What does the U.S. Medicare administrative claims database tell us about initial antiepileptic drug treatment for older adults with new-onset epilepsy?
Disparities in epilepsy treatment are not uncommon; therefore, we examined population-based estimates of initial antiepileptic drugs (AEDs) in new-onset epilepsy among racial/ethnic minority groups of older US Medicare beneficiaries.Methods
We conducted retrospective analyses of 2008–2010 Medicare administrative claims for a 5% random sample of beneficiaries augmented for minority representation. New-onset epilepsy cases in 2009 had ≥1 International Classification of Diseases, Ninth Revision (ICD-9) 345.x or ≥2 ICD-9 780.3x, and ≥1 AED, AND no seizure/epilepsy claim codes or AEDs in preceding 365 days. We examined AED use and concordance with Quality Indicators of Epilepsy Treatment (QUIET) 6 (monotherapy as initial treatment = ≥30 day first prescription with no other concomitant AEDs), and prompt AED treatment (first AED within 30 days of diagnosis). Logistic regression examined likelihood of prompt treatment by demographic (race/ethnicity, gender, age), clinical (number of comorbid conditions, neurology care, index event occurring in the emergency room (ER)), and economic (Part D coverage phase, eligibility for Part D Low Income Subsidy [LIS], and ZIP code level poverty) factors.Results
Over 1 year of follow-up, 79.6% of 3,706 new epilepsy cases had one AED only (77.89% of whites vs. 89% of American Indian/Alaska Native [AI/AN]). Levetiracetam was the most commonly prescribed AED (45.5%: from 24.6% AI/AN to 55.0% whites). The second most common was phenytoin (30.6%: from 18.8% Asians to 43.1% AI/AN). QUIET 6 concordance was 94.7% (93.9% for whites to 97.3% of AI/AN). Only 50% received prompt AED therapy (49.6% whites to 53.9% AI/AN). Race/ethnicity was not significantly associated with AED patterns, monotherapy use, or prompt treatment.Significance
Monotherapy is common across all racial/ethnic groups of older adults with new-onset epilepsy, older AEDs are commonly prescribed, and treatment is frequently delayed. Further studies on reasons for treatment delays are warranted. Interventions should be developed and tested to develop paradigms that lead to better care.
Young people with temporal lobe epilepsy are more likely to have mental health conditions than those with other types of epilepsy, a new study published in the scientific journal Epilepsy and Behavior suggests.
According to the authors Dr William Schraegle and Dr Jeffrey Titus, these findings reinforce the relationship between depression and temporal lobe epilepsy.
In order to determine whether the region of the brain causing the epilepsy (i.e. the seizure focus) had an impact on rates of psychiatric conditions, the researchers looked at data from 132 children and adolescents aged between six and 18 years with either generalised or partial epilepsy. Those with partial epilepsy had either frontal lobe epilepsy or temporal lobe epilepsy.
The researchers measured the rates of depression, anxiety and withdrawal behaviours using two questionnaires: the Behavior Assessment System for Children (BASC-2), a measure of a caregiver’s perceptions of a child’s emotional and behavioural functioning, and the Quality of Life in Childhood Epilepsy (QOLCE) scale.
The results showed that almost half of the children (41%) had evidence of a psychiatric condition. The rates of these conditions were similar between children with generalised epilepsy and those with partial epilepsy and did not differ depending on the side of the brain (i.e. left or right) from which the epilepsy arose.
However, when the researchers compared children with temporal lobe epilepsy against those with frontal lobe epilepsy, they found that those with temporal lobe epilepsy had higher rates of depression.
In addition, increased numbers of antiepileptic drugs used and higher depression scores, as assessed by their parents, were also associated with a reduction in health-related quality of life in children with temporal lobe epilepsy.
Children and young people with epilepsy often have additional psychiatric problems such as depression and anxiety associated with their epilepsy. It is important that these problems are examined carefully as they can reduce the patient’s overall quality of life.
