Long-term reduction of health care costs and utilization after epilepsy surgery.

OBJECTIVE: To assess long-term direct medical costs, health care utilization, and mortality following resective surgery in persons with uncontrolled epilepsy. METHODS: Retrospective longitudinal cohort study of Medicaid beneficiaries with epilepsy from 2000 to 2008. The study population included 7,835 persons with uncontrolled focal epilepsy ages 18-64 years, with an average follow-up time of 5 years. Of these, 135 received surgery during the study period. To account for selection bias, we used risk-set optimal pairwise matching on a time-varying propensity score, and inverse probability of treatment weighting. Repeated measures generalized linear models were used to model utilization and cost outcomes. Cox proportional hazard was used to model survival. RESULTS: The mean direct medical cost difference between the surgical group and control group was $6,806 after risk-set matching. The incidence rate ratio of inpatient, emergency room, and outpatient utilization was lower among the surgical group in both unadjusted and adjusted analyses. There was no significant difference in mortality after adjustment. Among surgical cases, mean annual costs per subject were on average $6,484 lower, and all utilization measures were lower after surgery compared to before. SIGNIFICANCE: Subjects that underwent epilepsy surgery had lower direct medical care costs and health care utilization. These findings support that epilepsy surgery yields substantial health care cost savings.

Epilepsy surgery in the United States: Analysis of data from the National Association of Epilepsy Centers.

OBJECTIVE: To examine trends in epilepsy-related surgical procedures performed at major epilepsy centers in the US between 2003 and 2012, and in the service provision infrastructure of epilepsy centers over the same time period. METHODS: We analyzed data from the National Association of Epilepsy Centers' (NAEC) annual surveys. The total annual figures, annual average figures per center and annual rates of each surgical procedure based on US population numbers for that year were calculated. Additional information on center infrastructure and manpower was also examined. RESULTS: The number of the NAEC's level 3 and level 4 epilepsy centers submitting annual survey reports increased from 37 centers in 2003 to 189 centers in 2012. The average reported number of Epilepsy Monitoring Unit (EMU) beds per center increased from 7 beds in 2008 to 8 beds in 2012. Overall annual EMU admission rates doubled between 2008 and 2012 but the average number of EMU admissions and epilepsy surgeries performed per center declined over the same period. The annual rate of anterior temporal lobectomies (ATL) for mesial temporal sclerosis (MTS) declined by >65% between 2006 and 2010. The annual rate of extratemporal surgery exceeded that of ATL for MTS from 2008 onwards, doubled between 2007 and 2012 and comprised 38% of all resective surgeries in 2012. Vagus nerve stimulator implant rates consistently increased year on year and exceeded resective surgeries in 2011 and 2012. CONCLUSION: The last decade has seen a major change in the US epilepsy surgery landscape. Temporal lobectomies, particularly for MTS, have declined despite an increase in EMU admissions. On the other hands, case complexity correspondingly increased as evidenced by more extratemporal surgery, intracranial recordings and palliative procedures.

SOX11 identified by target gene evaluation of miRNAs differentially expressed in focal and non-focal brain tissue of therapy-resistant epilepsy patients.

MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally control the expression of their target genes via RNA interference. There is increasing evidence that expression of miRNAs is dysregulated in neuronal disorders, including epilepsy, a chronic neurological disorder characterized by spontaneous recurrent seizures. Mesial temporal lobe epilepsy (MTLE) is a common type of focal epilepsy in which disease-induced abnormalities of hippocampal neurogenesis in the subgranular zone as well as gliosis and neuronal cell loss in the cornu ammonis area are reported. We hypothesized that in MTLE altered miRNA-mediated regulation of target genes could be involved in hippocampal cell remodeling. A miRNA screen was performed in hippocampal focal and non-focal brain tissue samples obtained from the temporal neocortex (both n=8) of MTLE patients. Out of 215 detected miRNAs, two were differentially expressed (hsa-miR-34c-5p: mean increase of 5.7 fold (p=0.014), hsa-miR-212-3p: mean decrease of 76.9% (p=0.0014)). After in-silico target gene analysis and filtering, reporter gene assays confirmed RNA interference for hsa-miR-34c-5p with 3'-UTR sequences of GABRA3, GRM7 and GABBR2 and for hsa-miR-212-3p with 3'-UTR sequences of SOX11, MECP2, ADCY1 and ABCG2. Reporter gene assays with mutated 3'-UTR sequences of the transcription factor SOX11 identified two different binding sites for hsa-miR-212-3p and its primary transcript partner hsa-miR-132-3p. Additionally, there was an inverse time-dependent expression of Sox11 and miR-212-3p as well as miR-132-3p in rat neonatal cortical neurons. Transfection of neurons with anti-miRs for miR-212-3p and miR-132-3p suggest that both miRNAs work synergistically to control Sox11 expression. Taken together, these results suggest that differential miRNA expression in neurons could contribute to an altered function of the transcription factor SOX11 and other genes in the setting of epilepsy, resulting not only in impaired neural differentiation, but also in imbalanced neuronal excitability and accelerated drug export.

Increasing utilization of pediatric epilepsy surgery in the United States between 1997 and 2009.

OBJECTIVE: To examine national trends of pediatric epilepsy surgery usage in the United States between 1997 and 2009. METHODS: We performed a serial cross-sectional study of pediatric epilepsy surgery using triennial data from the Kids' Inpatient Database from 1997 to 2009. The rates of epilepsy surgery for lobectomies, partial lobectomies, and hemispherectomies in each study year were calculated based on the number of prevalent epilepsy cases in the corresponding year. The age-race-sex adjusted rates of surgeries were also estimated. Mann-Kendall trend test was used to test for changes in the rates of surgeries over time. Multivariable regression analysis was also performed to estimate the effect of time, age, race, and sex on the annual incidence of epilepsy surgery. RESULTS: The rates of pediatric epilepsy surgery increased significantly from 0.85 epilepsy surgeries per 1,000 children with epilepsy in 1997 to 1.44 epilepsy surgeries per 1,000 children with epilepsy in 2009. An increment in the rates of epilepsy surgeries was noted across all age groups, in boys and girls, all races, and all payer types. The rate of increase was lowest in blacks and in children with public insurance. The overall number of surgical cases for each study year was lower than 35% of children who were expected to have surgery, based on the estimates from the Connecticut Study of Epilepsy. SIGNIFICANCE: In contrast to adults, pediatric epilepsy surgery numbers have increased significantly in the past decade. However, epilepsy surgery remains an underutilized treatment for children with epilepsy. In addition, black children and those with public insurance continue to face disparities in the receipt of epilepsy surgery.

A method for the inclusion of sphenoidal electrodes in realistic EEG source imaging.

SUMMARY: Although EEG source imaging (ESI) has become more popular over the last few years, sphenoidal electrodes (SPE) have never been incorporated in ESI using realistic head models. This is in part because of the true locations of these electrodes are not exactly known. In this study, we demonstrate the feasibility of determining the true locations of SPE and incorporating this information into realistic ESI. The impact of including these electrodes in ESI in mesial temporal lobe epilepsy is also discussed. Seventeen patients were retrospectively selected for this study. To determine the positions of SPE in each case, two orthogonal x-rays (sagittal and coronal) of the SPE needle stilette were taken in the presence of previously digitized scalp electrodes. An in-house computer program was then used to find the locations of the tip of the needle stilette relative to the surface electrodes. These locations were then incorporated in a realistic head model based on the finite element method. EEG source imaging was then performed using averaged spikes for included patients suspected of having mesial temporal lobe epilepsy. Including SPE significantly shifted the ESI result even in the presence of subtemporal electrodes, resulting in an inferior and mesial displacement.

Premature mortality in poor health and low income adults with epilepsy.

