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.
To evaluate the impact of epileptiform discharges (EDs) that do not occur within seizure patterns – such as spikes, sharp waves or spike waves – on cognitive function and to discuss the circumstances under which treatment of EDs might be considered. Methods used in this article is “Review of the literature”. EDs may disrupt short-term cognition in humans. Frequent EDs for a prolonged period can potentially impair long-term cognitive function in humans. However, there is conflicting evidence on the impact of EDs on long-term cognitive outcome because this relationship may be confounded by multiple factors such as underlying etiology, seizures, and medication effects. Limitations of existing studies include the lack of standardized ED quantification methods and of widely accepted automated spike quantification methods. Although there is no solid evidence for or against treatment of EDs, a non–evidence-based practical approach is suggested. EDs in otherwise asymptomatic individuals should not be treated because the risks of treatment probably outweigh its dubious benefits. A treatment trial for EDs may be considered when there is cognitive dysfunction or regression or neurologic symptoms that are unexplained by the underlying etiology, comorbid conditions, or seizure severity. In patients with cognitive or neurologic dysfunction with epilepsy or EDs, treatment may be warranted to control the underlying epileptic syndrome. EDs may cause cognitive or neurologic dysfunction in humans in the short term. There is conflicting evidence on the impact of EDs on long-term cognitive outcome. There is no evidence for or against treatment of asymptomatic ED.
Cognitive and developmental outcomes in patients with epileptic encephalopathy are hypothesized to result from an interplay between the underlying epileptic pathologic substrate and the acquired consequences of frequent and repetitive seizures and epileptiform discharges that often straddle the interictal and ictal boundaries. This article briefly reviews the evidence related to this assumption, presents critical questions that need to be answered to clarify this relationship, and advances a set of concrete steps that may help improve developmental patient outcomes.
In epileptic encephalopathy, the seizures and interictal epileptiform activity create additional neurocognitive dysfunction beyond that due to the underlying etiology. Treatment leading to a reduction in seizures or interictal abnormalities may help improve neurocognitive function in these situations. The focus of our discussion is reviewing data that support the concept that treatment can impact outcome independent of the etiology in some cases.
Epileptic activity is a surrogate for an underlying etiology and stopping the activity has a limited impact on developmental outcome
The concept of epileptic encephalopathy is important in clinical practice, but its relevance to an individual must be assessed in the appropriate context. Except in rare situations, epileptic activity is a surrogate for an underlying etiology, and stopping the activity has a limited impact on developmental outcome. Labeling a group of epilepsies as “the epileptic encephalopathies,” risks minimizing the impact of epileptic activity on cognition and behavior more widely in epilepsy. Similarly, describing the encephalopathy associated with many infantile onset epilepsies as “epileptic” may be misleading. Finally, concentrating on the epileptic activity alone and not considering the wider consequences of the underlying etiology on cognitive and behavioral development, may focus research efforts and the search for improved therapies on too narrow a target. Therefore, epileptic encephalopathies should not be considered as a specific group of epilepsies but, rather, the concept of epileptic encephalopathy should be applicable to all types of epilepsies and epilepsy syndromes, whenever it is relevant in the clinical course of a particular individual, at any age.
The baboon provides a natural model of genetic generalized epilepsy (GGE). This study compares the intrinsic connectivity networks of epileptic and healthy control baboons using resting-state functional magnetic resonance imaging (rs-fMRI) and data-driven functional connectivity mapping.Methods
Twenty baboons, matched for gender, age, and weight, were classified into two groups (10 epileptic [EPI], 10 control [CTL]) on the basis of scalp electroencephalography (EEG) findings. Each animal underwent one MRI session that acquired one 5-min resting state fMRI scan and one anatomic MRI scan—used for registration and spatial normalization. Using independent component analysis, we identified 14 unique components/networks, which were then used to characterize each group's functional connectivity maps of each brain network.Results
The epileptic group demonstrated network-specific differences in functional connectivity when compared to the control animals. The sensitivity and specificity of the two groups' functional connectivity maps differed significantly in the visual, motor, amygdala, insular, and default mode networks. Significant increases were found in the occipital gyri of the epileptic group's functional connectivity map for the default mode, cingulate, intraparietal, motor, visual, amygdala, and thalamic regions.Significance
This is the first study using resting-state fMRI to demonstrate intrinsic functional connectivity differences between epileptic and control nonhuman primates. These results are consistent with seed-based GGE studies in humans; however, our use of a data-driven approach expands the scope of functional connectivity mapping to include brain regions/networks comprising the whole brain.
Research in other disorders suggests that genetic causal attribution of epilepsy might be associated with increased stigma. We investigated this hypothesis in a unique sample of families containing multiple individuals with epilepsy.Methods
One hundred eighty-one people with epilepsy and 178 biologic relatives without epilepsy completed a self-administered survey. In people with epilepsy, felt stigma was assessed through the Epilepsy Stigma Scale (ESS), scored 1–7, with higher scores indicating more stigma and >4 indicating some felt stigma. Felt stigma related to having epilepsy in the family was assessed through the Family Epilepsy Stigma Scale (FESS), created by replacing “epilepsy” with “epilepsy in my family” in each ESS item. Genetic attribution was assessed through participants' perceptions of the (1) role of genetics in causing epilepsy in the family, (2) chance they had an epilepsy-related mutation, and (3) (in people with epilepsy) influence of genetics in causing their epilepsy.Results
Among people with epilepsy, 22% met criteria for felt stigma (ESS score >4). Scores were increased among individuals who were aged ≥60 years, were unemployed, reported epilepsy-related discrimination, or had seizures within the last year or >100 seizures in their lifetime. Adjusting for other variables, ESS scores in people with epilepsy were significantly higher among those who perceived genetics played a “medium” or “big” role in causing epilepsy in the family than in others (3.4 vs. 2.7, p = 0.025). Only 4% of relatives without epilepsy had felt stigma. Scores in relatives were unrelated to genetic attribution.Significance
In these unusual families, predictors of felt stigma in individuals with epilepsy are similar to those in other studies, and stigma levels are low in relatives without epilepsy. Felt stigma may be increased in people with epilepsy who believe epilepsy in the family has a genetic cause, emphasizing the need for sensitive communication about genetics.