Author: Dr Özge Özkaya
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Interictal network synchrony and local heterogeneity predict epilepsy surgery outcome among pediatric patients
Epilepsy is a disorder of aberrant cortical networks. Researchers have proposed that characterizing presurgical network connectivity may improve the surgical management of intractable seizures, but few studies have rigorously examined the relationship between network activity and surgical outcome. In this study, we assessed whether local and global measures of network activity differentiated patients with favorable (seizure-free) versus unfavorable (seizure-persistent) surgical outcomes.Methods
Seventeen pediatric intracranial electroencephalography (IEEG) patients were retrospectively examined. For each patient, 1,200 random interictal epochs of 1-s duration were analyzed. Functional connectivity networks were constructed using an amplitude-based correlation technique (Spearman correlation). Global network synchrony was computed as the average pairwise connectivity strength. Local signal heterogeneity was defined for each channel as the variability of EEG amplitude (root mean square) and absolute delta power (μV2/Hz) across epochs. A support vector machine learning algorithm used global and local measures to classify patients by surgical outcome. Classification was assessed using the Leave-One-Out (LOO) permutation test.Results
Global synchrony was increased in the seizure-persistent group compared to seizure-free patients (Student's t-test, p = 0.006). Seizure-onset zone (SOZ) electrodes exhibited increased signal heterogeneity compared to non-SOZ electrodes, primarily in seizure-persistent patients. Global synchrony and local heterogeneity measures were used to accurately classify 16 (94.1%) of 17 patients by surgical outcome (LOO test, iterations = 10,000, p < 0.001).Significance
Measures of global network synchrony and local signal heterogeneity represent promising biomarkers for assessing patient candidacy in pediatric epilepsy surgery.
Seizures are a common manifestation of neurologic dysfunction in neonates and carry a high risk for mortality and adverse long-term outcomes. U.S. birth certificates are a potentially valuable source for studying the epidemiology of neonatal seizures. However, the quality of the data is understudied.Methods
We reviewed all U.S. birth records from 2003 to 2013 to describe the following: (1) rates of missing data, (2) evidence of underreporting, and (3) effect of the 2003 revision of the birth certificate form. We evaluated missingness by state, year, demographic, infant health, and medical care factors using bivariate analyses. To measure potential underreporting, we compared estimates to a published reference (0.95 per 1,000 term births). We developed criteria for data plausibility, and reported which states met these criteria.Results
Of 22,834,395 live term births (≥36 weeks of gestation) recorded using the revised form from 2005 to 2015, there were 5,875 with neonatal seizures, suggesting an incidence of 0.26 per 1,000 term births, one fourth of the expected incidence. Although the overall degree of missing seizure data was low (0.5%), missingness varied significantly by state, year, demographic, infant health, and medical care factors. After the 2003 birth certificate form revision, missing data and evidence of potential underreporting increased. Nine states met criteria for plausibility.Significance
The value of U.S. birth certificate data for neonatal seizure epidemiology is limited by biased missingness, evidence suggestive of underreporting, and changes in reporting subsequent to the 2003 revision. There are plausible data from nine states, which merit investigation for further research.
Perampanel (PER) was used in 12 patients with Unverricht-Lundborg disease (ULD) to evaluate its efficacy against myoclonus and seizures.Methods
We treated 11 patients with EPM1 mutations (6 F, 5 M, aged 13–62 years) and a 43-year-old man with de novo KCNC1 mutation. PER was introduced by 2 mg steps at 2–4 week intervals until 6 mg/day, with a possible dose reduction or dose increase.Results
Ten patients had a clear clinical response of myoclonus, and five were able to reduce concomitant therapy. Improvement was noted sometimes as soon as with 2 mg/day. Epileptic seizures stopped on PER in the six patients who still had experienced generalized tonic–clonic or myoclonic seizures (100%). Some abatement of efficacy on myoclonus was seen in two patients who still retained some benefit. Weight gain was reported in six patients (50%). Psychological and behavioral side-effects were observed in six patients (50%) and led to withdrawal of PER in three cases and dose reduction in three, with abatement of the problems.Significance
This study provides evidence that for ULD patients, PER may show marked efficacy even in severe cases, particularly against myoclonus, but also against seizures. PER should thus be tried in ULD patients whose seizures are not satisfactorily controlled. Its use is limited because of psychological and behavioral side effects, with higher doses of approximately 6 mg/day or greater likely risk factors.
