We assessed whether presurgical resting state functional magnetic resonance imaging (fMRI) provides information for distinguishing temporal lobe epilepsy (TLE) with mesial temporal sclerosis (TLE-MTS) from TLE without MTS (TLE-noMTS).Methods
Thirty-four patients with TLE and 34 sex-/age-matched controls consented to a research imaging protocol. MTS status was confirmed by histologic evaluation of surgical tissue (TLE-MTS = 16; TLE-noMTS = 18). The fractional amplitude of low-frequency fluctuations (fALFFs) in the blood oxygen level–dependent (BOLD) resting-state fMRI signal, a marker of local metabolic demand at rest, was averaged at five regions of interest (ROIs; hippocampus, amygdala, frontal, occipital, and temporal lobe), along with corresponding volume and cortical thickness estimates. ROIs were labeled ipsilateral or contralateral according to seizure lateralization and compared across TLE-MTS, TLE-noMTS, and healthy controls (HCs). MTS status was regressed on ipsilateral hippocampal volume and fALFF to test for independent contributions.Results
The TLE-MTS group had reduced fALFF in the ipsilateral amygdala and hippocampus; whereas, the TLE-noMTS group had marginally reduced fALFF in the ipsilateral amygdala but not hippocampus. These results were consistently obtained with and without application of global signal regression (GSR). Ipsilateral hippocampal volume contributed to 37% of the variance in MTS status (p < 0.001) and fALFF contributed an additional 10% (p = 0.021). Two MTS cases were accurately classified with fALFF but not volume, and three were accurately classified with volume but not fALFF. At the lobar level, fALFF (with GSR) was reduced in the ipsilateral temporal and bilateral frontal lobes of patients with TLE-MTS and bilateral frontal lobes of patients with TLE-noMTS in the context of normal cortical thickness.Significance
This study indicates that resting-state fMRI provides complementary functional information for MTS classification. Findings validate fALFF as a measure of regional brain integrity in TLE and highlight the value of using multi-modal imaging to provide independent diagnostic information in presurgical epilepsy evaluations.
The SCN8A encephalopathy mutation p.Ile1327Val displays elevated sensitivity to the anticonvulsant phenytoin
SCN8A encephalopathy (early infantile epileptic encephalopathy; EIEE13) is caused by gain-of-function mutations resulting in hyperactivity of the voltage-gated sodium channel Nav1.6. The channel is concentrated at the axon initial segment (AIS) and is involved in establishing neuronal excitability. Clinical features of SCN8A encephalopathy include seizure onset between 0 and 18 months of age, intellectual disability, and developmental delay. Seizures are often refractory to treatment with standard antiepileptic drugs, and sudden unexpected death in epilepsy (SUDEP) has been reported in approximately 10% of patients. In a recent study, high doses of phenytoin were effective in four patients with SCN8A encephalopathy. In view of this observation, we have investigated the relationship between the functional effect of the SCN8A mutation p.Ile1327Val and its response to phenytoin.Methods
The mutation was introduced into the Scn8a cDNA by site-directed mutagenesis. Channel activity was characterized in transfected ND7/23 cells. The effects of phenytoin (100 μm) on mutant and wild-type (WT) channels were compared.Results
Channel activation parameters were shifted in a hyperpolarizing direction in the mutant channel, whereas inactivation parameters were shifted in a depolarizing direction, increasing Na channel window current. Macroscopic current decay was slowed in I1327V channels, indicating an impairment in the transition from open state to inactivated state. Channel deactivation was also delayed, allowing more channels to remain in the open state. Phenytoin (100 μm) resulted in hyperpolarized activation and inactivation curves as well as greater tonic block and use-dependent block of I1327V mutant channels relative to WT.Significance
SCN8A – I1327V is a gain-of-function mutation with altered features that are predicted to increase neuronal excitability and seizure susceptibility. Phenytoin is an effective inhibitor of the mutant channel and may be of use in treating patients with gain-of-function mutations of SCN8A.
Peripheral biomarkers have myriad potential uses for treatment, prediction, prognostication, and pharmacovigilance in epilepsy. To date, no single peripheral biomarker has demonstrated proven effectiveness, although multiple candidates are in development. In this review, we discuss the major areas of focus including inflammation, blood–brain barrier dysfunction, redox alterations, metabolism, hormones and growth factors.
