Gating of Long-Term Potentiation by Nicotinic Acetylcholine Receptors at the Cerebellum Input Stage

The brain needs mechanisms able to correlate plastic changes with local circuit activity and internal functional states. At the cerebellum input stage, uncontrolled induction of long-term potentiation or depression (LTP or LTD) between mossy fibres and granule cells can saturate synaptic capacity and impair cerebellar functioning, which suggests that neuromodulators are required to gate plasticity processes. Cholinergic systems innervating the cerebellum are thought to enhance procedural learning and memory. Here we show that a specific subtype of acetylcholine receptors, the α7-nAChRs, are distributed both in cerebellar mossy fibre terminals and granule cell dendrites and contribute substantially to synaptic regulation. Selective α7-nAChR activation enhances the postsynaptic calcium increase, allowing weak mossy fibre bursts, which would otherwise cause LTD, to generate robust LTP. The local microperfusion of α7-nAChR agonists could also lead to in vivo switching of LTD to LTP following sensory stimulation of the whisker pad. In the cerebellar flocculus, α7-nAChR pharmacological activation impaired vestibulo-ocular-reflex adaptation, probably because LTP was saturated, preventing the fine adjustment of synaptic weights. These results show that gating mechanisms mediated by specific subtypes of nicotinic receptors are required to control the LTD/LTP balance at the mossy fibre-granule cell relay in order to regulate cerebellar plasticity and behavioural adaptation

Efficacy of lacosamide in neonatal-onset super-refractory status epilepticus: a case report

: We report the case of a previously healthy newborn who developed super-refractory status epilepticus after Group B streptococcal meningoencephalitis. After administration of first-, second- and third-line anticonvulsants without resolution of status epilepticus, we started intravenous lacosamide as adjunctive therapy to phenobarbital, phenytoin and continuous infusion of ketamine and midazolam. After administration of lacosamide, we observed a clear-cut improvement in the neurological clinical condition coupled with seizure control on continuous video-EEG monitoring, even after suspension of all other medications except for phenobarbital. No adverse effects ascribable to lacosamide were reported. The available data regarding the use of lacosamide for status epilepticus in adults and children are promising, although there is as yet only anecdotal evidence for neonatal status epilepticus. Its lack of potential interactions, good tolerability and the option of intravenous use lend to its appeal as treatment for status epilepticus. To the best of our knowledge, this is one of the first reported cases of effective lacosamide infusion in neonatal-onset super-refractory status epilepticus. This evidence should prompt further investigation on efficacy and safety of lacosamide to support its use in this population

KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum

Item does not contain fulltex

Functional Effects of Epilepsy Associated <i>KCNT1</i> Mutations Suggest Pathogenesis via Aberrant Inhibitory Neuronal Activity

KCNT1 (K+ channel subfamily T member 1) is a sodium-activated potassium channel highly expressed in the nervous system which regulates neuronal excitability by contributing to the resting membrane potential and hyperpolarisation following a train of action potentials. Gain of function mutations in the KCNT1 gene are the cause of neurological disorders associated with different forms of epilepsy. To gain insights into the underlying pathobiology we investigated the functional effects of 9 recently published KCNT1 mutations, 4 previously studied KCNT1 mutations, and one previously unpublished KCNT1 variant of unknown significance. We analysed the properties of KCNT1 potassium currents and attempted to find a correlation between the changes in KCNT1 characteristics due to the mutations and severity of the neurological disorder they cause. KCNT1 mutations identified in patients with epilepsy were introduced into the full length human KCNT1 cDNA using quick-change site-directed mutagenesis protocol. Electrophysiological properties of different KCNT1 constructs were investigated using a heterologous expression system (HEK293T cells) and patch clamping. All mutations studied, except T314A, increased the amplitude of KCNT1 currents, and some mutations shifted the voltage dependence of KCNT1 open probability, increasing the proportion of channels open at the resting membrane potential. The T314A mutation did not affect KCNT1 current amplitude but abolished its voltage dependence. We observed a positive correlation between the severity of the neurological disorder and the KCNT1 channel open probability at resting membrane potential. This suggests that gain of function KCNT1 mutations cause epilepsy by increasing resting potassium conductance and suppressing the activity of inhibitory neurons. A reduction in action potential firing in inhibitory neurons due to excessively high resting potassium conductance leads to disinhibition of neural circuits, hyperexcitability and seizures