Heterozygous truncation mutations of the SMC1A gene cause a severe early onset epilepsy with cluster seizures in females: Detailed phenotyping of 10 new cases
The phenotype of seizure clustering with febrile illnesses in infancy/early childhood is well recognized. To date the only genetic epilepsy consistently associated with this phenotype is PCDH19, an X-linked disorder restricted to females, and males with mosaicism. The SMC1A gene, which encodes a structural component of the cohesin complex is also located on the X chromosome. Missense variants and small in-frame deletions of SMC1A cause approximately 5% of Cornelia de Lange Syndrome (CdLS). Recently, protein truncating mutations in SMC1A have been reported in five females, all of whom have been affected by a drug-resistant epilepsy, and severe developmental impairment. Our objective was to further delineate the phenotype of SMC1A truncation.Method
Female cases with de novo truncation mutations in SMC1A were identified from the Deciphering Developmental Disorders (DDD) study (n = 8), from postmortem testing of an affected twin (n = 1), and from clinical testing with an epilepsy gene panel (n = 1). Detailed information on the phenotype in each case was obtained.Results
Ten cases with heterozygous de novo mutations in the SMC1A gene are presented. All 10 mutations identified are predicted to result in premature truncation of the SMC1A protein. All cases are female, and none had a clinical diagnosis of CdLS. They presented with onset of epileptic seizures between <4 weeks and 28 months of age. In the majority of cases, a marked preponderance for seizures to occur in clusters was noted. Seizure clusters were associated with developmental regression. Moderate or severe developmental impairment was apparent in all cases.Significance
Truncation mutations in SMC1A cause a severe epilepsy phenotype with cluster seizures in females. These mutations are likely to be nonviable in males.
Toll-like receptor 3 deficiency decreases epileptogenesis in a pilocarpine model of SE-induced epilepsy in mice
Epilepsy affects 60 million people worldwide. Despite the development of antiepileptic drugs, up to 35% of patients are drug refractory with uncontrollable seizures. Toll-like receptors (TLRs) are central components of the nonspecific innate inflammatory response. Because TLR3 was recently implicated in neuronal plasticity, we hypothesized that it may contribute to the development of epilepsy after status epilepticus (SE).Methods
To test the involvement of TLR3 in epileptogenesis, we used the pilocarpine model for SE in TLR3-deficient mice and their respective wild-type controls. In this model, a single SE event leads to spontaneous recurrent seizures (SRS). Two weeks after SE, mice were implanted with wireless electroencephalography (EEG) transmitters for up to 1 month. The impact of TLR3 deficiency on SE was assessed using separate cohorts of mice regarding EEG activity, seizure progression, hippocampal microglial distribution, and expression of the proinflammatory cytokines tumor necrosis factor (TNF)α and interferon (IFN)β.Results
Our data indicate that TLR3 deficiency reduced SRS, microglial activation, and the levels of the proinflammatory cytokines TNFα and IFNβ, and increased survival following SE.Significance
This study reveals novel insights into the pathophysiology of epilepsy and the contribution of TLR3 to disease progression. Our results identify the TLR3 pathway as a potential future therapeutic target in SE.
