The active electrical properties of dendrites shape neuronal input and output and are fundamental to brain function. However, our knowledge of active dendrites has been almost entirely acquired from ...studies of rodents. In this work, we investigated the dendrites of layer 2 and 3 (L2/3) pyramidal neurons of the human cerebral cortex ex vivo. In these neurons, we discovered a class of calcium-mediated dendritic action potentials (dCaAPs) whose waveform and effects on neuronal output have not been previously described. In contrast to typical all-or-none action potentials, dCaAPs were graded; their amplitudes were maximal for threshold-level stimuli but dampened for stronger stimuli. These dCaAPs enabled the dendrites of individual human neocortical pyramidal neurons to classify linearly nonseparable inputs-a computation conventionally thought to require multilayered networks.
Objectives
Recommendations for EEG monitoring in the ICU are lacking. The Neurointensive Care Section of the ESICM assembled a multidisciplinary group to establish consensus recommendations on the ...use of EEG in the ICU.
Methods
A systematic review was performed and 42 studies were included. Data were extracted using the PICO approach, including: (a) population, i.e. ICU patients with at least one of the following: traumatic brain injury, subarachnoid hemorrhage, intracerebral hemorrhage, stroke, coma after cardiac arrest, septic and metabolic encephalopathy, encephalitis, and status epilepticus; (b) intervention, i.e. EEG monitoring of at least 30 min duration; (c) control, i.e. intermittent vs. continuous EEG, as no studies compared patients with a specific clinical condition, with and without EEG monitoring; (d) outcome endpoints, i.e. seizure detection, ischemia detection, and prognostication. After selection, evidence was classified and recommendations developed using the GRADE system.
Recommendations
The panel recommends EEG in generalized convulsive status epilepticus and to rule out nonconvulsive seizures in brain-injured patients and in comatose ICU patients without primary brain injury who have unexplained and persistent altered consciousness. We suggest EEG to detect ischemia in comatose patients with subarachnoid hemorrhage and to improve prognostication of coma after cardiac arrest. We recommend continuous over intermittent EEG for refractory status epilepticus and suggest it for patients with status epilepticus and suspected ongoing seizures and for comatose patients with unexplained and persistent altered consciousness.
Conclusions
EEG monitoring is an important diagnostic tool for specific indications. Further data are necessary to understand its potential for ischemia assessment and coma prognostication.
Patients with prolonged seizures that do not respond to intravenous benzodiazepines and a second-line anticonvulsant suffer from refractory status epilepticus and those with seizures that do not ...respond to continuous intravenous anesthetic anticonvulsants suffer from super-refractory status epilepticus. Both conditions are associated with significant morbidity and mortality. A strict pharmacological treatment regimen is urgently required, but the level of evidence for the available drugs is very low. Refractory complex focal status epilepticus generally does not require anesthetics, but all intravenous non-anesthetizing anticonvulsants may be used. Most descriptive data are available for levetiracetam, phenytoin and valproate. Refractory generalized convulsive status epilepticus is a life-threatening emergency, and long-term clinical consequences are eminent. Administration of intravenous anesthetics is mandatory, and drugs acting at the inhibitory gamma-aminobutyric acid (GABA)
receptor such as midazolam, propofol and thiopental/pentobarbital are recommended without preference for one of those. One in five patients with anesthetic treatment does not respond and has super-refractory status epilepticus. With sustained seizure activity, excitatory N-methyl-d-aspartate (NMDA) receptors are increasingly expressed post-synaptically. Ketamine is an antagonist at this receptor and may prove efficient in some patients at later stages. Neurosteroids such as allopregnanolone increase sensitivity at GABA
receptors; a Phase 1/2 trial demonstrated safety and tolerability, but randomized controlled data failed to demonstrate efficacy. Adjunct ketogenic diet may contribute to termination of difficult-to-treat status epilepticus. Randomized controlled trials are needed to increase evidence for treatment of refractory and super-refractory status epilepticus, but there are multiple obstacles for realization. Hitherto, prospective multicenter registries for pharmacological treatment may help to improve our knowledge.
