Increased Risk of Hospital Admission for ICD-9-CM Psychotic Episodes Following Admission for Epilepsy

SIGNIFICANCE: An epilepsy admission was independently associated with subsequent hospital readmission for psychotic episodes, even after adjustment for confounding variables.

OBJECTIVE: To determine whether epilepsy admissions are associated with a higher readmission risk for psychotic episodes compared to admissions for other medical causes.

METHODS: The Nationwide Readmissions Database is a nationally representative dataset from 2013. We used International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes to identify medical conditions. There were 58 278 index admissions for epilepsy, and this group was compared against admissions for stroke (n = 215 821) and common medical causes (pneumonia, urinary tract infection [UTI], congestive heart failure [CHF], and chronic obstructive pulmonary disease [COPD], n = 973 078). Readmission rates for psychotic episodes within 90 days from discharge for index hospitalizations were calculated. Cox regression was used to test for associations between admission type and re-admission for psychotic episodes up to 1 year after index admission, in univariate models and adjusted for multiple medical, social, and psychiatric variables.

RESULTS: Up to 90 days from index admission, there were 683/100 000 readmissions for psychotic episodes in the epilepsy group, 92/100 000 in the stroke group, and 58-206/100 000 in the medical group. The relative rate of readmission in the epilepsy group was highest in the first 30 days following index admission (311/100 000). Unadjusted hazard ratio (HR) for readmission for psychotic episodes within 1 year in the epilepsy group compared to the stroke group was 6.58 (95% confidence interval [CI] 5.69-7.61, P < 2 × 10-16 ), and 4.41 compared to the medical group (95% CI 4.00-4.85, P < 2 × 10-16 ). The fully adjusted HR for readmission in the epilepsy group remained elevated at 3.63 compared to the stroke group (95% CI 3.08-4.28, P < 2 × 10-16 ), and 1.95 compared to the medical group (95% CI 1.76-2.15, P < 2 × 10-16). Confounding factors most strongly associated with psychosis readmission were documented psychosis history at the time of index admission, younger age, and lower income quartile.

Mechanism Leading to Cortical Malformation from Brain-Only Mutations Identified

Focal malformations of cortical development (FMCDs) are a heterogeneous group of brain cortical abnormalities. These conditions are the most common causes of medically refractory epilepsy in children and are highly associated with intellectual disability, developmental delay, and autism-spectrum disorders. Despite a broad spectrum of cortical abnormalities in FMCDs, the defective migration of neuronal cells is considered a key pathological hallmark.

A Korean research team led by [CURE grantee] Professor Jeong Ho Lee at the Korea Advanced Institute of Science and Technology (KAIST) has recently investigated the molecular mechanism of defective neuronal migration in FMCDs.

The research team previously demonstrated that brain-only mutations in the mechanistic target of rapamycin (MTOR) gene causes focal cortical dysplasia, one major form of FMCDs leading to intractable epilepsy in children. However, the molecular mechanisms by which brain-only mutations in MTOR lead to cortical dyslamination and defective neuronal migration in FMCDs remain unclear.

Brand Name to Generic Substitution of Levetiracetam in Patients with Epilepsy

PURPOSE: Levetiracetam is one of the most widely used antiepileptic drugs, but the evidence related to the safety of substitution from brand name to generic levetiracetam is scarce. The present study evaluated the risk of increased frequency of seizures after replacement of a brand-name levetiracetam with a generic product.

METHODS: We enrolled patients with epilepsy who were treated with branded levetiracetam for at least 6 months of sustained use. Patients were advised to switch to the generic levetiracetam. We analyzed data from 6 months before, to 6 months after, generic substitution. Increased seizure frequency was defined as a? 50% increase in seizure frequency after conversion date compared with seizure frequency before the conversion date. We analyzed changes in seizure frequency and performed subgroup analysis according to changes in seizure frequency.

RESULTS: We analyzed 148 epilepsy patients. Among the 148 patients, 109 (73.6%) were seizure-free before substitution and 105 patients remained seizure-free after switching. After generic substitution, an increased seizure frequency was noted in seven patients (4.7%), and a decreased seizure frequency was noted in 10 (6.8%). Patients with decreased seizure frequency were significantly younger (p?=?0.035) than those with an unchanged seizure frequency.

CONCLUSION: This study suggests that the risk of increased seizure frequency after generic substitution was minimal. The generic substitution of levetiracetam was generally safe, although larger prospective studies are warranted to corroborate our findings.

Health Care Expenditures Among Elderly Patients with Epilepsy in the United States

OBJECTIVE: The purpose of this study was to evaluate health care expenditures among elderly patients with epilepsy in the United States.

