Electrical status epilepticus in slow-wave sleep (ESES) is characterized by nearly continuous spike–wave discharges during non–rapid eye movement (REM) sleep. ESES is present in Landau-Kleffner syndrome (LKS) and continuous spike and wave in slow-wave sleep (CSWS). Sulthiame has demonstrated reduction in spike–wave index (SWI) in ESES, but is not available in the United States. Acetazolamide (AZM) is readily available and has similar pharmacologic properties. Our aims were to assess the effect of AZM on SWI and clinical response in children with LKS and CSWS. Children with LKS or CSWS treated with AZM at our institution were identified retrospectively. Pre- and posttherapy electroencephalography (EEG) studies were evaluated for SWI. Parental and teacher report of clinical improvement was recorded. Six children met criteria for inclusion. Three children (50%) demonstrated complete resolution or SWI <5% after AZM. All children had improvement in clinical seizures and subjective improvement in communication skills and school performance. Five of six children had subjective improvement in hyperactivity and attention. AZM is a potentially effective therapy for children with LKS and CSWS. This study lends to the knowledge of potential therapies that can be used for these disorders, which can be challenging for families and providers.
Seizure-related disability is an important contributor to health-related quality of life in persons with epilepsy. Yet, there is little information on patient-centered reports of seizure-related disability, as most studies focus on specific constructs of health-related disability, rather than epilepsy. We investigated how patients rate their own disability and how these ratings correlate with various clinical and sociodemographic characteristics.Methods
In a prospective cohort of 250 adults with epilepsy consecutively enrolled in the Neurological Disease and Depression Study (NEEDs), we obtained a broad range of clinical and patient-reported measures, including patients' ratings of seizure-related disability and epilepsy severity using self-completed, single-item, 7-point response global assessment scales. Spearman's correlation, multiple linear regression, and mediation analyses were used to examine the association between seizure-related disability scores and clinical and demographic characteristics of persons with epilepsy.Results
The mean age and duration of epilepsy was 39.8 and 16.7 years, respectively. About 29.5% of the patients reported their seizures as “not at all disabling,” whereas 5.8% of the patients reported them as “extremely disabling.” Age, seizure freedom at 1 year, anxiety, and epilepsy severity were identified as statistically significant predictors of disability scores. The indirect effects of age and seizure freedom, attributable to mediation through epilepsy severity, accounted for 25.0% and 30.3% of the total effects of these determinants on seizure-related disability, respectively.Significance
Measuring seizure-related disability has heuristic value and it has important correlates and mediators that can be targeted for intervention in practice. Addressing modifiable factors associated with disability (e.g., seizure freedom and anxiety) could have a significant impact on decreasing the burden of disability in people with epilepsy.
Improving the inter-rater agreement of hypsarrhythmia using a simplified EEG grading scale for children with infantile spasms
Etiologic features and utilization of antiepileptic drugs in people with chronic epilepsy in China: Report from the Epilepsy Cohort of Huashan Hospital (ECoH)
Temporal lobe epilepsy patients with severe hippocampal neuron loss but normal hippocampal volume: Extracellular matrix molecules are important for the maintenance of hippocampal volume
Hippocampal sclerosis is a common finding in patients with temporal lobe epilepsy (TLE), and magnetic resonance imaging (MRI) studies associate the reduction of hippocampal volume with the neuron loss seen on histologic evaluation. Astrogliosis and increased levels of chondroitin sulfate, a major component of brain extracellular matrix, are also seen in hippocampal sclerosis. Our aim was to evaluate the association between hippocampal volume and chondroitin sulfate, as well as neuronal and astroglial populations in the hippocampus of patients with TLE.Methods
Patients with drug-resistant TLE were subdivided, according to hippocampal volume measured by MRI, into two groups: hippocampal atrophy (HA) or normal volume (NV) cases. Hippocampi from TLE patients and age-matched controls were submitted to immunohistochemistry to evaluate neuronal population, astroglial population, and chondroitin sulfate expression with antibodies against neuron nuclei protein (NeuN), glial fibrillary acidic protein (GFAP), and chondroitin sulfate (CS-56) antigens, respectively.Results
Both TLE groups were clinically similar. NV cases had higher hippocampal volume, both ipsilateral and contralateral, when compared to HA. Compared to controls, NV and HA patients had reduced neuron density, and increased GFAP and CS-56 immunopositive area. There was no statistical difference between NV and HA groups in neuron density or immunopositive areas for GFAP and CS-56. Hippocampal volume correlated positively with neuron density in CA1 and prosubiculum, and with immunopositive areas for CS-56 in CA1, and negatively with immunopositive area for GFAP in CA1. Multiple linear regression analysis indicated that both neuron density and CS-56 immunopositive area in CA1 were statistically significant predictors of hippocampal volume.Significance
Our findings indicate that neuron density and chondroitin sulfate immunopositive area in the CA1 subfield are crucial for the hippocampal volume, and that chondroitin sulfate is important for the maintenance of a normal hippocampal volume in some cases with severe neuron loss.
