Estimating the economic burden of status epilepticus to the health care system.

PURPOSE: Status epilepticus (SE) is a major neurological condition associated with significant morbidity and mortality. No studies to evaluate the cost burden of SE have been performed to date. This study estimates the direct cost related to an inpatient admission for SE in an urban academic medical center. METHODS: Cases of SE were defined based on a standard 30 min or greater seizure duration. The inpatient claims data were analyzed for 192 patients admitted with SE from 1 July 1993 through 30 June 1994. Patient demographic and clinical characteristics associated with increased cost were identified using multiple regression. The direct costs for SE were compared with other common DRGs. RESULTS: The median reimbursement for a patient with SE was dollar 8417. The average length of stay for all SE patients was 12.9 days. Age groups (17-45 and 46-64) and etiology (acute CNS) were the only patient factors significantly associated with increased cost. SE patients had 30-60% higher reimbursements than patients admitted for other acute health problems including acute myocardial infarction or congestive heart failure. CONCLUSIONS: The direct inpatient costs for SE are high compared with the direct costs of admissions for other major conditions such as acute myocardial infarction or congestive heart failure. Data from this study were used to estimate a dollar 4 billion annual direct cost for inpatient admissions for SE. Given the incidence and the high costs, further more detailed evaluation of these costs may be useful in assessing the adequacy of reimbursement for this subset of patients with epilepsy.

An exploration of the complex relationship of socioecologic factors in the treatment and outcomes of acute myocardial infarction in disadvantaged populations.

OBJECTIVE: To examine the relationship of patients' socioeconomic status (SES) as measured by race, health insurance status, and median income by zip code to in-hospital mortality of acute myocardial infarction (AMI), paying special attention to patients with multiple unfavorable socioeconomic risk factors. DATA SOURCES/STUDY SETTING: The data set was abstracted from patient-level hospital discharges in the Nationwide Inpatient Sample, Release 3, 1994. A total of 95,971 AMI discharges in 11 states were extracted. STUDY DESIGN: The risk adjustment methodology was adapted from the California Hospital Outcomes Project. Risk factors included demographic and clinical characteristics. Patients in double jeopardy had inferior insurance status and lived in poorer neighborhoods. PRINCIPAL FINDINGS: Compared with patients with health care coverage under Medicare and private insurance uninsured AMI patients had the highest risk-adjusted mortality odds and Medicaid AMI patients had the second highest odds. Probably because of the modest association of median income by zip code areas with mortality odds, the double jeopardy phenomenon was not observed. However, compared to patients who had two favorable SES attributes, patients who carried two unfavorable SES attributes had much higher mortality risk, more comorbidities, longer length of stay, and higher total hospital charges, while they received fewer AMI specialized procedures. Race did not seem to be a significant factor after adjustment for other SES attributes. CONCLUSIONS: SES is significantly related to the mortality of AMI patients. The disadvantaged patients receive fewer specialized procedures, possibly because of their higher levels of severity and financial barriers. The variation in mortality between patients who had favorable and unfavorable SES becomes wider when multiple socioeconomic risks are borne by the latter.

Clinical service standards at academic health centers.

OBJECTIVE: To describe the content and variability for clinical service standards related to quality of care among a convenience sample of academic health centers. DESIGN: We used the membership of the University HealthSystem Consortium, an alliance of academic health centers in the United States for clinical services, to survey electronically 53 of these centers regarding clinical service standards. The survey evaluated service standards in four areas; general communications, communications between physicians, ambulatory and inpatient clinical services and administrative standards. RESULTS: Thirty-four institutions responded to the survey (64%). Of these, 16 (47%) had clinical service standards, while the remaining 18 (53%) had not established formal standards. A few of the centers had established standards for patient communications, such as policies for answering telephones by staff. More had developed standards for communications between physicians and most centers had established standards for appointment availability, especially for urgent visits. However, clinical service standards were less typical for inpatient consultative or diagnostic services. A small number of the academic health centers had standards for hours of operation and for handling administrative matters, such as patient complaints. For many clinical service standards at the centers, there were notable variations (e.g. non-urgent primary care visits ranged 3-14 days). CONCLUSION: Some academic health centers have developed and implemented patient-centered clinical service standards for diverse areas of practice, however, the standards used appear to vary for some aspects of care, but not for others.

