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Voltage‐gated calcium channels (VGCC) are abundant in the central nervous system and serve a broad spectrum of functions, either directly in cellular excitability or indirectly to regulate Ca2+ homeostasis. Ca2+ ions act as one of the main connections in excitation–transcription coupling, muscle contraction and excitation–exocytosis coupling, including synaptic transmission. In recent years, many genes encoding VGCCs main α or additional auxiliary subunits have been associated with epilepsy. This review sums up the current state of knowledge on disease mechanisms and provides guidance on disease‐specific therapies where applicable. [ABSTRACT FROM AUTHOR]

KCNQ5 encodes the voltage-gated potassium channel K V 7.5, a member of the K V 7 channel family, which conducts the M-current. This current is a potent regulator of neuronal excitability by regulating membrane potential in the subthreshold range of action potentials and mediating the medium and slow afterhyperpolarization. Recently, we have identified five loss-of-function variants in KCNQ5 in patients with genetic generalized epilepsy. Using the most severe dominant-negative variant (R359C), we set out to investigate pharmacological therapeutic intervention by K V 7 channel openers on channel function and neuronal firing. Retigabine and gabapentin increased R359C-derived M-current amplitudes in HEK cells expressing homomeric or heteromeric mutant K V 7.5 channels. Retigabine was most effective in restoring K+ currents. Ten μM retigabine was sufficient to reach the level of WT currents without retigabine, whereas 100 μM of gabapentin showed less than half of this effect and application of 50 μM ZnCl 2 only significantly increased M-current amplitude in heteromeric channels. Overexpression of K V 7.5-WT potently inhibited neuronal firing by increasing the M-current, whereas R359C overexpression had the opposite effect and additionally decreased the medium afterhyperpolarization current. Both aforementioned drugs and Zn2+ reversed the effect of R359C expression by reducing firing to nearly normal levels at high current injections. Our study shows that a dominant-negative variant with a complete loss-of-function in K V 7.5 leads to largely increased neuronal firing which may explain a neuronal hyperexcitability in patients. K V 7 channel openers, such as retigabine or gabapentin, could be treatment options for patients currently displaying pharmacoresistant epilepsy and carrying loss-of-function variants in KCNQ5. K V 7.5 dominant-negative-LOF variants reduce the M-current in transfected HEK cells and primary hippocampal neuronal cultures. Neuronal firing in cultured hippocampal neurons transfected with K V 7.5-LOF channels is increased likely through a decrease in the medium afterhyperpolarization current resulting in an increased seizure susceptibility in the patients. This effect was fully counteracted by the K V 7 channel activators retigabine (RTG) and gabapentin (GBP). [Display omitted] • K V 7.5-LOF expression increases neuronal firing by decreasing I M and thus I mAHP. • K V 7.5-WT overexpression decreases neuronal firing by increasing I M. • Both retigabine and gabapentin counteract the LOF effect. • Gabapentin has potential as personalized treatment for patients carrying K V 7.5-LOF missense variants. [ABSTRACT FROM AUTHOR]

Despite the development of many new anti-seizure drugs over the past two decades, around one-third of individuals with epilepsy are without effective treatment. This pharmacoresistance is poorly understood, but new treatments targeting epileptogenesis instead of seizures have shown potential in animal models and are now being translated into the clinic. [ABSTRACT FROM AUTHOR]

Potassium (K) channels are encoded by approximately 80 genes in mammals. They are expressed in many tissues and have diverse physiological roles. Human K channels are divided mainly into calcium (Ca)-activated (K), inward-rectifying (K), two-pore (K), and voltage-gated (K) channels. The K channels form the largest family, with approximately 40 genes. Owing to their involvement in many diseases and their specific expression patterns and physiological roles, K channels present an attractive target for the development of new therapies. This review summarizes the physiological and pathophysiological roles of various potassium channels with respect to their therapeutic potential for disorders with a disturbed neuronal excitability such as epilepsy, migraine, neuropathic pain, or stroke. [ABSTRACT FROM AUTHOR]

Genetic mutations causing dysfunction of both voltage- and ligand-gated ion channels make a major contribution to the cause of many different types of familial epilepsy. Key mechanisms comprise defective Na+ channels of inhibitory neurons, or GABAA receptors affecting pre- or postsynaptic GABAergic inhibition, or a dysfunction of different types of channels at axon initial segments. Many of these ion channel mutations have been modelled in mice, which has largely contributed to the understanding of where and how the ion channel defects lead to neuronal hyperexcitability. Animal models of febrile seizures or mesial temporal epilepsy have shown that dendritic K+ channels, hyperpolarization-activated cation channels and T-type Ca2+ channels play important roles in the generation of seizures. For the latter, it has been shown that suppression of their function by pharmacological mechanisms or in knock-out mice can antagonize epileptogenesis. Defects of ion channel function are also associated with forms of acquired epilepsy. Autoantibodies directed against ion channels or associated proteins, such as K+ channels, LGI1 or NMDA receptors, have been identified in epileptic disorders that can largely be included under the term limbic encephalitis which includes limbic seizures, status epilepticus and psychiatric symptoms. We conclude that ion channels and associated proteins are important players in different types of genetic and acquired epilepsies. Nevertheless, the molecular bases for most common forms of epilepsy are not yet clear, and evidence to be discussed indicates just how much more we need to understand about the complex mechanisms that underlie epileptogenesis. [ABSTRACT FROM AUTHOR]

Missense variants in genes encoding ion channels are associated with a spectrum of severe diseases. Variant effects on biophysical function correlate with clinical features and can be categorized as gain- or loss-of-function. This information enables a timely diagnosis, facilitates precision therapy, and guides prognosis. Functional characterization presents a bottleneck in translational medicine. Machine learning models may be able to rapidly generate supporting evidence by predicting variant functional effects. Here, we describe a multi-task multi-kernel learning framework capable of harmonizing functional results and structural information with clinical phenotypes. This novel approach extends the human phenotype ontology towards kernel-based supervised machine learning. Our gain- or loss-of-function classifier achieves high performance (mean accuracy 0.853 SD 0.016, mean AU-ROC 0.912 SD 0.025), outperforming both conventional baseline and state-of-the-art methods. Performance is robust across different phenotypic similarity measures and largely insensitive to phenotypic noise or sparsity. Localized multi-kernel learning offered biological insight and interpretability by highlighting channels with implicit genotype-phenotype correlations or latent task similarity for downstream analysis. Author summary: Genetic variants can impact the function of voltage-gated ion channels, which are transmembrane channels that are important for the electrical signalling of neurons. Individuals affected by these variants may have severe neurological or cardiac disease. Knowing the functional effects of variants can help us improve the diagnosis and clinical care for these individuals, and may also enable precision medicine aimed at correcting channel function. Machine learning methods are capable of predicting these functional effects, but previous models have only included information from protein sequence and structure. Here, we have developed a novel algorithm that can integrate clinical information by using the Human Phenotype Ontology (HPO), a standardized vocabulary of phenotypic features encountered in human disease. These different sources of information are used to train a multi-kernel support-vector machine. Our results suggest that this model is robust, interpretable, and more accurate than previous methods. Variant functional effect prediction engines will be useful tools for clinical geneticists, neurologists and biophysicists. [ABSTRACT FROM AUTHOR]