Epilepsy has recently been redefined to include a single unprovoked seizure if the probability of recurrence is ≥60% over the following 10 years. This definition is based on the estimated risk of a third seizure after two unprovoked seizures, using the lower-limit 95% confidence interval (CI) at 4 years, and does not account for the initially high recurrence rate after first-ever seizure that rapidly falls with increasing duration of seizure freedom. We analyzed long-term outcomes after the first-ever seizure, and the influence of duration of seizure freedom on the likelihood of seizure recurrence, and their relevance to the new definition of epilepsy.Methods
Prospective analysis of 798 adults with a first-ever unprovoked seizure seen at a hospital-based first seizure clinic between 2000 and 2011. The likelihood of seizure recurrence was analyzed according to the duration of seizure freedom, etiology, electroencephalography (EEG), and neuroimaging findings.Results
The likelihood of seizure recurrence at 10 years was ≥60% in patients with epileptiform abnormalities on EEG or neuroimaging abnormalities, therefore, meeting the new definition of epilepsy. However, the risk of recurrence was highly time dependent; after a brief period (≤12 weeks) of seizure freedom, no patient group continued to fulfill the new definition of epilepsy. Of 407 patients who had a second seizure, the likelihood of a third seizure at 4 years was 68% (95% CI 63–73%) and at 10 years was 85% (95% CI 79–91%).Significance
The duration of seizure freedom following first-ever seizure substantially influences the risk of recurrence, with none of our patients fulfilling the new definition of epilepsy after a short period of seizure freedom. When a threshold was applied based on the 10-year risk of a third seizure from our data, no first-seizure patient group ever had epilepsy. These data may be utilized in a definition of epilepsy after a first-ever seizure.
The purpose of this study was to develop a quantitative framework to estimate the likelihood of multifocal epilepsy based on the number of unifocal seizures observed in the epilepsy monitoring unit (EMU).Methods
Patient records from the EMU at Massachusetts General Hospital (MGH) from 2012 to 2014 were assessed for the presence of multifocal seizures as well the presence of multifocal interictal discharges and multifocal structural imaging abnormalities during the course of the EMU admission. Risk factors for multifocal seizures were assessed using sensitivity and specificity analysis. A Kaplan-Meier survival analysis was used to estimate the risk of multifocal epilepsy for a given number of consecutive seizures. To overcome the limits of the Kaplan-Meier analysis, a parametric survival function was fit to the EMU subjects with multifocal seizures and this was used to develop a Bayesian model to estimate the risk of multifocal seizures during an EMU admission.Results
Multifocal interictal discharges were a significant predictor of multifocal seizures within an EMU admission with a p < 0.01, albeit with only modest sensitivity 0.74 and specificity 0.69. Multifocal potentially epileptogenic lesions on MRI were not a significant predictor p = 0.44. Kaplan-Meier analysis was limited by wide confidence intervals secondary to significant patient dropout and concern for informative censoring. The Bayesian framework provided estimates for the number of unifocal seizures needed to predict absence of multifocal seizures. To achieve 90% confidence for the absence of multifocal seizure, three seizures are needed when the pretest probability for multifocal epilepsy is 20%, seven seizures for a pretest probability of 50%, and nine seizures for a pretest probability of 80%.Significance
These results provide a framework to assist clinicians in determining the utility of trying to capture a specific number of seizures in EMU evaluations of candidates for epilepsy surgery.
