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In epilepsy, individual seizures can be triggered by a variety of external and internal stimuli. One of the most common trigger factors reported by patients is stress. However prevalent, stress-related triggering of episodes seems underappreciated in epilepsy for various reasons, and its misinterpretation often leads to other diagnoses, e.g., psychogenic nonepileptic seizures (PNES) or normal reactions. This article illustrates the significant role of stress as a seizure-provoking factor by referring to nine patient narratives. From this perspective, it appears that there are characteristic patterns of stress triggering, e.g., stress-induced sleep disruption, forms of acute stress, or relaxation after stress. Sometimes seizures are mistaken as symptoms of stress. Patient narratives contain interesting clues relating reports about stress and seizure histories to different epilepsy syndromes as well as nonepileptic episodes in a way that can strongly support the diagnostic process. A narrative approach is particularly valuable in this context. Therefore, accounts of stress triggering in seizures and other episodes should not be neglected, but rather taken seriously, sought and actively explored as a crucial element when taking clinical histories in patients with episodic attacks. [ABSTRACT FROM AUTHOR]

Clinical guidelines recommend screening people with epilepsy (PWE) regularly for mental distress, but it is unclear how guidelines are implemented. We surveyed epilepsy specialists in adult Scottish services to determine approaches used to screen for anxiety, depression, and suicidality; the perceived difficulty of screening; factors associated with intention to screen; and treatment decisions made following positive screens. An anonymous email-based questionnaire survey of epilepsy nurses and epilepsy neurology specialists (n = 38) was conducted. Two in every three specialists used a systematic screening approach; a third did not. Clinical interview was employed more often than standardized questionnaire. Clinicians reported positive attitudes towards screening but found screening difficult to implement. Intention to screen was associated with favorable attitude, perceived control, and social norm. Pharmacological and non-pharmacological interventions were proposed equally often for those screening positive for anxiety or depression. Routine screening for mental distress is carried out in Scottish epilepsy treatment settings but is not universal. Attention should be paid to clinician factors associated with screening, such as intention to screen and resulting treatment decisions. These factors are potentially modifiable, offering a means of closing the gap between guideline recommendations and clinical practice. [ABSTRACT FROM AUTHOR]

• The mental health burden for people with epilepsy (PWE) is considerable. • Screening for mental distress, though recommended, is often not done routinely. • We report the feasibility of a postal-telephone mental distress screening pathway. • Mood and quality of life (QOL) outcomes improved for PWE included in the pathway. • However, 1 in 3 PWE could not be screened, possibly those struggling most with mood. Mental distress is present in a significant proportion of people with epilepsy (PWE), with a negative impact across life domains. It is underdiagnosed and under-treated despite guidelines recommending screening for its presence (e.g., SIGN, 2015). We describe a tertiary-care epilepsy mental distress screening and treatment pathway, with a preliminary investigation of its feasibility. We selected psychometric screening instruments for depression, anxiety, quality of life (QOL), and suicidality, establishing treatment options matched to instrument scores on the Patient Health Questionnaire 9 (PHQ-9), along 'traffic light' lines. We determined feasibility outcomes including recruitment and retention rates, resources required to run the pathway, and level of psychological need. We undertook a preliminary investigation of change in distress scores over a 9-month interval and determined PWE engagement and the perceived usefulness of pathway treatment options. Two-thirds of eligible PWE were included in the pathway with an 88% retention rate. At the initial screen, 45.8% of PWE required either an 'Amber-2' intervention (for moderate distress) or a 'Red' one (for severe distress). The equivalent figure at the 9-month re-screen was 36.8%, reflective of an improvement in depression and QOL scores. Online charity-delivered well-being sessions and neuropsychology were rated highly for engagement and perceived usefulness, but computerized cognitive behavioral therapy was not. The resources required to run the pathway were modest. Outpatient mental distress screening and intervention are feasible in PWE. The challenge is to optimize methods for screening in busy clinics and to determine the best (and most acceptable) interventions for screening positive PWE. [ABSTRACT FROM AUTHOR]