Idiopathic epilepsies are considered to be genetically determined. The inheritance can be monogenic and the detected mutation considered sufficient to cause the phenotype. In contrast, when the inheritance is complex, the epileptic phenotype is determined by several minor genetic defects that are much more difficult to discover. In recent years, an increasing number of mutations, mainly associated with rare monogenic idiopathic epilepsy syndromes, have been identified in genes encoding subunits of voltage- or ligand-gated ion channels. A few mutations have also been found in the frequent classical forms of idiopathic generalized epilepsies which are thought to follow a complex genetic trait, for example, in absence or juvenile myoclonic epilepsies. Functional studies characterizing the molecular defects of the mutant channels point to an important role of GABAergic synaptic inhibition in the pathophysiology of idiopathic epilepsies. As a result of genetic and functional investigations, not only will the pathophysiology of epilepsy be better understood, but newly discovered genes and pathophysiological pathways may also determine novel targets for pharmacotherapy, as has been shown for the anticonvulsant drug retigabine, which enhances the activity of neuronal KCNQ potassium channels. [ABSTRACT FROM AUTHOR]

The article comments on a study about ion channel dysfunctions in idiopathic epilepsies. It is claimed that epilepsy is more frequent during childhood. Epilepsy as a medical condition is characterized. The causes of sporadic or recurrent seizures is identified. Details of the first ion channel gene defects found in rare monogenic idiopathic epilepsy, is discussed.

The formation of disulfide bridges is a classical approach used to study the mobility, proximity and distances of residues in a variety of proteins, including ligand- and voltage-gated ion channels. We performed patch-clamp studies to investigate the interaction of a pair of cysteines introduced into the human skeletal muscle voltage-gated Na+ channel (hNav1.4) using the oxidation catalyst, Cu2+(1,10-phenanthroline)3 (CuPhen).Our experiments resulted in a surprising finding, a reversible current inhibition of the mutant I1160C/L1482C containing two cysteines in the D3/and D4/S4–S5 loops, subjected to oxidative cross-linking in the presence of CuPhen.We report here that CuPhen is an open channel blocker of both mutant and wild-type (WT) hNav1.4 channels, however, for WT channels a more than 10-fold higher concentration was needed to induce the same effect. Moreover, 1,10-phenanthroline was capable of blocking Na+ channels in the absence of Cu2+ ions. Our results indicate a use- and voltage-dependent binding and unbinding of CuPhen, reminiscent of the lidocaine quaternary derivative QX-314 and the neurotoxin batrachotoxin.Care should be taken when using CuPhen as an oxidizing reagent in cross-linking experiments, since it may directly affect channel activity. Our results identify CuPhen (and phenantroline) as a novel use-dependent inhibitor of Na+ channels, a mechanism that is shared by drugs widely used in the treatment of epilepsy, neuropathic pain, cardiac arrhythmia and myotonia. We hypothesize that I1160C in D3/S4–S5 and the corresponding L1482C mutation in D4/S4–S5 could allosterically affect a binding site located in the inner pore region of the channel.British Journal of Pharmacology (2006) 147, 808–814. doi:10.1038/sj.bjp.0706667; published online 23 January 2006 [ABSTRACT FROM AUTHOR]

This scientific commentary refers to ‘Targeting pharmacoresistant epilepsy and epileptogenesis with a dual-purpose antiepileptic drug’ by Doeser et al. (doi: 10.1093/brain/awu339). [ABSTRACT FROM AUTHOR]

Objective Methods Results Significance Defined as prospective single‐patient crossover studies with repeated paired cycles of active and control intervention, N‐of‐1 trials have gained attention as an option to obtain high‐quality evidence of efficacy, particularly for patients with rare epilepsies in whom conduction of well‐powered randomized controlled trials can be challenging. The objective of this systematic review is to provide an appraisal of the literature on N‐of‐1 trials in individuals with epilepsy.We searched PubMed and Embase on January 12, 2024, for studies meeting the following criteria: prospectively planned, within‐patient, multiple‐crossover design in individuals with epilepsy and outcomes related to comorbidities. Information on design, outcome measurements, intervention, and analyses was retrieved. Risk of bias assessment was performed using the Risk of Bias in N‐of‐1 Trials (RoBiNT) scale. We highlighted methodological aspects of the N‐of‐1 trials identified and discuss future recommendations.Five studies met our inclusion criteria. An additional multiple‐crossover trial that evaluated treatment effects exclusively at group level was also included because of its relevance to N‐of‐1 study methodology. The studies enrolled individuals with focal seizures, absences or cognitive impairement and electrographic discharges. Treatments included established or investigational antiseizure medications, off‐label medications, neurostimulation or lifestyle intervention. Three of the five N‐of‐1 trials reported on individual cases. The studies' strengths were the use of individualized treatment dosages and symptom‐specific patient‐reported outcomes. Limitations were related to minimal reporting of baseline characteristics and seizure burden.The trials identified by our search exemplify how the N‐of‐1 design can be applied to assess interventions in individuals with epilepsy‐related disorders. Future N‐of‐1 trials of antiseizure interventions should take into account baseline seizure frequency, should apply statistical models suited to capture seizure frequency changes reliably and make predefined interim assessments. Non‐seizure outcome measures evaluable over short periods should be considered. Tailored N‐of‐1 methodology could pave the way to evidence‐based, treatment selection for patients with rare epilepsies. [ABSTRACT FROM AUTHOR]

Abstract Transitions between distinct kinetic states of an ion channel are described by a Markov process. Hidden Markov models (HMM) have been successfully applied in the analysis of single ion channel recordings with a small signal-to-noise ratio. However, we have recently shown that the anti-aliasing low-pass filter misleads parameter estimation. Here, we show for the case of a Na[sup +] channel recording that the standard HMM do neither allow parameter estimation nor a correct identification of the gating scheme. In particular, the number of closed and open states is determined incorrectly, whereas a modified HMM considering the anti-aliasing filter (moving-average filtered HMM) is able to reproduce the characteristic properties of the time series and to perform gating scheme identification. [ABSTRACT FROM AUTHOR]

Background: Itch is a frequent complaint reported by patients and is usually ascribed to dermatological or metabolic causes. In neurological disorders, however, it is a very unusual symptom and thus its neurological aetiology is likely to be overlooked. There are only very few reports about permanent itch related to lesions of the central nervous system. To our knowledge we report the first case of episodic itch associated with a central nervous lesion. Case presentation: A 74-year-old female suffered from long-standing episodes of itch of the dermatomes C2 to C6 on the right side that was refractory to any treatment. On occurrence it propagated in a proximal to distal fashion. Between the episodes the patient was asymptomatic. MRI of the cervical spine uncovered a spinal glioma that matched the location of the symptoms. Treatment with gabapentin led to a prompt reduction of the symptoms. Conclusion: Patients with intractable pruritus and dermatomal presentation ought to undergo neurological examination and spinal cord imaging. Thus, ongoing frustrating and sometimes even harmful treatment trials could be avoided. [ABSTRACT FROM AUTHOR]

A letter to the editor which presents the common symptoms of painful seizures associated with a lesion in the midcingulate cortex is presented.