Revised version of quality guidelines for presurgical epilepsy evaluation and surgical epilepsy therapy issued by the Austrian, German, and Swiss working group on presurgical epilepsy diagnosis and operative epilepsy treatment
The definition of minimal standards remains pivotal as a basis for a high standard of care and as a basis for staff allocation or reimbursement. Only limited publications are available regarding the required staffing or methodologic expertise in epilepsy centers. The executive board of the working group (WG) on presurgical epilepsy diagnosis and operative epilepsy treatment published the first guidelines in 2000 for Austria, Germany, and Switzerland. In 2014, revised guidelines were published and the WG decided to publish an unaltered English translation in this report. Because epilepsy surgery is an elective procedure, quality standards are particularly high. As detailed in the first edition of these guidelines, quality control relates to seven different domains: (1) establishing centers with a sufficient number of sufficiently and specifically trained personnel, (2) minimum technical standards and equipment, (3) continuous medical education of employees, (4) surveillance by trained personnel during video electroencephalography (EEG) monitoring (VEM), (5) systematic acquisition of clinical and outcome data, (6) the minimum number of preoperative evaluations and epilepsy surgery procedures, and (7) the cooperation of epilepsy centers. These standards required the certification of the different professions involved and minimum numbers of procedures. In the subsequent decade, quite a number of colleagues were certified by the trinational WG; therefore, the executive board of the WG decided in 2013 to make these standards obligatory. This revised version is particularly relevant given that the German procedure classification explicitly refers to the guidelines of the WG with regard to noninvasive/invasive preoperative video-EEG monitoring and invasive intraoperative diagnostics in epilepsy.
Development and validation of the NDDI-E-Y: a screening tool for depressive symptoms in pediatric epilepsy
To validate the revised 12-item revised Neurological Disorders Depression Inventory-Epilepsy for Youth (NDDI-E-Y), a self-report screening tool for depressive symptoms tailored to youth ages 12–17 with epilepsy.Methods
Youth at two sites completed the NDDI-E-Y during a routine epilepsy visit. Youth at one site also completed the Children's Depression Inventory-2 (CDI-2). Seizure and demographic data were abstracted from the electronic medical record. Exploratory factor analyses were conducted. Internal consistency, area under the curve (AUC), and construct validity were assessed.Results
NDDI-E-Y questionnaires were analyzed for 143 youth. The coefficient for internal consistency for the NDDI-E-Y was 0.92. Factor analyses suggested a one-factor solution with all 12 items loading on the factor. The NDDI-E-Y was positively correlated with the CDI-2 (N = 99). Sensitivity and specificity of the NDDI-E-Y were high.Significance
Reliability and construct validity were established for the revised 12-item NDDI-E-Y. The NDDI-E-Y is a brief, free measure of depressive symptoms that can be administered during a routine epilepsy visit.
Impact of frequency and lateralization of interictal discharges on neuropsychological and fine motor status in children with benign epilepsy with centrotemporal spikes
Despite a positive prognosis for seizure remission, children with benign epilepsy with centrotemporal spikes (BECTS) have been reported to exhibit subtle neuropsychological difficulties. We examined the relationship between patterns of centrotemporal spikes (the typical electroencephalography [EEG] finding in BECTS) and neuropsychological and motor outcomes in children with new-onset BECTS. Thirty-four patients with new-onset BECTS (not taking antiepileptic medication) and 48 typically developing children participated in the study. In BECTS patients, centrotemporal spikes (CTS) were evaluated in the first hour awake and first 2 h of sleep in a 24-h EEG recording and left or right-sided origin was noted. General intellectual function, language, visuospatial skill, processing speed, and fine motor skill were assessed in all participants. We found no significant difference between BECTS patients and controls on measures of general intellectual function, or visuospatial or language testing. There were significant differences in processing speed index and nondominant hand fine motor scores between groups. Significant negative relationships were observed between rates of left-sided CTS and right hand fine motor scores. This suggests that psychomotor and fine motor speed are affected in BECTS, but the extent of affected domains may be more limited than previously suggested, especially in untreated patients early in the course of their epilepsy.
