Academic literature on the topic 'Epilepsy and sleep'

A close relationship exists between sleep and epilepsy. While many forms of epilepsy may be influenced by the sleep-wake cycle, this phenomenon is particularly evident in frontal lobe epilepsy where affected individuals may experience seizures exclusively during sleep (nocturnal frontal lobe epilepsy, NFLE). In this thesis, three aspects of the relationship between sleep and frontal lobe epilepsy are examined. Firstly, serotonergic neurotransmission across the human sleep-wake cycle was studied using the novel PET ligand l8F-MPPF, a serotonergic 5HT)A receptor radioligand sensitive to endogenous serotonin release. Fourteen individuals with narcolepsy underwent 18F-MPPF PET scans during sleep and wakefulness. The study demonstrated a 13% increase in 18F-MPPF binding potential (p < 0.01) during sleep, indicating a reduction in serotoninergic neurotransmission, in line with existing animal data. Secondly, the characterisation of benign, non-epileptic parasomnias and their distinction from nocturnal frontal lobe seizures was addressed in two studies. The first comprised an analysis of the historical features of these conditions, and included the development and validation of a clinical scale for the diagnosis of nocturnal events. The second comprised a detailed semiological analysis of a series of parasomnias recorded on video-EEG monitoring, and a statistical comparison with seizures in NFLE. Although similarities between NFLE and parasomnias were observed, the results provide an evidence base for the confident distinction of these disorders. Finally, the familial form of NFLE (autosomal dominant nocturnal frontal lobe epilepsy, ADNFLE) is associated with mutations in genes for nicotinic acetylcholine receptor subunits, but recognised mutations account for only a minority of reported cases. The last study presented here is a clinical and genetic analysis of two large families with an unusually severe ADNFLE phenotype. Affected individuals had refractory epilepsy and increased rates of mental retardation and psychiatric disorders and, in one family, linkage studies suggest a previously unrecognised underlying mechanism.

Objective: Given the well-established association between epilepsy and sleep disturbance and the evidence suggesting the importance of sleep in memory consolidation, there is reason to investigate the relationship between sleep and rate of forgetting in children with epilepsy. This study aimed to investigate the relationship between sleep and forgetting in children with Genetic Generalised Epilepsy (GGE). Methods: Participants were 19 children with GGE (9-15 years old). Actigraphy, sleep diaries and standardised questionnaires were used to measure sleep over a week long period. Rate of forgetting was measured using neuropsychological tests at the beginning and end of the study week. Spearman’s correlation analysis was used to determine if poorer sleep was associated with poorer initial learning and rate of forgetting in verbal memory recall and recognition. Results: No association was found between sleep efficiency or duration and rate of forgetting. Measures of sleep disturbance were mixed, with sleep onset latency found to be associated with rate of forgetting on the Word Lists test. However, increased wake after sleep onset was associated with decreased rate of forgetting. Conclusions: Whilst there was limited evidence of a relationship between some actigraphic sleep parameters and rate of forgetting for verbal information, the results were mixed and likely biased by the small sample size. There is need for further research with a larger sample to establish the nature of the relationship between sleep and rate of forgetting in children with GGE.