Intranasal midazolam during presurgical epilepsy monitoring is well tolerated, delays seizure recurrence, and protects from generalized tonic–clonic seizures
To evaluate the tolerability and efficacy of the ictal and immediate postictal application of intranasal midazolam (in-MDZ) in adolescents and adults during video–electroencephalography (EEG) monitoring.Methods
Medical records of all patients treated with in-MDZ between 2008 and 2014 were reviewed retrospectively. For each single patient, the time span until recurrence of seizures was analyzed after an index seizure with and without in-MDZ application. To prevent potential bias, we defined the first seizure with application of in-MDZ as the in-MDZ index seizure. The control index seizure was the preceding, alternatively the next successive seizure without application of in-MDZ.Results
In total, 75 epilepsy patients (mean age 34 ± 14.7 years; 42 male, 33 female) were treated with in-MDZ (mean dose 5.1 mg). Adverse events were observed in four patients (5.3%), and no serious adverse events occurred. The median time after EEG seizure onset before administration of in-MDZ was 2.17 min (interquartile range [IQR] 03.82; range 0.13–15.0 min). Over the next 12 h after in-MDZ, the number of seizures was significantly lower (p = 0.031). The median seizure-free interval was significantly longer following treatment with in-MDZ (5.83 h; IQR 6.83, range 0.4–23.87) than it was for those with no in-MDZ treatment (2.37 h; IQR 4.87, range 0.03–21.87; p = 0.015). Conversely, the likelihood of the patient developing a subsequent seizure was four times higher (odds ratio [OR] 4.33, 95% confidence interval [CI] 1.30–14.47) in the first hour and decreased gradually after 12 h (OR 1.5, 95% CI 1.06–2.12). The occurrence of generalized tonic–clonic seizures was lower in the in-MDZ group in the 24-h observation period (OR 4.67, 95% CI 1.41–15.45; p = 0.009).Significance
Ictal and immediate postictal administration of in-MDZ was well tolerated and not associated with serious adverse events. We demonstrated a significant reduction of subsequent seizures (all seizure types) for a 12 h period and of generalized tonic–clonic seizures for 24 h following in-MDZ.
To develop estimates of the direct cost of epilepsy in the United States for the general epilepsy population and sub-populations by systematically comparing similarities and differences in types of estimates and estimation methods from recently published studies.Methods
Papers published since 1995 were identified by systematic literature search. Information on types of estimates, study designs, data sources, types of epilepsy, and estimation methods was extracted from each study. Annual per person cost estimates from methodologically similar studies were identified, converted to 2013 U.S. dollars, and compared.Results
From 4,104 publications discovered in the literature search, 21 were selected for review. Three were added that were published after the search. Eighteen were identified that reported estimates of average annual direct costs for the general epilepsy population in the United States. For general epilepsy populations (comprising all clinically defined subgroups), total direct healthcare costs per person ranged from $10,192 to $47,862 and epilepsy-specific costs ranged from $1,022 to $19,749. Four recent studies using claims data from large general populations yielded relatively similar epilepsy-specific annual cost estimates ranging from $8,412 to $11,354. Although more difficult to compare, studies examining direct cost differences for epilepsy sub-populations indicated a consistent pattern of markedly higher costs for those with uncontrolled or refractory epilepsy, and for those with comorbidities.Significance
This systematic review found that various approaches have been used to estimate the direct costs of epilepsy in the United States. However, recent studies using large claims databases and similar methods allow estimation of the direct cost burden of epilepsy for the general disease population, and show that it is greater for some patient subgroups. Additional research is needed to further understand the broader economic burden of epilepsy and how it varies across subpopulations.
Applying a perceptions and practicalities approach to understanding nonadherence to antiepileptic drugs
Nonadherence to antiepileptic drugs (AEDs) is a common cause of poor seizure control. This study examines whether reported adherence to AEDs is related to variables identified in the National Institute for Health and Clinical Excellence (NICE) Medicines Adherence Guidelines as being important to adherence: perceptual factors (AED necessity beliefs and concerns), practical factors (limitations in capability and resources), and perceptions of involvement in treatment decisions.Methods
This was a cross-sectional study of people with epilepsy receiving AEDs. Participants completed an online survey hosted by the Epilepsy Society (n = 1,010), or as an audit during inpatient admission (n = 118). Validated questionnaires, adapted for epilepsy, assessed reported adherence to AEDs (Medication Adherence Report Scale [MARS]), perceptions of AEDs (Beliefs about Medicines Questionnaire [BMQ]), and patient perceptions of involvement in treatment decisions (Treatment Empowerment Scale [TES]).Results
Low adherence was related to AED beliefs (doubts about necessity: t(577) = 3.90, p < 0.001; and concerns: t(995) = 3.45, p = 0.001), reported limitations in capability and resources (t(589) = 7.78, p < 0.001), and to perceptions of a lack of involvement in treatment decisions (t(623) = 4.48, p < 0.001). In multiple logistic regression analyses, these factors significantly (p < 0.001) increased variance in reported adherence, above that which could be explained by age and clinical variables (seizure frequency, type, epilepsy duration, number of AEDs prescribed).Significance
Variables identified in the NICE Medicines Adherence Guidelines as potentially important factors for adherence were found to be related to adherence to AEDs. These factors are potentially modifiable. Interventions to support optimal adherence to AEDs should be tailored to address doubts about AED necessity and concerns about harm, and to overcome practical difficulties, while engaging patients in treatment decisions.