Summary Non-convulsive status epilepticus (NCSE) is one of the great diagnostic and therapeutic challenges of modern neurology. Because the clinical features of this disorder may be very discrete and ...sometimes hard to differentiate from normal behaviour, NCSE is usually overlooked and consequently not treated properly. It is important to be familiar with the clinical subtypes such as absence, simple and complex partial, and subtle status epilepticus because each requires tailored management. In order to improve overall care of patients with NCSE, strict diagnostic criteria are needed that should be based on clinical alterations and ictal electroencephalographic changes. NCSE should be terminated rapidly to prevent patients from serious injuries, particularly if consciousness is impaired.
The combination of signals from different sensory modalities can enhance perception and facilitate behavioral responses. While previous research described crossmodal influences in a wide range of ...tasks, it remains unclear how such influences drive performance enhancements. In particular, the neural mechanisms underlying performance-relevant crossmodal influences, as well as the latency and spatial profile of such influences are not well understood. Here, we examined data from high-density electroencephalography (N = 30) recordings to characterize the oscillatory signatures of crossmodal facilitation of response speed, as manifested in the speeding of visual responses by concurrent task-irrelevant auditory information. Using a data-driven analysis approach, we found that individual gains in response speed correlated with larger beta power difference (13–25 Hz) between the audiovisual and the visual condition, starting within 80 ms after stimulus onset in the secondary visual cortex and in multisensory association areas in the parietal cortex. In addition, we examined data from electrocorticography (ECoG) recordings in four epileptic patients in a comparable paradigm. These ECoG data revealed reduced beta power in audiovisual compared with visual trials in the superior temporal gyrus (STG). Collectively, our data suggest that the crossmodal facilitation of response speed is associated with reduced early beta power in multisensory association and secondary visual areas. The reduced early beta power may reflect an auditory-driven feedback signal to improve visual processing through attentional gating. These findings improve our understanding of the neural mechanisms underlying crossmodal response speed facilitation and highlight the critical role of beta oscillations in mediating behaviorally relevant multisensory processing.
Up to date, preclinical screening for new antiepileptic substances is performed by a combination of different
models of acute seizures, for which large numbers of animals are necessary. So far, ...little attention has been paid to
models, which are also able to detect antiepileptic efficacy and in principle could likewise serve for exploratory preclinical screening. One of the established
models of acute seizures is the 4-aminopyridine (4-AP) model. Previous studies have shown that the 4-AP model is capable to recapitulate the antiepileptic efficacy of standard antiepileptic drugs (AEDs) such as valproate or carbamazepine. Here, we employed a dual methodological approach using electrophysiology and optical imaging to systematically test the antiepileptic efficacy of three new-generation AEDs with distinct mechanisms of action (lacosamide, zonisamide, and levetiracetam). We found that frequency of 4-AP induced seizure like events (SLE) was the most sensitive parameter to detect dose-dependent antiepileptic effects in these compounds. Specifically, levetiracetam reduced SLE frequency while lacosamide and zonisamide at higher doses completely blocked SLE incidence. Analysis of the intrinsic optical signal additionally revealed a subiculum-specific reduction of the area involved in the propagation of ictal activity when lacosamide or zonisamide were administered. Taken together, our data adds some evidence that acute seizure models
are in principle capable to detect antiepileptic effects across different mechanisms of action with efficacy similar to acute models
. Further studies with negative controls, e.g., penicillin as a proconvulsant, and other clinically relevant AEDs are needed to determine if this acute
model might be useful as exploratory screening tool. In view of the increasing sensitivity toward animal welfare, an affective
model may help to reduce the number of laboratory animals deployed in burdening
experiments and to preselect substances for subsequent testing in time- and cost-laborious models of chronic epilepsy.
Summary
Objective
Depression and anxiety are highly prevalent among people with epilepsy (PwE) but often remain unrecognized and treated inadequately. Effective psychosocial treatments such as ...cognitive behavioral therapy (CBT) are rarely available to most PwE, which is one reason electronically delivered CBT (eCBT) is regarded as promising. This study examined an eCBT intervention, termed Emyna, that was tailored to suit the needs of PwE. It includes CBT‐related content on depression, stress and anxiety, seizure triggers and auras, and lifestyle habits. The trial examined the efficacy of Emyna in reducing symptoms of depression (primary outcome) and anxiety as well as improving quality of life.
