To determine whether multiple subpial transection in the posterior temporal lobe has an impact on long-term outcome in children who have drug-resistant Landau-Kleffner syndrome (LKS) or other “electrical status epilepticus during sleep” (ESES)-related regression. Given the wide variability in outcomes reported in the literature, a secondary aim was to explore predictors of outcome.Methods
The current study includes a surgery group (n = 14) comprising patients who underwent multiple subpial transection of the posterior temporal lobe and a nonsurgery comparison group (n = 21) comprising patients who underwent presurgical investigations for the procedure, but who did not undergo surgery. Outcomes were assessed utilizing clinical note review as well as direct assessment and questionnaires.Results
The distribution of nonclassical cases was comparable between groups. There were some differences between the surgery and nonsurgery groups at presurgical investigation including laterality of discharges, level of language impairment, and age; therefore, follow-up analyses focused on change over time and predictors of outcome. There were no statistically significant differences between the groups in language, nonverbal ability, adaptive behavior, or quality of life at follow-up. There was no difference in the proportion of patients showing improvement or deterioration in language category over time for either group. Continuing seizures and an earlier age of onset were most predictive of poorer quality of life at long-term follow-up (F2,23 = 26.2, p = <0.001, R2 = 0.714).Significance
Both surgery and nonsurgery groups had similar proportions of classic LKS and ESES-related regression. Because no significant differences were found in the changes observed from baseline to follow-up between the two groups, it is argued that there is insufficient evidence to suggest that multiple subpial transection provides additional benefits over and above the mixed recovery often seen in LKS and related regressive epilepsies.
A definition and classification of status epilepticus – Report of the ILAE Task Force on Classification of Status Epilepticus
The Commission on Classification and Terminology and the Commission on Epidemiology of the International League Against Epilepsy (ILAE) have charged a Task Force to revise concepts, definition, and classification of status epilepticus (SE). The proposed new definition of SE is as follows: Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1). It is a condition, which can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures. This definition is conceptual, with two operational dimensions: the first is the length of the seizure and the time point (t1) beyond which the seizure should be regarded as “continuous seizure activity.” The second time point (t2) is the time of ongoing seizure activity after which there is a risk of long-term consequences. In the case of convulsive (tonic–clonic) SE, both time points (t1 at 5 min and t2 at 30 min) are based on animal experiments and clinical research. This evidence is incomplete, and there is furthermore considerable variation, so these time points should be considered as the best estimates currently available. Data are not yet available for other forms of SE, but as knowledge and understanding increase, time points can be defined for specific forms of SE based on scientific evidence and incorporated into the definition, without changing the underlying concepts. A new diagnostic classification system of SE is proposed, which will provide a framework for clinical diagnosis, investigation, and therapeutic approaches for each patient. There are four axes: (1) semiology; (2) etiology; (3) electroencephalography (EEG) correlates; and (4) age. Axis 1 (semiology) lists different forms of SE divided into those with prominent motor systems, those without prominent motor systems, and currently indeterminate conditions (such as acute confusional states with epileptiform EEG patterns). Axis 2 (etiology) is divided into subcategories of known and unknown causes. Axis 3 (EEG correlates) adopts the latest recommendations by consensus panels to use the following descriptors for the EEG: name of pattern, morphology, location, time-related features, modulation, and effect of intervention. Finally, axis 4 divides age groups into neonatal, infancy, childhood, adolescent and adulthood, and elderly.