METHODS: We performed an analysis with 2003-2014 data of weighted 37,738,607 US participants aged 65 years to estimate health care expenditures in the elderly with and without epilepsy using the Medical Expenditure Panel Survey Household Component. Unadjusted health care expenditures were estimated. Independent health care expenditures were estimated, using a 2-part model.

RESULTS: We identified 416,496 (1.1%) older individuals with epilepsy. Comorbidities were more prevalent among older individuals with epilepsy versus younger individuals. Mean unadjusted yearly medical cost of epilepsy in elderly patients with epilepsy was $18 712 (95% confidence interval [CI] = $15 947-$21 476) during the pooled period 2003-2014, which was nearly double the equivalent cost in elderly subjects without epilepsy at $10 168 (95% CI = $9925-$10 410). Mean unadjusted annual medical cost of epilepsy in the elderly increased by $2135 from $15 850 (95% CI = $10 668-$21 032) in 2003-2006 to $17 985 (95% CI = $13 710-$22 260) in 2011-2014. Adjusted mean total health care expenditures per person per year for elderly patients with epilepsy were $12 526 in 2003-2006, $13 423 in 2007-2010, and $10 569 in 2011-2014. Adjusted incremental health care costs associated with epilepsy in the elderly accrued by $4595 (95% CI = $2399-$6791) when compared to elderly subjects without epilepsy. We estimated the mean annual aggregate cost of epilepsy at $7.8 billion to the US population.

SIGNIFICANCE: Epilepsy is common among elderly individuals, and health care expenditures among this growing group are 2 times higher than in those without epilepsy.

Environmental enrichment Alleviates Cognitive and Behavioral Impairments in EL Mice (a Genetic Model of Human Idiopathic Epilepsy)

Epilepsy in children is occasionally associated with comorbidities, such as cognitive impairment, behavioral disturbances, and social deficits. These neurobehavioral comorbidities are closely related to environmental factors and the severity of the seizures. Previous studies show that environmental enrichment has a beneficial effect in animal models of temporal lobe epilepsy following systemic chemoconvulsant administration. However, the effect of environmental enrichment on behavioral impairments in the EL mouse, a genetic model of human idiopathic epilepsy, remains unknown.

In the present study, we examined the effect of environmental enrichment on cognitive and behavioral impairments in this murine model. The EL mice, under standard laboratory conditions, exhibited impairments in spatial memory in the Morris water maze test, hyperactivity and impaired habituation in the open-field test, and a deficit in social novelty preference in the three-chamber social approach test, compared with control DDY mice, a genetically related nonepileptic strain. These impairments in EL mice were ameliorated by exposure to an enriched environment. These findings suggest that environmental enrichment effectively ameliorates cognitive and behavioral deficits in EL mice.

Pediatric Epilepsies Misdiagnosed as Gastrointestinal Disorders

In the last years, several cases of pediatric epilepsies misdiagnosed and treated as gastrointestinal (GI) disorders have been reported. The aim of this study was to evaluate both frequency and characteristics of these erroneous diagnoses. We identified children who had received a previous misdiagnosis of GI disorder out of 858 consecutive patients with a diagnosis of epilepsy at our hospital from 2010 to 2015.

Misdiagnosis was observed in 21 patients (2.4%): 7 children with West syndrome, 10 with temporal lobe epilepsy, and 4 with Panayiotopoulos syndrome. The majority of children with a misdiagnosis (12/21) were younger than 1 year at epilepsy onset, and median diagnostic delay was 15.5 months. The most frequently diagnosed GI disorder was gastroesophageal reflux disease, especially in younger children.

The study confirms that epilepsy in a significant percentage of children is wrongly identified and treated as GI disorders. In particular, epilepsy should be considered in the differential diagnosis of “atypical” gastroesophageal reflux in younger children in order to avoid serious prognostic consequences.

Prospective Study of the Efficacy of a Ketogenic Diet in 20 Patients with Dravet Syndrome

PURPOSE: We evaluated the efficacy and tolerability of the ketogenic diet (KD) on generalized convulsions and status epilepticus (SE) in patients with Dravet syndrome (DS).

METHODS: Patients with DS having ?2 generalized convulsions/month despite drug treatment were included in this study and placed on a KD for 6 months. From 3 months before (baseline) to 6 months after KD initiation, caregivers recorded patients’ seizure activity, antiepileptic drug use, and adverse events. The KD efficacy was determined by examining the frequency and duration of seizures at 3 and 6 months vs. baseline. Responders were defined as individuals whose generalized convulsions decreased in frequency by ?50% vs. baseline. Seizures lasting ?5?min and SE were specifically evaluated. Patients’ cognition was also assessed at 3 and 6 months via questionnaire.

