Corticotropin Releasing Factor Mediates KCa3.1 Inhibition, Hyperexcitability, and Seizures in Acquired Epilepsy.

Temporal lobe epilepsy (TLE), the most common focal seizure disorder in adults, can be instigated in experimental animals by convulsant-induced status epilepticus (SE). Principal hippocampal neurons from SE-experienced epileptic male rats (post-SE neurons) display markedly augmented spike output compared with neurons from nonepileptic animals (non-SE neurons). This enhanced firing results from a cAMP-dependent protein kinase A-mediated inhibition of KCa3.1, a subclass of Ca2+-gated K+ channels generating the slow afterhyperpolarizing Ca2+-gated K+ current (IsAHP). The inhibition of KCa3.1 in post-SE neurons leads to a marked reduction in amplitude of the IsAHP that evolves during repetitive firing, as well as in amplitude of the associated Ca2+-dependent component of the slow afterhyperpolarization potential (KCa-sAHP). Here we show that KCa3.1 inhibition in post-SE neurons is induced by corticotropin releasing factor (CRF) through its Type 1 receptor (CRF1R). Acute application of CRF1R antagonists restores KCa3.1 activity in post-SE neurons, normalizing KCa-sAHP/IsAHP amplitudes and neuronal spike output, without affecting these variables in non-SE neurons. Moreover, pharmacological antagonism of CRF1Rs in vivo reduces the frequency of spontaneous recurrent seizures in post-SE chronically epileptic rats. These findings may provide a new vista for treating TLE.SIGNIFICANCE STATEMENT Epilepsy, a common neurologic disorder, often develops following a brain insult. Identifying key cellular mechanisms underlying acquired epilepsy is critical for developing effective antiepileptic therapies. In an experimental model of acquired epilepsy, principal hippocampal neurons manifest hyperexcitability because of downregulation of KCa3.1, a subtype of Ca2+-gated K+ ion channels. We show that KCa3.1 downregulation is mediated by corticotropin releasing factor (CRF) acting through its Type 1 receptor (CRF1R). Congruently, acute application of selective CRF1R antagonists restores KCa3.1 channel activity, leading to normalization of neuronal excitability. In the same model, injection of a CRF1R antagonist to epileptic animals markedly decreases the frequency of electrographic seizures. Therefore, targeting CRF1Rs may provide a new strategy in the treatment of acquired epilepsy.

Optimizing Electrode Configurations for Wearable EEG Seizure Detection Using Machine Learning.

Epilepsy, a prevalent neurological disorder, profoundly affects patients' quality of life due to the unpredictable nature of seizures. The development of a reliable and user-friendly wearable EEG system capable of detecting and predicting seizures has the potential to revolutionize epilepsy care. However, optimizing electrode configurations for such systems, which is crucial for balancing accuracy and practicality, remains to be explored. This study addresses this gap by developing a systematic approach to optimize electrode configurations for a seizure detection machine-learning algorithm. Our approach was applied to an extensive database of prolonged annotated EEG recordings from 158 epilepsy patients. Multiple electrode configurations ranging from one to eighteen were assessed to determine the optimal number of electrodes. Results indicated that the performance was initially maintained as the number of electrodes decreased, but a drop in performance was found to have occurred at around eight electrodes. Subsequently, a comprehensive analysis of all eight-electrode configurations was conducted using a computationally intensive workflow to identify the optimal configurations. This approach can inform the mechanical design process of an EEG system that balances seizure detection accuracy with the ease of use and portability. Additionally, this framework holds potential for optimizing hardware in other machine learning applications. The study presents a significant step towards the development of an efficient wearable EEG system for seizure detection.

[CHANGING CONCEPTS IN THE CLINICAL APPROACH FOR EPILEPSY SURGERY].

INTRODUCTION: Epilepsy is a common disease state, occurring in approximately 1% of the population worldwide, including both pediatric and adult populations. It is characterized by recurrent episodes of unpredictable pathologic cortical brain activity. One-third of patients develop drug intractability and experience recurrent seizures, despite optimal treatment. These result in cognitive decline, behavioral changes, decreased quality of life, and increased risk for trauma and death (SUDEP- sudden unprovoked death from epilepsy). Therefore, the international league against epilepsy (ILAE) recommends referral of intractable patients to highly specialized epilepsy centers, for further evaluation for epilepsy surgery.

