Localization of a gene for partial epilepsy to chromosome 10q.

There is strong evidence for a genetic contribution to epilepsy, but it is commonly assumed that this genetic contribution is limited to 'generalized' epilepsies, and that most forms of 'partial' epilepsy are nongenetic. In a linkage analysis of a single family containing 11 affected individuals, we obtained strong evidence for localization of a gene for partial epilepsy. This susceptibility gene maps to chromosome 10q, with a maximum two-point lod score for D10S192 of 3.99 at theta = 0.0. All affected individuals share a single haplotype for seven tightly linked contiguous markers; the maximum lod score for this haplotype is 4.83 at theta = 0.0. Key recombinants place the susceptibility locus within a 10 centimorgan interval.

Management issues for women with epilepsy--focus on pregnancy (an evidence-based review): III. Vitamin K, folic acid, blood levels, and breast-feeding: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

A committee assembled by the American Academy of Neurology (AAN) reassessed the evidence related to the care of women with epilepsy (WWE) during pregnancy, including preconceptional folic acid and prenatal vitamin K use and the clinical implications of placental and breast-milk transfer of antiepileptic drugs (AEDs). The committee evaluated the available evidence based on a structured literature review and classification of relevant articles. Preconceptional folic acid supplementation is possibly effective in preventing major congenital malformations in the newborns of WWE taking AEDs. There is inadequate evidence to determine if the newborns of WWE taking AEDs have a substantially increased risk of hemorrhagic complications. Primidone and levetiracetam probably transfer into breast milk in clinically important amounts. Valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts. Pregnancy probably causes an increase in the clearance and a decrease in the concentrations of lamotrigine, phenytoin, and, to a lesser extent carbamazepine, and possibly decreases the level of levetiracetam and the active oxcarbazepine metabolite, the monohydroxy derivative (MHD). Supplementing WWE with at least 0.4 mg of folic acid before pregnancy may be considered. Monitoring of lamotrigine, carbamazepine, and phenytoin levels during pregnancy should be considered, and monitoring of levetiracetam and oxcarbazepine (as MHD) levels may be considered. A paucity of evidence limited the strength of many recommendations.

The association of host age and gender with inflammation around neurocysticercosis cysts.

The results of previous investigations indicate that age and gender may influence the strength of the human host's immune response to infection of the central nervous system with the larvae of Taenia solium. Most of the relevant research on such neurocysticercosis (NCC) has, however, been conducted on hospital-based samples in developing countries, where differential access to healthcare may bias the study results. Using data from 171 NCC patients participating in a treatment trial, the associations of patient age and gender with the presence of inflammation around NCC cysts (i.e. cysts in the transitional phase) have recently been explored, after controlling for measures of economic and geographical access to healthcare. Data on cysts were collected from computed-tomography or magnetic-resonance images taken at four time-points, from baseline to 12-months post-treatment. The odds of having transitional cysts were evaluated by logistic regression whereas Poisson regression was used to explore the numbers of transitional cysts, with generalised estimating equations (GEE) used to account for the multiple observations over time. After controlling for healthcare access, the odds of having transitional cysts were found to be 1.5-fold higher for the female patients than for the male, although this association was not statistically significant (P = 0.136). In the Poisson model, however, the number of transitional cysts was found to be 1.8-fold higher in the female patients than in the male, and this gender effect was not only statistically significant (P = 0.002) but also constant over time. The association of host age with transitional cysts was more complicated, with significant interaction between age and time. It therefore appears that there are significant gender and age differences in the local immune response to NCC, even after adjusting for differences in healthcare access.

Effects of albendazole treatment on neurocysticercosis: a randomised controlled trial.

AIM: The aim of this trial was to evaluate the effects of albendazole (ALB) on cyst disappearance, reduction of the number of cysts and seizure recurrence. METHODS: 178 patients with new onset symptoms due to active or transitional neurocysticercosis were randomly assigned to receive either 800 mg of ALB daily or placebo for 8 days. All patients also received prednisone. Imaging studies were done at baseline and at months 1, 6 and 12 of follow-up. RESULTS: Active cysts were identified in 59 of 88 people randomised to ALB and 57 of the 90 in the placebo arm. By 1 month, 31% were free of active cysts in the treatment group compared with 7% in the placebo group (p = 0.001). In addition, the ALB group had a greater reduction in the number of active cysts compared with the placebo group (p = 0.001). After 1 month following treatment there was no additional gain by treatment group in the disappearance or reduction in the number of active cysts. ALB treatment had little effect on cysts in the transitional or calcification stage. We found no difference between the ALB and placebo groups in symptoms during treatment or in seizure recurrence during the 12 months after treatment. CONCLUSION: Albendazole plus symptomatic treatment leads to the disappearance of active cysts in 31% of patients compared with 7% of those with symptomatic treatment alone. This treatment effect occurs within the first 30 days after treatment. TRIAL REGISTRATION NUMBER: NCT00283699.