Sleep disorders in children provide a frequent cause for parents to seek medical care. If a child has several kinds of sleep disorders and (or) has another illness, their diagnosis and treatment typically become more complicated. Sleep disorders are a frequent comorbidity to epilepsy. In the clinical practice, synthetic melatonin is prescribed for treatment of sleep disorders in children with epilepsy. Clinical trials suggest that melatonin may shorten the duration to sleep onset and balance the sleep structure, leading to decrease in the number of epileptic attacks. However, the melatonin system in these trials has not been explored, and changes of the melatonin system in children with epilepsy are not yet understood. The main objectives of the present study were: i) to determine the most frequent kinds of sleep disorders in children with epilepsy; ii) to characterize the melatonin (MLT) system in children with epilepsy in detail: to describe full diurnal profile, to search correlation with anthropometric data, seizure characteristics (time, type of seizures, antiepileptic medications), as well as the other physiological circadian rhythms (body temperature, pulse, blood pressure). The study results have shown that sleep disorders were more frequent in the group of children with epilepsy (Sleep disorders scale for children (SDSC) (Bruni O et al, 1996)).The most frequent were: the disorders of excessive somnolence (DOES) and sleep - wake transition disorders (SWTD)... [to full text]<br>Vaikų miego sutrikimai – dažna problema, dėl kurios tėvai kreipiasi į gydytoją. Jei vaikui būdingi keli miego sutrikimai ir (ar) jis serga kita liga, tai diagnozuoti ir gydyti miego sutrikimus yra sudėtinga. Miego sutrikimams ir epilepsijai būdingas komorbidiškumas. Literatūros duomenimis, vaikams, sergantiems epilepsija, empiriškai skiriama sintetinių melatonino preparatų. Įrodyta, kad jie sutrumpina užmigimo laiką, reguliuoja miego struktūrą, todėl retėja epilepsijos priepuoliai. Tačiau epilepsija sergančių vaikų melatonino sistema dar nebuvo tiriama. Darbo tikslas – išsiaiškinti epilepsija sergančių vaikų dažniausius miego sutrikimus ir kankorėžinės liaukos hormono melatonino, jo metabolito 6-sulfatoksimelatonino (aMT6s) paros cirkadinio profilio ypatumus bei ryšį su epilepsijos formomis, priepuoliais, priepuolių laiku, vartojamais vaistais nuo epilepsijos (VNE) bei kitų fiziologinių rodiklių cirkadiniu ritmu (kūno temperatūros, širdies susitraukimų dažnio, arterinio kraujo spaudimo). Rezultatai parodė, kad epilepsija sergančių vaikų miego sutrikimų skalės (VMSS) rodikliai buvo aukštesni visuose miego sutrikimų pogrupiuose. Dažnesni buvo padidėjusio mieguistumo bei miego ir budrumo ritmo sutrikimai. Kontrolinėje ir sergančių epilepsija vaikų grupėse melatonino apykaita, išreikšta ekskrecijos metabolito aMT6s kiekis kūno svorio vienetui, turėjo neigiamą ryšį su amžiumi ir lytinės brandos stadija. Vaikų, sergančių epilepsija, cirkadinis melatonino sekrecijos ir ekskrecijos... [toliau žr. visą tekstą]

Cognitive impairment is the major co-morbidity in childhood epilepsy, and in many cases will have a larger long-term impact than the seizures themselves. However, the mechanisms contributing to this are poorly understood, precluding targetted intervention. Sleep is crucial for intelllectual functioning. Yet sleep in children with epilepsy, and its impact on intellectual function has scarcely been studied. This thesis aims to examine the structure and regulation of sleep in children with epilepsy, and to provide direct evidence of the impact of sleep on cognitive function by correlating neurophysiological characteristics with performance on sleep dependent neuropsychological tasks administered over the same interval as the sleep recorded. To examine sleep architecture in children with epilepsy, I developed a modified system for visual sleep scoring, taking into account nocturnal seizures and interictal activity. This was validated in a pilot sample, then applied to the scoring of 52 recordings from children with epilepsy. Based on established memory consolidation tasks and open-source psycholinguistic data, I developed and piloted a memory consolidation task battery suitable for testing school-aged English-speaking children, comprising parallel versions of a visuospatial and a verbal task. With these tools, I performed a prospective, within-subject comparison of memory retention across similar length intervals with or without sleep, in order to determine the contribution of sleep to memory consolidation. I compared results from patient (n=22) and healthy control (n=21) samples, finding – contrary to expectations – that sleep benefits memory consolidation in children with epilepsy to the same degree as controls. However, the benefit of sleep showed an inverse relationship to the nocturnal interictal discharge load. I also employed quantitative EEG analysis of slow wave activity to examine sleep homeostasis in patients with epilepsy, studying a retrospective sample (n=16) who had undergone partial sleep deprivation. Sleep homeostasis was fundamentally intact in these patients, who had similar clinical characteristics to the prospective sample. Findings from this thesis provide the first direct evidence that sleep benefits intellectual functioning in children with epilepsy, particularly where its structure and regulation is intact. Sleep-related memory consolidation may represent a compensatory mechanism, perhaps accounting for the relative cognitive preservation in this cohort of children with epilepsy with a structural aetiology, despite the early onset of seizures.