A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy.

The developmental and epileptic encephalopathies (DEEs) are heterogeneous disorders with a strong genetic contribution, but the underlying genetic etiology remains unknown in a significant proportion of individuals. To explore whether statistical support for genetic etiologies can be generated on the basis of phenotypic features, we analyzed whole-exome sequencing data and phenotypic similarities by using Human Phenotype Ontology (HPO) in 314 individuals with DEEs. We identified a de novo c.508C>T (p.Arg170Trp) variant in AP2M1 in two individuals with a phenotypic similarity that was higher than expected by chance (p = 0.003) and a phenotype related to epilepsy with myoclonic-atonic seizures. We subsequently found the same de novo variant in two individuals with neurodevelopmental disorders and generalized epilepsy in a cohort of 2,310 individuals who underwent diagnostic whole-exome sequencing. AP2M1 encodes the µ-subunit of the adaptor protein complex 2 (AP-2), which is involved in clathrin-mediated endocytosis (CME) and synaptic vesicle recycling. Modeling of protein dynamics indicated that the p.Arg170Trp variant impairs the conformational activation and thermodynamic entropy of the AP-2 complex. Functional complementation of both the µ-subunit carrying the p.Arg170Trp variant in human cells and astrocytes derived from AP-2µ conditional knockout mice revealed a significant impairment of CME of transferrin. In contrast, stability, expression levels, membrane recruitment, and localization were not impaired, suggesting a functional alteration of the AP-2 complex as the underlying disease mechanism. We establish a recurrent pathogenic variant in AP2M1 as a cause of DEEs with distinct phenotypic features, and we implicate dysfunction of the early steps of endocytosis as a disease mechanism in epilepsy.

Paroxysmal slow wave events predict epilepsy following a first seizure.

OBJECTIVE: Management of a patient presenting with a first seizure depends on the risk of additional seizures. In clinical practice, the recurrence risk is estimated by the treating physician using the neurological examination, brain imaging, a thorough history for risk factors, and routine scalp electroencephalogram (EEG) to detect abnormal epileptiform activity. The decision to use antiseizure medication can be challenging when objective findings are missing. There is a need for new biomarkers to better diagnose epilepsy following a first seizure. Recently, an EEG-based novel analytical method was reported to detect paroxysmal slowing in the cortical network of patients with epilepsy. The aim of our study is to test this method's sensitivity and specificity to predict epilepsy following a first seizure. METHODS: We analyzed interictal EEGs of 70 patients admitted to the emergency department of a tertiary referral center after a first seizure. Clinical data from a follow-up period of at least 18 months were available. EEGs of 30 healthy controls were also analyzed and included. For each EEG, we applied an automated algorithm to detect paroxysmal slow wave events (PSWEs). RESULTS: Of patients presenting with a first seizure, 40% had at least one additional recurring seizure and were diagnosed with epilepsy. Sixty percent did not report additional seizures. A significantly higher occurrence of PSWEs was detected in the first interictal EEG test of those patients who were eventually diagnosed with epilepsy. Conducting the EEG test within 72 h after the first seizure significantly increased the likelihood of detecting PSWEs and the predictive value for epilepsy up to 82%. SIGNIFICANCE: The quantification of PSWEs by an automated algorithm can predict epilepsy and help the neurologist in evaluating a patient with a first seizure.

Towards Unification of General Relativity and Quantum Theory: Dendrogram Representation of the Event-Universe.