Sleep disturbances in SCN8A‐related disorders

Objectives: People with neurodevelopmental disorders frequently experience sleep disturbances, negatively impairing their quality of life. We aimed to determine the prevalence and nature of sleep disturbances in patients with SCN8A‐related disorders. Methods: Through a collaborative network of caregivers and clinicians, we collected data about epilepsy, cognitive/motor abilities, medications, and relevant comorbidities of patients harboring a pathogenic SCN8A variant. The Sleep Disturbance Scale for Children (SDSC), the Children's Sleep Habits Questionnaire (CSHQ‐22‐items), and the Pediatric Daytime Sleepiness Scale (PDSS) were distributed and evaluated by factor scores and Composite Sleep Index. Video‐EEG‐polysomnographic recordings were performed. Results: We enrolled 47 patients (age range: 2–39 years), whose phenotypes ranged from SCN8A‐DEE to intellectual disability without epilepsy. In the majority of them (82%), sleep disturbances were reported and/or observed at the SDSC. The most frequent were difficulty in initiating and maintaining sleep (64%), followed by sleep breathing disorder (43%), sleep–wake transition disorder (34%), and daytime sleepiness (34%). Sleep disturbances were more frequent in patients with severe DEE (96%) and ongoing seizures (93%) and were more severe in patients with sleep‐related seizures. The CSHQ and PDSS confirmed difficulty in initiating and maintaining sleep. Polysomnographic recordings (9 patients/20 nights) showed an altered sleep structure in 95%, with frequent arousals, mainly not seizure related. Significance: More than 80% of patients with SCN8A‐related disorders presented with sleep disturbances, primarily consisting of sleep instability with difficulty of initiating and maintaining sleep. Animal studies showed sleep disturbances in SCN8A‐ and SCN1A‐Dravet Syndrome mice models, suggesting a role for voltage‐gated sodium channels in the regulation of sleep. Understanding the effects of SCN8A dysfunction on sleep stability may guide future therapeutic efforts to alleviate this often distressing symptom also in seizure‐free SCN8A patients. Plain language summary: In this study, we analyzed sleep disturbances in patients with disorders related to a genetic mutation in the gene SCN8A. We found that the majority of the patients experienced sleep disturbances, mainly consisting in difficulty of initiating and maintaining sleep. Sleep disturbances were more frequent in patients with severe cognitive impairment and active epilepsy and more severe in patients with seizures during sleep

NA2RE is reliable but aims for improvement: an answer to Vamberger and Fritz (2018)

A recent paper has suggested that NA2RE, the New Atlas of Amphibians and Reptiles of Europe, does not provide a reliable basis for ecological niche modelling studies due to errors flagging introductions and missing data for the native range of the pond turtle genus Emys. We point out that the original NA2RE paper already acknowledged that it was not aimed for fine-scale ecological distribution modelling and that it had the objective of stimulating research for improving the maps. New works now complement the Atlas in improving the coverage and providing new distribution maps for species within species complex. Moreover, we stress that the NA2RE web platform at present hosts only the distribution data compiled in 2014 from different sources, using the taxonomy adopted by the authors at the time. As with any large database, it is advisable that these data are carefully evaluated and quality-filtered before their use in scientific studies. We defend the reliability of the NA2RE web platform as the currently most comprehensive resource for the comparative chorological study of amphibians and reptiles in Europe, and encourage publication of updates and additions following the most recent taxonomic changes, to continuously improve this database and the Atlas.The authors thank the Societas Europaea Herpetologica for funding the NA2RE project. NS is supported by an IF contract (IF/01526/2013) from Fundação para a Ciência e a Tecnologia (Portugal)

Natural history study of STXBP1-developmental and epileptic encephalopathy into adulthood