Risk factors for intermediate-term survival after coronary artery bypass grafting.

BACKGROUND: Risk factors for short-term mortality after coronary artery bypass grafting are well established, but little is known about risk factors for intermediate-term mortality. METHODS: We analyzed the outcomes of 11,815 patients undergoing coronary artery bypass grafting in one of the 43 cardiac surgery programs of the Department of Veteran Affairs. Risk factors for intermediate- and short-term mortality were determined using Cox proportional hazards regression models. Effects of risk factors during these two periods were explicitly compared. RESULTS: We found important differences in mortality risk-factor sets between the intermediate- and short-term periods after coronary artery bypass grafting. The majority of predictors of intermediate-term mortality were noncardiac-related variables, whereas the majority of predictors of short-term mortality were cardiac-related variables. Impaired functional status, chronic obstructive pulmonary disease, and renal dysfunction had greater effects in the intermediate-term period. Previous heart operation, angina class III or IV, previous myocardial infarction, and preoperative use of an intraaortic balloon pump had greater effects in the short-term period. CONCLUSIONS: The risk factors for intermediate-term mortality identified in this study can augment preoperative risk assessment and counseling of patients. Clinicians should be aware of the importance of noncardiac-related variables as predictors of mortality in the intermediate-term period after coronary artery bypass grafting.

E-mail medicine: dawn of a new era in physician-patient communication.

Computer-based electronic mail has opened up new opportunities for physician-patient communication. In many ways, electronic communication is more convenient than either the telephone or the postal service. However, it is important to recognize the limitations of electronic mail. In this article, we review important issues and recommend minimal standards for physician-patient communication via electronic mail.

Kindling produces long-lasting and selective changes in gene expression of hippocampal neurons.

To test the hypothesis that repeated subconvulsive stimulations required to induce kindling can permanently alter gene expression of hippocampal neurons, we used Northern and in situ hybridization analyses to measure steady-state mRNA levels encoding several phenotypic proteins. mRNA encoding a membrane-bound protein, ligatin, was significantly reduced in kindled brains relative to naive and sham control animals. This change in gene expression persisted for over 4 months after kindling, was associated with a decrease in ligatin protein expression, was not produced by single or multiple seizures that did not induce the kindling phenomena, and was blocked by MK801. These results provide direct evidence that kindling can cause persistent changes in the expression of specific genes in hippocampal neurons and suggest that N-methyl-D-aspartate receptor-activated changes in gene expression may be a basic molecular mechanism underlying some of the long-lasting plasticity changes seen in kindling or models of long-term memory.

Loss of type II calcium/calmodulin-dependent kinase activity correlates with stages of development of electrographic seizures in status epilepticus in rat.

Understanding the molecular basis of altered neuronal excitability in epilepsy is a major challenge in neuroscience research. The present study suggests an inverse correlation between changes in neuronal excitability in status epilepticus and the activity of type II multifunctional calcium/calmodulin-dependent kinase II (CaM kinase II), a major Ca(2+)-signal transducing system in brain. 'Continuous' hippocampal stimulation (CHS), a new model of non-convulsive limbic status epilepticus (SE), mimics the progression of electrographic changes characteristic in human SE and allows for quantitation of post-stimulus seizure severity. In the present study, hippocampus and anterior neocortex from CHS-stimulated rats and paired surgical controls were assayed for CaM kinase II activity by incorporation of radiolabeled phosphate from [gamma-32P]ATP into the 50-kDa subunit of the kinase itself (autophosphorylation). In all instances, CHS induced sustained interictal bursting and/or electrographic seizures. Decreased CaM kinase II activity was seen in all preparations from electrically stimulated hippocampus. CaM kinase II activity in CHS animals was diminished by 37% relative to controls (P less than 0.01; Student's paired t-test). The progressive intensity of the EEG discharges correlated directly with the decrement of CaM kinase II activity (P less than 0.05; Spearman's rank correlation test, n = 5). This is the first report of a dynamic modulation of a biochemical system that has been implicated in neuronal excitability in coordination with the characterized developmental stages of SE.