Summary: Variants in the SCN2A gene, encoding the voltage‐gated sodium channel NaV1.2, cause a variety of neuropsychiatric syndromes with different severity ranging from self‐limiting epilepsies with early onset to developmental and epileptic encephalopathy with early or late onset and intellectual disability (ID), as well as ID or autism without seizures. Functional analysis of channel defects demonstrated a genotype‐phenotype correlation and suggested effective treatment options for one group of affected patients carrying gain‐of‐function variants. Here, we sum up the functional mechanisms underlying different phenotypes of patients with SCN2A channelopathies and present currently available models that can help in understanding SCN2A‐related disorders. [ABSTRACT FROM AUTHOR]

Summary: Variants in the SCN2A gene, encoding the voltage‐gated sodium channel NaV1.2, cause a variety of neuropsychiatric syndromes with different severity ranging from self‐limiting epilepsies with early onset to developmental and epileptic encephalopathy with early or late onset and intellectual disability (ID), as well as ID or autism without seizures. Functional analysis of channel defects demonstrated a genotype‐phenotype correlation and suggested effective treatment options for one group of affected patients carrying gain‐of‐function variants. Here, we sum up the functional mechanisms underlying different phenotypes of patients with SCN2A channelopathies and present currently available models that can help in understanding SCN2A‐related disorders. [ABSTRACT FROM AUTHOR]

Ataxia due to an autosomal dominant intronic GAA repeat expansion in FGF14 [GAA- FGF14 ataxia, spinocerebellar ataxia 27B (SCA27B)] has recently been identified as one of the most common genetic late-onset ataxias. We here aimed to characterize its phenotypic profile, natural history progression, and 4-aminopyridine (4-AP) treatment response. We conducted a multi-modal cohort study of 50 GAA- FGF14 patients, comprising in-depth phenotyping, cross-sectional and longitudinal progression data (up to 7 years), MRI findings, serum neurofilament light (sNfL) levels, neuropathology, and 4-AP treatment response data, including a series of n -of-1 treatment studies. GAA- FGF14 ataxia consistently presented as late-onset [60.0 years (53.5–68.5), median (interquartile range)] pancerebellar syndrome, partly combined with afferent sensory deficits (55%) and dysautonomia (28%). Dysautonomia increased with duration while cognitive impairment remained infrequent, even in advanced stages. Cross-sectional and longitudinal assessments consistently indicated mild progression of ataxia [0.29 Scale for the Assessment and Rating of Ataxia (SARA) points/year], not exceeding a moderate disease severity even in advanced stages (maximum SARA score: 18 points). Functional impairment increased relatively slowly (unilateral mobility aids after 8 years in 50% of patients). Corresponding to slow progression and low extra-cerebellar involvement, sNfL was not increased relative to controls. Concurrent second diseases (including progressive supranuclear palsy neuropathology) represented major individual aggravators of disease severity, constituting important caveats for planning future GAA- FGF14 trials. A treatment response to 4-AP with relevance for everyday living was reported by 86% of treated patients. A series of three prospective n -of-1 treatment experiences with on/off design showed marked reduction in daily symptomatic time and symptom severity on 4-AP. Our study characterizes the phenotypic profile, natural history progression, and 4-AP treatment response of GAA- FGF14 ataxia. It paves the way towards large-scale natural history studies and 4-AP treatment trials in this newly discovered, possibly most frequent, and treatable late-onset ataxia. [ABSTRACT FROM AUTHOR]

We report a young wheelchair-dependent patient with an unclear proximal myopathy and a heterozygous, de-novo Cav1.1-R1239G mutation suggesting hypokalemic periodic paralysis (HypoPP). Sonography showed a loss of the pennate pattern indicative of an edema, whereas fatty degeneration was excluded. Within 7 days of therapy with spironolactone, potassium and physical therapy, muscle strength almost completely normalized, a normal pennate pattern appeared and the edema was markedly reduced. She learned to walk without aid and to do sports and has continued to do so for 11 years until now. Over the years, we tested serum potassium values, muscle strength, muscle edema and muscular sodium content by 1.5 T, 3 T and 7 T 1H and 23Na magnetic resonance imaging. No fatty muscle degeneration developed. Muscular edema-like changes only occurred when she was pregnant and was set to reduced therapy. Because of the ability to do sports again, her mobility was further increased. Our observational study on this single patient may suggest that: (1) muscle imaging and molecular genetics are important diagnostic tools, (2) weakness in periodic paralysis may be reversible, and (3) continued adequate therapy may preserve muscle structure and strength on a longterm, whereas weakness due to fatty degeneration could be considered progressive and irreversible. Although HypoPP is a rare disease, it should be included in differential diagnosis not only if there is paroxysmal weakness, but also in cases of myopathy of unknown origin. [ABSTRACT FROM AUTHOR]

The axon initial segment (AIS) is a highly specialized neuronal compartment that regulates the generation of action potentials and maintenance of neuronal polarity. Live imaging of the AIS is challenging due to the limited number of suitable labeling methods. To overcome this limitation, we established a novel approach for live labeling of the AIS using unnatural amino acids (UAAs) and click chemistry. The small size of UAAs and the possibility of introducing them virtually anywhere into target proteins make this method particularly suitable for labeling of complex and spatially restricted proteins. Using this approach, we labeled two large AIS components, the 186 kDa isoform of neurofascin (NF186; encoded by Nfasc) and the 260 kDa voltage-gated Na+ channel (NaV1.6, encoded by Scn8a) in primary neurons and performed conventional and super-resolution microscopy. We also studied the localization of epilepsy-causing NaV1.6 variants with a loss-of-function effect. Finally, to improve the efficiency of UAA incorporation, we developed adeno-associated viral (AAV) vectors for click labeling in neurons, an achievement that could be transferred to more complex systems such as organotypic slice cultures, organoids, and animal models. [ABSTRACT FROM AUTHOR]

Background and Purpose: Variants in SCN8A, the NaV1.6 channel's coding gene, are characterized by a variety of symptoms, including intractable epileptic seizures, psychomotor delay, progressive cognitive decline, autistic features, ataxia or dystonia. Standard anticonvulsant treatment has a limited impact on the course of disease. Experimental Approach: We investigated the therapeutic potential of eslicarbazepine (S‐licarbazepine; S‐lic), an enhancer of slow inactivation of voltage gated sodium channels, on two variants with biophysical and neuronal gain‐of‐function (G1475R and M1760I) and one variant with biophysical gain‐of‐function but neuronal loss‐of‐function (A1622D) in neuroblastoma cells and in murine primary hippocampal neuron cultures. These three variants cover the broad spectrum of NaV1.6‐associated disease and are linked to representative phenotypes of mild to moderate epilepsy (G1475R), developmental and epileptic encephalopathy (M1760I) and intellectual disability without epilepsy (A1622D). Key Results: Similar to known effects on NaV1.6 wildtype channels, S‐lic predominantly enhances slow inactivation on all tested variants, irrespective of their particular biophysical mechanisms. Beyond that, S‐lic exhibits variant‐specific effects including a partial reversal of pathologically slowed fast inactivation dynamics (A1622D and M1760I) and a trend to reduce enhanced persistent Na+ current by A1622D variant channels. Furthermore, our data in primary transfected neurons reveal that not only variant‐associated hyperexcitability (M1760I and G1475R) but also hypoexcitability (A1622D) can be modulated by S‐lic. Conclusions and Implications: S‐lic has not only substance‐specific effects but also variant‐specific effects. Personalized treatment regimens optimized to achieve such variant‐specific pharmacological modulation may help to reduce adverse side effects and improve the overall therapeutic outcome of SCN8A‐related disease. [ABSTRACT FROM AUTHOR]