Utility of EEG Activation Procedures in Epilepsy: A Population-Based Study.

PURPOSE: No previous population-based study has addressed the contribution of activation procedures to the yield of epileptiform abnormalities on serial EEGs. We assessed yield of activation-related epileptiform abnormalities and predictors of finding an activation-related abnormality with multiple EEGs in a population-based study of newly diagnosed epilepsy. METHODS: We used the resources of the Rochester Epidemiology Project to identify 449 residents of Rochester, Minnesota with a diagnosis of newly diagnosed epilepsy at age 1 year or older, between 1960 and 1994, who had at least one EEG. Information on all activation procedures (i.e., sleep, hyperventilation, and photic activation) and seizure/epilepsy characteristics was obtained by comprehensive review of medical records. RESULTS: At the first EEG, the yield of epileptiform abnormalities was greatest for individuals 1 to 19 years of age at diagnosis, for each activation procedure. The yield in patients aged 1 to 19 versus ≥20 years was 21.6% versus 10.3% for sleep, 6.5% versus 3.3% for photic stimulation, and 10.3% versus 5% for hyperventilation. Among young people (aged 1-19 years), sleep was associated with an increased likelihood of finding an activation-related abnormality on any EEG. The likelihood of finding an activation-related abnormality on any EEG was decreased for postnatal symptomatic and for unknown etiology. CONCLUSIONS: Among activation procedures, sleep showed the highest yield of epileptiform abnormalities. There was a low yield for photic stimulation and hyperventilation. Within each activation procedure, younger age at diagnosis had the greatest yield. Sleep is the most effective activation procedure, especially in younger patients, and should be performed when possible.

Cancer incidence in a cohort of patients with seizure disorders.

The incidence of cancer was evaluated in a population-based cohort of 959 patients diagnosed with seizure disorders while residents of Rochester, MN, between 1935 and 1979. For all cancer sites combined, there were 65 incidence cases for a standard morbidity ratio of 1.4. Most of the excess was attributable to a 22-fold increase in the incidence of primary brain tumors among these patients. Most of the brain tumors occurred within 5 years of the seizure disorder diagnosis, suggesting that the seizure disorder was due to the brain tumor. The incidence of cancer of other sites, exclusive of brain, was not elevated. There was no evidence of an association of cancer incidence with duration of seizures or with the use of anticonvulsant drugs.

Is the course of neurocysticercosis modified by treatment with antihelminthic agents?

BACKGROUND: Neurocysticercosis, occasionally associated with long-term neurologic sequelae such as epilepsy or hydrocephalus, is more often a condition characterized by a benign course and spontaneous remission without permanent neurologic symptoms. This variability in outcome has led to difficulties in the interpretation of studies of the effectiveness of drugs used to treat this condition. OBJECTIVE: To evaluate the relative efficacy of two antihelminthic agents against each other and against symptomatic treatment alone. METHODS: Randomized clinical trial of treatment of patients with newly identified active neurocysticercosis with oral prednisolone alone (27 patients), praziquantel with prednisolone (54 patients), or albendazole with prednisolone (57 patients). RESULTS: At 6 months and at 1 year after treatment, there were no differences in the three treatment groups in terms of the proportion of patients who were free of cysts or the relative reduction of number of cysts. At 2 years, there was no difference in the proportion of patients free of seizures during the entire follow-up period. Early and late sequelae occurred in a higher proportion of patients treated with praziquantel and albendazole, compared with those receiving only prednisolone. CONCLUSIONS: Previous reports of favorable response to treatment of neurocysticercosis with either praziquantel or albendazole are by no means definitive and may be a reflection of the natural history of the condition. The present study, with randomized treatment assignment and including a control group, raises questions as to what extent and in whom treatment with these drugs is effective, and suggests that treatment with antihelminthic agents may be associated with an increased frequency of long-term sequelae.

Race-ethnic disparities in the impact of stroke risk factors: the northern Manhattan stroke study.