Following Smolin, we proceed to unification of general relativity and quantum theory by operating solely with events, i.e., without appealing to physical systems and space-time. The universe is modelled as a dendrogram (finite tree) expressing the hierarchic relations between events. This is the observational (epistemic) model; the ontic model is based on p-adic numbers (infinite trees). Hence, we use novel mathematics: not only space-time but even real numbers are not in use. Here, the p-adic space (which is zero-dimensional) serves as the base for the holographic image of the universe. In this way our theory is connected with p-adic physics; in particular, p-adic string theory and complex disordered systems (p-adic representation of the Parisi matrix for spin glasses). Our Dendrogramic-Holographic (DH) theory matches perfectly with the Mach's principle and Brans-Dicke theory. We found a surprising informational interrelation between the fundamental constants, h, c, G, and their DH analogues, h(D), c(D), G(D). DH theory is part of Wheeler's project on the information restructuring of physics. It is also a step towards the Unified Field theory. The universal potential V is nonlocal, but this is relational DH nonlocality. V can be coupled to the Bohm quantum potential by moving to the real representation. This coupling enhances the role of the Bohm potential.

Herpes simplex encephalitis in patients receiving chemotherapy and whole-brain radiation therapy.

Herpes simplex encephalitis (HSE) is a very severe infection of the central nervous system (CNS) caused mainly by herpes simplex virus type 1 (HSV-1) and occasionally by herpes simplex virus type 2 (HSV-2). After relapse or drug-resistant to chemotherapy, whole-brain radiation therapy (WBRT) is a mainstay of treatment in patients with both identifiable brain metastases and CNS lymphoma. Although HSV-1 encephalitis predominantly affects immunocompetent host, HSV encephalitis may be more common in immune-suppressed patients than is currently recognized. Disease presentation may be atypical including lack of pleocytosis in cerebrospinal fluid (CSF). We report four patients diagnosed with HSE following chemotherapy and WBRT. The occurrence of HSE in patients with cancer seems not to be increased compared to the general population, but as our case series shows, a high level of suspicion is needed by the treating physician to diagnose HSE early in patients presenting with new neurological symptoms following WBRT.

Representation of the Universe as a Dendrogramic Hologram Endowed with Relational Interpretation.

A proposal for a fundamental theory is described in which classical and quantum physics as a representation of the universe as a gigantic dendrogram are unified. The latter is the explicate order structure corresponding to the purely number-theoretical implicate order structure given by p-adic numbers. This number field was zero-dimensional, totally disconnected, and disordered. Physical systems (such as electrons, photons) are sub-dendrograms of the universal dendrogram. Measurement process is described as interactions among dendrograms; in particular, quantum measurement problems can be resolved using this process. The theory is realistic, but realism is expressed via the the Leibniz principle of the Identity of Indiscernibles. The classical-quantum interplay is based on the degree of indistinguishability between dendrograms (in which the ergodicity assumption is removed). Depending on this degree, some physical quantities behave more or less in a quantum manner (versus classic manner). Conceptually, our theory is very close to Smolin's dynamics of difference and Rovelli's relational quantum mechanics. The presence of classical behavior in nature implies a finiteness of the Universe-dendrogram. (Infinite Universe is considered to be purely quantum.) Reconstruction of events in a four-dimensional space type is based on the holographic principle. Our model reproduces Bell-type correlations in the dendrogramic framework. By adjusting dendrogram complexity, violation of the Bell inequality can be made larger or smaller.

Dendrogramic Representation of Data: CHSH Violation vs. Nonergodicity.

This paper is devoted to the foundational problems of dendrogramic holographic theory (DH theory). We used the ontic-epistemic (implicate-explicate order) methodology. The epistemic counterpart is based on the representation of data by dendrograms constructed with hierarchic clustering algorithms. The ontic universe is described as a p-adic tree; it is zero-dimensional, totally disconnected, disordered, and bounded (in p-adic ultrametric spaces). Classical-quantum interrelations lose their sharpness; generally, simple dendrograms are "more quantum" than complex ones. We used the CHSH inequality as a measure of quantum-likeness. We demonstrate that it can be violated by classical experimental data represented by dendrograms. The seed of this violation is neither nonlocality nor a rejection of realism, but the nonergodicity of dendrogramic time series. Generally, the violation of ergodicity is one of the basic features of DH theory. The dendrogramic representation leads to the local realistic model that violates the CHSH inequality. We also considered DH theory for Minkowski geometry and monitored the dependence of CHSH violation and nonergodicity on geometry, as well as a Lorentz transformation of data.