Precision medicine for Mendelian epilepsy is rapidly developing. We describe an early infant with severely pharmacoresistant multifocal epilepsy. Exome sequencing revealed the de novo variant p.(Leu296Phe) in the gene KCNA1, encoding the voltage‐gated K+ channel subunit KV1.1. So far, loss‐of‐function variants in KCNA1 have been associated with episodic ataxia type 1 or epilepsy. Functional studies of the mutated subunit in oocytes revealed a gain‐of‐function caused by a hyperpolarizing shift of voltage dependence. Leu296Phe channels are sensitive to block by 4‐aminopyridine. Clinical use of 4‐aminopyridine was associated with reduced seizure burden, enabled simplification of co‐medication and prevented rehospitalization. [ABSTRACT FROM AUTHOR]

Background: Itch is a frequent complaint reported by patients and is usually ascribed to dermatological or metabolic causes. In neurological disorders, however, it is a very unusual symptom and thus its neurological aetiology is likely to be overlooked. There are only very few reports about permanent itch related to lesions of the central nervous system. To our knowledge we report the first case of episodic itch associated with a central nervous lesion.Case Presentation: A 74-year-old female suffered from long-standing episodes of itch of the dermatomes C2 to C6 on the right side that was refractory to any treatment. On occurrence it propagated in a proximal to distal fashion. Between the episodes the patient was asymptomatic. MRI of the cervical spine uncovered a spinal glioma that matched the location of the symptoms. Treatment with gabapentin led to a prompt reduction of the symptoms.Conclusion: Patients with intractable pruritus and dermatomal presentation ought to undergo neurological examination and spinal cord imaging. Thus, ongoing frustrating and sometimes even harmful treatment trials could be avoided. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "AERRPS, DESC, NORSE, FIRES: multilabeling or distinct epileptic entities?" by F.Y. Ismail and E.H. Kossoff in a 2011 issue of the journal.

The genetic basis of many epilepsies is increasingly understood, giving rise to the possibility of precision treatments tailored to specific genetic etiologies. Despite this, current medical therapy for most epilepsies remains imprecise, aimed primarily at empirical seizure reduction rather than targeting specific disease processes. Intellectual and technological leaps in diagnosis over the past 10 years have not yet translated to routine changes in clinical practice. However, the epilepsy community is poised to make impressive gains in precision therapy, with continued innovation in gene discovery, diagnostic ability, and bioinformatics; increased access to genetic testing and counseling; fuller understanding of natural histories; agility and rigor in preclinical research, including strategic use of emerging model systems; and engagement of an evolving group of stakeholders (including patient advocates, governmental resources, and clinicians and scientists in academia and industry). In each of these areas, we highlight notable examples of recent progress, new or persistent challenges, and future directions. The future of precision medicine for genetic epilepsy looks bright if key opportunities on the horizon can be pursued with strategic and coordinated effort. [ABSTRACT FROM AUTHOR]

This document is a correction to an article titled "Cenobamate: real-world data from a retrospective multicenter study" published in the Journal of Neurology. The original article contained an incorrect abstract. The study analyzed the efficacy and safety of cenobamate, an anti-seizure medication, in a large real-world cohort of patients with epilepsy. The results showed that cenobamate was highly effective and generally well-tolerated in patients with drug-resistant epilepsy. The article provides detailed information on treatment response, seizure freedom rates, adverse drug reactions, and changes in concomitant medications. [Extracted from the article]

Background: Clinical trials have shown that cenobamate (CNB) is an efficacious and safe anti-seizure medication (ASM) for drug-resistant focal epilepsy. Here, we analyzed one of the largest real-world cohorts, covering the entire spectrum of epilepsy syndromes, the efficacy and safety of CNB, and resulting changes in concomitant ASMs.We conducted a retrospective observational study investigating CNB usage in two German tertiary referral centers between October 2020 and June 2023 with follow-up data up to 27 months of treatment. Our primary outcome was treatment response. Secondary outcomes comprised drug response after 12 and 18 months, seizure freedom rates, CNB dosage and retention, adverse drug reactions (ADRs), and changes in concomitant ASMs.116 patients received CNB for at least two weeks. At 6 months, 98 patients were eligible for evaluation. Thereof 50% (49/98) were responders with no relevant change at 12 and 18 months. Seizure freedom was achieved in 18.4% (18/98) at 6 months, 16.7% (11/66), and 3.0% (1/33) at 12 and 18 months. The number of previous ASMs did not affect the seizure response rate. Overall, CNB was well-tolerated, however, in 7.7% (9/116), ADRs led to treatment discontinuation. The most frequent changes of concomitant ASMs included the discontinuation or reduction of sodium channel inhibitors, clobazam reduction, and perampanel discontinuation, while brivaracetam doses were usually left unchanged.CNB proved to be a highly effective and generally well-tolerated ASM in patients with severe drug-resistant epilepsy, comprising a broad array of epilepsy syndromes beyond focal epilepsy.Methods: Clinical trials have shown that cenobamate (CNB) is an efficacious and safe anti-seizure medication (ASM) for drug-resistant focal epilepsy. Here, we analyzed one of the largest real-world cohorts, covering the entire spectrum of epilepsy syndromes, the efficacy and safety of CNB, and resulting changes in concomitant ASMs.We conducted a retrospective observational study investigating CNB usage in two German tertiary referral centers between October 2020 and June 2023 with follow-up data up to 27 months of treatment. Our primary outcome was treatment response. Secondary outcomes comprised drug response after 12 and 18 months, seizure freedom rates, CNB dosage and retention, adverse drug reactions (ADRs), and changes in concomitant ASMs.116 patients received CNB for at least two weeks. At 6 months, 98 patients were eligible for evaluation. Thereof 50% (49/98) were responders with no relevant change at 12 and 18 months. Seizure freedom was achieved in 18.4% (18/98) at 6 months, 16.7% (11/66), and 3.0% (1/33) at 12 and 18 months. The number of previous ASMs did not affect the seizure response rate. Overall, CNB was well-tolerated, however, in 7.7% (9/116), ADRs led to treatment discontinuation. The most frequent changes of concomitant ASMs included the discontinuation or reduction of sodium channel inhibitors, clobazam reduction, and perampanel discontinuation, while brivaracetam doses were usually left unchanged.CNB proved to be a highly effective and generally well-tolerated ASM in patients with severe drug-resistant epilepsy, comprising a broad array of epilepsy syndromes beyond focal epilepsy.Results: Clinical trials have shown that cenobamate (CNB) is an efficacious and safe anti-seizure medication (ASM) for drug-resistant focal epilepsy. Here, we analyzed one of the largest real-world cohorts, covering the entire spectrum of epilepsy syndromes, the efficacy and safety of CNB, and resulting changes in concomitant ASMs.We conducted a retrospective observational study investigating CNB usage in two German tertiary referral centers between October 2020 and June 2023 with follow-up data up to 27 months of treatment. Our primary outcome was treatment response. Secondary outcomes comprised drug response after 12 and 18 months, seizure freedom rates, CNB dosage and retention, adverse drug reactions (ADRs), and changes in concomitant ASMs.116 patients received CNB for at least two weeks. At 6 months, 98 patients were eligible for evaluation. Thereof 50% (49/98) were responders with no relevant change at 12 and 18 months. Seizure freedom was achieved in 18.4% (18/98) at 6 months, 16.7% (11/66), and 3.0% (1/33) at 12 and 18 months. The number of previous ASMs did not affect the seizure response rate. Overall, CNB was well-tolerated, however, in 7.7% (9/116), ADRs led to treatment discontinuation. The most frequent changes of concomitant ASMs included the discontinuation or reduction of sodium channel inhibitors, clobazam reduction, and perampanel discontinuation, while brivaracetam doses were usually left unchanged.CNB proved to be a highly effective and generally well-tolerated ASM in patients with severe drug-resistant epilepsy, comprising a broad array of epilepsy syndromes beyond focal epilepsy.Conclusions: Clinical trials have shown that cenobamate (CNB) is an efficacious and safe anti-seizure medication (ASM) for drug-resistant focal epilepsy. Here, we analyzed one of the largest real-world cohorts, covering the entire spectrum of epilepsy syndromes, the efficacy and safety of CNB, and resulting changes in concomitant ASMs.We conducted a retrospective observational study investigating CNB usage in two German tertiary referral centers between October 2020 and June 2023 with follow-up data up to 27 months of treatment. Our primary outcome was treatment response. Secondary outcomes comprised drug response after 12 and 18 months, seizure freedom rates, CNB dosage and retention, adverse drug reactions (ADRs), and changes in concomitant ASMs.116 patients received CNB for at least two weeks. At 6 months, 98 patients were eligible for evaluation. Thereof 50% (49/98) were responders with no relevant change at 12 and 18 months. Seizure freedom was achieved in 18.4% (18/98) at 6 months, 16.7% (11/66), and 3.0% (1/33) at 12 and 18 months. The number of previous ASMs did not affect the seizure response rate. Overall, CNB was well-tolerated, however, in 7.7% (9/116), ADRs led to treatment discontinuation. The most frequent changes of concomitant ASMs included the discontinuation or reduction of sodium channel inhibitors, clobazam reduction, and perampanel discontinuation, while brivaracetam doses were usually left unchanged.CNB proved to be a highly effective and generally well-tolerated ASM in patients with severe drug-resistant epilepsy, comprising a broad array of epilepsy syndromes beyond focal epilepsy. [ABSTRACT FROM AUTHOR]