Health-related quality of life (HRQL) is compromised in children with epilepsy. The current study aimed to identify correlates of HRQL in children with drug resistant epilepsy.Methods
Data came from 115 children enrolled in the Impact of Pediatric Epilepsy Surgery on Health-Related Quality of Life Study (PEPSQOL), a multicenter prospective cohort study. Individual, clinical, and family factors were evaluated. HRQL was measured using the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE), a parent-rated epilepsy-specific instrument, with composite scores ranging from 0 to 100. A series of univariable linear regression analyses were conducted to identify significant associations with HRQL, followed by a multivariable regression analysis.Results
Children had a mean age of 11.85 ± 3.81 years and 65 (56.5%) were male. The mean composite QOLCE score was 60.18 ± 16.69. Child age, sex, age at seizure onset, duration of epilepsy, caregiver age, caregiver education, and income were not significantly associated with HRQL. Univariable regression analyses revealed that a higher number of anti-seizure medications (p = 0.020), lower IQ (p = 0.002), greater seizure frequency (p = 0.048), caregiver unemployment (p = 0.010), higher caregiver depressive and anxiety symptoms (p < 0.001 for both), poorer family adaptation, fewer family resources, and a greater number of family demands (p < 0.001 for all) were associated with lower HRQL. Multivariable regression analysis showed that lower child IQ (β = 0.20, p = 0.004), fewer family resources (β = 0.43, p = 0.012), and caregiver unemployment (β = 6.53, p = 0.018) were associated with diminished HRQL in children.Significance
The results emphasize the importance of child cognition and family variables in the HRQL of children with drug-resistant epilepsy. The findings speak to the importance of offering comprehensive care to children and their families to address the nonmedical features that impact on HRQL.
(1) To describe patient adverse events (PAEs) experienced by hospitalized individuals with epilepsy and examine the association of an epilepsy diagnosis on risk of specific PAEs; (2) to examine the impact of a PAE on (a) length of stay (LOS), (b) inpatient death, and (c) use of institutional post-acute care.Methods
We applied the Agency for Healthcare Research and Quality (AHRQ) Patient Safety Indicator (PSI) software to the National Inpatient Sample database to identify potential medical and postoperative PAEs among >72 million hospitalizations of adults in the United States from 2000 to 2010. Logistic regression models compared the odds of experiencing each PAE between hospitalizations of persons with epilepsy (PWE) and the general inpatient population. We also examined the impact of experiencing a PAE on LOS, inpatient death, and discharge disposition.Results
Hospitalized PWEs were at increased risk for specific postoperative PAEs: fall with hip fracture (Adjusted Odds Ratio, AOR 1.90, 1.21–2.99), respiratory failure (AOR 2.64, 2.43–2.87), sepsis (AOR 1.41, 1.21–1.63), and preventable postoperative death (AOR 1.25, 1.15–1.36). The odds of perioperative pulmonary embolism/deep vein thrombosis (AOR 1.65, 1.57–1.73), skin pressure ulcer (AOR 1.25, 1.22–1.29), and central venous catheter-related bloodstream infections (AOR 1.24, 1.17–1.32) were also greater among hospitalizations of PWEs. Experiencing a PAE was associated with a prolonged mean length of stay (15 days vs. 5 days, t-test p < 0.001), a 416% increase in the odds of inpatient death (AOR 4.16, 3.95–4.38), and a 282% increase in use of high-level post-acute care (AOR 2.82, 2.72–2.93).Significance
Hospitalized adults with epilepsy are vulnerable to specific safety-related adverse events, and these potential patient safety failures substantially impact outcomes and resource use. Efforts to reduce long-term disability and improve the value of care delivered to PWEs may need to consider provider-level interventions to reduce adverse events.
Ketogenic diet treatment increases longevity in Kcna1-null mice, a model of sudden unexpected death in epilepsy
Individuals with poorly controlled epilepsy have a higher risk for sudden unexpected death in epilepsy (SUDEP). With approximately one third of people with epilepsy not achieving adequate seizure control with current antiseizure drugs, there is a critical need to identify treatments that reduce risk factors for SUDEP. The Kcna1-null mutant mouse models risk factors and terminal events associated with SUDEP. In the current study, we demonstrate the progressive nature of epilepsy and sudden death in this model (mean age of mortality (± SEM), postnatal day [P] 42.8 ± 1.3) and tested the hypothesis that long-term treatment with the ketogenic diet (KD) will prolong the life of Kcna1-null mice. We found that the KD postpones disease progression by delaying the onset of severe seizures and increases the lifespan of these mutant mice by 47%. Future studies are needed to determine the mechanisms underlying the KD effects on longevity.
