression meeting DSM-III-R criteria or medical therapies for depression increase the risk for unprovoked seizures. Major depression was associated with a sixfold increased risk for unprovoked seizures (95% CI, 1.56-22). The risk remained increased even when controlling for age, sex, length of medical follow-up, and medical therapies for depression. In the absence of known prior neurological insult, major depression is associated with an increased risk for unprovoked seizures.

Incidence of neonatal seizures in Harris County, Texas, 1992-1994.

This study estimated the incidence of clinical neonatal seizures among infants born between 1992 and 1994 in Harris County, Texas, a county with a large and ethnically diverse population. Infants with neonatal seizures were ascertained from four sources: hospital discharge diagnoses, birth certificates, death certificates, and a study of neonatal seizures conducted concurrently with this study at a large tertiary care center in Houston, Texas. There were 207 cases of clinical neonatal seizures among 116,048 live births (an incidence of 1.8 per 1,000 live births). The incidence was highest among infants weighing less than 1,500 g (19/1,000) and decreased as birth weight increased. There was no significant difference in incidence by ethnicity. Twenty-six percent of the seizures (54/207) occurred after the infants had been discharged from the hospital where they were born. The incidence of neonatal seizures in Harris County was lower than the incidence reported recently for Fayette County, Kentucky, for 1985-1989 (3.5/1,000) and for Newfoundland, Canada, for 1990-1995 (2.5/1,000), but was higher than the incidence estimated for Rochester, Minnesota, for 1935-1984 (1/1,000).

SUDEP: overview of definitions and review of incidence data.

The classification, occurrence, and predictors of sudden unexpected and unexplained death in individuals with epilepsy (SUDEP) have received considerable attention over the last few years. Specific criteria for the classification of definite, probable, possible, and not SUDEP implemented in United States epidemiologic studies are presented. The incidence of SUDEP in different epilepsy populations is presented. SUDEP is a real phenomenon, because the occurrence of such deaths, especially at relatively young ages, among individuals with epilepsy is far greater (perhaps 40-fold) than among those without epilepsy. SUDEP incidence rates are lower in population-based studies, higher in referral populations and clinical trials of adjunct drugs for complex partial epilepsy, and highest for surgical series. Seizure severity appears to be the strongest risk factor for SUDEP because higher rates are reported from studies of individuals with intractable epilepsy. Other potential risk factors, including sex, seizure etiology, younger age at onset, and partial-onset seizures, are unresolved.

A case-control study of diet and testicular carcinoma.

No risk factor other than cryptorchidism has been consistently associated with testicular cancer, and the influence of diet on testicular cancer risk has not been extensively explored. A few studies have found increased testicular cancer risk in men whose diets are high in fat, red meats, and milk or low in fruits and vegetables. We evaluated the relationship of dietary factors and risk of testicular cancer and also examined whether this risk varied by type of testicular cancer. We conducted a hospital-based case-control study at The University of Texas M. D. Anderson Cancer Center (Houston, TX) of 160 testicular cancer cases diagnosed between 1990 and 1996 and 136 friend-matched controls. The results of multivariable logistic regression analysis showed that after adjustment for age, education, income, ethnicity, cryptorchidism, and total daily calories, increasing total fat, saturated fat, and cholesterol consumption were associated with increasing risk of nonseminoma testicular cancer, with odds ratios (ORs) for the highest vs. the lowest quartiles of 6.3, 5.3, and 4.6, respectively. The risk for seminoma testicular cancer marginally increased with increasing intake of total fat and saturated fat, with ORs for the highest vs. lowest quartiles of 1.9 and 2.1, respectively. Higher total fat consumption was nearly significantly related to increased mixed germ cell tumor risk, with an OR for highest vs. lowest quartile of 4.2. This study supports the hypothesis that diet (particularly high fat consumption) increases testicular cancer risk in young men. However, the small sample size and the possibility that these observations may be due to bias indicate that the relationship of diet and testicular cancer risk needs to be further examined within a prospective or incident case-control study.

The incidence of epilepsy and unprovoked seizures in multiethnic, urban health maintenance organizations.

PURPOSE: Studies of the incidence of epilepsy are limited to a few populations in which new cases can be ascertained. Health maintenance organization (HmO) populations were studied to determine the incidence in a multiethnic, urban United States population. METHODS: Cases of initial unprovoked seizure disorder or epilepsy while enrolled in an HMO between 1988 and 1994 were ascertained. Ethnicity was obtained from the medical records and was part of a nested case-control study. RESULTS: There were 197 incidence cases of epilepsy and 275 of initial unprovoked seizure diagnosis. The incidence rate in the age range 0-64 years was 35.5 per 100,000 for epilepsy and 50.9 for initial unprovoked seizure. When compared with population-based studies, rates were slightly higher in children younger than 15, similar for the 15- to 24-year age group, but lower for ages 25-64 years. The ethnicity-specific odds ratios for initial unprovoked seizure, by using non-Hispanic white as the referent, were 1.04 (0.73-1.49) for African-American, 0.97 (0.64-1.48) for Hispanic, and 0.25 (0.08-0.84) for Asian-American. CONCLUSIONS: The lower rate in the HMO population is presumably due to a healthy-worker effect. The ethnicity-specific incidence rates do not differ in this population.

Methodological issues in estimating the cost of epilepsy.

Changes in treatment alternatives and the emphasis on cost containment and managed care have increased the interest in information on the cost of epilepsy. The last comprehensive cost study in the USA was in 1975. That study estimated the national cost of epilepsy at $3.6 billion for 2.1 million cases. On a per patient basis the 1975 figure represents $7440 in 1995 US dollars, $1150 (15%) for direct treatment-related costs and $6290 (85%) for indirect employment-related costs. Since then, various cost-of-illness (COI) studies in the USA and other countries have offered estimates ranging from $6000 to $15000 per patient per year, with percentages of direct and indirect cost varying greatly. To assist those interested in interpreting or producing cost information, this paper reviews the state of research on the cost of epilepsy and discusses several methodological issues. A comprehensive study begun in 1993 to update the 1975 estimates for the USA is also described. Recommendations are provided to stimulate discussion about the best methods to use in future research.

Traumatic brain injury and time to onset of Alzheimer's disease: a population-based study.

Controversy continues as to whether traumatic brain injury is a risk factor for Alzheimer's disease. The authors examined a related hypothesis that among persons with traumatic brain injury who develop Alzheimer's disease, time to onset of the disease is reduced. They used data on all documented episodes of traumatic brain injury that occurred from 1935 to 1984 among Olmsted County, Minnesota, residents. Community-based medical records were used to follow traumatic brain injury cases who were aged 40 years or older at last contact prior to June 1, 1988, for Alzheimer's disease until last contact, death, or June 1, 1988. The test of the hypothesis was restricted to those cases who developed Alzheimer's disease. The expected time to onset of Alzheimer's disease was derived from a life table constructed by using age-of-onset distributions within sex groups for a previously identified cohort of Rochester, Minnesota, Alzheimer's disease incidence cases without a history of head trauma. The authors found that of the 1,283 traumatic brain injury cases followed, 31 developed Alzheimer's disease, a number similar to that expected (standardized incidence ratio = 1.2, 95% confidence interval 0.8-1.7). However, the observed time from traumatic brain injury to Alzheimer's disease was less than the expected time to onset of Alzheimer's disease (median = 10 vs. 18 years, p = 0.015). The results suggest that traumatic brain injury reduces the time to onset of Alzheimer's disease among persons at risk of developing the disease.