There remains a need for more efficacious treatments for status epilepticus. Prolonged seizures result in the release of ATP from cells which activates the P2 class of ionotropic and metabotropic purinoceptors. The P2X receptors gate depolarizing sodium and calcium entry and are expressed by both neurons and glia throughout the brain, and a number of subtypes are upregulated after status epilepticus. Recent studies have explored the in vivo effects of targeting ATP-gated P2X receptors in preclinical models of status epilepticus, with particular focus on the P2X7 receptor (P2X7R). The P2X7R mediates microglial activation and the release of the proepileptogenic inflammatory cytokine interleukin 1β. The receptor may also directly modulate neurotransmission and gliotransmission and promote the recruitment of immune cells into brain parenchyma. Data from our group and collaborators show that status epilepticus produced by intraamygdala microinjection of kainic acid increases P2X7R expression in the hippocampus and neocortex of mice. Antagonism of the P2X7R in the model reduced seizure severity, microglial activation and interleukin 1β release, and neuronal injury. Coadministration of a P2X7R antagonist with a benzodiazepine also provided seizure suppression in a model of drug-refractory status epilepticus when either treatment alone was minimally effective. More recently, we showed that status epilepticus in immature rats is also reduced by P2X7R antagonism. Together, these findings suggest that P2X receptors may be novel targets for seizure control and interruption of neuroinflammation after status epilepticus. This article is part of a Special Issue entitled “Status Epilepticus”. [ABSTRACT FROM AUTHOR]

Abstract: Fatigue and excessive daytime sleepiness are common symptoms in patients with neurological injury. Modafinil has been shown to ameliorate these symptoms, but its use in patients with seizures has been limited because of safety concerns. Using a large centralized clinical registry, we performed a retrospective chart review of patients with a diagnosis of epilepsy who were given modafinil over a 10-year period. A total of 205 patients were analyzed. There were 91 patients who had seizures while taking modafinil; there was no relationship between modafinil dosage and whether the patient had seizures. There were 6 patients in whom modafinil was discontinued because of concern for seizure exacerbation, and 4 patients had de novo seizures after starting modafinil. In 29 patients with epilepsy only, no major seizure exacerbation was seen. Modafinil is potentially safe in patients with epilepsy, but further prospective studies are needed to fully determine its safety and efficacy. [Copyright &y& Elsevier]

Detailed studies of the association between the epilepsies and the schizophrenias extend over 40 years. Recent studies are abundant and make fertile use of new technologies. However, the pathological changes described in schizophrenias are quite varied. Studies fail to recognize that “epilepsies” and “schizophrenias” have varied in definition over time, and have always been weak categories with which to do science. Now that it is possible to measure deficits in brain structure, it would be better to see what behavioral problems are associated with specific cerebral pathology. It would be wise to be very precise in describing the behaviors and the nature and timing of their emergence rather than using terms such as psychoses. Schizophrenias have neurological, neuropsychological, and behavioral antecedents in childhood. Those associated with later epilepsies show biases, persistent in many studies over a number of years, toward relative excess of females, left temporal lobe structural deficits, and non-right-handedness. Schizophrenia should now be a predictable eventuality in certain people with epilepsies, an important factor in medical and surgical treatment. [Copyright &y& Elsevier]

Epilepsy is a network disorder driven by fundamental changes in the function of the cells which compose these networks. Driving this aberrant cellular function are large scale changes in gene expression and gene expression regulation. Recent studies have revealed rapid and persistent changes in epigenetic control of gene expression as a critical regulator of the epileptic transcriptome. Epigenetic-mediated gene output regulates many aspects of cellular physiology including neuronal structure, neurotransmitter assembly and abundance, protein abundance of ion channels and other critical neuronal processes. Thus, understanding the contribution of epigenetic-mediated gene regulation could illuminate novel regulatory mechanisms which may form the basis of novel therapeutic approaches to treat epilepsy. In this review we discuss the effects of epileptogenic brain insults on epigenetic regulation of gene expression, recent efforts to target epigenetic processes to block epileptogenesis and the prospects of an epigenetic-based therapy for epilepsy, and finally we discuss technological advancements which have facilitated the interrogation of the epigenome. [ABSTRACT FROM AUTHOR]

