Epilepsy in adults Thijs, Roland D; Surges, Rainer; O'Brien, Terence J ...
The Lancet (British edition),
02/2019, Letnik:
393, Številka:
10172
Journal Article
Recenzirano
Epilepsy is one of the most common serious brain conditions, affecting over 70 million people worldwide. Its incidence has a bimodal distribution with the highest risk in infants and older age ...groups. Progress in genomic technology is exposing the complex genetic architecture of the common types of epilepsy, and is driving a paradigm shift. Epilepsy is a symptom complex with multiple risk factors and a strong genetic predisposition rather than a condition with a single expression and cause. These advances have resulted in the new classification of epileptic seizures and epilepsies. A detailed clinical history and a reliable eyewitness account of a seizure are the cornerstones of the diagnosis. Ancillary investigations can help to determine cause and prognosis. Advances in brain imaging are helping to identify the structural and functional causes and consequences of the epilepsies. Comorbidities are increasingly recognised as important aetiological and prognostic markers. Antiseizure medication might suppress seizures in up to two-thirds of all individuals but do not alter long-term prognosis. Epilepsy surgery is the most effective way to achieve long-term seizure freedom in selected individuals with drug-resistant focal epilepsy, but it is probably not used enough. With improved understanding of the gradual development of epilepsy, epigenetic determinants, and pharmacogenomics comes the hope for better, disease-modifying, or even curative, pharmacological and non-pharmacological treatment strategies. Other developments are clinical implementation of seizure detection devices and new neuromodulation techniques, including responsive neural stimulation.
Neuroinflammation is implicated in the pathogenesis of a wide range of neurologic and neuropsychiatric diseases. For over 20 years, (11)C-PK11195 PET, which aims to image expression of the ...translocator protein (TSPO) on activated microglia in the brain, has been used in preclinical and clinical research to investigate neuroinflammation in vivo in patients with brain diseases. However, (11)C-PK11195 suffers from two major limitations: its low brain permeability and high nonspecific and plasma binding results in a low signal-to-noise ratio, and the use of (11)C restricts its use to PET research centers and hospitals with an on-site cyclotron. In recent years, there has been a great deal of work into the development of new TSPO-specific PET radiotracers. This work has focused on fluorinated radiotracers, which would enable wider use and improved signal-to-noise ratios. These radiotracers have been utilized in preclinical and clinical studies of several neurologic diseases with varying degrees of success. Unfortunately, the application of these second-generation TSPO radiotracers has revealed additional problems, including a polymorphism that affects TSPO binding. In this review, the developments in TSPO imaging are discussed, and current limitations and suggestions for future directions are explored.
Epilepsy is a common and debilitating consequence of traumatic brain injury (TBI). Seizures contribute to progressive neurodegeneration and poor functional and psychosocial outcomes for TBI ...survivors, and epilepsy after TBI is often resistant to existing anti-epileptic drugs. The development of post-traumatic epilepsy (PTE) occurs in a complex neurobiological environment characterized by ongoing TBI-induced secondary injury processes. Neuroinflammation is an important secondary injury process, though how it contributes to epileptogenesis, and the development of chronic, spontaneous seizure activity, remains poorly understood. A mechanistic understanding of how inflammation contributes to the development of epilepsy (epileptogenesis) after TBI is important to facilitate the identification of novel therapeutic strategies to reduce or prevent seizures. BODY: We reviewed previous clinical and pre-clinical data to evaluate the hypothesis that inflammation contributes to seizures and epilepsy after TBI. Increasing evidence indicates that neuroinflammation is a common consequence of epileptic seizure activity, and also contributes to epileptogenesis as well as seizure initiation (ictogenesis) and perpetuation. Three key signaling factors implicated in both seizure activity and TBI-induced secondary pathogenesis are highlighted in this review: high-mobility group box protein-1 interacting with toll-like receptors, interleukin-1β interacting with its receptors, and transforming growth factor-β signaling from extravascular albumin. Lastly, we consider age-dependent differences in seizure susceptibility and neuroinflammation as mechanisms which may contribute to a heightened vulnerability to epileptogenesis in young brain-injured patients.