BACKGROUND AND OBJECTIVES: Pathogenic STXBP1 variants cause a severe early-onset developmental and epileptic encephalopathy (STXBP1-DEE). We aimed to investigate the natural history of STXBP1-DEE in adults focusing on seizure evolution, the presence of movement disorders, and the level of functional (in)dependence. METHODS: In this observational study, patients with a minimum age of 18 years carrying a (likely) pathogenic STXBP1 variant were recruited through medical genetics departments and epilepsy centers. Treating clinicians completed clinical questionnaires and performed semistructured video examinations while performing tasks from the (modified) Unified Parkinson Disease Rating Scale when possible. RESULTS: Thirty adult patients were included for summary statistics, with video recordings available for 19 patients. The median age at last follow-up was 24 years (range 18–58 years). All patients had epilepsy, with a median onset age of 3.5 months. At last follow-up, 80% of adults had treatment-resistant seizures despite long periods of seizure freedom in 37%. Tonic-clonic, focal, and tonic seizures were most frequent in adults. Epileptic spasms, an unusual feature beyond infancy, were present in 3 adults. All individuals had developmental impairment. Periods of regression were present in 59% and did not always correlate with flare-ups in seizure activity. Eighty-seven percent had severe or profound intellectual disability, 42% had autistic features, and 65% had significant behavioral problems. Video examinations showed gait disorders in all 12 patients able to walk, including postural abnormalities with external rotation of the feet, broad-based gait, and asymmetric posture/dystonia. Tremor, present in 56%, was predominantly of the intention/action type. Stereotypies were seen in 63%. Functional outcome concerning mobility was variable ranging from independent walking (50%) to wheelchair dependence (39%). Seventy-one percent of adults were nonverbal, and all were dependent on caregivers for most activities of daily living. DISCUSSION: STXBP1-DEE warrants continuous monitoring for seizures in adult life. Periods of regression are more frequent than previously established and can occur into adulthood. Movement disorders are often present and involve multiple systems. Although functional mobility is variable in adulthood, STXBP1-DEE frequently leads to severe cognitive impairments and a high level of functional dependence. Understanding the natural history of STXBP1-DEE is important for prognostication and will inform future therapeutic trials

Natural History Study of STXBP1-Developmental and Epileptic Encephalopathy Into Adulthood

Background and Objectives Pathogenic STXBP1 variants cause a severe early-onset developmental and epileptic encephalopathy (STXBP1-DEE). We aimed to investigate the natural history of STXBP1-DEE in adults focusing on seizure evolution, the presence of movement disorders, and the level of functional (in)dependence. Methods In this observational study, patients with a minimum age of 18 years carrying a (likely) pathogenic STXBP1 variant were recruited through medical genetics departments and epilepsy centers. Treating clinicians completed clinical questionnaires and performed semistructured video examinations while performing tasks from the (modified) Unified Parkinson Disease Rating Scale when possible. Results Thirty adult patients were included for summary statistics, with video recordings available for 19 patients. The median age at last follow-up was 24 years (range 18-58 years). All patients had epilepsy, with a median onset age of 3.5 months. At last follow-up, 80% of adults had treatment-resistant seizures despite long periods of seizure freedom in 37%. Tonic-clonic, focal, and tonic seizures were most frequent in adults. Epileptic spasms, an unusual feature beyond infancy, were present in 3 adults. All individuals had developmental impairment. Periods of regression were present in 59% and did not always correlate with flare-ups in seizure activity. Eighty-seven percent had severe or profound intellectual disability, 42% had autistic features, and 65% had significant behavioral problems. Video examinations showed gait disorders in all 12 patients able to walk, including postural abnormalities with external rotation of the feet, broad-based gait, and asymmetric posture/dystonia. Tremor, present in 56%, was predominantly of the intention/action type. Stereotypies were seen in 63%. Functional outcome concerning mobility was variable ranging from independent walking (50%) to wheelchair dependence (39%). Seventy-one percent of adults were nonverbal, and all were dependent on caregivers for most activities of daily living. Discussion STXBP1-DEE warrants continuous monitoring for seizures in adult life. Periods of regression are more frequent than previously established and can occur into adulthood. Movement disorders are often present and involve multiple systems. Although functional mobility is variable in adulthood, STXBP1-DEE frequently leads to severe cognitive impairments and a high level of functional dependence. Understanding the natural history of STXBP1-DEE is important for prognostication and will inform future therapeutic trials