Mutations in the DEPDC5 (DEP domain–containing protein 5) gene are a major cause of familial focal epilepsy with variable foci (FFEVF) and are predicted to account for 12–37% of families with inherited focal epilepsies. To assess the clinical impact of DEPDC5 mutations in familial temporal lobe epilepsy, we screened a collection of Italian families with either autosomal dominant lateral temporal epilepsy (ADLTE) or familial mesial temporal lobe epilepsy (FMTLE). The probands of 28 families classified as ADLTE and 17 families as FMTLE were screened for DEPDC5 mutations by whole exome or targeted massive parallel sequencing. Putative mutations were validated by Sanger sequencing. We identified a DEPDC5 nonsense mutation (c.918C>G; p.Tyr306*) in a family with two affected members, clinically classified as FMTLE. The proband had temporal lobe seizures with prominent psychic symptoms (déjà vu, derealization, and forced thoughts); her mother had temporal lobe seizures, mainly featuring visceral epigastric auras and anxiety. In total, we found a single DEPDC5 mutation in one of (2.2%) 45 families with genetic temporal lobe epilepsy, a proportion much lower than that reported in other inherited focal epilepsies.
Hippocampal-thalamic wiring in medial temporal lobe epilepsy: Enhanced connectivity per hippocampal voxel
Medial temporal lobe epilepsy (TLE) with hippocampal sclerosis is often accompanied by widespread changes in ipsilateral and contralateral white matter connectivity. Recent studies have proposed that patients may show pathologically enhanced wiring of the limbic circuits. To better address this issue, we specifically probed connection patterns between hippocampus and thalamus and examined their impact on cognitive function.Methods
A group of 44 patients with TLE (22 with right and 22 with left hippocampal sclerosis) and 24 healthy control participants were examined with high-resolution T1 imaging, memory functional magnetic resonance imaging (fMRI) and probabilistic diffusion tractography. Thirty-four patients had further extensive neuropsychological testing. After whole brain segmentation with FreeSurfer, tractography streamline samples were drawn with hippocampus as the seed and thalamus as the target region. Two tractography strategies were applied: The first targeted the anatomic thalamic volume segmented in FreeSurfer and the second a functional region of interest in the mediodorsal thalamus derived from the activation during delayed recognition memory.Results
We found a pronounced enhancement of connectivity between the sclerotic hippocampus and the ipsilateral thalamus both in the right and left TLE as compared to healthy control participants. This finding held for both the anatomically and the functionally defined thalamic target. Although differences were apparent in the number of absolute fibers, they were most pronounced when correcting for hippocampal volume. In terms of cognitive function, the number of hippocampal-thalamic connections was negatively correlated with performance in a variety of executive tasks, notably in the Trail Making Test, thus suggesting that the pathologic wiring did not compensate cognitive curtailing.Significance
We suggest that TLE is accompanied by an abnormal and dysfunctional enhancement of connectivity between the hippocampus and the thalamus, which is maximal on the side of the sclerosis. This pathologic pattern of limbic wiring might reflect structural remodeling along common pathways of seizure propagation.
Epilepsy Surgery In The United States: Analysis Of Data From The National Association Of Epilepsy Centers
Recurrent secondary generalization in frontal lobe epilepsy: Predictors and a potential link to surgical outcome?
Frontal lobe epilepsy (FLE) frequently leads to secondary generalized tonic–clonic seizures (SGTCS). However, little is known about the clinical, electrophysiologic, and radiologic correlates of SGTCS and whether these could influence diagnosis and treatment.Methods
A cohort of 48 patients with confirmed FLE was retrospectively identified and dichotomized into a group with and a group without SGTCS defined by history (≥1/year) or video–electroencephalography (vEEG). Demographics, seizure semiology, vEEG, neuroimaging data, and estimated seizure-onset zone were tabulated, and their association with the occurrence of SGTCS was evaluated with use of a chi-square test. Independent predictors of SGTCS were confirmed using a stepwise multivariate analysis. Similarly, these predictors as well as a history of SGTCS were tested as multivariate predictors of the postoperative International League Against Epilepsy (ILAE) score in the surgical subgroup (n = 25).Results
We identified three independent predictors of a history of SGTCS in FLE, including loss of responsiveness at seizure onset (corrected p = 0.04), a semiology involving early elementary motor signs (corrected p = 0.01), and multifocal spikes on EEG (corrected p = 0.02). A seizure-free outcome occurred in 57% of surgical cases and was more likely in the group without SGTCS (100%, p = 0.001). When considering only SGTCS occurring during video-EEG monitoring, the association with semiology and surgical outcome vanished, but the association with preserved awareness and a multifocal EEG persisted.Significance
A history of SGTCS is related to a specific ictal semiology and interictal EEG, and may have a role in surgical risk stratification.