BACKGROUND AND PURPOSE: Stroke risk factors have been determined in large part through epidemiological studies in white cohorts; as a result, race-ethnic disparities in stroke incidence and mortality rates remained unexplained. The aim in the present study was to compare the prevalence, OR, and etiological fraction (EF) of stroke risk factors among white, blacks, and Caribbean Hispanics living in the same urban community of northern Manhattan. METHODS: In this population-based incident case-control study, cases (n=688) of first ischemic stroke were prospectively matched 1:2 by age, sex, and race-ethnicity with community controls (n=1156). Risk factors were determined through in-person assessment. Conditional logistic regression was used to calculate adjusted ORs in each race-ethnic group. Prevalence and multivariate EFs were determined in each race-ethnic group. RESULTS: Hypertension was an independent risk factor for whites (OR 1.8, EF 25%), blacks (OR 2.0, EF 37%), and Caribbean Hispanics (OR 2.1, EF 32%), but greater prevalence led to elevated EFs among blacks and Caribbean Hispanics. Greater prevalence rates of diabetes increased stroke risk in blacks (OR 1.8, EF 14%) and Caribbean Hispanics (OR 2.1 P<0.05, EF 10%) compared with whites (OR 1.0, EF 0%), whereas atrial fibrillation had a greater prevalence and EF for whites (OR 4.4, EF 20%) compared with blacks (OR 1.7, EF 3%) and Caribbean Hispanics (OR 3.0, EF 2%). Coronary artery disease was most important for whites (OR 1.3, EF 16%), followed by Caribbean Hispanics (OR 1.5, EF 6%) and then blacks (OR 1.1, EF 2%). Prevalence of physical inactivity was greater in Caribbean Hispanics, but an elevated EF was found in all groups. CONCLUSIONS: The prevalence, OR, and EF for stroke risk factors vary by race-ethnicity. These differences are crucial to the etiology of stroke, as well as to the design and implementation of stroke prevention programs.

Recent developments in the epidemiology of epilepsy.

Epidemiological incidence data are important to determine those who are at risk of epilepsy and to understand the aetiology of the condition. A number of studies have been reported recently, which allow comparisons across populations. There appears to be geographical variation in the incidence of epilepsy, with a higher incidence in rural South America than in developed countries: no large scale incidence studies have yet been carried out in Africa or Asia. A consistent pattern suggesting that the onset of epilepsy occurs at the extremes of life has also been shown. Although a number of factors are often identified as causes of epilepsy, studies have identified a definitive aetiology in only one-third of all newly diagnosed cases. Epidemiological studies have, however, confirmed the importance of postnatal insults and quantified the risk. Family history may also be considered a risk factor for epilepsy in epidemiological terms.

Pleocytosis after status epilepticus.

OBJECTIVE: To determine the incidence of pleocytosis in patients experiencing status epilepticus (SE), regardless of seizure type or cause. DESIGN: A retrospective medical chart review. SETTING: Columbia-Presbyterian Medical Center, New York, NY. PATIENTS: Of 217 patients seen by the Neurology Service for SE during a 3-year period, 138 had a cerebrospinal fluid (CSF) analysis performed and were included in the study. All seizure types and etiologies were included. MAIN OUTCOME MEASURES: Status epilepticus was defined as a seizure or a series of continuing seizures lasting longer than 30 minutes. An abnormal CSF specimen was defined as a white blood cell (WBC) count of 6 x 10(6)/L or greater or one or more polymorphonuclear leukocytes present. RESULTS: Overall, 22.5% of patients demonstrated abnormal WBC count or morphology. There were 21 patients (15%) with a WBC count of 6 x 10(6)/L or greater, and another 10 patients with a normal WBC count, who had polymorphonuclear leukocytes present. Among patients with illnesses usually associated with pleocytosis (such as meningitis or acute head trauma), a large proportion had abnormal CSF WBC counts. Among patients with conditions usually associated with normal CSF (including idiopathic epilepsy), a small proportion had abnormal CSF WBC counts, and the abnormalities were less severe. The highest CSF WBC count in patients with no acute insult was 28 x 10(6)/L. CONCLUSIONS: The most important influence on the CSF WBC count is the underlying cause of the SE. Although minor elevations in WBC count can occur after SE of any type, pleocytosis should not be attributed to SE alone unless all other causes have been eliminated.

Neuroanatomical and electroencephalographic correlations in Sanfilippo syndrome, type A.

Waking and all-night-sleeping electroencephalographic recordings were obtained on a boy with Sanfilippo disease, type A. The most striking abnormalities were noted during sleep and included (1) lack of progression through normal sleep stages, (2) absence of vertex waves and normal sleep spindles, (3) inability to stage sleep by the usual criteria, and (4) an unusual alteration of low-amplitude (12 to 15 Hz) activity with generalized delta frequencies. Subsequently, neuropathological examination was performed. The electrophysiological phenomena may be correlated with severe cortical involvement.