Nodding syndrome (NS) is a poorly understood form of childhood‐onset epilepsy that is characterized by the pathognomonic ictal phenomenon of repetitive vertical head drops. To evaluate the underlying ictal neurophysiology, ictal EEG features were evaluated in nine participants with confirmed NS from South Sudan, Tanzania, and Uganda and ictal presence of high frequency gamma oscillations on scalp EEG were assessed. Ictal EEG during the head nodding episode predominantly showed generalized slow waves or sharp‐and‐slow wave complexes followed by electrodecrement. Augmentation of gamma activity (30–70 Hz) was seen during the head nodding episode in all the participants. We confirm that head nodding episodes in persons with NS from the three geographically distinct regions in sub‐Saharan Africa share the common features of slow waves with electrodecrement and superimposed gamma activity. ANN NEUROL 2022;92:75–80 [ABSTRACT FROM AUTHOR]

Aims: To find out which variables may be associated with comfort of patients in an epilepsy monitoring unit. Design: Exploratory, quantitative study design. Methods: Data were collected from October 2018 to November 2019 in Austria and Southern Germany. A total of 267 patients of 10 epilepsy centres completed the Epilepsy Monitoring Unit Comfort Questionnaire which is based on Kolcaba's General Comfort Questionnaire. Secondary data analysis were conducted by using descriptive statistics and an exploratory model building approach, including different linear regression models and several sensitivity analyses. Results: Total comfort scores ranged from 83 to 235 points. Gender, occupation and centre turned out to be possible influential variables. On average, women had a total comfort score 4.69 points higher than men, and retired persons 28.2 points higher than high school students ≥18 years. Comfort scores of younger patients were lower than those of older patients. However, age did not show a statistically significant effect. The same could be observed in marital status and educational levels. Conclusion: When implementing comfort measures, nurses must be aware of variables which could influence the intervention negatively. Especially, high school students ≥18 years should be supported by epilepsy specialist nurses, in order to reduce uncertainty, anxiety and discomfort. But, since the identified variables account only for a small proportion of the inter‐individual variability in comfort scores, further studies are needed to find out additional relevant aspects and to examine centre‐specific effects more closely. Impact: Nurses ensure patient comfort during a hospital stay. However, there are variables that may impair the effectiveness of the nursing measures. Our study showed that the experience of comfort was highly individual and could be explained by sociodemographic variables only to a limited extent. Nurses must be aware that additional factors, such as the situation in the individual setting, may be relevant. [ABSTRACT FROM AUTHOR]

Objective: Genetic generalized epilepsy (GGE) is characterized by aberrant neuronal dynamics and subtle structural alterations. We evaluated whether a combination of magnetic and electrical neuronal signals and cortical thickness would provide complementary information about network pathology in GGE. We also investigated whether these imaging phenotypes were present in healthy siblings of the patients to test for genetic influence. Methods: In this cross‐sectional study, we analyzed 5 min of resting state data acquired using electroencephalography (EEG) and magnetoencephalography (MEG) in patients, their siblings, and controls, matched for age and sex. We computed source‐reconstructed power and connectivity in six frequency bands (1–40 Hz) and cortical thickness (derived from magnetic resonance imaging). Group differences were assessed using permutation analysis of linear models for each modality separately and jointly for all modalities using a nonparametric combination. Results: Patients with GGE (n = 23) had higher power than controls (n = 35) in all frequencies, with a more posterior focus in MEG than EEG. Connectivity was also increased, particularly in frontotemporal and central regions in theta (strongest in EEG) and low beta frequencies (strongest in MEG), which was eminent in the joint EEG/MEG analysis. EEG showed weaker connectivity differences in higher frequencies, possibly related to drug effects. The inclusion of cortical thickness reinforced group differences in connectivity and power. Siblings (n = 18) had functional and structural patterns intermediate between those of patients and controls. Significance: EEG detected increased connectivity and power in GGE similar to MEG, but with different spectral sensitivity, highlighting the importance of theta and beta oscillations. Cortical thickness reductions in GGE corresponded to functional imaging patterns. Our multimodal approach extends the understanding of the resting state in GGE and points to genetic underpinnings of the imaging markers studied, providing new insights into the causes and consequences of epilepsy. [ABSTRACT FROM AUTHOR]