[NEUROLOGIC COMPLICATIONS AROUND THE DIAGNOSIS OF KIKUCHI-FUJIMOTO DISEASE: A RARE PRESENTATION OF THE DISEASE OR A HINT OF AN ADDITIONAL DIAGNOSIS?]

INTRODUCTION: Neurologic symptoms are an extremely rare presentation of Kikuchi-Fujimoto disease. We report a case of a young female patient diagnosed with Kikuchi-Fujimoto disease, presenting with neurologic symptoms compatible with aseptic meningitis, along with radiographic findings which improved with steroidal treatment. Despite the rarity of these findings, they were reported as part of the disease manifestation, however, since Kikuchi-Fujimoto disease is associated with other diseases, such as systemic lupus erythematosus (SLE), other diagnoses cannot be ruled out.

Incidence of AChR Ab-positive myasthenia gravis in Israel: A population-based study.

BACKGROUND: The incidence of myasthenia gravis (MG) has traditionally been low, ranging between 2-6/106 . Several recent epidemiological studies have reported a higher incidence. We, therefore, aimed to assess and characterize the incidence of MG in Israel. METHODS: We retrospectively reviewed the records of all four laboratories that performed the acetylcholine receptor antibody (AChR Ab) test in Israel between 1994 and 2013 and documented the number of newly diagnosed seropositive MG patients each year. To assure that data indeed reflect only newly diagnosed patients, patient's names and ID numbers were screened at the Hadassah medical center database since 1978, the year when the test was first performed in Israel. In order to calculate the annual incidence of the disease, the population at risk was derived from the annual publication of the Israeli Central Bureau of Statistics. RESULTS: The annual incidence of MG for this time period was 13.1/106 inhabitants. The mean incidence of MG between 1994 and 2003 was 7.695/106 /y, while the mean incidence between 2004 and 2013 was 18.49/106 (P < .0001). Mean age of diagnosis between 1994 and 2003 was 56.65 ± 0.9351, while between 2004 and 2013, it was 59.89 ± 0.5336 (P = .0012). Male to female (M:F) incidence ratio in the years 1994-2003 and 2004-2013 was 2:3.2 and 3:1.8, respectively, reflecting increased incidence among males (P < .0001). CONCLUSIONS: The incidence of MG in Israel has increased significantly during the last decade, especially among males of older age. These findings may reflect an etiological role of an environmental factor, increased awareness, and increased longevity in general.

Myoclonus epilepsy and ataxia due to KCNC1 mutation: Analysis of 20 cases and K+ channel properties.

OBJECTIVE: To comprehensively describe the new syndrome of myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK), including cellular electrophysiological characterization of observed clinical improvement with fever. METHODS: We analyzed clinical, electroclinical, and neuroimaging data for 20 patients with MEAK due to recurrent KCNC1 p.R320H mutation. In vitro electrophysiological studies were conducted using whole cell patch-clamp to explore biophysical properties of wild-type and mutant KV 3.1 channels. RESULTS: Symptoms began at between 3 and 15 years of age (median = 9.5), with progressively severe myoclonus and rare tonic-clonic seizures. Ataxia was present early, but quickly became overshadowed by myoclonus; 10 patients were wheelchair-bound by their late teenage years. Mild cognitive decline occurred in half. Early death was not observed. Electroencephalogram (EEG) showed generalized spike and polyspike wave discharges, with documented photosensitivity in most. Polygraphic EEG-electromyographic studies demonstrated a cortical origin for myoclonus and striking coactivation of agonist and antagonist muscles. Magnetic resonance imaging revealed symmetrical cerebellar atrophy, which appeared progressive, and a prominent corpus callosum. Unexpectedly, transient clinical improvement with fever was noted in 6 patients. To explore this, we performed high-temperature in vitro recordings. At elevated temperatures, there was a robust leftward shift in activation of wild-type KV 3.1, increasing channel availability. INTERPRETATION: MEAK has a relatively homogeneous presentation, resembling Unverricht-Lundborg disease, despite the genetic and biological basis being quite different. A remarkable improvement with fever may be explained by the temperature-dependent leftward shift in activation of wild-type KV 3.1 subunit-containing channels, which would counter the loss of function observed for mutant channels, highlighting KCNC1 as a potential target for precision therapeutics. Ann Neurol 2017;81:677-689.