Benzodiazepines remain as the first-line treatment for status epilepticus (SE), but debate continues as to the choice and delivery route of pharmacotherapy. Lorazepam is currently the preferred anticonvulsant for clinical use, but midazolam has become a popular alternative, particularly as it can be given by nonintravenous routes. Anticonvulsants are also commonly used to terminate SE in animal models. Here, we aimed to compare the efficacy of midazolam with that of lorazepam in an experimental model of focal-onset SE. Status epilepticus was induced by intra-amygdala microinjection of kainic acid in 8 week old C57Bl/6 mice. Forty minutes later, mice were treated with an intraperitoneal injection of either lorazepam or midazolam (8 mg/kg). Electroencephalogram (EEG) activity, histology, and behavioral tests assessing recovery of function were evaluated and compared between groups. Intraperitoneal injection of either lorazepam or midazolam resulted in similar patterns of reduced EEG epileptiform activity during 1-hour recordings. Damage to the hippocampus and presentation of postinsult anxiety-related behavior did not significantly differ between treatment groups at 72 h. However, return of normal behaviors such as grooming, levels of activity, and the evaluation of overall recovery of SE mice were all superior at 24 h in animals given midazolam compared with lorazepam. Our results indicate that midazolam is as effective as lorazepam as an anticonvulsant in this model while also providing improved animal recovery after SE. These data suggest that midazolam might be considered by researchers as an anticonvulsant in animal models of SE, particularly as it appears to satisfy the requirements of refining procedures involving experimental animals at early time-points after SE. [ABSTRACT FROM AUTHOR]

Abstract: The relationship between amygdalar volume and anxiety after epilepsy surgery was explored. Participants comprised patients who underwent mesial temporal (n =26) or non-mesial temporal resections (n =16) and 41 neurologically normal controls. Anxiety was prospectively measured preoperatively and for the first 12months postoperatively using criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Amygdalar volumetry was performed on preoperative and control T1-weighted MRI scans. Resection of an ipsilateral amygdala of normal volume, relative to controls, was associated with postoperative anxiety in patients with mesial temporal resections, regardless of seizure outcome [F(1, 22)=5.17, P <0.05]. There was no relationship between amygdalar volume and anxiety in patients with non-mesial temporal resections, or between contralateral amygdalar volume and anxiety in patients with mesial temporal resections (P >0.05 for all comparisons). In conclusion, resection or deafferentation of an amygdala with a volume within the normal range was associated with increased postoperative anxiety. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to investigate the lateralizing and localizing value of ictal coprolalia and brain areas involved in its production. Methods A retrospective search for patients manifesting ictal coprolalia was conducted in our EMU database. Continuous video-EEG recordings were reviewed, and EEG activity before and during coprolalia was analyzed using independent component analysis (ICA) technique and was compared to the seizures without coprolalia among the same patients. Results Nine patients were evaluated (five women), eight with intracranial video-EEG recordings (icVEEG). Four had frontal or temporal lesions, and five had normal MRIs. Six patients showed impairment in the language functions and five in the frontal executive tasks. Two hundred six seizures were reviewed (60.7% from icVEEG). Ictal coprolalia occurred in 46.6% of them, always associated with limbic auras or automatisms. They arose from the nondominant hemisphere in five patients, dominant hemisphere in three, and independently from the right and left hippocampus–parahippocampus in one. Electroencephalographic activity always involved orbitofrontal and/or mesial temporal regions of the nondominant hemisphere when coprolalia occurred. Independent component analysis of 31 seizures in seven patients showed a higher number of independent components in the nondominant hippocampus–parahippocampus before and during coprolalia and in the dominant lateral temporal region in those seizures without coprolalia (p = 0.009). Five patients underwent surgery, and all five had an ILAE class 1 outcome. Significance Ictal coprolalia occurs in both males and females with temporal or orbitofrontal epilepsy and has a limited lateralizing value to the nondominant hemisphere but can be triggered by seizures from either hemisphere. It involves activation of the paralimbic temporal–orbitofrontal network. [ABSTRACT FROM AUTHOR]