Interrater agreement in the interpretation of neonatal electroencephalography in hypoxic-ischemic encephalopathy
Research using neonatal electroencephalography (EEG) has been limited by a lack of a standardized classification system and interpretation terminology. In 2013, the American Clinical Neurophysiology Society (ACNS) published a guideline for standardized terminology and categorization in the description of continuous EEG in neonates. We sought to assess interrater agreement for this neonatal EEG categorization system as applied by a group of pediatric neurophysiologists.Methods
A total of 60 neonatal EEG studies were collected from three institutions. All EEG segments were from term neonates with hypoxic-ischemic encephalopathy. Three pediatric neurophysiologists independently reviewed each record using the ACNS standardized scoring system. Unweighted kappa values were calculated for interrater agreement of categorical data across multiple observers.Results
Interrater agreement was very good for identification of seizures (κ = 0.93, p < 0.001), with perfect agreement in 95% of records (57 of 60). Interrater agreement was moderate for classifying records as normal or having any abnormality (κ = 0.49, p < 0.001), with perfect agreement in 78% of records (47 of 60). Interrater agreement was good in classifying EEG backgrounds on a 5-category scale (normal, excessively discontinuous, burst suppression, status epilepticus, or electrocerebral inactivity) (κ = 0.70, p < 0.001), with perfect agreement in 72% of records (43 of 60). Other specific background features had lower agreement, including voltage (κ = 0.41, p < 0.001), variability (κ = 0.35, p < 0.001), symmetry (κ = 0.18, p = 0.01), presence of abnormal sharp waves (κ < 0.20, p < 0.05), and presence of brief rhythmic discharges (κ < 0.20, p < 0.05).Significance
We found good or very good interrater agreement applying the ACNS system for identification of seizures and classification of EEG background. Other specific EEG features showed limited interrater agreement. Of importance to both clinicians and researchers, our findings support using the ACNS system in identifying seizures and classifying backgrounds of neonatal EEG recordings, but also suggest limited reproducibility for certain other EEG features.
Efficacy of mGlu2-positive allosteric modulators alone and in combination with levetiracetam in the mouse 6 Hz model of psychomotor seizures
The metabotropic glutamate receptor subtype 2 (mGlu2) possesses both orthosteric and allosteric modulatory sites, are expressed in the frontal cortex and limbic structures, and can affect excitatory synaptic transmission. Therefore, mGlu2 is a potential therapeutic target in the treatment of epilepsy. The present study seeks to evaluate the anticonvulsant potential of mGlu2-acting compounds.Methods
The anticonvulsant efficacy of two selective mGlu2-positive allosteric modulators (PAMs) (JNJ-42153605 and JNJ-40411813/ADX71149) and one mGlu2/3 receptor agonist (LY404039) were evaluated alone and in combination with the antiseizure drug levetiracetam (LEV) in the mouse 6 Hz model.Results
In the 6 Hz (32 mA stimulus intensity) model, median effective dose (ED50) values were determined for JNJ-42153605 (3.8 mg/kg), JNJ-40411813 (12.2 mg/kg), and LY404039 (10.9 mg/kg). At the 44 mA stimulus intensity, ED50 values were determined for JNJ-42153605 (5.9 mg/kg), JNJ-40411813 (21.0 mg/kg), LY404039 (14.1 mg/kg), and LEV (345 mg/kg). In addition, subprotective doses of each mGlu2-acting compound, administered in combination with various doses of LEV, were able to shift the 6 Hz 44 mA ED50 for LEV by >25-fold. When JNJ-42153605 was administered at varying doses in combination with a single dose of LEV (10 mg/kg), the potency of JNJ-42153605 was increased 3.7-fold. Similarly, when a moderately effective dose of LEV (350 mg/kg) was administered in combination with varying doses of JNJ-40411813, the potency of JNJ-40411813 was increased approximately 14-fold. Plasma levels of JNJ-40411813 and LEV were not different when administered alone or in combination, suggesting that increases in potency are not due to pharmacokinetic effects.Significance
These studies suggest a potential positive pharmacodynamic effect of mGlu2-acting compounds in combination with LEV. If this effect is translated in a clinical setting, it can support a rational polypharmacy concept in treatment of epilepsy patients.
This event is the first of its kind in Glasgow, held at the University of Glasgow, on the 28th February 2017. The day has a neurological / genetics theme with a number of local speakers with a specialism in epilepsy.
The event is open to the public and is free to attend but registration is essential. Policy makers, researchers, clinicians, charities or anyone with an interest in the area are also welcome.