RESULTS: Twenty patients continued the KD for at least 3 months. Of the 17 responders identified at month 3, seizures decreased by 50-89% and 90-99% in nine and two patients, respectively; six patients were seizure free. The KD was ineffective in three patients, who discontinued the diet. By month 6, seizures decreased by 50-89% and 90-99% in six and one patient(s), respectively; 10 patients were seizure free. The frequency of other seizure types also improved. During all 6 months, neither generalized convulsions lasting ?5?min nor SE was detected in the 17 responders. The KD also improved patients’ cognition.

CONCLUSION: The ketogenic diet is a good treatment option for medically intractable epilepsy.

Timing Matters: Impact of Anticonvulsant Drug Treatment and Spikes on Seizure Risk in Benign Epilepsy with Centrotemporal Spikes

Objective: BECTS is a common, self?limited epilepsy syndrome affecting school?age children. Classic interictal epileptiform discharges (IEDs) confirm diagnosis and BECTS is presumed to be pharmacoresponsive. As seizure risk decreases in time in this disease, we hypothesize that the impact of IEDs and ACD treatment on the risk of subsequent seizure will differ based on disease duration.

Methods: We calculate subsequent seizure risk following diagnosis in a large retrospective cohort of children with BECTS (n=130), evaluating the impact of IEDs and ACD treatment in the first, second, third, and fourth years of disease. We use a Kaplan?Meier survival analysis and logistic regression models. Patients were censored if they were lost to follow?up or if they changed group status.

Results: Two?thirds of children had a subsequent seizure within 2 years of diagnosis. The majority of children had a subsequent seizure within three years in spite of treatment. The presence of IEDs on EEG did not impact subsequent seizure risk early in the disease. By the fourth year of disease, all children without IEDs remained seizure free, whereas 1/3 of children with IEDs at this stage had a subsequent seizure. Conversely, ACD treatment corresponded with lower risk of seizure early in the disease, but did not impact seizure risk in later years.

Significance: In this cohort, the majority of children with benign epilepsy with cetrotemporal spikes had a subsequent seizure in spite of treatment. In addition, anticonvulsant drug treatment treatment and interictal epileptiform discharges predicted seizure risk at specific points of disease duration. Future prospective studies are needed to validate these exploratory findings.

Next-Generation Sequencing May Improve Pediatric Epilepsy Tx

Next-generation sequencing (NGS) can improve treatment efficacy and reduce hospitalization in children with drug-resistant epilepsy (DRE), according to a study published CNS Neuroscience & Therapeutics.

Jing Peng, Ph.D., from Central South University in China, and colleagues conducted genetic testing on 273 pediatric DRE patients with no obvious acquired etiology; 74 underwent whole-exome sequencing (WES), 141 had epilepsy-related gene panel testing, and 58 had clinical WES gene panel testing. Frequency of seizures, outpatient visits, and hospitalization was also assessed.

The researchers found that a genetic diagnosis was made in 86 patients (31.5 percent; 93 likely disease-causing mutations in 33 genes). By testing type, detection rates were 32.6% for the epilepsy-related gene panel, 44.8% for the clinical WES gene panel, and 17.3% for WES. Also, 34 patients accepted therapy based on their mutant genes, after which 52.9% became seizure-free and 38.2% experienced seizure reduction. Hospitalization incidents were significantly lower for patients after testing than before regardless of positive or negative genetic results.

Modulation of Epileptiform EEG Discharges in Patients with Juvenile Myoclonic Epilepsy

PURPOSE: To study modulation of epileptiform EEG discharges in patients with juvenile myoclonic epilepsy (JME).

METHOD: 50 subjects with JME underwent a sleep deprived EEG recording along with conventional provocative methods and testing with cognitive tasks (CTs). Both categories of tests were evaluated for their effect on occurrence of IEDs. Number of IEDs per unit time was calculated at baseline as well as with each task. Statistical and arbitrary methods were used to assess modulation. By arbitrary method if frequency of IEDs was more than twice that of baseline, it was considered as provocation and if less than half, it was considered as inhibition. To account for spontaneous fluctuation of IEDs, 95% CI was calculated for baseline IEDs in each patient and provocation/inhibition was considered if frequency of IEDs exceeded/remained below limits of CI respectively.

RESULTS: There was no significant difference in rates of provocation of IEDs by conventional or CTs. However there was exclusive provocation of IEDs by CTs in 4 patients, 3 of whom were already on AEDs. There was a significant inhibitory effect of CTs as mean baseline discharge frequency was 0.4?±?1.16 IEDS/min and during CTs was 0.1?±?0.38 IEDs/min. However when spontaneous fluctuation was accounted for, inhibition was seen in only 22.23% patients by statistical method as compared to 90.91% by arbitrary method.

CONCLUSIONS: Inclusion of cognitive tasks (CTs) may assist in provocation of interictal epileptiform discharges (IEDs), thereby increasing yield of routine EEG. Spontaneous fluctuation of IEDs accounts for much observed inhibition by CTs in juvenile myoclonic epilepsy patients.