Benign epilepsy with centrotemporal spikes (BECTS), the most common focal childhood epilepsy, is associated with subtle abnormalities in cognition and possible developmental alterations in brain structure when compared to healthy participants, as indicated by previous cross-sectional studies. To examine the natural history of BECTS, we investigated cognition, cortical thickness, and subcortical volumes in children with new/recent onset BECTS and healthy controls (HC).Methods
Participants were 8–15 years of age, including 24 children with new-onset BECTS and 41 age- and gender-matched HC. At baseline and 2 years later, all participants completed a cognitive assessment, and a subset (13 BECTS, 24 HC) underwent T1 volumetric magnetic resonance imaging (MRI) scans focusing on cortical thickness and subcortical volumes.Results
Baseline cognitive abnormalities associated with BECTS (object naming, verbal learning, arithmetic computation, and psychomotor speed/dexterity) persisted over 2 years, with the rate of cognitive development paralleling that of HC. Baseline neuroimaging revealed thinner cortex in BECTS compared to controls in frontal, temporal, and occipital regions. Longitudinally, HC showed widespread cortical thinning in both hemispheres, whereas BECTS participants showed sparse regions of both cortical thinning and thickening. Analyses of subcortical volumes showed larger left and right putamens persisting over 2 years in BECTS compared to HC.Significance
Cognitive and structural brain abnormalities associated with BECTS are present at onset and persist (cognition) and/or evolve (brain structure) over time. Atypical maturation of cortical thickness antecedent to BECTS onset results in early identified abnormalities that continue to develop abnormally over time. However, compared to anatomic development, cognition appears more resistant to further change over time.
Epileptic encephalopathy with electrical status epilepticus in sleep (ESES) is a pediatric epilepsy syndrome with sleep-induced epileptic discharges and acquired impairment of cognition or behavior. Treatment of ESES is assumed to improve cognitive outcome. The aim of this study is to create an overview of the current evidence for different treatment regimens in children with ESES syndrome.Methods
A literature search using PubMed and Embase was performed. Articles were selected that contain original treatment data of patients with ESES syndrome. Authors were contacted for additional information. Individual patient data were collected, coded, and analyzed using logistic regression analysis. The three predefined main outcome measures were improvement in cognitive function, electroencephalography (EEG) pattern, and any improvement (cognition or EEG).Results
The literature search yielded 1,766 articles. After applying inclusion and exclusion criteria, 112 articles and 950 treatments in 575 patients could be analyzed. Antiepileptic drugs (AEDs, n = 495) were associated with improvement (i.e., cognition or EEG) in 49% of patients, benzodiazepines (n = 171) in 68%, and steroids (n = 166) in 81%. Surgery (n = 62) resulted in improvement in 90% of patients. In a subgroup analysis of patients who were consecutively reported (585 treatments in 282 patients), we found improvement in a smaller proportion treated with AEDs (34%), benzodiazepines (59%), and steroids (75%), whereas the improvement percentage after surgery was preserved (93%). Possible predictors of improved outcome were treatment category, normal development before ESES onset, and the absence of structural abnormalities.Significance
Although most included studies were small and retrospective and their heterogeneity allowed analysis of only qualitative outcome data, this pooled analysis suggests superior efficacy of steroids and surgery in encephalopathy with ESES.
Brain regions with abnormal network properties in severe epilepsy of Lennox-Gastaut phenotype: Multivariate analysis of task-free fMRI
Lennox-Gastaut syndrome, and the similar but less tightly defined Lennox-Gastaut phenotype, describe patients with severe epilepsy, generalized epileptic discharges, and variable intellectual disability. Our previous functional neuroimaging studies suggest that abnormal diffuse association network activity underlies the epileptic discharges of this clinical phenotype. Herein we use a data-driven multivariate approach to determine the spatial changes in local and global networks of patients with severe epilepsy of the Lennox-Gastaut phenotype.Methods
We studied 9 adult patients and 14 controls. In 20 min of task-free blood oxygen level–dependent functional magnetic resonance imaging data, two metrics of functional connectivity were studied: Regional homogeneity or local connectivity, a measure of concordance between each voxel to a focal cluster of adjacent voxels; and eigenvector centrality, a global connectivity estimate designed to detect important neural hubs. Multivariate pattern analysis of these data in a machine-learning framework was used to identify spatial features that classified disease subjects.Results
Multivariate pattern analysis was 95.7% accurate in classifying subjects for both local and global connectivity measures (22/23 subjects correctly classified). Maximal discriminating features were the following: increased local connectivity in frontoinsular and intraparietal areas; increased global connectivity in posterior association areas; decreased local connectivity in sensory (visual and auditory) and medial frontal cortices; and decreased global connectivity in the cingulate cortex, striatum, hippocampus, and pons.Significance
Using a data-driven analysis method in task-free functional magnetic resonance imaging, we show increased connectivity in critical areas of association cortex and decreased connectivity in primary cortex. This supports previous findings of a critical role for these association cortical regions as a final common pathway in generating the Lennox-Gastaut phenotype. Abnormal function of these areas is likely to be important in explaining the intellectual problems characteristic of this disorder.