Termination of pregnancy in women with epilepsy - A retrospective single center study.

Antiepileptic drugs (AEDs) are commonly prescribed to women of childbearing age. As 0.3%-0.7% of all pregnancies occur in women with epilepsy (WWE), the effect of recurrent seizures and teratogenicity on pregnancy outcome and the fetus have been widely studied. Most of these studies have focused on live births. A significant number of terminated pregnancies in WWE were ignored in past studies, thus reducing the calculated incidence of congenital malformations and possible influence of AED exposure. We scrutinized the medical records at our medical center for termination of pregnancy (TOP) in WWE for the years 2004-2016. Fifty-eight TOPs occurred in WWE during these years. Reasons for TOP included spontaneous abortions necessitating medical intervention (46.6%), patient's request (31.0%), medically recommended (10.3%), and unknown (12.1%).

Toll-like receptor 3 deficiency decreases epileptogenesis in a pilocarpine model of SE-induced epilepsy in mice.

OBJECTIVE: Epilepsy affects 60 million people worldwide. Despite the development of antiepileptic drugs, up to 35% of patients are drug refractory with uncontrollable seizures. Toll-like receptors (TLRs) are central components of the nonspecific innate inflammatory response. Because TLR3 was recently implicated in neuronal plasticity, we hypothesized that it may contribute to the development of epilepsy after status epilepticus (SE). METHODS: To test the involvement of TLR3 in epileptogenesis, we used the pilocarpine model for SE in TLR3-deficient mice and their respective wild-type controls. In this model, a single SE event leads to spontaneous recurrent seizures (SRS). Two weeks after SE, mice were implanted with wireless electroencephalography (EEG) transmitters for up to 1 month. The impact of TLR3 deficiency on SE was assessed using separate cohorts of mice regarding EEG activity, seizure progression, hippocampal microglial distribution, and expression of the proinflammatory cytokines tumor necrosis factor (TNF)α and interferon (IFN)ß. RESULTS: Our data indicate that TLR3 deficiency reduced SRS, microglial activation, and the levels of the proinflammatory cytokines TNFα and IFNß, and increased survival following SE. SIGNIFICANCE: This study reveals novel insights into the pathophysiology of epilepsy and the contribution of TLR3 to disease progression. Our results identify the TLR3 pathway as a potential future therapeutic target in SE.

Seizures as presenting and prominent symptom in chorea-acanthocytosis with c.2343del VPS13A gene mutation.

OBJECTIVE: The aim of the study was to characterize the clinical features of nine patients in three families with chorea-acanthocytosis (ChAc) sharing the same rare c.2343del mutation in the VPS13A gene. METHODS: Genetic test results, clinical description, magnetic resonance imaging (MRI), and electroencephalography (EEG), as well as laboratory results are summarized. RESULTS: ChAc is a rare genetic disorder characterized by hyperkinetic movements, seizures, cognitive decline, neuropsychiatric symptoms, and acanthocytes on peripheral blood smear. This unique cohort of nine patients is characterized by seizures as a first and prominent symptom. In our patients, other features of ChAc appeared later, including tics, other movement disorders, dysarthria, and mild to moderate cognitive decline. SIGNIFICANCE: Patients with chorea-acanthocytosis carrying the described rare mutation can present with focal, treatment-resistant seizures.

Role of small conductance Ca²âº-activated K⁺ channels in controlling CA1 pyramidal cell excitability.