Several inflammatory mediators exhibit epileptogenic and ictogenic properties, acting on glia and neurons both directly and indirectly influence neuronal excitability. Further research is required to establish causality between inflammatory signaling cascades and the development of epilepsy post-TBI, and to evaluate the therapeutic potential of pharmaceuticals targeting inflammatory pathways to prevent or mitigate the development of PTE.
Early posttraumatic seizures (EPS) that may occur following a traumatic brain injury (TBI) are associated with poorer outcomes and development of posttraumatic epilepsy (PTE).
To evaluate risk ...factors for EPS, associated morbidity and mortality, and contribution to PTE.
Data were collected from an Australian registry-based cohort study of adults (age ≥18 years) with moderate to severe TBI from January 2005 to December 2019, with 2-year follow-up. The statewide trauma registry, conducted on an opt-out basis in Victoria (population 6.5 million), had 15 152 patients with moderate to severe TBI identified via Abbreviated Injury Scale (AIS) head severity score, with an opt-out rate less than 0.5% (opt-out n = 136).
EPS were identified via International Statistical Classification of Diseases, Tenth Revision, Australian Modification (ICD-10-AM) codes recorded after the acute admission. Outcome measures also included in-hospital metrics, 2-year outcomes including PTE, and post-discharge mortality. Adaptive least absolute shrinkage and selection operator (LASSO) regression was used to build a prediction model for risk factors of EPS.
Among the 15 152 participants (10 457 69% male; median IQR age, 60 35-79 y), 416 (2.7%) were identified with EPS, including 27 (0.2%) with status epilepticus. Significant risk factors on multivariable analysis for developing EPS were younger age, higher Charlson Comorbidity Index, TBI sustained from a low fall, subdural hemorrhage, subarachnoid hemorrhage, higher Injury Severity Score, and greater head injury severity, measured using the AIS and Glasgow Coma Score. After adjustment for confounders, EPS were associated with increased ICU admission and ICU length of stay, ventilation and duration, hospital length of stay, and discharge to inpatient rehabilitation rather than home, but not in-hospital mortality. Outcomes in TBI admission survivors at 24 months, including mortality (relative risk RR = 2.14; 95% CI, 1.32-3.46; P = .002), development of PTE (RR = 2.91; 95% CI, 2.22-3.81; P < .001), and use of antiseizure medications (RR = 2.44; 95% CI, 1.98-3.02; P < .001), were poorer for cases with EPS after adjustment for confounders. The prediction model for EPS had an area under the receiver operating characteristic curve of 0.72 (95% CI, 0.66-0.79), sensitivity of 66%, and specificity of 73% in the validation set.
We identified important risk factors for EPS following moderate to severe TBI. Early posttraumatic seizures were associated with longer ICU and hospital admissions, ICU ventilation, and poorer 24-month outcomes including mortality and development of PTE.
Epilepsy is seen historically as a disease of aberrant neuronal signaling manifesting as seizures. With the discovery of numerous auto‐antibodies and the subsequent growth in understanding of ...autoimmune encephalitis, there has been an increasing emphasis on the contribution of the innate and adaptive immune system to ictogenesis and epileptogenesis. Pathogenic antibodies, complement activation, CD8+ cytotoxic T cells, and microglial activation are seen, to various degrees, in different seizure‐associated neuroinflammatory and autoimmune conditions. These aberrant immune responses are thought to cause disruptions in neuronal signaling, generation of acute symptomatic seizures, and, in some cases, the development of long‐term autoimmune epilepsy. Although early treatment with immunomodulatory therapies improves outcomes in autoimmune encephalitides and autoimmune epilepsies, patient identification and treatment selection are not always clear‐cut. This review examines the role of the different components of the immune system in various forms of seizure disorders including autoimmune encephalitis, autoimmune epilepsy, Rasmussen encephalitis, febrile infection–related epilepsy syndrome (FIRES), and new‐onset refractory status epilepticus (NORSE). In particular, the pathophysiology and unique cytokine profiles seen in these disorders and their links with diagnosis, prognosis, and treatment decision‐making are discussed.
Perampanel and pregnancy Vazquez, Blanca; Tomson, Torbjörn; Dobrinsky, Cindy ...