Children with epilepsy have elevated rates of behavior problems. Research findings on the impact of epilepsy surgery on children's behavior have been mixed, with some studies showing improvements in behavior 3 to 18 months after surgery and other studies finding no change within this time interval. We examined behavior in a large surgical sample and in a nonsurgical comparison group. We also examined for potential effects of epilepsy-related and cognitive/linguistic variables.Methods
Behavior was assessed by parent report in 147 children who underwent epilepsy surgery and 40 children who did not, using the Child Behavior Checklist (CBCL). For the surgical group, the CBCL was completed prior to surgery (baseline) and approximately 1 year after surgery (follow-up); ratings of the nonsurgical group were also conducted twice, at comparable intervals.Results
At baseline, the groups did not differ on age, sex, age at seizure onset, antiepileptic drugs (AEDs), or intelligence quotient (IQ). Baseline Social and Attention Problems were higher in the nonsurgical group. At follow-up, 65% of the surgical group and 20% of the nonsurgical group were seizure-free. Behavioral change was not related to surgical status or seizure outcome. Children with temporal lobe seizure focus had more Externalizing Behaviors compared to those with frontal or multilobar foci. Attention was poorer in children who underwent frontal lobe excisions relative to temporal or multilobar excisions. Baseline IQ did not predict behavioral change.Significance
Our results suggest that surgery and seizure outcome do not affect behavior in the first year following surgery; it may be the abnormal neural substrate and not seizure control that influences behavior in children with epilepsy. If changes are to occur due to seizure freedom, they may require a longer time to emerge. Some behaviors may be resistant to change in children with epilepsy or may require even longer intervals for improvement.
Latencies from intracranial seizure onset to ictal tachycardia: A comparison to surface EEG patterns and other clinical signs
Information on the relative timing of electroencephalography (EEG) seizure onset, ictal tachycardia (ITC), and first other clinical seizure manifestations is crucial for an understanding of the potential benefit of ITC-detection based closed-loop intervention systems for epilepsy treatment. This study analyzes the temporal relation of ITC, other clinical signs, and seizure onset in relation to intracranial and surface EEG.Methods
Seventy-eight seizures with ITC from 13 patients undergoing invasive EEG recordings with simultaneous recordings of electrocardiography (ECG), intracranial EEG (iEEG) and surface EEG, and video recordings to determine clinical onset were analyzed. Latencies for ITC were calculated for thresholds of 100 bpm and for a 20% heart rate increase above baseline obtained 60 s prior to seizure onset on iEEG. Patient-based, seizure-based, and seizure origin–based analyses were performed.Results
Mean latencies between seizure onset in invasive EEG and the following onset of ITC in the seizure- and patient-based analysis for both thresholds varied between 21.6 and 23.7 s, showing that ITC is an ictal rather a preictal phenomenon. In 10 of 13 patients and in 56 of 78 seizures, at least one of the thresholds for ITC was crossed before any other clinical sign. In the majority of cases, ITC also preceded ictal onset as determined in surface EEG. Latencies to ictal tachycardia were shorter for hippocampal than for extrahippocampal temporal seizure onset. ITC occurred earlier in right than in left temporal seizures.Significance
iEEG preceded other seizure manifestations, but ictal tachycardia was an early sign particularly in mesial temporal and in right temporal seizure onset and often preceded not only other clinical manifestations but also first visible patterns in surface EEG. Detection of ictal tachycardia was thus the best noninvasively assessed marker for closed-loop interventions in this multimodally assessed patient group.
The HLA-A*2402/Cw*0102 haplotype is associated with lamotrigine-induced maculopapular eruption in the Korean population
The use of lamotrigine (LTG) can be limited by the occurrence of cutaneous adverse drug reactions (cADRs) that range from maculopapular eruption (MPE) to the more severe Steven-Johnson syndrome and toxic epidermal necrolysis. A few human leukocyte antigen (HLA)–related genetic risk factors for carbamazepine-induced cADR have been identified. However, the HLA-related genetic risk factors associated with LTG-induced cADR are not yet well known. We performed HLA genotyping in 50 Korean patients with epilepsy, including 21 patients presenting LTG-induced MPE and 29 LTG-tolerant patients. A significant association between the HLA-A*2402 allele and LTG-induced MPE was identified, in comparison with the LTG-tolerant group (odds ratio [OR] 4.09, p = 0.025) and the general Korean population (OR 3.949, p = 0.005). The frequencies of the Cw*0102 or Cw*0702 alleles were significantly higher in the LTG-MPE group than in the Korean population, whereas the frequency of the A*3303 allele was lower. The coexistence of the A*2402 and Cw*0102 alleles was significantly associated with the LTG-MPE group when compared to the LTG-tolerant group (OR 7.88, p = 0.007). In addition, the Cw*0701 allele was more frequent in the LTG-tolerant group than in the Korean population. These findings suggest the presence of HLA-related genetic risk factors for LTG-induced MPE in the Korean population.