Lunch, tea and coffee will be provided. Click here for more information.
Re-interpreting the results of “controversial” electroencephalogram (EEG) results leads to a different opinion in more than half of the cases, according to a new study published in the journal Clinical Neurophysiology.
The study also found that re-interpreting existing EEG results is less time consuming and more cost effective than obtaining a new EEG.
The diagnosis of epilepsy often relies on a combination of clinical information and findings from EEGs and brain scans. When these investigations are inadequate or where there are inconsistencies, there is a risk of mis-diagnosing the epilepsy.
In order to assess the diagnostic value and effectiveness of re-interpreting EEG results, researchers led by Dr Machiel Zwartsa at Kempenhaeghe Epilepsy Centre in The Netherlands, re-classified the EEGs of 100 people with epilepsy, the results of which were considered to be inconsistent with the clinical diagnosis of the patients.
To evaluate the effectiveness of the re-interpretation process, the researchers included a matched control group of patients in whom a new EEG was performed but no re-interpretation of the earlier EEGs was undertaken. They assessed the diagnostic value of the re-interpretation using questionnaires, and the costs by calculating the number of technician hours required.
The clinical conclusions reached from previous EEGs were known for 85 patients and for 43 of these (50.6%), the re-interpretation led to a change in those conclusions.
In 23 cases, the presence of epileptic activity in the brain changed from positive to negative (17 cases) or from negative to positive (six cases). In 15 cases, the site of origin of the epilepsy was revised and in five cases the epilepsy syndrome changed altogether.
Fifty-seven percent of the patients whose EEGs were re-interpreted did not need new EEGs. Almost all re-interpretations (96%) were considered useful by the neurologists who had initially requested a second EEG and 72% of them were also considered useful by other neurologists not directly involved in the study.
The average time spent by a technician interpreting new EEG results was almost nine hours per patient. This was reduced to five and a half hours when the technician was re-interpreting existing EEG data.
The researchers concluded that re-interpreting “controversial” EEGs is worthwhile. They advise that in cases where there is conflict between clinical information and EEG findings, it is more cost-effective and less time-consuming to re-evaluate existing results than to request a new EEG.
Author: Dr Özge Özkaya
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A novel animal model of acquired human temporal lobe epilepsy based on the simultaneous administration of kainic acid and lorazepam
Kainic acid (KA) is a potent glutamate analog that is used to induce neurodegeneration and model temporal lobe epilepsy (TLE) in rodents. KA reliably induces severe, prolonged seizures, that is, convulsive status epilepticus (cSE), which is typically fatal without pharmacologic intervention. Although the use of KA to model human epilepsy has proven unquestionably valuable for >30 years, significant variability and mortality continue to confound results. These issues are probably the consequence of cSE, an all-or-nothing response that is inherently capricious and uncontrollable. The relevance of cSE to the human condition is dubious, however, as most patients with epilepsy never experienced it. We sought to develop a simple, KA-based animal model of TLE that avoids cSE and its confounds.Methods
Adult, male Sprague-Dawley rats received coincident subcutaneous injections of KA (5 mg) and lorazepam (0.25 mg), approximately 15.0 and 0.75 mg/kg, respectively. Continuous video–electroencephalography (EEG) was used to monitor acute seizure activity and detect spontaneous seizures. Immunocytochemistry, Fluoro-Jade B staining, and Timm staining were used to characterize both acute and chronic neuropathology.Results
Acutely, focal hippocampal seizures were induced, which began after about 30 min and were self-terminating after a few hours. Widespread hippocampal neurodegeneration was detected after 4 days. Spontaneous, focal hippocampal seizures began after an average of 12 days in all animals. Classic hippocampal sclerosis and mossy fiber sprouting characterized the long-term neuropathology. Morbidity and mortality rates were both 0%.Significance
We show here that the effects of systemic KA can be limited to the hippocampus simply with coadministration of a benzodiazepine at a low dose. This means that lorazepam can block convulsive seizures without truly stopping seizure activity. This novel, cSE-free animal model reliably mimics the defining characteristics of acquired mesial TLE: hippocampal sclerosis and spontaneous hippocampal-onset seizures after a prolonged seizure-free period, without significant morbidity, mortality, or nonresponders.
