Childhood epilepsy is frequently associated with neurobehavioral comorbidities such as depression, anxiety, cognitive impairments, and social dysfunction, as revealed by both clinical and experimental studies. Despite extensive neurophysiological research, behavioral studies in developing animals remain limited and underreported. Here, we review the behavioral impact of early-life seizures (ELSs) in commonly used rat models in developmental studies. We outline suitable tests and provide guidance on how traditional tests should be adapted and interpreted in this context. Finally, we examine factors influencing behavioral analysis in developmental studies, exploring confounding variables and offering strategies to minimize their impact.
- MeSH
- Behavior, Animal physiology MeSH
- Comorbidity MeSH
- Rats MeSH
- Humans MeSH
- Disease Models, Animal * MeSH
- Animals, Newborn MeSH
- Seizures * epidemiology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
- MeSH
- Affective Symptoms etiology pathology MeSH
- Automatism etiology MeSH
- Epileptic Syndromes pathology MeSH
- Cognition Disorders etiology MeSH
- Humans MeSH
- Motor Disorders etiology MeSH
- Autonomic Nervous System Diseases etiology pathology MeSH
- Consciousness Disorders etiology pathology MeSH
- Signs and Symptoms * MeSH
- Seizures * classification pathology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
BACKGROUND: Definitions are essential for effective communication and discourse, particularly in science. They allow the shared understanding of a thought or idea, generalization of knowledge, and comparison across scientific investigation. The current terms describing olfactory dysfunction are vague and overlapping. SUMMARY: As a group of clinical olfactory researchers, we propose the standardization of the terms "dysosmia," "anosmia," "hyposmia," "normosmia," "hyperosmia," "olfactory intolerance," "parosmia," and "phantosmia" (or "olfactory hallucination") in olfaction-related communication, with specific definitions in this text. KEY MESSAGES: The words included in this paper were determined as those which are most frequently used in the context of olfactory function and dysfunction, in both clinical and research settings. Despite widespread use in publications, however, there still exists some disagreement in the literature regarding the definitions of terms related to olfaction. Multiple overlapping and imprecise terms that are currently in use are confusing and hinder clarity and universal understanding of these concepts. There is a pressing need to have a unified agreement on the definitions of these olfactory terms by researchers working in the field of chemosensory sciences. With the increased interest in olfaction, precise use of these terms will improve the ability to integrate and advance knowledge in this field.
We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1-3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested gain-of-function variant had either focal (n = 97, Groups 1-3) or unclassifiable (n = 39) epilepsy, whereas 34 individuals with a loss-of-function variant had either generalized (n = 14), no (n = 11) or unclassifiable (n = 6) epilepsy; only three had developmental and epileptic encephalopathy. Computational modelling in the gain-of-function group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. Gain-of-function variant carriers responded significantly better to sodium channel blockers than to other anti-seizure medications, and the same applied for all individuals in Groups 1-3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of loss-of-function variant carriers and the extent of the electrophysiological dysfunction of the gain-of-function variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that sodium channel blockers present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life.