Small-conductance Ca(2+)-activated K(+) (SK or K(Ca)2) channels are widely expressed in the CNS. In several types of neurons, these channels were shown to become activated during repetitive firing, causing early spike frequency adaptation. In CA1 pyramidal cells, SK channels in dendritic spines were shown to regulate synaptic transmission. However, the presence of functional SK channels in the somata and their role in controlling the intrinsic firing of these neurons has been controversial. Using whole-cell voltage-clamp and current-clamp recordings in acute hippocampal slices and focal applications of irreversible and reversible SK channel blockers, we provide evidence that functional SK channels are expressed in the somata and proximal dendrites of adult rat CA1 pyramidal cells. Although these channels can generate a medium duration afterhyperpolarizing current, they play only an auxiliary role in controlling the intrinsic excitability of these neurons, secondary to the low voltage-activating, noninactivating K(V)7/M channels. As long as K(V)7/M channels are operative, activation of SK channels during repetitive firing does not notably affect the spike output of CA1 pyramidal cells. However, when K(V)7/M channel activity is compromised, SK channel activation significantly and uniquely reduces spike output of these neurons. Therefore, proximal SK channels provide a "second line of defense" against intrinsic hyperexcitability, which may play a role in multiple conditions in which K(V)7/M channels activity is compromised, such as hyposmolarity.

Asystole in the epilepsy unit.

BACKGROUND: Early identification of cardiac asystole as a reason for syncope is of uttermost significance, as insertion of a cardiac pacemaker can save the patient's life and prevent severe injury. The aim of this work was to emphasize the subtle and unusual presentations of asystole in patients evaluated in epilepsy units. METHODS: We reviewed the clinical presentation, ECG and EEG data of a series of seven patients who were evaluated in four epilepsy units and were diagnosed with asystole. RESULTS: Three patients had unusual clinical manifestations of cardiac asystole, resembling epileptic seizures. Three patients had asystole induced by epileptic seizures and in one patient the diagnosis was not clear. All patients except one were implanted with a pacemaker and improved clinically. CONCLUSIONS: Seizure-induced asystole is a rare complication of epilepsy and asystole may clinically mimic epileptic seizures. A high level of suspicion and thorough prolonged cardiac and EEG monitoring are mandatory for reaching the right diagnosis. As the diagnosis is rare and difficult to reach, a flow chart to assist diagnosis is suggested.

Comparing the efficacy of anti-seizure medications using matched cohorts on a large insurance claims database.

Epilepsy is a severe chronic neurological disease affecting 60 million people worldwide. Primary treatment is with anti-seizure medicines (ASMs), but many patients continue to experience seizures. We used retrospective insurance claims data on 280,587 patients with uncontrolled epilepsy (UE), defined as status epilepticus, need for a rescue medicine, or admission or emergency visit for an epilepsy code. We conducted a computational risk ratio analysis between pairs of ASMs using a causal inference method, in order to match 1034 clinical factors and simulate randomization. Data was extracted from the MarketScan insurance claims Research Database records from 2011 to 2015. The cohort consisted of individuals over 18 years old with a diagnosis of epilepsy who took one of eight ASMs and had more than a year of history prior to the filling of the drug prescription. Seven ASM exposures were analyzed: topiramate, phenytoin, levetiracetam, gabapentin, lamotrigine, valproate, and carbamazepine or oxcarbazepine (treated as the same exposure). We calculated the risk ratio of UE between pairs of ASM after controlling for bias with inverse propensity weighting applied to 1034 factors, such as demographics, confounding illnesses, non-epileptic conditions treated by ASMs, etc. All ASMs exhibited a significant reduction in the prevalence of UE, but three drugs showed pair-wise differences compared to other ASMs. Topiramate consistently was associated with a lower risk of UE, with a mean risk ratio range of 0.68-0.93 (average 0.82, CI: 0.56-1.08). Phenytoin and levetiracetam were consistently associated with a higher risk of UE with mean risk ratio ranges of 1.11 to 1.47 (average 1.13, CI 0.98-1.65) and 1.15 to 1.43 (average 1.2, CI 0.72-1.69), respectively. Large-scale retrospective insurance claims data - combined with causal inference analysis - provides an opportunity to compare the effect of treatments in real-world data in populations 1,000-fold larger than those in typical randomized trials. Our causal analysis identified the clinically unexpected finding of topiramate as being associated with a lower risk of UE; and phenytoin and levetiracetam as associated with a higher risk of UE (compared to other studied drugs, not to baseline). However, we note that our data set for this study only used insurance claims events, which does not comprise actual seizure frequencies, nor a clear picture of side effects. Our results do not advocate for any change in practice but demonstrate that conclusions from large databases may differ from and supplement those of randomized trials and clinical practice and therefore may guide further investigation.