Methods
Participants (N = 200) with epilepsy, a diagnosis of a depressive disorder, and at least moderate depressive symptoms were randomized to Emyna or care as usual. At baseline and after 3, 6, and 9 months, participants were invited to complete online questionnaires. The primary outcome was improvement of depressive symptoms at 3 months.
Results
Relative to the control group, intervention group participants experienced significantly greater improvements in depression, anxiety, stress, social‐occupational impairment, and epilepsy‐related quality of life, in both intention‐to‐treat (ITT) and per‐protocol analyses. In ITT analyses, effects of medium magnitude were observed, as measured by the Patient Health Questionnaire–9 items (Cohen d = 0.54, 95% confidence interval CI = 0.25‐0.82, P < 0.001) and the Neurological Disorders Depression Inventory for Epilepsy (d = 0.51, 95% CI = 0.23‐0.79, P < 0.01). At 3 months, intervention group participants also reported fewer illness‐related days off work and fewer days hospitalized over the preceding months, compared to control group participants (P ≤ 0.05), whereas no such differences were present at baseline (P > 0.30).
Significance
These findings showed that Emyna, used adjunctively to usual care, could help improve mental health, social‐occupational functioning, and quality of life among PwE. The program provides an additional treatment option that could produce clinically relevant symptom reductions and reduce key cost drivers (ie, hospitalization rates and illness‐related inability to work).
Focal epilepsy represents one of the most common chronic CNS diseases. The high incidence of drug resistance, devastating comorbidities, and insufficient responsiveness to surgery pose unmet medical ...challenges. In the quest of novel, disease‐modifying treatment strategies of neuropeptides represent promising candidates. Here, we provide the “proof of concept” that gene therapy by adeno‐associated virus (AAV) vector transduction of preprodynorphin into the epileptogenic focus of well‐accepted mouse and rat models for temporal lobe epilepsy leads to suppression of seizures over months. The debilitating long‐term decline of spatial learning and memory is prevented. In human hippocampal slices obtained from epilepsy surgery, dynorphins suppressed seizure‐like activity, suggestive of a high potential for clinical translation. AAV‐delivered preprodynorphin expression is focally and neuronally restricted and release is dependent on high‐frequency stimulation, as it occurs at the onset of seizures. The novel format of “release on demand” dynorphin delivery is viewed as a key to prevent habituation and to minimize the risk of adverse effects, leading to long‐term suppression of seizures and of their devastating sequel.
Synopsis
Temporal lobe epilepsy is a prevalent CNS disease with high medical need. In this proof‐of‐principle study, AAV vector‐based expression of dynorphin in the epileptogenic focus leads to long‐lasting suppression of seizures and rescues cognitive functions in clinically relevant disease models.
AAV‐mediated expression of preprodynorphin in the epileptogenic hippocampus suppresses seizures in mouse and rat models of temporal lobe epilepsy (TLE).
Dynorphin‐based gene therapy rescues cognitive impairment in epileptic mice.
Dynorphins suppress induced seizure‐like events in human hippocampal slices obtained from TLE surgery.
Focally restricted gene therapy combined with excitation‐induced release of dynorphins reduces risks of tolerance and side effects.
Temporal lobe epilepsy is a prevalent CNS disease with high medical need. In this proof‐of‐principle study, AAV vector‐based expression of dynorphin in the epileptogenic focus leads to long‐lasting suppression of seizures and rescues cognitive functions in clinically relevant disease models.
Background and Purpose
The KCNQ2 gene encodes for the Kv7.2 subunit of non‐inactivating potassium channels. KCNQ2‐related diseases range from autosomal dominant neonatal self‐limited epilepsy, often ...caused by KCNQ2 haploinsufficiency, to severe encephalopathies caused by KCNQ2 missense variants. In vivo and in vitro effects of the sodium channel blocker eslicarbazepine acetate (ESL) and eslicarbazepine metabolite (S‐Lic) in a mouse model of self‐limited neonatal epilepsy as a first attempt to assess the utility of ESL in the KCNQ2 disease spectrum was investigated.