Self-sustaining limbic status epilepticus induced by 'continuous' hippocampal stimulation: electrographic and behavioral characteristics.

A model of status epilepticus centered in the limbic system and elicited by 'continuous' focal electrical stimulation of the hippocampus is presented. Under appropriate conditions, the status epilepticus persisted for many hours after discontinuing the electrical stimulus. The critical determinant for the establishment of this self-sustaining limbic status epilepticus (SSLSE) was the length of stimulation, rather than the side (left vs. right) of stimulation or kindling before stimulation. Observations, obtained from stimulus-free intervals spaced regularly during the stimulus protocol and from the period after stimulation had been completed, revealed a distinct and stereotyped electrographic progression of SSLSE though several stages. Brief monitoring periods throughout the stimulus protocol yielded electrographic criteria that predicted which animals would experience experience SSLSE. The presence of synchronous, stimulus-independent seizure activity bilaterally in the hippocampi during stimulation was necessary to establish SSLSE. Intense motor seizure activity, like that seen with kindled motor seizures, occurred intermittently during SSLSE. However, 'limbic' behavioral seizures identical to those seen after low doses of kainic acid or during the early stages of kindling were nearly continuous. These studies indicate that there is a predictable course to limbic status epilepticus and point to the hippocampus as a key element involved in initiating and maintaining this syndrome.

Response properties of rapidly recurring hippocampal seizures in rats.

Previous work has shown that closely spaced stimuli can activate short-term and long-term inhibitory processes that suppress kindling and the expression of kindled responses. The present experiments employed stimulus trains of longer duration than traditionally used in kindling work. Hippocampal seizures were triggered in rats at rates considerably faster than those reported to activate these inhibitory processes. Such rapidly recurring hippocampal seizures (RRHS) promptly led to a persistent, fully kindled state in which consistent kindled motor responses, constant duration electrographic seizures and stable afterdischarge thresholds were present. These kindled responses could be elicited every 30 min for 6-8 h/day on an alternate day schedule, but the kindled responses depended on delivery of supramaximal stimuli. Extending the number of RRHS on a given test day led to the appearance of a slowly developing but enduring suppression of kindled responses and an elevation of afterdischarge thresholds. Restricting the study period to 6 h on a given day, but using a consecutive instead of alternate day schedule, also led to a long-duration suppression of kindled responses. These results show that the short-duration inhibitory processes associated with kindled seizures can be more easily overcome than long-duration processes. The latter seem to involve an elevation of afterdischarge thresholds. The experiments also establish procedures by which detailed investigations of the effects of experimental manipulations on kindled responses can be examined.

Screening and characterization of antiepileptic drugs with rapidly recurring hippocampal seizures in rats.

A method to efficiently screen antiepileptic drugs (AED) for their actions against complex partial and secondarily generalized seizures is presented. The procedure relies on rapidly recurring hippocampal seizures (RRHS) in rats which are first used to bring epileptic responses to a stable, fully kindled state and then to test 3 parameters--behavioral seizures, electrographic seizures, and afterdischarge thresholds--before and after drug administration. With the methods described, the effects of a given drug treatment can be thoroughly determined in a single study period. Quantitative determinations of dose-response, time-action and relative potency characteristics are readily ascertained. A battery of known AED, encompassing those in common clinical use, was studied with this system. Kindled motor seizures (classes 4 and 5) were more readily suppressed than limbic behavioral seizures (classes 1-3). Electrographic seizures were usually, but not always, shortened concurrently with suppression of behavioral seizures. Under the conditions of this study, afterdischarge thresholds were not elevated, indicating that a critical role of AED is to counteract seizure spread and prolongation. The overall behavior of the RRHS test system with AED was identical to that with traditional amygdala kindled seizures and results were in good agreement with the clinical responsiveness of the kinds of seizures that these experimental systems model. The features of RRHS make it a useful system for screening new agents for antiepileptic effects, even in circumstances where little or no information about the drug under study is available.

Alterations in neurotransmitter amino acids in hippocampal kindled seizures.