Does status epilepticus induced at early postnatal period change excitability after cortical epileptic afterdischarges?
Possible changes of cortical excitability after status epilepticus (SE) elicited in 12-day-old rats were studied by means of paired cortical afterdischarges (ADs). Consequences of lithium-pilocarpine status were studied in animals with implanted electrodes 3, 6, 9, 13, and 26 days after SE. Paired low-frequency stimulation with a 1-min interval was repeated after 10 min, and duration of ADs was measured. Control rats received saline instead of pilocarpine; other treatments were the same as in SE group. Postictal refractoriness (i.e., the testing response significantly shorter than the conditioning one) appeared at the age of 18 days in lithium-paraldehyde controls, whereas SE animals exhibited this phenomenon since postnatal day 21. The only significant difference between SE and lithium-paraldehyde controls was found in the second conditioning AD in the oldest group studied–it was longer in 38-day-old SE animals. Our results demonstrated moderate signs of higher excitability of SE rats in comparison with control ones long before appearance of spontaneous seizures.
Bioavailability and bioequivalence comparison of brivaracetam 10, 50, 75, and 100 mg tablets and 100 mg intravenous bolus
To determine the bioequivalence of brivaracetam oral tablet formulations (10, 75, and 100 mg) versus 50 mg oral tablet and to compare the bioavailability of brivaracetam 100 mg intravenous (i.v.) bolus versus 50 and 100 mg tablets, in healthy participants.Methods
Phase 1, randomized, open-label, five-period crossover study. Participants received five single doses of brivaracetam: 10, 50 (reference), 75, and 100 mg oral tablets; 100 mg, i.v., bolus injection. Pharmacokinetic parameters (maximum plasma concentration [Cmax], area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration [AUCt], area under the plasma concentration-time curve extrapolated to infinity [AUCinf]) were compared using analysis of variance (ANOVA) following dose normalization and logarithmic transformation. Bioavailability comparisons were based on the 90% confidence intervals (CIs) around the geometric least squares mean ratios (test: reference).Results
Twenty-five participants were randomized. The 90% CIs around Cmax, AUCt, and AUCinf ratios for brivaracetam 10, 75, and 100 mg tablets versus 50 mg tablet were entirely contained within the bioequivalence limits (0.8000–1.2500). For brivaracetam 100 mg, i.v., bolus, bioequivalence versus 50 and 100 mg tablets was met for AUCt and AUCinf, but Cmax was partly outside the limits (90% CI: 1.1867–1.3863 and 1.1222–1.3136, respectively).Significance
Brivaracetam 10, 75, and 100 mg tablets were bioequivalent to the 50 mg tablet. Brivaracetam 100 mg, i.v., bolus had bioavailability similar to that of 50 and 100 mg tablets.
Vigabatrin is a highly effective antiseizure medication, but its use is limited due to concerns about retinal toxicity. One proposed mechanism for this toxicity is vigabatrin-mediated reduction of taurine. Herein we assess plasma taurine levels in a retrospective cohort of children with epilepsy, including a subset receiving vigabatrin. All children who underwent a plasma amino acid analysis as part of their clinical evaluation between 2006 and 2015 at Stanford Children's Health were included in the analysis. There were no significant differences in plasma taurine levels between children taking vigabatrin (n = 16), children taking other anti-seizure medications, and children not taking any anti-seizure medication (n = 556) (analysis of variance [ANOVA] p = 0.841). There were, however, age-dependent decreases in plasma taurine levels. Multiple linear regression revealed no significant association between vigabatrin use and plasma taurine level (p = 0.87) when controlling for age. These results suggest that children taking vigabatrin maintain normal plasma taurine levels, although they leave unanswered whether taurine supplementation is necessary or sufficient to prevent vigabatrin-associated visual field loss. They also indicate that age should be taken into consideration when evaluating taurine levels in young children.