- MeSH
- Sodium Channel Blockers therapeutic use MeSH
- Epilepsy, Generalized * drug therapy genetics MeSH
- Epileptic Syndromes * drug therapy genetics MeSH
- Genetic Association Studies MeSH
- Infant MeSH
- Humans MeSH
- Intellectual Disability * genetics MeSH
- Mutation MeSH
- NAV1.6 Voltage-Gated Sodium Channel * genetics MeSH
- Prognosis MeSH
- Seizures drug therapy genetics MeSH
- Check Tag
- Infant MeSH
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
Cíl: Komplexní přehled neurologických příznaků u osob nakažených virem SARS-CoV-2 v rámci ČR dosud není znám. Naším cílem proto bylo zjistit zastoupení, četnost a trvání nových neurologických příznaků, které se objevily v souvislosti s onemocněním COVID-19 u dospělých osob na území celé ČR. Metodika: Pro tyto účely byl vyvinut online dotazník Neurocovid. Předkládáme vyhodnocená data z období 1. 6. až 30. 8. 2021. Výsledky: Elektronický dotazník vyplnilo 1 012 osob ve věkovém rozmezí 18–79 let (průměrný věk 45,6 ±12,88 let, medián 45 let, 65 % žen). Pokrytí krajů ČR většinově odpovídalo demografickému rozložení obyvatelstva. Nejčastěji udávané nové neurologické příznaky asociované s onemocněním COVID-19 zahrnovaly kognitivní změny (pomalé myšlení, poruchy paměti, nesoustředěnost, problémy s řečí a dezorientace), přičemž alespoň jeden z těchto příznaků uvedlo 70 % účastníků. Obdobně četné byly poruchy spánku, které se objevily u více než 70 % osob. U obou skupin příznaků bylo zároveň časté dlouhodobé trvání. Kognitivní změny přetrvávaly déle než 3 měsíce u 46 %, poruchy spánku u 72 %. Častým neurologickým příznakem byla rovněž porucha čichu a/nebo chuti, kterou pociťovalo 67 % účastníků. K dalším obtížím patřily závratě (32 %), brnění na těle/končetinách (27 %), nemotornost nebo ztráta stability při chůzi (20 %), tinnitus (15 %), porucha zraku (14 %) a třes (13 %). Nebyla zjištěna žádná souvislost mezi tíží akutního onemocnění COVID-19 a počtem nebo typem nových neurologických příznaků. Závěr: Tento celostátní online průzkum na reprezentativní skupině obyvatel ČR potvrdil široké spektrum neurologických příznaků v souvislosti s onemocněním COVID-19. Dotazník Neurocovid je vhodné šířit a vyplňovat k dalšímu zvyšování kvality dat a sledování problematiky v čase.
Aim: There are no broad-scale data available on the presence of neurological symptoms in persons afflicted by COVID-19 in the Czech Republic. Therefore, our goal was to establish the incidence, frequency and duration of new neurological symptoms present in the adult population in the Czech Republic in connection with the COVID-19 disease. Methods: For this purpose, an online questionnaire Neurocovid was developed. The data presented were collected during the period of June 6–August 30, 2021. Results: The questionnaire was fi lled in by 1,012 individuals aged between 18–79 years (average age 45.6 ±12.88 years, median age 45 years, 65% female). Regional coverage of the Czech Republic mostly corresponded with the demographic distribution of the population. The most common new neurological symptoms that occurred in connection with COVID-19 were cognitive changes such as “slow thinking”, memory difficulties, lack of concentration, speech disorders and disorientation. About 70% of the participants reported at least one of these symptoms. Similar frequency was noted for sleep disorders which were present in more than 70% of the participants. Both groups of symptoms also had a higher tendency to persist long-term. Cognitive changes persisted for over 3 months in 46%, whereas sleep disorders in 72%. Another frequent neurological symptom was olfactory/gustatory dysfunction, which was observed by 67% of the participants. Other symptoms included vertigo (32%), tingling in the body/ limbs (27%), clumsiness/loss of stability while walking (20%), tinnitus (15%), issues with eyesight (14%), and tremor (13%). We did not find a correlation between the severity of the acute phase of the COVID-19 disease and the number or type of new neurological symptoms. Conclusion: This nation-wide online survey of a representative group of the Czech population confirmed a variety of neurological symptoms that occur in connection with COVID-19. The Neurocovid questionnaire should be distributed further to increase data quality and provide an insight into the long-term development of these symptoms.