Rats were rapidly kindled with electrical stimuli to the hippocampus, and the concentrations of GABA and related amino acids were measured in several brain regions, both in the baseline kindled state and during active seizures. In the baseline kindled state, a consistent pattern was found throughout the hippocampus where GABA levels were depressed and glutamate and glutamine levels were elevated. During seizures GABA rose slightly while glutamate and glutamine increased to twice control values. These changes were seen to various degrees in other brain areas. Turnover in the GABA-glutamate-glutamine cycle was measured in kindled rats experiencing seizures and compared to control animals. During seizures there was an increased turnover of the excitatory compounds glutamate and aspartate relative to GABA. The data indicate that kindling produces a change of presynaptic GABA metabolism which results in diminished inhibition.

In vitro and in vivo distribution and binding of phenytoin to rat brain.

The distribution and binding of phenytoin (PHT) were studied in rat brain using anatomically intact tissue. The pattern and kinetics of PHT distribution in vivo were examined with quantitative carbon-14 autoradiography. Initially gray matter levels were greater than white matter levels, but after 30 min the opposite condition was found. At a given time point, the levels of PHT among various gray matter structures as a group or among white matter structures as a group were uniform. The ratio of radioactivity in white matter to that in gray matter was 3:1 120 min after injection of radiolabeled PHT. Thin-layer chromatography showed only PHT in the brain 15 min after injection of PHT and both PHT and its hydroxylated metabolite [5-(p-hydroxyphenyl)-5-phenylhydantoin] 120 min after injection. The proportions of PHT and 5-(p-hydroxyphenyl)-5-phenylhydantoin were the same in white as in gray matter. Direct chemical measurements of brain samples obtained after coinjections of tracer amounts of radiolabeled PHT with increasing doses of unlabeled PHT corroborated the autoradiographic findings and revealed no displacement of the tracer by pharmacologic doses of the unlabeled drug. In vitro binding of PHT was investigated with sections obtained from frozen brains and with physiologically intact brain slices. Both high (4-10 nM) and low (1 microM) affinity conditions were examined. In no case was specific binding detected. Binding was greater in gray matter than in white matter in sections, whereas binding was greater in white matter than in gray matter in slices. We conclude that PHT distribution and binding reflect physico-chemical factors, such as lipid content, and physiological factors, such as blood flow and selective partitioning into white matter in living tissue, rather than specific receptors.

Somatostatin augments the spread of limbic seizures from the hippocampus.

The role of the neuropeptide somatostatin in limbic seizures was studied using electrical stimulation of the hippocampus in kindled rats. Cysteamine, an agent which selectively and reversibly depletes brain somatostatin stores, had a biphasic action. An early proconvulsant effect was seen within a few hours, consisting of prolonged electrographic seizures in the hippocampus and more severe behavioral convulsions. A later anticonvulsant effect, maximal at 1 to 2 days and dissipating within a week, was manifested by less intense behavioral convulsions without change in the duration of electrical seizure activity. Both effects were dose-dependent. No change in afterdischarge thresholds was detected at any time after the administration of cysteamine. Intraventricular administration of somatostatin to animals with behavioral seizures attenuated by cysteamine treatment restored the responses to precysteamine levels. We conclude that somatostatin facilitates the spread of seizures over limbic circuits from a region of focal seizure initiation.

Kindling with rapidly recurring hippocampal seizures.

Bipolar electrodes, stereotactically implanted in the hippocampus of adult rats, were used to deliver 10 s trains of suprathreshold tetanic electrical stimuli every few minutes. As indices of seizure intensity, durations of the afterdischarges triggered by these stimuli were measured, and the accompanying behaviors were scored on a 5-point scale. After 2-3 h, prolonged afterdischarges appeared in conjunction with severe limbic seizures, separated by periods of approximately 60 min. After 3-9 h, the stimulation was withheld until the following day. Upon reinstitution of the stimuli, intense seizures were seen at the onset, and the cycle time between them was shortened. Enhanced responsiveness to a fixed stimulus persisted for several months, the longest period tested. In addition, the enhanced epileptogenicity showed transference and was not stimulus-specific. These studies, using stimuli with low intertrain frequency and short interstimulus intervals, establish a robust and rapidly-developing model of epileptogenesis in the hippocampus that is comparable to traditional kindling.