Epilepsia,
March 2021, Letnik:
62, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Objective
The objective was to summarize pregnancy and fetal/postnatal outcomes following maternal perampanel exposure using preclinical and clinical data, and to use physiologically based ...pharmacokinetic (PBPK) modeling to improve understanding of perampanel pharmacokinetics (PK) during pregnancy.
Methods
Preclinical developmental studies with perampanel were conducted in pregnant rats and rabbits. Clinical data were collated from the Eisai global perampanel safety database, comprising reports of perampanel exposure during pregnancy from routine clinical settings, interventional studies, and non‐interventional post‐marketing studies, searched for events coded to Medical Dictionary for Regulatory Activities (MedDRA) high‐level group terms of Pregnancy, Labor, Delivery, and Postpartum Conditions and/or the Standardized MedDRA Query terms of Congenital, Familiar, and Genetic Disorders. A PBPK model was used to predict clinical perampanel PK throughout pregnancy.
Results
Preclinical studies indicated that perampanel may be linked with post‐implantation loss and/or some specific physical development delays but not fertility and early embryonic development. As of August 31, 2018, 96 pregnancies in 90 women receiving perampanel had been reported. No concomitant medications were reported in 26 (28.9%) women taking perampanel. Overall, 43 pregnancies reached full term (all normal live births), 28 did not reach term (induced abortion, n = 18; spontaneous miscarriage, n = 6; incomplete spontaneous miscarriage, n = 2; premature delivery, n = 1; stillbirth Fallot’s tetralogy, n = 1), 18 were lost to follow‐up, and seven were ongoing at data cut‐off. Adverse events were reported in five full‐term neonates (low Apgar score, n = 2; fatal neonatal aspiration, n = 1; cystic fibrosis and congenital deafness, n = 1; poor sucking reflex and shallow breathing, n = 1). PK simulations predicted perampanel exposure decreases throughout pregnancy and is up to four‐ and three‐fold lower towards the end of pregnancy compared with non‐pregnant women for total and unbound perampanel, respectively.
Significance
These data provide preliminary information on perampanel use during pregnancy and should be interpreted with caution. Further outcome data are required to estimate the prevalence of adverse pregnancy outcomes with perampanel exposure.
Objective
We sought to determine which combination of clinical and electroencephalography (EEG) characteristics differentiate between an antiseizure medication (ASM)–resistant vs ASM‐responsive ...outcome for patients with idiopathic generalized epilepsy (IGE).
Methods
This was a case‐control study of ASM‐resistant cases and ASM‐responsive controls with IGE treated at five epilepsy centers in the United States and Australia between 2002 and 2018. We recorded clinical characteristics and findings from the first available EEG study for each patient. We then compared characteristics of cases vs controls using multivariable logistic regression to develop a predictive model of ASM‐resistant IGE.
Results
We identified 118 ASM‐resistant cases and 114 ASM‐responsive controls with IGE. First, we confirmed our recent finding that catamenial epilepsy is associated with ASM‐resistant IGE (odds ratio OR 3.53, 95% confidence interval CI 1.32–10.41, for all study subjects) after covariate adjustment. Other independent factors seen with ASM resistance include certain seizure‐type combinations (absence, myoclonic, and generalized tonic‐clonic seizures OR 7.06, 95% CI 2.55–20.96; absence and generalized tonic‐clonic seizures OR 4.45, 95% CI 1.84–11.34), as well as EEG markers of increased generalized spike‐wave discharges (GSWs) in sleep (OR 3.43, 95% CI 1.12–11.36 for frequent and OR 7.21, 95% CI 1.50–54.07 for abundant discharges in sleep) and the presence of generalized polyspike trains (GPTs; OR 5.49, 95% CI 1.27–38.69). The discriminative ability of our final multivariable model, as measured by area under the receiver‐operating characteristic curve, was 0.80.
Significance
Multiple clinical and EEG characteristics independently predict ASM resistance in IGE. To improve understanding of a patient's prognosis, clinicians could consider asking about specific seizure‐type combinations and track whether they experience catamenial epilepsy. Obtaining prolonged EEG studies to record the burden of GSWs in sleep and assessing for the presence of GPTs may provide additional predictive value.