Il termine epilessia notturna del lobo frontale (NFLE) descrive un ampio gruppo di epilessie parziali presentanti origine eterogenea. Gli attacchi originano a livello del lobo frontale, solitamente durante la fase 2 del sonno, e sono caratterizzati da complessi cluster ipercinetici stereotipati. Circa il 12% dei soggetti affetti dalla forma autosomica dominante di questa patologia (ADNFLE) presentano mutazioni nei geni codificanti le subunità dei recettori nicotinici neuronali (nAChRs) eteromerici. Oltre a promuovere direttamente l’eccitabilità neuronale in un network neuronale maturo, nAChRs mutanti possono contribuire alla patogenesi di questo disturbo durante lo sviluppo del SNC, influenzando il rimodellamento sinaptico. Un’alterata trasmissione colinergica potrebbe perciò condurre ad uno sbilancio tra input eccitatori ed inibitori a livello della corteccia prefrontale (PFC) facilitando così l’insorgenza di accessi epilettici. Abbiamo preso in considerazione gli effetti di una mutazione della subunità β2 associata a un fenotipo ADNFLE (β2-V287L) in fasi precoci dello sviluppo cerebrale. L’espressione della mutazione durante le prime due settimane di vita postnatale risulta necessaria per l’instaurarsi del fenotipo epilettico. Sfruttando un modello murino condizionale abbiamo analizzato come nAChRs mutanti contribuiscano a alterare il bilancio tra eccitazione ed inibizione nel cervello. Abbiamo dapprima analizzato come la mutazione β2-V287L influenzi lo sviluppo del sistema GABAergico. Registrazioni di patch-clamp evidenziano che la mutazione non influenza lo switch eccitatorio/inibitorio della trasmissione GABAergica (il quale presenta un ruolo chiave nel remodelling sinaptico), né influenza l’espressione dei recettori GABAA. Abbiamo quindi considerato il contributo della mutazione a carico del sistema glutamatergico. I risultati evidenziano che i nAChRs eteromerici iniziano ad esercitare il loro effetto verso la fine della prima settimana di vita postnatale in topo. Non sono state osservate correnti somatiche nicotiniche in questo stadio né in fasi più avanzate in neuroni piramidali: tale dato suggerisce che i nAChRs eteromerici sono siti principalmente a livello presinaptico, dove la loro attivazione promuove il rilascio di neurotrasmettitore. L’analisi dei mutanti mutazione mette in luce una più alta frequenza delle EPSCs sia in condizioni di controllo che in seguito a somministrazione di nicotina, rispetto al gruppo di controllo. L’analisi della distribuzione delle ampiezze delle EPSC mette in luce un incremento delle stesse tra P7-9 e P10-12 più pronunciato nei topi transgenici. Il nostro lavoro ha inoltre messo in luce come anche mutazioni loss-of-function possono condurre ad un fenotipo NFLE: abbiamo considerato l’effetto patogenico di una mutazione a carico della subunità α2 (Ile297Phe) identificato in una coorte di pazienti affetti da ADNFLE e NFLE. nAChRs ipofunzionali potrebbero limitare la capacità degli interneuroni inibitori di contenere la propagazione degli accessi epilettici, favorendo perciò l’insorgenza degli attacchi. Risulta quindi chiaro che mutazioni in geni codificanti per nAChRs eteromerici possono contribuire ad un fenotipo epilettico a diversi livelli, promuovendo l’eccitabilità in una rete neuronale adulta (che è ancora suscettibile al rimodellamento) o influenzando lo sviluppo di una rete neuronale funzionale, o entrambi. L’ADNFLE risulta perciò non classificabile semplicemente come una canalopatia, ma come un disturbo più complesso dello sviluppo. Il nostro obiettivo è comprendere meglio il ruolo dei nAChRs nello sviluppo del SNC ed il loro contributo nella nella epileptogenesi, oltre che il loro ruolo nella corteccia prefrontale matura. Speriamo così di identificare una finestra temporale precoce per approntare una terapia farmacologica che impedisca l’insorgenza della ADNFLE.<br>The nocturnal frontal lobe epilepsy (NFLE) comprises a large group of partial epilepsies with heterogeneous origin. Approximately 12% of the families affected by the autosomal dominant form of NFLE (ADNFLE) carry mutations on genes coding for subunits of the heteromeric neuronal nicotinic receptors (nAChRs). Attacks arise in the frontal lobe, usually during stage 2 of sleep, and are characterized by clusters of complex and stereotyped hyperkinetic seizures.This is consistent with the widespread expression of nAChRs, and particularly α4β2, in the mammalian brain.Besides directly promoting hyperexcitability in mature networks through cell depolarization and/or altered neurotransmitter release, mutant nAChRs could determine the pathogenetic process during early developmental phases, by affecting synaptic remodeling. Cholinergic signaling has been recently found to affect the development of both GABAergic and glutamatergic systems. . Aberrant cholinergic transmission can lead to an unbalance between excitatory and inhibitory transmission in prefrontal cortex (PFC), therefore facilitating the epileptic fits.We investigated the effect of β2-V287L, a mutant nAChR subunit linked to ADNFLE, in early developmental stages, during which its expression is crucial for the epileptic phenotype to manifest. By using a murine strain which conditionally expresses β2-V287L, we analyzed how the mutant nAChR modifies the balance between excitation and inhibition in the adult brain, leading to the formation of a neuronal network susceptible to seizures. We first considered how β2-V287L (a gain-of-function mutation) affects the development of GABAergic system. By patch-clamp recordings, we observed that mutant nAChRs did not interphere with the GABAergic excitatory/inhibitory transition during early developmental stages (which is known to play a role in synaptic remodelling) nor influenced GABAA receptors’ expression.We then considered the contribute of the mutation to the development of glutamatergic signaling. Our findings revealed that heteromeric nAChRs start to exert their effect on glutamatergic transmission at the end of the first postnatal week in mice. No somatic nicotinic currents have been detected at this as well as at later developmental stages in pyramidal neurons, suggesting that heteromeric nAChRs are mainly located at synaptic level where they stimulate neurotransmitter release. Analysis of transgenic mice highlighted an increase in EPSC frequency both in control condition and following nicotine exposure, compared to control littermates. Cumulative distribution of the EPSC amplitudes showed a larger increase in EPSC amplitude between P7-9 and P10-12 in transgenic mice compared to controls.In our work we also showed how loss of function mutations can lead to a NFLE-like phenotype: in particular, we considered the pathogenic effect of an α2 subunit mutation (Ile297Phe) identified in a cohort including ADNFLE and NFLE patients. A hypofunctional nAChR could hinder the ability of inhibitory interneurons to contain seizure propagation, therefore contributing to seizures.It appears clear that mutations in genes coding for heteromeric nAChRs can contribute to an epileptic phenotype at different levels, promoting excitability in adult neuronal networks (which are still susceptible to remodelling), or affecting the development of a functional cortical circuitry, or both. ADNFLE appears therefore not only to be a channelopaty but a more complex developmental disease.Our aim is to shed new light on the nAChR contribution to brain development and its role in the establishment of an epileptic phenotype, besides its direct effect on excitability in mature prefrontal networks. In this way, we should be able to identify a temporal window for early pharmacological treatment during the pathogenetic process in order to prevent the establishment of ADNFLE