OBJECTIVE: To examine mortality and causes of death (CODs) in socioeconomically disadvantaged persons with epilepsy (PWEs) in the United States. METHODS: We performed a retrospective open cohort analysis using Ohio Medicaid claims data between 1992 and 2008 to assess mortality and COD in 68,785 adult Medicaid beneficiaries with epilepsy. Case fatality (CF), mortality rates (MRs), standardized mortality ratios (SMRs), and years of potential life lost (YPLLs) were calculated. The SMRs were estimated to compare risk of death in PWEs with that in the general Medicaid population with and without disabilities. Proportionate mortality ratios (PMRs), YPLLs, and SMRs for specific COD were also obtained. RESULTS: There were 12,630 deaths in PWEs. CF was 18.4%, the age-race-sex adjusted MR was 18.6/1,000 person-years (95% confidence interval [CI], 18.3-18.9). The SMR was 1.8 (95% CI, 1.8-1.9) when compared to the general Medicaid population, and was 1.4 (95% CI, 1.3-1.6) when compared to those with disabilities. The average YPLL was 16.9 years (range 1-47 years). Both epilepsy and comorbid conditions significantly contributed to premature mortality in PWEs. Cardiovascular diseases, cancer, and unintentional injuries were the most common COD and account for a large proportion of YPLLs. Deaths from epilepsy-related causes occurred in about 10% of the cases. SIGNIFICANCE: Socioeconomically deprived PWEs, especially young adults, experience high mortality and die 17 years prematurely. The high mortality in Medicaid beneficiaries with epilepsy affirms that comorbid conditions and epilepsy play a crucial role in premature death. Management of comorbid conditions is, at a minimum, as important as epilepsy management, and therefore deserves more attention from physicians, particularly those who care for Medicaid beneficiaries with epilepsy.

Proposal: different types of alteration and loss of consciousness in epilepsy.

There are at least five types of alterations of consciousness that occur during epileptic seizures: auras with illusions or hallucinations, dyscognitive seizures, epileptic delirium, dialeptic seizures, and epileptic coma. Each of these types of alterations of consciousness has a specific semiology and a distinct pathophysiologic mechanism. In this proposal we emphasize the need to clearly define each of these alterations/loss of consciousness and to apply this terminology in semiologic descriptions and classifications of epileptic seizures. The proposal is a consensus opinion of experienced epileptologists, and it is hoped that it will lead to systematic studies that will allow a scientific characterization of the different types of alterations/loss of consciousness described in this article.

Automated removal of EKG artifact from EEG data using independent component analysis and continuous wavelet transformation.

The electrical potential produced by the cardiac activity sometimes contaminates electroencephalogram (EEG) recordings, resulting in spiky activities that are referred to as electrocardiographic (EKG) artifact. For a variety of reasons it is often desirable to automatically detect and remove these artifacts. Especially, for accurate source localization of epileptic spikes in an EEG recording from a patient with epilepsy, it is of great importance to remove any concurrent artifact. Due to similarities in morphology between the EKG artifacts and epileptic spikes, any automated artifact removal algorithm must have an extremely low false-positive rate in addition to a high detection rate. In this paper, an automated algorithm for removal of EKG artifact is proposed that satisfies such criteria. The proposed method, which uses combines independent component analysis and continuous wavelet transformation, uses both temporal and spatial characteristics of EKG related potentials to identify and remove the artifacts. The method outperforms algorithms that use general statistical features such as entropy and kurtosis for artifact rejection.

Age-specific periictal electroclinical features of generalized tonic-clonic seizures and potential risk of sudden unexpected death in epilepsy (SUDEP).