Intravenous Anesthesia in Treatment of Nonconvulsive Status Epilepticus: Characteristics and Outcomes
Generic lamotrigine versus brand-name Lamictal bioequivalence in patients with epilepsy: A field test of the FDA bioequivalence standard
To test the current U.S. Food and Drug Administration (FDA) bioequivalence standard in a comparison of generic and brand-name drug pharmacokinetic (PK) performance in “generic-brittle” patients with epilepsy under clinical use conditions.Methods
This randomized, double-blind, multiple-dose, steady-state, fully replicated bioequivalence study compared generic lamotrigine to brand-name Lamictal in “generic-brittle” patients with epilepsy (n = 34) who were already taking lamotrigine. Patients were repeatedly switched between masked Lamictal and generic lamotrigine. Intensive PK blood sampling at the end of each 2-week treatment period yielded two 12-h PK profiles for brand-name and generic forms for each patient. Steady-state area under the curve (AUC), peak plasma concentration (Cmax), and minimum plasma concentration (Cmin) data were subjected to conventional average bioequivalence (ABE) analysis, reference-scaled ABE analysis, and within-subject variability (WSV) comparisons. In addition, generic-versus-brand comparisons in individual patients were performed. Secondary clinical outcomes included seizure frequency and adverse events.Results
Generic demonstrated bioequivalence to brand. The 90% confidence intervals of the mean for steady-state AUC, Cmax, and Cmin for generic-versus-brand were 97.2–101.6%, 98.8–104.5%, and 93.4–101.0%, respectively. The WSV of generic and brand were also similar. Individual patient PK ratios for generic-versus-brand were similar but not identical, in part because brand-versus-brand profiles were not identical, even though subjects were rechallenged with the same product. Few subjects had seizure exacerbations or tolerability issues with product switching. One subject, however, reported 267 focal motor seizures, primarily on generic, although his brand and generic PK profiles were practically identical.Significance
Some neurologists question whether bioequivalence in healthy volunteers ensures therapeutic equivalence of brand and generic antiepileptic drugs in patients with epilepsy, who may be at increased risk for problems with brand-to-generic switching. Bioequivalence results in “generic-brittle” patients with epilepsy under clinical conditions support the soundness of the FDA bioequivalence standards. Adverse events on generic were not related to the small, allowable PK differences between generic and brand.
The ketogenic diet (KD) is currently a well-established treatment for patients with medically refractory, nonsurgical epilepsy. However, despite its efficacy, the KD is highly restrictive and constitutes a treatment with serious potential adverse effects, and often with difficulties in its implementation and compliance. Patients on the KD require strict follow-up and constant supervision by a medical team highly experienced in its management in order to prevent complications. Other alternative treatments for patients with refractory epilepsy include vagus nerve stimulation (VNS), new-generation antiepileptic drugs (AEDs), corpus callosotomy (CC), and responsive focal cortical stimulation (RNS). In this review, we explain not only the difficulties of the KD as a therapeutic option for refractory epilepsy but also the benefits of other therapeutic strategies, which, in many cases, have proven to have better efficacy than the KD itself.
Ketogenic diet therapies for epilepsy have been described since the fifth century and published in scientific literature since the early 1900s. Since that time, the diet's popularity has waxed and waned as newer drugs and other treatments have been introduced. However, in recent years, dietary therapy for epilepsy has been increasingly accepted by physicians and desired by patients as an alternative to new drugs and neurostimulation. The introduction of less restrictive versions of the classic ketogenic diet, such as the modified Atkins diet (MAD), have led to increased numbers of adult patients with refractory epilepsy who are initiating dietary treatment. Approximately half of adults and children who start a ketogenic diet have a >50% seizure reduction, which is impressive given that these patients typically have medically refractory epilepsy. We believe that ketogenic dietary treatment is the best option for children and adults with refractory nonsurgical epilepsy due to its efficacy, rapid seizure reduction, synergistic effects with other antiseizure treatments, known and treatable side effects, potential to treat comorbid medical conditions, and worldwide availability.