- Keywords
- postcovidový syndrom,
- MeSH
- COVID-19 * complications MeSH
- Cognition Disorders etiology MeSH
- Humans MeSH
- Neurologic Manifestations * MeSH
- Sleep Wake Disorders etiology MeSH
- Surveys and Questionnaires MeSH
- SARS-CoV-2 MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency usually presents as a severe neonatal disease. This study aimed to characterize natural history, biological and molecular data, and response to treatment of patients with late-onset MTHFR deficiency. The patients were identified through the European Network and Registry for Homocystinuria and Methylation Defects and the Adult group of the French Society for Inherited Metabolic Diseases; data were retrospectively colleted. To identify juvenile to adult-onset forms of the disease, we included patients with a diagnosis established after the age of 10 years. We included 14 patients (median age at diagnosis: 32 years; range: 11-54). At onset (median age: 20 years; range 9-38), they presented with walking difficulties (n = 8), cognitive decline (n = 3) and/or seizures (n = 3), sometimes associated with mild mental retardation (n = 6). During the disease course, symptoms were almost exclusively neurological with cognitive dysfunction (93%), gait disorders (86%), epilepsy (71%), psychiatric symptoms (57%), polyneuropathy (43%), and visual deficit (43%). Mean diagnostic delay was 14 years. Vascular events were observed in 28% and obesity in 36% of the patients. One patient remained asymptomatic at the age of 55 years. Upon treatment, median total homocysteine decreased (from 183 μmol/L, range 69-266, to 90 μmol/L, range 20-142) and symptoms improved (n = 9) or stabilized (n = 4). Missense pathogenic variants in the C-terminal regulatory domain of the protein were over-represented compared to early-onset cases. Residual MTHFR enzymatic activity in skin fibroblasts (n = 4) was rather high (17%-58%). This series of patients with late-onset MTHFR deficiency underlines the still unmet need of a prompt diagnosis of this treatable disease.
- MeSH
- Child MeSH
- Adult MeSH
- Epilepsy diagnosis pathology MeSH
- Homocystinuria diagnosis pathology MeSH
- Middle Aged MeSH
- Humans MeSH
- Intellectual Disability diagnosis pathology MeSH
- Methylenetetrahydrofolate Reductase (NADPH2) deficiency MeSH
- Adolescent MeSH
- Young Adult MeSH
- Delayed Diagnosis MeSH
- Psychotic Disorders diagnosis pathology MeSH
- Retrospective Studies MeSH
- Muscle Spasticity diagnosis pathology MeSH
- Age of Onset MeSH
- Seizures diagnosis pathology MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
- Research Support, Non-U.S. Gov't MeSH
Hallucinatory experiences (HEs) can be pronounced in psychosis, but similar experiences also occur in nonclinical populations. Cognitive mechanisms hypothesized to underpin HEs include dysfunctional source monitoring, heightened signal detection, and impaired attentional processes. Using data from an international multisite study on non-clinical participants (N = 419), we described the overlap between two sets of variables - one measuring cognition and the other HEs - at the level of individual items. We used a three-step method to extract and examine item-specific signal, which is typically obscured when summary scores are analyzed using traditional methodologies. The three-step method involved: (1) constraining variance in cognition variables to that which is predictable from HE variables, followed by dimension reduction, (2) determining reliable HE items using split-halves and permutation tests, and (3) selecting cognition items for interpretation using a leave-one-out procedure followed by repetition of Steps 1 and 2. The results showed that the overlap between HEs and cognition variables can be conceptualized as bi-dimensional, with two distinct mechanisms emerging as candidates for separate pathways to the development of HEs: HEs involving perceptual distortions on one hand (including voices), underpinned by a low threshold for signal detection in cognition, and HEs involving sensory overload on the other hand, underpinned by reduced laterality in cognition. We propose that these two dimensions of HEs involving distortions/liberal signal detection, and sensation overload/reduced laterality may map onto psychosis-spectrum and dissociation-spectrum anomalous experiences, respectively.