Mutations in a gene called SCN2A can cause either infantile epilepsy or autism spectrum disorder (ASD) according to a new study published in the journal Biological Psychiatry.
SCN2A is responsible for making a protein called NaV1.2 in the brain. NaV1.2 determines the electrical properties of neurons and their ability to communicate with each other, especially during early brain development. Mutations in SCN2A that cause a reduction in NaV1.2 activity lead to ASD, whereas mutations that cause increased activity of NaV1.2 lead to epilepsy.
In a press release, one of the senior authors of the study Dr Stephan Sanders said: “The genetics of neuropsychiatric disease is often complicated, but here we have a single gene in which specific mutations can cause either infantile seizures or autism in a consistent and predictable manner. This gives us an opportunity to understand both what these disorders have in common and what makes them different.”
In this study, the researchers from the University of California San Francisco, Lawrence Berkley National Laboratory and the University of Puerto Rico, analysed 11 different mutations in the SCN2A gene that were originally discovered in children with ASD. The team studied how those mutations affected the function of NaV1.2 in human cells grown in the laboratory.
They saw that all mutations reduced the activity of the protein, but depending on their location on the gene, they either inhibited the production of the protein or blocked its function. The researchers then used these data to develop computer models predicting how these mutations, together with those that had previously been reported to cause infantile seizures, would affect the behaviour of nerve cells, especially during development.
They found that while the mutations seen in children with infantile seizures made the neurons more excitable, those seen in children with ASD made them “unwilling” to send electrical signals.
The lead author of the study, Dr Roy Ben-Shalom said: “It was remarkable to see how consistently neuronal function was disrupted by these different mutations [which] all affected the [protein] in slightly different ways, but they ended up affecting neurons in almost exactly the same way.”
According to the authors, these findings are a first step toward understanding how different subtle changes in neuronal function inside the mother’s womb might lead to the development of either a seizure-prone brain or an autism-prone brain in infancy.
Author: Dr Özge Özkaya
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To assess long-term outcome and identify prognostic factors of radiofrequency thermocoagulation (RFTC) following stereoelectroencephalography (SEEG) explorations in particularly complex cases of focal epilepsy.Methods
We retrospectively reviewed the medical charts, video-SEEG recordings, and outcomes for 23 patients (aged 6–53 years) treated with SEEG-guided RFTC, of whom 15 had negative magnetic resonance imaging (MRI) findings, and 10 were considered noneligible for resective surgery after SEEG. Two to 11 RFTCs per patient (mean 5) were produced by applying 40–50 V, 75–110 mA current for 10–60 s on SEEG electrode contacts within the epileptogenic region, which was very close to eloquent cortices in 12 cases. The general features, SEEG findings, and RFTC extent of the patients were analyzed to extract potential preoperative predictors of post-RFTC seizure outcomes.Results
After a mean follow-up of 32 months (range 2–119 months), eight patients experienced a ≥50% decrease of seizure frequency after RFTC (R+, 34.8%), of whom one had a sustained seizure freedom and 15 patients did not benefit from RFTC (R−, 65.2%). The presence of an MRI lesion was the only significant predictor of a positive outcome, whereas location of epilepsy, extent of interictal epileptiform discharges (IEDs) and of the seizure onset zone, induction of seizures by electrical stimulation, as well as the ratio of the coagulated sites did not show a significant correlation to the RFTC response. However, (sub-)continuous IEDs were more frequently found in R+ than in R− patients, thus suggesting that this EEG marker of the epileptogenic tissue might predict a positive outcome even in patients without obvious MRI lesion.Significance
Our study confirms that RFTC, although less effective than resective surgery, can be a reasonable therapeutic option in complex cases where anatomic constraints make impossible any cortical resection. Further prospective studies are needed to better define RFTC indications and to optimize its methodology.