Dravet Syndrome (DS) is a catastrophic form of paediatric epilepsy associated with multiple comorbidities mainly caused by mutations in the SCN1A gene. DS progresses in three different phases termed febrile, worsening and stabilization stage. Mice that are haploinsufficient for Scn1a faithfully model each stage of DS, although various aspects have not been fully described, including the temporal appearance and sex differences of the epilepsy and comorbidities. The aim of the present study was to investigate the epilepsy landscape according to the progression of DS and the long-term co-morbidities in the Scn1a(+/−) tm1Kea DS mouse line that are not fully understood yet. Male and female F1. Scn1a(+/+) and F1. Scn1a(+/−) tm1Kea mice were assessed in the hyperthermia model or monitored by video electroencephalogram (vEEG) and wireless video-EEG according to the respective stage of DS. Long-term comorbidities were investigated through a battery of behaviour assessments in ~6 month-old mice. At P18, F1. Scn1a(+/−) tm1Kea mice showed the expected sensitivity to hyperthermia-induced seizures. Between P21 and P28, EEG recordings in F1. Scn1a(+/−) tm1Kea mice combined with video monitoring revealed a high frequency of SRS and SUDEP (sudden unexpected death in epilepsy). Power spectral analyses of background EEG activity also revealed that low EEG power in multiple frequency bands was associated with SUDEP risk in F1. Scn1a(+/−) tm1Kea mice during the worsening stage of DS. Later, SRS and SUDEP rates stabilized and then declined in F1. Scn1a(+/−) tm1kea mice. Incidence of SRS ending with death in F1. Scn1a(+/−) tm1kea mice displayed variations with the time of day and sex, with female mice displaying higher numbers of severe seizures resulting in greater SUDEP risk. F1. Scn1a(+/−) tm1kea mice ~6 month-old displayed fewer behavioural impairments than expected including hyperactivity, impaired exploratory behaviour and poor nest building performance. These results reveal new features of this model that will optimize use and selection of phenotype assays for future studies on the mechanisms, diagnosis, and treatment of DS. Main findings of epilepsy and behaviour phenotypes in F1.Scn1a(+/−) tm1kea mice. Febrile stage : At P18, males and females F1. Scn1a (+/−)tm1kea mice similarly show sensitivity to hyperthermia-induced seizures at temperatures ~39.4C to 41.2C, with duration falling into two categories (short ~10s and long duration ~20s). Worsening stage: From P20 to P28/32, F1. Scn1a (+/−)tm1kea mice experience a high frequency of SRS and SUDEP. Interestingly, females displayed higher frequency of severe SRS and SUDEP than males F1. Scn1a (+/−)tm1kea mice. Stabilization stage: After P28-P32, SRS and SUDEP rates stabilized and then declined, nevertheless females F1. Scn1a (+/−)tm1kea mice remain experiencing a higher frequency of SRS ending with hindlimb extension and SUDEP than males. Lastly, F1. Scn1a (+/−)tm1kea mice ~6 month old displayed some behaviour impairments charaterized by hyperactivity, impaired exploratory behaviour and poor nest building performance. No sex differences were observed in the behaviour phenotype of F1. Scn1a (+/−)tm1kea mice. [Display omitted] • Scn1a(+/−) tm1kea DS mouse model faithfully reproduces the three stages of DS. • Sex of F1. Scn1a(+/−) tm1kea mice influences the epilepsy phenotype. • F1. Scn1a(+/−) tm1kea mice develop some of the long-term comorbidities of DS. [ABSTRACT FROM AUTHOR]

Abstract: Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a nonlesional condition associated with mutation of the gene coding for the α4 nicotinic acetylcholine receptor (nAChR). The nAChR modulates aspects of memory and attention. We examined the neuropsychological phenotype of ADNFLE, with a particular emphasis on understanding the impact on frontal lobe functions. We used standard clinical tests as well as focused measures of frontal lobe function in a well-defined group of patients with ADNFLE. Their performance was compared with that of a group of age-, sex-, and education-matched control participants. Patients with ADNFLE showed impairments on tasks requiring cognitive flexibility against a background of well-preserved intellectual abilities. In accord with existing research, verbal memory impairments were identified in the patient group; the level of impairment on these tasks correlated with disease-related factors. In our study of ADNFLE associated with one mutation, cognitive flexibility appears to be the core cognitive deficit. [Copyright &y& Elsevier]