ATP-binding cassette transporter B1 (ABCB1; P-glycoprotein; multidrug resistance protein 1) is an adenosine triphosphate (ATP)-dependent efflux transporter located in the plasma membrane of many different cell types. Numerous structurally unrelated compounds, including drugs and environmental toxins, have been identified as substrates. ABCB1 limits the absorption of xenobiotics from the gut lumen, protects sensitive tissues (e.g. the brain, fetus and testes) from xenobiotics and is involved in biliary and renal secretion of its substrates. In recent years, a large number of polymorphisms of the ABCB1 [ATP-binding cassette, sub-family B (MDR/TAP), member 1] gene have been described. The variants 1236C>T (rs1128503, p.G412G), 2677G>T/A (rs2032582, p.A893S/T) and 3435C>T (rs1045642, p.I1145I) occur at high allele frequencies and create a common haplotype; therefore, they have been most widely studied. This review provides an overview of clinical studies published between 2002 and March 2015. In summary, the effect of ABCB1 variation on P-glycoprotein expression (messenger RNA and protein expression) and/or activity in various tissues (e.g. the liver, gut and heart) appears to be small. Although polymorphisms and haplotypes of ABCB1 have been associated with alterations in drug disposition and drug response, including adverse events with various ABCB1 substrates in different ethnic populations, the results have been majorly conflicting, with limited clinical relevance. Future research activities are warranted, considering a deep-sequencing approach, as well as well-designed clinical studies with appropriate sample sizes to elucidate the impact of rare ABCB1 variants and their potential consequences for effect sizes. [ABSTRACT FROM AUTHOR]

Objective: Levetiracetam (LEV) is an effective antiseizure medicine, but 10%–20% of people treated with LEV report psychiatric side‐effects, and up to 1% may have psychotic episodes. Pharmacogenomic predictors of these adverse drug reactions (ADRs) have yet to be identified. We sought to determine the contribution of both common and rare genetic variation to psychiatric and behavioral ADRs associated with LEV. Methods: This case‐control study compared cases of LEV‐associated behavioral disorder (n = 149) or psychotic reaction (n = 37) to LEV‐exposed people with no history of psychiatric ADRs (n = 920). All samples were of European ancestry. We performed genome‐wide association study (GWAS) analysis comparing those with LEV ADRs to controls. We estimated the polygenic risk scores (PRS) for schizophrenia and compared cases with LEV‐associated psychotic reaction to controls. Rare variant burden analysis was performed using exome sequence data of cases with psychotic reactions (n = 18) and controls (n = 122). Results: Univariate GWAS found no significant associations with either LEV‐associated behavioural disorder or LEV‐psychotic reaction. PRS analysis showed that cases of LEV‐associated psychotic reaction had an increased PRS for schizophrenia relative to contr ols (p =.0097, estimate =.4886). The rare‐variant analysis found no evidence of an increased burden of rare genetic variants in people who had experienced LEV‐associated psychotic reaction relative to controls. Significance: The polygenic burden for schizophrenia is a risk factor for LEV‐associated psychotic reaction. To assess the clinical utility of PRS as a predictor, it should be tested in an independent and ideally prospective cohort. Larger sample sizes are required for the identification of significant univariate common genetic signals or rare genetic signals associated with psychiatric LEV ADRs. [ABSTRACT FROM AUTHOR]

A potential link between GABRD encoding the δ subunit of extrasynaptic GABAA receptors and neurodevelopmental disorders has largely been disregarded due to conflicting conclusions from early studies. However, we identified seven heterozygous missense GABRD variants in 10 patients with neurodevelopmental disorders and generalized epilepsy. One variant occurred in two sibs of healthy parents with presumed somatic mosaicism, another segregated with the disease in three affected family members, and the remaining five occurred de novo in sporadic patients. Electrophysiological measurements were used to determine the functional consequence of the seven missense δ subunit variants in receptor combinations of α1β3δ and α4β2δ GABAA receptors. This was accompanied by analysis of electroclinical phenotypes of the affected individuals. We determined that five of the seven variants caused altered function of the resulting α1β3δ and α4β2δ GABAA receptors. Surprisingly, four of the five variants led to gain-of-function effects, whereas one led to a loss-of-function effect. The stark differences between the gain-of-function and loss-of function effects were mirrored by the clinical phenotypes. Six patients with gain-of-function variants shared common phenotypes: neurodevelopmental disorders with behavioural issues, various degrees of intellectual disability, generalized epilepsy with atypical absences and generalized myoclonic and/or bilateral tonic-clonic seizures. The EEG showed qualitative analogies among the different gain-of-function variant carriers consisting of focal slowing in the occipital regions often preceding irregular generalized epileptiform discharges, with frontal predominance. In contrast, the one patient carrying a loss-of-function variant had normal intelligence and no seizure history, but has a diagnosis of autism spectrum disorder and suffers from elevated internalizing psychiatric symptoms. We hypothesize that increase in tonic GABA-evoked current levels mediated by δ-containing extrasynaptic GABAA receptors lead to abnormal neurotransmission, which represent a novel mechanism for severe neurodevelopmental disorders. In support of this, the electroclinical findings for the gain-of-function GABRD variants resemble the phenotypic spectrum reported in patients with missense SLC6A1 (GABA uptake transporter) variants. This also indicates that the phenomenon of extrasynaptic receptor overactivity is observed in a broader range of patients with neurodevelopmental disorders, because SLC6A1 loss-of-function variants also lead to overactive extrasynaptic δ-containing GABAA receptors. These findings have implications when selecting potential treatment options, as a substantial portion of available antiseizure medication act by enhancing GABAergic function either directly or indirectly, which could exacerbate symptoms in patients with gain-of-function GABRD variants. [ABSTRACT FROM AUTHOR]

Mutations in the SCN8A gene, encoding the voltage-gated sodium channel Na V 1.6, are associated with a range of neurodevelopmental syndromes. The p.(Gly1625Arg) (G1625R) mutation was identified in a patient diagnosed with developmental epileptic encephalopathy (DEE). While most of the characterized DEE-associated SCN8A mutations were shown to cause a gain-of-channel function, we show that the G1625R variant, positioned within the S4 segment of domain IV, results in complex effects. Voltage-clamp analyses of Na V 1.6G1625R demonstrated a mixture of gain- and loss-of-function properties, including reduced current amplitudes, increased time constant of fast voltage-dependent inactivation, a depolarizing shift in the voltage dependence of activation and inactivation, and increased channel availability with high-frequency repeated depolarization. Current-clamp analyses in transfected cultured neurons revealed that these biophysical properties caused a marked reduction in the number of action potentials when firing was driven by the transfected mutant Na V 1.6. Accordingly, computational modeling of mature cortical neurons demonstrated a mild decrease in neuronal firing when mimicking the patients' heterozygous SCN8A expression. Structural modeling of Na V 1.6G1625R suggested the formation of a cation-π interaction between R1625 and F1588 within domain IV. Double-mutant cycle analysis revealed that this interaction affects the voltage dependence of inactivation in Na V 1.6G1625R. Together, our studies demonstrate that the G1625R variant leads to a complex combination of gain and loss of function biophysical changes that result in an overall mild reduction in neuronal firing, related to the perturbed interaction network within the voltage sensor domain, necessitating personalized multi-tiered analysis for SCN8A mutations for optimal treatment selection. [Display omitted] • The SCN8A G1625R mutation was identified in a child with mild epilepsy and profound developmental delay. • Voltage-clamp analyses demonstrated a mixture of gain- and loss-of-function properties. • Current-clamp analyses in transfected cultured neurons showed reduced firing. • Computational modeling revealed an overall loss-of-function effect. • The biophysical changes may be associated with the formation of cation-π interaction between R1625 and F1588. [ABSTRACT FROM AUTHOR]