Epilepsy is a group of neurological conditions in which there is a pathological and enduring predisposition to generate recurrent seizures. Evidence over the last few decades suggests that epilepsy ...may be associated with increased sleep-disordered breathing, which may contribute towards sleep fragmentation, daytime somnolence, reduced seizure control, and cardiovascular-related morbidity and mortality. Chronic sleep-disordered breathing can result in loss of gray matter and cause deficits to memory and global cognitive function. Sleep-disordered breathing is a novel and independent predictor of sudden cardiac death and, as such, may be involved in the mechanisms leading to sudden unexpected death in epilepsy. Despite this, the long-term consequences of sleep-disordered breathing in epilepsy remain unknown, and there are no guidelines for screening or treating this population. There is currently insufficient evidence to indicate continuous positive airway pressure (CPAP) for the primary or secondary prevention of cardiovascular disease, and recent evidence has failed to show any reduction of fatal or nonfatal cardiovascular endpoints. Treatment of sleep-disordered breathing may potentially improve seizure control, daytime somnolence, and neurocognitive outcomes, but few studies have examined this relationship. In this review, we examine sleep-disordered breathing in epilepsy, and discuss the potential effect of epilepsy treatments. We consider the role of CPAP and other interventions for sleep-disordered breathing and discuss their implications for epilepsy management.
Epilepsy after pediatric traumatic brain injury (TBI) is associated with poor quality of life. This study aimed to characterize post-traumatic epilepsy in a mouse model of pediatric brain injury, and ...to evaluate the role of interleukin-1 (IL-1) signaling as a target for pharmacological intervention. Male mice received a controlled cortical impact or sham surgery at postnatal day 21, approximating a toddler-aged child. Mice were treated acutely with an IL-1 receptor antagonist (IL-1Ra; 100 mg/kg, s.c.) or vehicle. Spontaneous and evoked seizures were evaluated from video-EEG recordings. Behavioral assays tested for functional outcomes, postmortem analyses assessed neuropathology, and brain atrophy was detected by
magnetic resonance imaging. At 2 weeks and 3 months post-injury, TBI mice showed an elevated seizure response to the convulsant pentylenetetrazol compared with sham mice, associated with abnormal hippocampal mossy fiber sprouting. A robust increase in IL-1β and IL-1 receptor were detected after TBI. IL-1Ra treatment reduced seizure susceptibility 2 weeks after TBI compared with vehicle, and a reduction in hippocampal astrogliosis. In a chronic study, IL-1Ra-TBI mice showed improved spatial memory at 4 months post-injury. At 5 months, most TBI mice exhibited spontaneous seizures during a 7 d video-EEG recording period. At 6 months, IL-1Ra-TBI mice had fewer evoked seizures compared with vehicle controls, coinciding with greater preservation of cortical tissue. Findings demonstrate this model's utility to delineate mechanisms underlying epileptogenesis after pediatric brain injury, and provide evidence of IL-1 signaling as a mediator of post-traumatic astrogliosis and seizure susceptibility.
Epilepsy is a common cause of morbidity after traumatic brain injury in early childhood. However, a limited understanding of how epilepsy develops, particularly in the immature brain, likely contributes to the lack of efficacious treatments. In this preclinical study, we first demonstrate that a mouse model of traumatic injury to the pediatric brain reproduces many neuropathological and seizure-like hallmarks characteristic of epilepsy. Second, we demonstrate that targeting the acute inflammatory response reduces cognitive impairments, the degree of neuropathology, and seizure susceptibility, after pediatric brain injury in mice. These findings provide evidence that inflammatory cytokine signaling is a key process underlying epilepsy development after an acquired brain insult, which represents a feasible therapeutic target to improve quality of life for survivors.
Highlights • Dysfunction in cardiac electrophysiology is an established consequence of chronic epilepsy. • Cardiac ion channel expression is believed to be secondarily altered as a result of seizure ...activity. • Cardiac arrhythmia development may predispose to SUDEP. • Here, we discuss the role of the autonomic nervous system, as well as key ion channels expressed both in the brain and heart that may underlie this phenomenon
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