- MeSH
- Hallucinations * MeSH
- Cognition MeSH
- Humans MeSH
- Multivariate Analysis MeSH
- Attention MeSH
- Psychotic Disorders * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
OBJECTIVE: Verbal memory dysfunction is common in focal, drug-resistant epilepsy (DRE). Unfortunately, surgical removal of seizure-generating brain tissue can be associated with further memory decline. Therefore, localization of both the circuits generating seizures and those underlying cognitive functions is critical in presurgical evaluations for patients who may be candidates for resective surgery. We used intracranial electroencephalographic (iEEG) recordings during a verbal memory task to investigate word encoding in focal epilepsy. We hypothesized that engagement in a memory task would exaggerate local iEEG feature differences between the seizure onset zone (SOZ) and neighboring tissue as compared to wakeful rest ("nontask"). METHODS: Ten participants undergoing presurgical iEEG evaluation for DRE performed a free recall verbal memory task. We evaluated three iEEG features in SOZ and non-SOZ electrodes during successful word encoding and compared them with nontask recordings: interictal epileptiform spike (IES) rates, power in band (PIB), and relative entropy (REN; a functional connectivity measure). RESULTS: We found a complex pattern of PIB and REN changes in SOZ and non-SOZ electrodes during successful word encoding compared to nontask. Successful word encoding was associated with a reduction in local electrographic functional connectivity (increased REN), which was most exaggerated in temporal lobe SOZ. The IES rates were reduced during task, but only in the non-SOZ electrodes. Compared with nontask, REN features during task yielded marginal improvements in SOZ classification. SIGNIFICANCE: Previous studies have supported REN as a biomarker for epileptic brain. We show that REN differences between SOZ and non-SOZ are enhanced during a verbal memory task. We also show that IESs are reduced during task in non-SOZ, but not in SOZ. These findings support the hypothesis that SOZ and non-SOZ respond differently to task and warrant further exploration into the use of cognitive tasks to identify functioning memory circuits and localize SOZ.
- MeSH
- Electroencephalography MeSH
- Electrocorticography MeSH
- Epilepsies, Partial * surgery MeSH
- Humans MeSH
- Brain MeSH
- Drug Resistant Epilepsy * surgery MeSH
- Seizures MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
BACKGROUND: Primary hypomagnesemia with secondary hypocalcemia (HSH) is a rare genetic disorder. Dysfunctional transient receptor potential melastatin 6 causes impaired intestinal absorption of magnesium, leading to low serum levels accompanied by hypocalcemia. Typical signs at initial manifestation are generalized seizures, tetany, and/or muscle spasms. CASE REPORT: We present a 5 w/o female manifesting tonic-clonic seizures. Laboratory tests detected severe hypomagnesemia and hypocalcemia. The molecular genetic analysis revealed two novel mutations within the TRPM6 gene c.3308dupC (p.Pro1104Thrfs*28) (p.P1104Tfs*28) and c.3958C>T (p.Gln1302*) (p.Q1302*) and the patient was successfully treated with Mg supplementation. CONCLUSION: Ion disbalance should be taken into account in the differential diagnosis of infantile seizures. Accurate diagnosis of HSH together with appropriate treatment are crucial to prevent irreversible neurological outcomes.
- MeSH
- Magnesium MeSH
- Hypercalciuria MeSH
- Hypocalcemia * genetics MeSH
- TRPM Cation Channels * genetics MeSH
- Humans MeSH
- Mutation MeSH
- Magnesium Deficiency * congenital genetics MeSH
- Nephrocalcinosis MeSH
- Renal Tubular Transport, Inborn Errors MeSH
- Seizures genetics MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
Defects in DNA single-strand break repair (SSBR) are linked with neurological dysfunction but the underlying mechanisms remain poorly understood. Here, we show that hyperactivity of the DNA strand break sensor protein Parp1 in mice in which the central SSBR protein Xrcc1 is conditionally deleted (Xrcc1Nes-Cre ) results in lethal seizures and shortened lifespan. Using electrophysiological recording and synaptic imaging approaches, we demonstrate that aberrant Parp1 activation triggers seizure-like activity in Xrcc1-defective hippocampus ex vivo and deregulated presynaptic calcium signalling in isolated hippocampal neurons in vitro. Moreover, we show that these defects are prevented by Parp1 inhibition or deletion and, in the case of Parp1 deletion, that the lifespan of Xrcc1Nes-Cre mice is greatly extended. This is the first demonstration that lethal seizures can be triggered by aberrant Parp1 activity at unrepaired SSBs, highlighting PARP inhibition as a possible therapeutic approach in hereditary neurological disease.
- MeSH
- DNA-Binding Proteins * genetics metabolism MeSH
- DNA MeSH
- Mice MeSH
- Neurons metabolism MeSH
- DNA Repair genetics MeSH
- Poly (ADP-Ribose) Polymerase-1 genetics metabolism MeSH
- Calcium * MeSH
- Seizures genetics MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