Nontraumatic coma. Glasgow coma score and coma etiology as predictors of 2-week outcome.

In 1987 and 1988, we carried out a prospective study of patients older than 10 years with nontraumatic coma in the intensive care units of Columbia-Presbyterian Medical Center, New York, NY. Of 188 patients with Glasgow Coma Scale (GCS) determinations within 72 hours, 61% were dead or in persistent coma by 2 weeks from onset. Age, sex, and ethnicity did not influence outcome. The 2-week outcome for patients with initial GCS of 3 to 5 was 14.8% awake; 85.2% were dead or in persistent coma. For the GCS 6 to 8 group, 53.1% were awake and 46.9% were dead or in persistent coma. Hypoxic or ischemic coma had the worst 2-week outcome (79% dead or comatose); coma caused by metabolic disease or sepsis (68%), focal cerebral lesions (66%), and general cerebral diseases (55%) were intermediate, while drug-induced coma had a favorable outcome (27% dead or comatose). The independent predictors of 2-week outcome were the first GCS and drug-induced coma. The predicted probability of waking at 2 weeks was eight times better for drug-induced coma than other causes when GCS was held constant. Patients with an initial GCS score of 6 to 8 were seven times more likely to waken than those with a score of 3 to 5. The motor subscore alone was a significant independent predictor of 2-week outcome. Modification of coma score to include etiology may give more accurate predictions of 2-week outcome after nontraumatic coma.

Electrocardiographic changes during electrographic seizures.

The occurrence of high-risk cardiac arrhythmias during electrographic seizures has been proposed as a possible cause for sudden unexpected death in patients with epilepsy. Several anecdotal case reports have documented various cardiac irregularities during seizures. We reviewed simultaneous 24-hour electroencephalographic - electrocardiographic studies obtained by ambulatory cassette electroencephalography in 45 patients who experienced 106 electrographic seizures. An increase in heart rate was seen in 96% of seizures, while in four seizures, the rate was unchanged. Heart rate increase measured from 1 minute preictally to intraictal peak ranged from 0% to 160% (mean, 60%). The onset of tachycardia was usually within several seconds (before or after) of the seizure onset, and often persisted for several minutes after termination of the discharge. No difference was found in patients with lateralized vs generalized seizures. Neither ventricular ectopia, conduction defects, or bradycardia were observed during the ictal episodes. We conclude that ictal tachycardia is the rule during electrographic seizures, and that high-risk cardiac arrhythmias are uncommon.

Are generalized and localization-related epilepsies genetically distinct?

BACKGROUND: Whether the genetic influences are distinct for generalized and localization-related epilepsies or whether some susceptibility genes raise the risk for both types of epilepsy is uncertain. OBJECTIVE: To evaluate genetic heterogeneity in epilepsy. METHODS: We used Cox proportional hazards analysis to compute rate ratios (RRs) for generalized and localization-related idiopathic or cryptogenic epilepsy in the first-degree relatives of 1498 adult probands with idiopathic or cryptogenic epilepsy ascertained from voluntary organizations. The reference group comprised the first-degree relatives of 362 probands from the same study with postnatal symptomatic epilepsy in whom the genetic contributions appear to be minimal. RESULTS: In the parents and siblings, the risk for all idiopathic or cryptogenic epilepsy was greater if the proband's epilepsy was generalized than if it was localization-related (RR, 4.7 vs 2.4). However, in the parents and siblings of each group of probands, the increased risk was not restricted to the same type of epilepsy as in the proband. The results differed in offspring, with a greater risk for all types of epilepsy if the proband's epilepsy was localization-related than if it was generalized (RR, 4.2 vs 1.6) and a greater risk for localization-related epilepsy than for generalized epilepsy (RR, 7.8 vs 1.8) if the proband's epilepsy was localization-related. CONCLUSIONS: These findings in parents and siblings suggest that some susceptibility genotypes raise the risk for both generalized and localization-related epilepsies but are more common in persons affected with generalized epilepsy. The different findings in offspring may reflect a different influence on susceptibility in that subgroup.

Status epilepticus: epidemiologic considerations.