To quantify the risk of unprovoked seizures after traumatic brain injury (TBI)Methods
We used the Stockholm Incidence Registry on Epilepsy to carry out a population-based case–control study, including 1,885 cases with incident unprovoked seizures from September 1, 2000 through August 31, 2008, together with 15,080 matched controls. Information of prior hospitalizations for TBI was obtained through record linkage with the Swedish National Inpatient Registry for the period 1980–2008. Relative risks (RRs) for unprovoked seizures were estimated after various TBI diagnoses, and influences of TBI severity and time since trauma were studied in detail.Results
After hospitalization for mild TBI, the RR was 2.0 (95% confidence interval [CI] 1.5–2.7). The RR was higher after brain contusion (5.9, 95% CI 2.4–15.0) or intracranial hemorrhage (ICH) (4.5, 95% CI 2.2–9.0), whereas a combination of both diagnoses led to a further sevenfold increase in RR (42.6, 95% CI 12.2–148.5). The risk was greatest during the first 6 months after severe TBI (RR 48.9, 95% CI 10.9–218.9) or mild TBI (RR 8.1, 95% CI 3.1–21.7), but was still elevated >10 years after any TBI.Significance
Herein we present a large population-based case–control study on TBI as a risk factor for unprovoked epileptic seizures, including cases of all ages with individually validated seizure diagnoses. The risk for epileptic seizures was substantially increased after TBI, especially during the first 6 months after the injury and in patients with a combination of ICH and brain contusion.
Pharmacokinetics, pharmacodynamics, and safety of USL261, a midazolam formulation optimized for intranasal delivery, in a randomized study with healthy volunteers
To compare the pharmacokinetics, pharmacodynamics, and tolerability of USL261, a midazolam formulation optimized for intranasal delivery, versus midazolam intravenous (IV) solution administered intranasally (MDZ-inj IN) or intravenously (MDZ-inj IV) in healthy adults.Methods
In this phase 1, five-way crossover, open-label study, 25 healthy adults (aged 18–42 years) were randomly assigned to receive 2.5, 5.0, and 7.5 mg USL261; 2.5 mg MDZ-inj IV; and 5.0 mg MDZ-inj IN. Blood samples were collected for 12 h post dose to determine pharmacokinetic profiles. Pharmacodynamic assessments of sedation and psychomotor impairment also were conducted. Adverse events, oxygen saturation, and vital signs were recorded.Results
Increasing USL261 dose corresponded with increases in midazolam area under the concentration time curve (AUC) and maximum observed plasma concentration (Cmax), with all doses demonstrating rapid median time to Cmax (Tmax; 10–12 min). USL261 also demonstrated increased absorption, with a 134% relative bioavailability, compared with the same MDZ-inj IN dose. USL261 was associated with dose-dependent increases in sedation and psychomotor impairment (p < 0.05); however, these effects lasted <4 h and generally did not differ from MDZ-inj IN or MDZ-inj IV at comparable doses. No serious adverse events (SAEs) or deaths were reported, and no treatment-emergent adverse events (TEAEs) led to study discontinuation.Significance
Compared with intranasal delivery of a midazolam formulation intended for IV delivery, USL261, optimized for intranasal administration demonstrated improved bioavailability with similar pharmacodynamic effects. Therefore, USL261 may be a preferable alternative to the currently approved rectal diazepam treatment for intermittent bouts of increased seizure activity.