Experimental Approach
Effects of S‐Lic on in vitro physiological and pathological hippocampal neuronal activity in slices from mice carrying a heterozygous deletion of Kcnq2 (Kcnq2+/−) and Kcnq2+/+ mice were investigated. ESL in vivo efficacy was investigated in the 6‐Hz psychomotor seizure model in both Kcnq2+/− and Kcnq2+/+ mice.
Key Results
S‐Lic increased the amplitude and decreased the incidence of physiological sharp wave–ripples in a concentration‐dependent manner and slightly decreased gamma oscillations frequency. 4‐Aminopyridine‐evoked seizure‐like events were blocked at high S‐Lic concentrations and substantially reduced in incidence at lower concentrations. These results were not different in Kcnq2+/+ and Kcnq2+/− mice, although the EC50 estimation implicated higher efficacy in Kcnq2+/−animals. In vivo, Kcnq2+/− mice had a lower seizure threshold than Kcnq2+/+ mice. In both genotypes, ESL dose‐dependently displayed protection against seizures.
Conclusions and Implications
S‐Lic slightly modulates hippocampal oscillations and blocks epileptic activity in vitro and in vivo. Our results suggest that the increased excitability in Kcnq2+/− mice is effectively targeted by S‐Lic high concentrations, presumably by blocking diverse sodium channel subtypes.
Summary
Purpose: Surgery in frontal lobe epilepsy (FLE) has a worse prognosis regarding seizure freedom than anterior lobectomy in temporal lobe epilepsy. The current study aimed to assess whether ...intracranial interictal and ictal EEG findings in addition to clinical and scalp EEG data help to predict outcome in a series of patients who needed invasive recording for FLE surgery.
Methods: Patients with FLE who had resective surgery after chronic intracranial EEG recording were included. Outcome predictors were compared in patients with seizure freedom (group 1) and those with recurrent seizures (group 2) at 19–24 months after surgery.
Key Findings: Twenty‐five patients (16 female) were included in this study. Mean age of patients at epilepsy surgery was 32.3 ± 15.6 years (range 12–70); mean duration of epilepsy was 16.9 ± 13.4 years (range 1–48). In each outcome group, magnetic resonance imaging revealed frontal lobe lesions in three patients. Fifteen patients (60%) were seizure‐free (Engel class 1), 10 patients (40%) continued to have seizures (two were class II, three were class III, and five were class IV). Lack of seizure freedom was seen more often in patients with epilepsy surgery on the left frontal lobe (group 1, 13%; group 2, 70%; p = 0.009) and on the dominant (27%; 70%; p = 0.049) hemisphere as well as in patients without aura (29%; 80%; p = 0.036), whereas sex, age at surgery, duration of epilepsy, and presence of an MRI lesion in the frontal lobe or extrafrontal structures were not different between groups. Electroencephalographic characteristics associated with lack of seizure freedom included presence of interictal epileptiform discharges in scalp recordings (31%; 90%; p = 0.01). Detailed analysis of intracranial EEG revealed widespread (>2 cm) (13%; 70%; p = 0.01) in contrast to focal seizure onset as well as shorter latency to onset of seizure spread (5.8 ± 6.1 s; 1.5 ± 2.3 s; p = 0.016) and to ictal involvement of brain structures beyond the frontal lobe (23.5 ± 22.4 s; 5.8 ± 5.4 s; p = 0.025) in patients without seizure freedom. The distribution of ictal onset patterns was similar in both groups, and fast rhythmic activity in the beta to gamma range was found in 57% of seizure‐free patients compared to 70% of patients with recurrent seizures. Analysis of the temporal relation between first clinical alterations and EEG seizure onset did not reveal significant differences between both groups of patients. In multivariate analysis, resection in the left hemisphere (odds ratio OR 12.197 95% confidence interval 95% CI 1.33–111.832; p = 0.027) and onset of seizure spread (odds ratio OR 0.733, 95% CI 0.549–0.978, p = 0.035) were independent predictors of ongoing seizures.
Significance: Widespread epileptogenicity as indicated by rapid onset of spread of ictal activity likely explains lack of seizure freedom following frontal resective surgery. The negative prognostic effect of surgery on the left hemisphere is less clear. Future study is needed to determine if neuronal network properties in this hemisphere point to intrinsic interhemispheric differences or if neurosurgeons are restrained by proximity to eloquent cortex.
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