The voltage-gated potassium channels K7.2 and K7.3 ( KCNQ2/ 3 genes) play an important role in regulating neuronal excitability. More than 50 KCNQ2/ 3 mutations have been identified to cause an inherited form of epilepsy in newborns. For two of those (E119G and S122L) found in the S1-S2 region of K7.2, we previously showed a decreased channel availability mainly at action potential subthreshold voltages caused by a slight depolarizing shift of the activation curve. Interestingly, recent studies revealed that a threonine residue within the S1-S2 loop, highly conserved among different classes of K channels, is crucial for both their function and surface expression. To investigate the functional role of the homologous threonine residues in K7.2 (T114) and K7.3 (T144) channels, we replaced them with alanine and examined the electrophysiological properties using heterologous expression in CHO cells and whole cell patch clamping. Channels comprising mutant subunits yielded decreased potassium currents with slowed activation and accelerated deactivation kinetics. However, the most striking effect was a depolarizing shift in the voltage dependence of activation reaching +30 mV upon co-expression of both mutant subunits. Potential interactions of T114 within the channel were analyzed by creating a 3D homology model of K7.2 in an open state suggesting that this residue plays a central role in the formation of a stable interface between the S1-S2 and the S5 segment helices. This could be the explanation why substitution of the conserved threonine in K7.2 and K7.3 channels destabilizes the open and favors the closed state of these channels. [ABSTRACT FROM AUTHOR]

SCN8A , encoding the voltage-gated sodium channel subunit Na V 1.6, has been associated with a wide spectrum of neuropsychiatric disorders. Missense variants in SCN8A which increase the channel activity can cause a severe developmental and epileptic encephalopathy (DEE). One DEE variant (p.(Arg223Gly)) was described to cause a predominant loss-of-function (LOF) mechanism when expressed in neuroblastoma cells, which is not consistent with the genotype-phenotype correlations in this gene. To resolve this discrepancy and understand the pathophysiological mechanism of this variant, we performed comprehensive electrophysiological studies in both neuroblastoma cells and primary hippocampal neuronal cultures. Although we also found that p.(Arg223Gly) significantly decreased Na+ current density and enhanced fast inactivation compared to the wild type (WT) channel in transfected neuroblastoma cells (both LOF mechanisms), it also caused a strong hyperpolarizing shift of steady-state activation and accelerated the recovery from fast inactivation (both gain-of-function (GOF) mechanisms). In cultured neurons transfected with mutant vs. WT Na V 1.6 channels, we found more depolarized resting membrane potentials and a decreased rheobase leading to enhanced action potential firing. We conclude that SCN8A p.(Arg223Gly) leads to a net GOF resulting in neuronal hyperexcitability and a higher firing rate, fitting with the central role of GOF mechanisms in DEE. • SCN8A p. (Arg223Gly) variant is associated with developmental and epileptic encephalopathy (DEE). • This variant caused both gain- and loss-of function gating changes in neuroblastoma cells. • Characterizations of this variant in neuronal cultures revealed a predominantly gain-of-function mechanism for DEE. [ABSTRACT FROM AUTHOR]

Similar to apoptosis of nucleated cells, suicidal erythrocyte death or eryptosis is characterized by cell shrinkage, membrane blebbing and membrane phospholipid scrambling with phosphatidylserine exposure at the cell surface. Signaling of eryptosis involves formation of prostaglandin E2 with subsequent activation of cation channels and Ca2+-entry and/or release of platelet activating factor (PAF) with subsequent activation of sphingomyelinase and formation of ceramide. Ca2+ and ceramide stimulate cell membrane scrambling. Ca2+ further activates Ca2+-sensitive K+-channels leading to cellular KCl loss and cell shrinkage and stimulates the protease calpain resulting in degradation of the cytoskeleton. Injuries triggering eryptosis may similarly compromise survival of nucleated cells. The case is made that analysis of enhanced eryptosis may direct to the pathophysiology of systemic disease. Examples presented include drug side effects, sepsis, haemolytic uremic syndrome, Wilson´s disease, phosphate depletion and a rare condition caused by a mutation in GLUT1 turning the carrier into a cation channel. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Voltage-gated K+ channels of the KV7 (KCNQ) family have been identified in the last 10–15 years by discovering the causative genes for three autosomal dominant diseases: cardiac arrhythmia (long QT syndrome) with or without congenital deafness ( KCNQ1), a neonatal epilepsy ( KCNQ2 and KCNQ3) and progressive deafness alone ( KCNQ4). A fifth member of this gene family ( KCNQ5) is not affected in a disease so far. Four genes ( KCNQ2–5) are expressed in the nervous system. This review is focused on recent findings on the neuronal KV7 channelopathies, in particular on benign familial neonatal seizures (BFNS) and peripheral nerve hyperexcitability (PNH, neuromyotonia, myokymia) caused by KCNQ2 mutations. The phenotypic spectrum associated with KCNQ2 mutations is probably broader than initially thought, as patients with severe epilepsies and developmental delay, or with Rolando epilepsy have been described. With regard to the underlying molecular pathophysiology, it has been shown that mutations with very subtle changes restricted to subthreshold voltages can cause BFNS thereby proving in a human disease model that this is the relevant voltage range for these channels to modulate neuronal firing. The two mutations associated with PNH induce much more severe channel dysfunction with a dominant negative effect on wild type (WT) channels. Finally, KV7 channels present interesting targets for new therapeutic approaches to diseases caused by neuronal hyperexcitability, such as epilepsy, neuropathic pain, and migraine. The molecular mechanism of KV7 activation by retigabine, which is in phase III clinical testing to treat pharmacoresistant focal epilepsies, has been recently elucidated as a stabilization of the open conformation by binding to the pore region. [ABSTRACT FROM AUTHOR]

Epileptic nystagmus (EN) is characterized by repetitive eye movements as a symptom of seizure activity. Two cases of EN are reported including ictal EEG, video recordings and MRI. In addition, we review the published cases and pathophysiological background of EN. The cardinal cortical region for EN is located at the junction of Brodmann areas 19/37/39 correlating with the main epileptogenic region observed in the analyzed cases. [ABSTRACT FROM AUTHOR]