The feasibility of automated detection of cortical-onset epileptic seizures from subcortical structures such as the thalamus was investigated via simultaneous recording of electroencephalography (EEG) and anterior and centromedian thalamic nuclei electrical signals (electrothalamography) in nine subjects with pharmacoresistant seizures admitted to an epilepsy monitoring unit after deep brain stimulating electrode implantation. Thalamic electrical signals were analyzed using a validated seizure detection algorithm, and times of seizure onset and termination were compared to those determined through visual analysis of video-EEG. Ictal activity was recorded from the scalp and thalamic nuclei in three subjects who had seizures during the 3–4-day recording period. In the majority of seizures, ictal activity in the thalamic nuclei preceded electrographic onset as determined from the EEG or clinical onset as determined from behavioral observations. Interictal epileptiform discharges were also recorded from the thalamus and in certain instances had no scalp representation. Subcortical/thalamic detection of cortical-onset seizures is feasible. This approach would enable contingent therapy delivery and may be particularly valuable for subjects with multiple or difficult-to-localize epileptogenic regions.
Up to half of patients assessed for suspected new-onset epileptic seizures report previous undiagnosed events. This suggests that delay to timely and expert assessment is a major issue. Very little is known about the degree of delay or nature of the undiagnosed events, impacting on our understanding of new-onset epilepsy. In this study we aimed to examine events that occur before presentation, as well as the extent and risk factors for delay to assessment.Method
Included in this retrospective study were 220 patients diagnosed at the First Seizure Clinic (Austin Health, Australia) between 2003 and 2006 with an epileptic index seizure. Patients with a prior diagnosis of epileptic seizures were excluded. Chart review was undertaken, including detailed interviews conducted by an epileptologist at first assessment. Logistic regression assessed risk factors for delay from first event to presentation, including event characteristics, socioeconomic disadvantage, employment, and distance to medical facility.Results
Forty-one percent (n = 90) of patients had one or more event before their index seizure. Of these, 50% had multiple or more than five prior events and 28% experienced one or more convulsive event before the index seizure. Of the total 220 patients, 36% had delayed presentation >4 weeks, 21% delayed >6 months, and 14% delayed >2 years. First events without convulsions or features likely to disrupt behaviour were strongly associated with delay (p = <0.001). Relative socioeconomic disadvantage was also associated with delay to presentation (p = 0.04).Significance
Our findings suggest a gap in early diagnosis and care in a sizable proportion of new-onset cases, despite a “first world” urban environment and the availability of free basic medical care. Delay appears particularly likely when events are nonconvulsive or low-impact, suggesting that these seizure types may be underrepresented in studies of new-onset epilepsy. This has implications for our understanding of the incidence, evolution, impact, and treatment response of new-onset epilepsy.
Incidence, risk factors, and longitudinal outcome of seizures in long-term survivors of pediatric brain tumors
Seizures are common during and after treatment for a primary brain tumor. Our objective was to describe the incidence and risk factors for seizures in long-term survivors of pediatric brain tumors.Methods
In a retrospective, longitudinal study, we reviewed all consecutive patients during a 12-month period who were at least 2 years post initial diagnosis of a brain tumor. Data collection included age at diagnosis, length of follow-up, extent of initial resection, tumor histology, and treatment modalities. For patients who had experienced seizures at any time, the timing and frequency of seizures, seizure semiology, electroencephalography results, and anticonvulsant use were recorded. Univariate analyses and logistic regression were performed to assess risk factors.Results
The cohort included 298 patients (140 female). Average duration of follow-up was 7.6 years. Initial surgical resection was gross-total in 109 patients, and subtotal for 143. Twenty-nine patients underwent biopsy alone and 17 had no surgical intervention. Tumor location included posterior fossa (104; 36%), midline (98; 34%), cortical (85; 29%), and other (11; 3%). Most frequent diagnoses were low grade glioma, medulloblastoma, and ependymoma. Other treatments included cranial irradiation (N = 163) and chemotherapy (n = 127). Tumor recurrence occurred in 92 patients (30%). Seventy-one patients had seizures (24%). Ongoing seizures at the time of most recent follow-up were present in 42 patients. Risk factors for seizures included tumor location, tumor histology, tumor recurrence, and incomplete resection at time of initial presentation.Significance
Seizures are a frequent comorbidity in pediatric brain tumor survivors, seen at presentation in 24% of patients and ongoing in 14%. Factors predisposing to seizures include tumor pathology (low/high grade glioma, glioneuronal tumor), cortical location, and subtotal resection. These data may assist in identification and management of patients at highest risk for seizures as well as identification of patients for potential treatment trials with antiepileptogenic agents.