Generalized tonic-clonic seizure (GTCS) is the commonest seizure type associated with sudden unexpected death in epilepsy (SUDEP). This study examined the semiological and electroencephalographic differences (EEG) in the GTCSs of adults as compared with those of children. The rationale lies on epidemiological observations that have noted a tenfold higher incidence of SUDEP in adults. We analyzed the video-EEG data of 105 GTCS events in 61 consecutive patients (12 children, 23 seizure events and 49 adults, 82 seizure events) recruited from the Epilepsy Monitoring Unit. Semiological, EEG, and 3-channel EKG features were studied. Periictal seizure phase durations were analyzed including tonic, clonic, total seizure, postictal EEG suppression (PGES), and recovery phases. Heart rate variability (HRV) measures including RMSSD (root mean square successive difference of RR intervals), SDNN (standard deviation of NN intervals), and SDSD (standard deviation of differences) were analyzed (including low frequency/high frequency power ratios) during preictal baseline and ictal and postictal phases. Generalized estimating equations (GEEs) were used to find associations between electroclinical features. Separate subgroup analyses were carried out on adult and pediatric age groups as well as medication groups (no antiepileptic medication cessation versus unchanged or reduced medication) during admission. Major differences were seen in adult and pediatric seizures with total seizure duration, tonic phase, PGES, and recovery phases being significantly shorter in children (p<0.01). Generalized estimating equation analysis, using tonic phase duration as the dependent variable, found age to correlate significantly (p<0.001), and this remained significant during subgroup analysis (adults and children) such that each 0.12-second increase in tonic phase duration correlated with a 1-second increase in PGES duration. Postictal EEG suppression durations were on average 28s shorter in children. With cessation of medication, total seizure duration was significantly increased by a mean value of 8s in children and 11s in adults (p<0.05). Tonic phase duration also significantly increased with medication cessation, and although PGES durations increased, this was not significant. Root mean square successive difference was negatively correlated with PGES duration (longer PGES durations were associated with decreased vagally mediated heart rate variability; p<0.05) but not with tonic phase duration. This study clearly points out identifiable electroclinical differences between adult and pediatric GTCSs that may be relevant in explaining lower SUDEP risk in children. The findings suggest that some prolonged seizure phases and prolonged PGES duration may be electroclinical markers of SUDEP risk and merit further study.

Disparities in access to specialized epilepsy care.

OBJECTIVE: To examine the impact of individual and community characteristics on access to specialized epilepsy care. METHODS: This retrospective cross-sectional study analyzed data from the California State Inpatient Sample, the State Ambulatory Surgery Database, and the State Emergency Department Database, that were linked with the 2009 Area Resource File and the location of the National Association of Epilepsy Center's epilepsy centers. The receipt of video-EEG monitoring was measured and used to indicate access to specialized epilepsy care in subjects with persistent seizures, identified as those who had frequent seizure-related hospital admissions and/or ER visits. A hierarchical logistic regression model was employed to assess barriers to high quality care at both individual and contextual levels. RESULTS: Among 115,632 persons with persistent seizures, individuals who routinely received care in an area where epilepsy centers were located were more likely to have access to specialized epilepsy care (OR: 1.81, 95% CI: 1.20, 2.72). Interestingly, the availability of epilepsy centers did not influence access to specialized epilepsy care in people who had private insurance. In contrast, uninsured individuals and those with public insurance programs including Medicaid and Medicare had significant gaps in access to specialized epilepsy care. Other individual characteristics such as age, race/ethnicity, and the presence of comorbid conditions were also associated with disparities in access to specialized care in PWE. CONCLUSION: Both individual and community characteristics play substantial roles in access to high quality epilepsy care. Policy interventions that incorporate strategies to address disparities at both levels are necessary to improve access to specialized care for PWE.

Significant postictal hypotension: expanding the spectrum of seizure-induced autonomic dysregulation.