Status epilepticus (SE) will occur in 50,000 to 60,000 individuals in the United States annually: one third as the presenting symptom in patients with a 1st unprovoked seizure or with epilepsy, one third in patients with established epilepsy, and one third in individuals with no history of epilepsy. The greatest number of cases will occur in children, although the risk is equally high in the over-60 population. In patients with epilepsy, SE is more likely to occur in those with partial seizures and in those with remote symptomatic epilepsy. The presence of a preexisting neurologic abnormality is associated with an increased risk of SE in those with acute systemic insults. There is a high mortality reported, but this is related predominantly to the underlying condition. The 1 to 2% mortality attributed to SE probably reflects an overestimation of the risk. There is an increased risk of seizures and of intellectual dysfunction following the occurrence of an episode of SE, although the causal association is not clear. Individuals with epilepsy who experience an episode of SE probably have a lower likelihood of remission of epilepsy.

Status epilepticus: the interaction of epilepsy and acute brain disease.

We identified 217 patients with status epilepticus (SE), including all seizure types from all etiologies, over a 3-year period. There was a significant interaction between organic brain disease and a history of epilepsy in the development of SE. The majority of patients (59%) had no history of epilepsy. These patients were more likely to have acute precipitants associated with SE and less likely to have had prior brain disease. They were older, were more likely to have generalized convulsive seizures, and had a high proportionate mortality. Among the 88 patients with a history of epilepsy, a higher proportion had prior brain insults, but fewer had acute precipitants. These patients were younger and their mortality was low, but they often had recurrent SE before and after the identified episode. Significant acute or prior brain disease is an important factor in the development of SE, even in patients with a history of epilepsy.

Status epilepticus and antiepileptic medication levels.

To investigate the association between withdrawal from antiepileptic drugs (AEDs) and status epilepticus (SE), we evaluated AED levels at the time of, and prior to, an episode of SE in 65 patients with epilepsy. At least one AED was therapeutic in 65% of patients at the time of SE, and all prescribed AEDs were therapeutic in 48%. Ten patients had subtherapeutic AED levels before, and at the time of, SE. Sixteen patients with previously therapeutic levels (25%) had one or more subtherapeutic AED level at the time of SE. Many of the patients had other acute or remote factors that could be associated with SE, and 46 had had previous episodes of SE. Low AED levels or withdrawal can explain only some cases of SE. Citing AED irregularity as the major cause of SE in patients with epilepsy oversimplifies a complex, poorly understood situation.

A population-based study of prognosis of ruptured cerebral aneurysm: mortality and recurrence of subarachnoid hemorrhage.

OBJECTIVE: To determine the risk of recurrent subarachnoid hemorrhage (SAH), mortality, and relative survivorship following SAH caused by ruptured cerebral aneurysm (RCA). DESIGN/METHODS: The 86 individuals with a first diagnosis of SAH caused by RCA in Iceland from 1958 through 1968 were followed a minimum of 24 years (range, 24 to 32.5 years) or until death to determine mortality and to identify those with recurrent SAH. RESULTS: Thirty-eight patients (44%) died within 30 days of the index event. Two additional (both comatose from onset of ictus) died in the following month. There were no deaths between 3 and 6 months after onset. Based upon the age/gender-specific person years of observation for the population of Iceland, the Standardized Mortality Ratio for the 44 surgically treated patients surviving 6 months was 1.3. Those neurologically normal or with only mild impairment at 6 months had no identified increase in mortality. Excess mortality that was limited to individuals with severe neurologic deficit at 6 months could be identified through the first 10 years after onset. Two 6-month survivors experienced recurrent SAH. CONCLUSIONS: Early mortality is high (47%) in patients with RCA. In patients operated on for RCA and surviving 6 months, recurrent SAH occurred in 5%. Survivorship among patients surgically treated and neurologically normal or with mild residual neurologic impairment at 6 months following presentation was similar to that expected in the general population. Survivorship among patients surgically treated who had severe residual neurologic impairment at 6 months was significantly reduced.

Fertility in patients with epilepsy: a population-based study.

OBJECTIVE: Several studies have suggested that people with epilepsy have altered fertility, but comparison groups have been imperfect. METHOD: A retrospective cohort study of all live births to 209 incident patients with epilepsy in Iceland from 1960 to 1964 and live births to 418 age- (to the closest day of birth) and gender-matched residents without epilepsy. RESULTS: Incident patients with epilepsy had an average of 2.0 children; the controls also had an average of 2.0 children. When people with idiopathic/cryptogenic epilepsy were compared with controls, there was no difference in number of children or number of partners overall, nor were there differences when stratified by seizure type or age at diagnosis. There was a deficit in the number of children among patients with remote symptomatic epilepsy. This was attributed to a reduced number of offspring of patients with mental retardation (MR) or cerebral palsy (CP) when compared with their controls. CONCLUSION: There is no evidence of altered fertility among people with idiopathic/cryptogenic epilepsy or remote symptomatic epilepsy (other than MR or CP) within this population-based incidence cohort.