Huperzine A prophylaxis against pentylenetetrazole-induced seizures in rats is associated with increased cortical inhibition
Pivotal global Phase III study data for Fycompa® (perampanel) in primary generalised tonic-clonic seizures now published in Neurology
Risk factors for postoperative depression: A retrospective analysis of 248 subjects operated on for drug-resistant epilepsy
The aim of this retrospective case series analysis was to identify the predictors of postoperative depression (PostOp-D) in a sample of 248 subjects with focal drug-resistant focal epilepsy. The presence or absence of PostOp-D during a 12-month follow-up period was the outcome variable. Demographic, neurologic, psychiatric characteristics, and antiepileptic therapy were the explanatory variables. After preliminary bivariate analysis, a multivariate logistic regression model was fitted to identify variables associated with PostOp-D. Sixty-seven patients (27%) experienced PostOp-D. At multivariate analysis, lifetime depression, age at surgery, and levetiracetam (LEV) are positive predictors of PostOp-D; carbamazepine (CBZ) and anxiety disorders are protective factors. LEV increases the risk for PostOp-D by about half; the relative risk (RR) is 1.48. Conversely, CBZ decreases the risk for PostOp-D by about half (RR 0.59). Our results suggest that careful psychiatric evaluation and follow-up should be recommended for subjects at risk. It is advisable to treat patients with depression before surgery. Antiepileptic drugs should be selected carefully when patients present with not modifiable risk factors, such as positive personal history for depression.
A major limitation of intracranial electroencephalography (iEEG) is recording from a confined region. This may falsely localize seizure onset if the distinction between ictal onset zone, proximity, and spread is unclear, or if the ictal rhythm is not clearly identified. Delineation of the ictal onset zone is crucial for surgical success. We appraised the evidence to determine whether specific iEEG ictal patterns are associated with the ictal onset zone.Methods
We searched Embase for articles in English until September 30, 2014, with MeSH keywords related to intracranially implanted electrodes and seizures. Two authors independently screened abstracts, reviewed full text articles, and abstracted data. The association between seizure outcome and type of ictal onset pattern (IOP), and its extent, location, and spread were explored visually or by univariate analysis when sufficient data were provided. Methodologic quality of each study was assessed.Results
We reviewed 1,987 abstracts from which 21 articles were analyzed. Fifteen IOPs were reported. Low frequency high amplitude repetitive spiking (LFRS) was the most frequently reported IOP by studies that dealt with mesial temporal lobe epilepsy (mTLE) and investigated with depth electrodes. In neocortical epilepsy, low voltage fast activity (LVFA) was the most commonly described IOP. Delta activity was an infrequently reported IOP and was described mostly as a spread pattern.Significance
LFRS is associated with good surgical outcome in mTLE and has a strong relation with mesial temporal pathology and its severity. LVFA is associated with neocortical temporal epilepsy and focal LVFA is associated with better surgical outcome. Electrodecrement may be associated with regional or widespread onsets. Rhythmic delta is a propagation rhythm rather than an IOP. Focal IOPs and slower propagation times are associated with better outcomes. The quality of the studies is suboptimal and there are methodological problems. Interobserver agreement is poorly documented.