Periictal autonomic dysregulation is best studied using a "polygraphic" approach: electroencephalography ([EEG]), 3-channel electrocardiography [ECG], pulse oximetry, respiration, and continuous noninvasive blood pressure [BP]), which may help elucidate agonal pathophysiologic mechanisms leading to sudden unexpected death in epilepsy (SUDEP). A number of autonomic phenomena have been described in generalized tonic-clonic seizures (GTCS), the most common seizure type associated with SUDEP, including decreased heart rate variability, cardiac arrhythmias, and changes in skin conductance. Postictal generalized EEG suppression (PGES) has been identified as a potential risk marker of SUDEP, and PGES has been found to correlate with post-GTCS autonomic dysregulation in some patients. Herein, we describe a patient with a GTCS in whom polygraphic measurements were obtained, including continuous noninvasive blood pressure recordings. Significant postictal hypotension lasting >60 s was found, which closely correlated with PGES duration. Similar EEG changes are well described in hypotensive patients with vasovagal syncope and a similar vasodepressor phenomenon, and consequent cerebral hypoperfusion may account for the PGES observed in some patients after a GTCS. This further raises the possibility that profound, prolonged, and irrecoverable hypotension may comprise one potential SUDEP mechanism.

Defining incident cases of epilepsy in administrative data.

PURPOSE: To determine the minimum enrollment duration for identifying incident cases of epilepsy in administrative data. METHODS: We performed a retrospective dynamic cohort study using Ohio Medicaid data from 1992 to 2006 to identify a total of 5037 incident epilepsy cases who had at least 1 year of follow-up prior to epilepsy diagnosis (epilepsy-free interval). The incidence for epilepsy-free intervals from 1 to 8 years, overall and stratified by pre-existing disability status, was examined. The graphical approach between the slopes of incidence estimates and the epilepsy-free intervals was used to identify the minimum epilepsy-free interval that minimized misclassification of prevalent as incident epilepsy cases. RESULTS: As the length of epilepsy-free interval increased, the incidence rates decreased. A graphical plot showed that the decline in incidence of epilepsy became nearly flat beyond the third epilepsy-free interval. CONCLUSION: The minimum of 3-year epilepsy-free interval is needed to differentiate incident from prevalent cases in administrative data. Shorter or longer epilepsy-free intervals could result in over- or under-estimation of epilepsy incidence.

Incidence and prevalence of treated epilepsy among poor health and low-income Americans.

OBJECTIVES: To determine the incidence and prevalence of treated epilepsy in an adult Medicaid population. METHODS: We performed a retrospective, dynamic cohort analysis using Ohio Medicaid claims data between 1992 and 2006. Individuals aged 18-64 years were identified as prevalent cases if they had ≥2 claims of epilepsy (ICD-9-CM: 345.xx) or ≥3 claims of convulsion (ICD-9-CM: 780.3 or 780.39) and ≥2 claims of antiepileptic drugs. Incident cases were required to have no epilepsy or convulsion claims for ≥5 years before epilepsy diagnosis. Subjects were determined as having preexisting disability and/or comorbid conditions, including brain tumor, depression, developmental disorders, migraine, schizophrenia, stroke, and traumatic brain injury, when at least one of these conditions occurred before epilepsy onset. RESULTS: There were 9,056 prevalent cases of treated epilepsy in 1992-2006 and 1,608 incident cases in 1997-2006. The prevalence was 13.2/1,000 (95% confidence interval, 13.0-13.5/1,000). The incidence was 362/100,000 person-years (95% confidence interval, 344-379/100,000 person-years). The incidence and prevalence were significantly higher in men, in older people, in blacks, and in people with preexisting disability and/or comorbid conditions. The most common preexisting conditions in epilepsy subjects were depression, developmental disorders, and stroke, whereas people with brain tumor, traumatic brain injury, and stroke had the higher risk of developing epilepsy. CONCLUSIONS: The Medicaid population has a high incidence and prevalence of epilepsy, in an order of magnitude greater than that reported in the US general population. This indigent population carries a disproportionate amount of the epilepsy burden and deserves more attention for its health care needs and support services.

Temporal trends in pre-surgical evaluations and epilepsy surgery in the U.S. from 1998 to 2009.