Cortical spreading depression (CSD), a wave of depolarization followed by depression of cortical activity, is a pathophysiological process implicated in migraine with aura and various other brain pathologies, such as ischemic stroke and traumatic brain injury. To gain insight into the pathophysiology of CSD, we generated a mouse model for a severe monogenic subtype of migraine with aura, familial hemiplegic migraine type 3 (FHM3). FHM3 is caused by mutations in SCN1A, encoding the voltage-gated Na+ channel NaV1.1 predominantly expressed in inhibitory interneurons. Homozygous Scn1aL1649Q knock-in mice died prematurely, whereas heterozygous mice had a normal lifespan. Heterozygous Scn1aL1649Q knock-in mice compared with WT mice displayed a significantly enhanced susceptibility to CSD. We found L1649Q to cause a gain-of-function effect with an impaired Na+ -channel inactivation and increased ramp Na+ currents leading to hyperactivity of fast-spiking inhibitory interneurons. Brain slice recordings using K+ -sensitive electrodes revealed an increase in extracellular K+ in the early phase of CSD in heterozygous mice, likely representing the mechanistic link between interneuron hyperactivity and CSD initiation. The neuronal phenotype and premature death of homozygous Scn1aL1649Q knock-in mice was partially rescued by GS967, a blocker of persistent Na+ currents. Collectively, our findings identify interneuron hyperactivity as a mechanism to trigger CSD. [ABSTRACT FROM AUTHOR]

• First evidence that quantum sensors (optically pumped magnetometer OPM), can non-invasively detect fasciculations in neuromuscular patients. • Proposal of the necessary technical solutions to detect other forms of pathological spontaneous activity. • Introduction of magnetomyography as a new clinical neurophysiological diagnostic tool. This proof-of-principle-study evaluated the extent to which spontaneous activity (SA) of the muscle can be detected via non-invasive magnetomyography (MMG) with optically pumped magnetometers (OPM). Five patients, who together exhibited all forms of SA (fibrillations, positive sharp waves, fasciculations, myotonic discharges, complex-repetitive discharges) with conventional needle electromyography (EMG), were studied by OPM-MMG and simultaneous surface EMG (sEMG) while at rest, during light muscle activation, and when a muscle stretch reflex was elicited. Three healthy subjects were measured as controls. SA was considered apparent in the OPM-MMG if a signal could be visually detected that corresponded in shape and frequency to the SA in the respective needle EMG. SA in the context of fasciculations could be detected in 2 of 5 patients by simultaneous OPM-MMG/sEMG. Other forms of SA could not be detected at rest, during light muscle activation, or after provocation of a muscle stretch reflex. Results show that fasciculations could be detected non-invasively via a new method (OPM). We show that other forms of SA are not detectable with current OPM and propose necessary technical solutions to overcome this circumstance. Our results motivate to pursue OPM-MMG as a new clinical neurophysiological diagnostic. [ABSTRACT FROM AUTHOR]

PRUNE1 is linked to a wide range of neurodevelopmental and neurodegenerative phenotypes. Multiple pathogenic missense and stop‐gain PRUNE1 variants were identified in its DHH and DHHA2 phosphodiesterase domains. Conversely, a single splice alteration was previously reported. We investigated five patients from two unrelated consanguineous Sudanese families with an inherited severe neurodevelopmental disorder using whole‐exome sequencing coupled with homozygosity mapping, segregation, and haplotype analysis. We identified a founder haplotype transmitting a homozygous canonical splice‐donor variant (NM_021222.3:c.132+2T > C) in intron 2 of PRUNE1 segregated with the phenotype in all the patients. This splice variant possibly results in an in‐frame deletion in the DHH domain or premature truncation of the protein. The phenotypes of the affected individuals showed phenotypic similarities characterized by remarkable pyramidal dysfunction and prominent extrapyramidal features (severe dystonia and bradykinesia). In conclusion, we identified a novel founder variant in PRUNE1 and corroborated abnormal splicing events as a disease mechanism in PRUNE1‐related disorders. Given the phenotypes' consistency coupled with the founder effect, canonical and cryptic PRUNE1 splice‐site variants should be carefully evaluated in patients presenting with prominent dystonia and pyramidal dysfunction. [ABSTRACT FROM AUTHOR]

Objective: Resistance to antiseizure medications (ASMs) is one of the major concerns in the treatment of epilepsy. Despite the increasing number of ASMs available, the proportion of individuals with drug‐resistant epilepsy remains unchanged. In this study, we aimed to investigate the role of rare genetic variants in ASM resistance. Methods: We performed exome sequencing of 1,128 individuals with non‐familial non‐acquired focal epilepsy (NAFE) (762 non‐responders, 366 responders) and were provided with 1,734 healthy controls. We undertook replication in a cohort of 350 individuals with NAFE (165 non‐responders, 185 responders). We performed gene‐based and gene‐set‐based kernel association tests to investigate potential enrichment of rare variants in relation to drug response status and to risk for NAFE. Results: We found no gene or gene set that reached genome‐wide significance. Yet, we identified several prospective candidate genes – among them DEPDC5, which showed a potential association with resistance to ASMs. We found some evidence for an enrichment of truncating variants in dominant familial NAFE genes in our cohort of non‐familial NAFE and in association with drug‐resistant NAFE. Interpretation: Our study identifies potential candidate genes for ASM resistance. Our results corroborate the role of rare variants for non‐familial NAFE and imply their involvement in drug‐resistant epilepsy. Future large‐scale genetic research studies are needed to substantiate these findings. [ABSTRACT FROM AUTHOR]

Nodding Syndrome is a poorly understood epilepsy disorder in sub-Saharan Africa. The cause(s) of the disease, risk factors and long-term outcomes are unknown or controversial. The objectives of this study were to describe the long-term clinical course and treatment outcomes of individuals suffering from Nodding Syndrome. In addition, we aimed to provide a comprehensive characterization of the epileptological and social features of patients with Nodding Syndrome. From 11/2014 to 4/2015, we conducted a hospital-based, cross-sectional and observational study in Mahenge, Tanzania. Seventy-eight individuals (female:male ratio: 40:38, age at examination: 21.1 ± 6.39 (SD) years) have been enrolled, of whom 38 (49%) had also been examined in 2005 and in 2009. The 10-year clinical course analysis of this revisited subgroup revealed a calculated case fatality of 0.8–2.3%. Progressive physical or cognitive deterioration has not been observed in any of the 78 individuals and more than half of the people studied (38/69; 55%) managed to live and work independently. 14/78 individuals (18%) were seizure-free, (no head nodding, no other seizure types), 13 of whom were taking antiseizure medication. Phenytoin was more effective against head nodding seizures (14/19 (74%)) than monotherapy with other available antiseizure medication (phenobarbitone 12/25 (48%) and carbamazepine 7/22 (32%), p = 0.02, chi-square test). Our ten-year clinical outcome data show that Nodding Syndrome is not a fatal disease, however, the response to treatment is worse than in epilepsy patients in general. Phenytoin may be more effective than carbamazepine and phenobarbitone, but further studies are needed to confirm this observation. • Nodding Syndrome in Tanzania is usually non-progressive and non-fatal. • The case fatality rate seems to be even lower than for epilepsy per se in Africa. • >50% of patients with Nodding Syndrome managed to live independently. • Phenytoin was highly effective against head nodding seizures. [ABSTRACT FROM AUTHOR]