Abstract: Preconditioning brain with a sub-lethal stressor can temporarily generate a damage-refractory state. Microarray analyses have defined the changes in hippocampal gene expression that follow brief preconditioning seizures, but not the transcriptome after a prolonged and otherwise injurious seizure in previously preconditioned brain. Presently, microarray analysis was performed 24 h after status epilepticus in mice that had received previously either seizure preconditioning (tolerance) or sham-preconditioning (injury). Transcriptional changes in the hippocampal CA3 subfield of ≥2 fold were detected for 1357 genes in the tolerance group compared to a non-seizure control group, with 54% up-regulated. Of these regulated genes, 792 were also regulated in the injury group. Among the remaining 565 genes regulated only in tolerance, 73% were down-regulated. Analysis of the genes differentially suppressed in tolerance identified calcium signaling, ion channels and excitatory neurotransmitter receptors, and the synapse as over-represented among pathways, functions and compartments. Finally, 12 days continuous EEG recordings determined mice with induced tolerance had fewer spontaneous electrographic seizures compared to the injury group. Our data suggest the transcriptional phenotype of neuroprotection in tolerance may be dictated by the biology of the preconditioning stressor, functions by transcriptional reduction of vulnerability to excitotoxicity, and has anti-epileptogenic effects. [Copyright &y& Elsevier]

Abstract: Seizures, particularly when prolonged, may cause neuronal loss within vulnerable brain structures such as the hippocampus, in part by activating programmed (apoptotic) cell death pathways. Experimental modeling suggests that seizures activate tumor necrosis factor receptor 1 (TNFR1) and engage downstream pro- and anti-apoptotic signaling cascades. Whether such TNFR1-mediated signaling occurs in human temporal lobe epilepsy (TLE) is unknown. Presently, we examined this pathway in hippocampus surgically obtained from refractory TLE patients and contrasted findings to matched autopsy controls. Western blotting established that total protein levels of the TNFR1 proximal signaling adaptor TNFR-associated protein with death domain (TRADD), cleaved initiator caspase-8 and apoptosis signal-regulating kinase 1 (ASK1) were higher in TLE samples than controls. Intracellular distribution analyses revealed raised cytoplasmic levels of TNFR1, TRADD and the caspase-8 recruitment adaptor Fas-associated protein with death domain (FADD), and higher levels of TRADD and cleaved caspase-8 in the microsomal fraction, in TLE samples. Immunoprecipitation studies detected TRADD–FADD binding, and fluorescence microscopy revealed TRADD co-localization with FADD in TLE hippocampus. These data suggest that TNFR1 signaling is engaged in the hippocampus of patients with refractory temporal lobe epilepsy. [Copyright &y& Elsevier]

Abstract: Understanding the consequences of newly discovered single gene mutations causing human epilepsy has the potential to yield new insights into the underlying mechanisms of this disorder. A mutation of the γ2 subunit of the GABAA receptor, which substitutes glutamine for arginine at position 43 (R43Q) has been found in a familial generalized epilepsy. We tested the hypothesis that individuals affected by the GABRG2(R43Q) mutation have reduced binding to the GABAA receptor complex using positron emission tomography (PET) and the benzodiazepine receptor ligand [11C]-flumazenil. Fourteen subjects with the GABRG2(R43Q) mutation and 20 controls were studied. Benzodiazepine receptor binding was reduced in subjects with the mutation (mean whole brain binding potential for [11C]-flumazenil: GABAA mutation 0.66±0.1; controls 0.89±0.1; P <0.003). The greatest change in benzodiazepine binding occurred anteriorly, with peak differences in insular and anterior cingulate cortices revealed by statistical parametric mapping. Our findings provide in vivo evidence of reduced benzodiazepine receptor binding in subjects with the mutation. As synaptic inhibition in the human brain is largely mediated by the GABAA receptor, these findings are likely to represent an important clue to the mechanisms linking this gene defect and the epilepsy phenotype. [Copyright &y& Elsevier]