OBJECTIVE: To analyze trends in utilization of pre-surgical evaluations including video-EEG (VEEG) monitoring, intracranial EEG (IEEG) monitoring, and epilepsy surgery from 1998 to 2009 in the U.S. METHODS: Data from the Nationwide Inpatient Sample were used to identify admissions for pre-surgical evaluations and surgery. Surgical treatment of epilepsy was identified by the presence of primary ICD-9-CM procedure codes 01.52 (hemispherectomy), 01.53 (lobectomy), or 01.59 (other excision of the brain, including amygdalohippocampectomy). We calculated annual rates of pre-surgical evaluations and surgery based on published estimates of prevalence of epilepsy in the U.S. In addition, we examined variations by region and hospital characteristics, and conducted multivariable analysis to detect temporal trends, adjusting for changes in the population. Sensitivity analysis was also conducted using different algorithms to identify the study population and outcomes. RESULTS: We detected an increase in the rate of hospitalizations related to intractable epilepsy. Similarly, we noted a significant increase in hospitalizations for VEEG monitoring, but not in IEEG monitoring or in surgery. Multivariable analysis and sensitivity analysis confirmed these results. In addition, there was a significant increase in the proportion of pre-surgical evaluations and surgery performed in non-teaching hospitals. CONCLUSIONS: Despite the increase in VEEG monitoring, the availability of guideline and evidences demonstrating benefits of epilepsy surgery was not associated with a greater employment of surgery over time. Nevertheless, access to pre-surgical evaluations and epilepsy surgery is no longer limited to large medical centers.

EEG source imaging in epilepsy--practicalities and pitfalls.

EEG source imaging (ESI) is a model-based imaging technique that integrates temporal and spatial components of EEG to identify the generating source of electrical potentials recorded on the scalp. Recent advances in computer technologies have made the analysis of ESI data less time-consuming, and have rekindled interest in this technique as a clinical diagnostic tool. On the basis of the available body of evidence, ESI seems to be a promising tool for epilepsy evaluation; however, the precise clinical value of ESI in presurgical evaluation of epilepsy and in localization of eloquent cortex remains to be investigated. In this Review, we describe two fundamental issues in ESI; namely, the forward and inverse problems, and their solutions. The clinical application of ESI in surgical planning for patients with medically refractory focal epilepsy, and its use in source reconstruction together with invasive recordings, is also discussed. As ESI can be used to map evoked responses, we discuss the clinical utility of this technique in cortical mapping-an essential process when planning resective surgery for brain regions that are in close proximity to eloquent cortex.

Upward gaze and head deviation with frontal eye field stimulation.

Using electrical stimulation to the deep, most caudal part of the right frontal eye field (FEF), we demonstrate a novel pattern of vertical (upward) eye movement that was previously only thought possible by stimulating both frontal eye fields simultaneously. If stimulation was started when the subject looked laterally, the initial eye movement was back to the midline, followed by upward deviation. Our finding challenges current view of topological organisation in the human FEF and may have general implications for concepts of topological organisation of the motor cortex, since sustained stimulation also induced upward head movements as a component of the vertical gaze shift. [Published with video sequences].

Modern technology calls for a modern approach to classification of epileptic seizures and the epilepsies.

In the last 10-15 years the ILAE Commission on Classification and Terminology has been presenting proposals to modernize the current ILAE Classification of Epileptic Seizures and Epilepsies. These proposals were discussed extensively in a series of articles published recently in Epilepsia and Epilepsy Currents. There is almost universal consensus that the availability of new diagnostic techniques as also of a modern understanding of epilepsy calls for a complete revision of the Classification of Epileptic Seizures and Epilepsies. Unfortunately, however, the Commission is still not prepared to take a bold step ahead and completely revisit our approach to classification of epileptic seizures and epilepsies. In this manuscript we critically analyze the current proposals of the Commission and make suggestions for a classification system that reflects modern diagnostic techniques and our current understanding of epilepsy.