Epilepsy is a neurological disorder characterized by recurrent seizures. Sleep problems can cooccur with epilepsy, and adversely affect seizure diagnosis and treatment. In fact, the relationship between sleep and seizures in individuals with epilepsy is a complex one. Seizures disturb sleep and sleep deprivation aggravates seizures. Antiepileptic drugs may also impair sleep quality at the cost of controlling seizures. In general, particular vigilance states may inhibit or facilitate seizure generation, and changes in vigilance state can affect the predictability of seizures. A clear understanding of sleep-seizure interactions will therefore benefit epilepsy care providers and improve quality of life in patients. Notable progress in neuroscience research—and particularly sleep and epilepsy—has been achieved through experimentation on animals. Experimental models of epilepsy provide us with the opportunity to explore or even manipulate the sleep-seizure relationship in order to decipher different aspects of their interactions. Important in this process is the development of techniques for modeling and tracking sleep dynamics using electrophysiological measurements. In this dissertation experimental and computational approaches are proposed for modeling vigilance dynamics and their utility demonstrated in nonepileptic control mice. The general framework of hidden Markov models is used to automatically model and track sleep state and dynamics from electrophysiological as well as novel motion measurements. In addition, a closed-loop sensory stimulation technique is proposed that, in conjunction with this model, provides the means to concurrently track and modulate 3 vigilance dynamics in animals. The feasibility of the proposed techniques for modeling and altering sleep are demonstrated for experimental applications related to epilepsy. Finally, preliminary data from a mouse model of temporal lobe epilepsy are employed to suggest applications of these techniques and directions for future research. The methodologies developed here have clear implications the design of intelligent neuromodulation strategies for clinical epilepsy therapy.

INTRODUCTION: Dopamine is a catecholaminergic neurotransmitter. A variety of sleep disorders implicate a dysfunction in the dopaminergic system, particularly REM Behaviour Disorder (RBD), Restless Leg Syndrome (RLS) and Periodic Limb Movements during Sleep (PLMS). PLMS involve stereotyped, rhythmic extension movements of the big toe and dorsiflexion of the foot during sleep. PLMS is particularly frequent in Restless Legs Syndrome (RLS) and other sleep disorders. Few studies have documented a pathological PLMS index in patients with Epilepsy. AIMS: The aims of this study were to evaluate the possibility of an association between Epilepsy and PLMS and to define the polysomnographic characteristics of PLMS. Given the dopaminergic nature of PLMS, the association between PLMS and Epilepsy might have represented an additional, indirect evidence of the involvement of dopamine in the pathogenesis of Epilepsy. Another aim was to evaluate the influence of some dopamine agonists commonly used in the treatment of PLMS on the PLMS pattern of some of the patients constituting our sample, as well as any impact these might have on epileptiform discharges. MATERIALS AND METHOD: We selected all patients referred to our neurological clinic from 2008 to 2012, who had previously been diagnosed with epilepsy based on the ILAE criteria, who showed no signs of Sleep Apnea, RLS, RBD and other degenerative neurologic conditions and who were not being treated with antidopaminergic and/or antidepressant drugs. All patients underwent nocturnal video-polisomnographic recordings . We selected patients who had a PLM index considered as pathological (PLMI>5). Subsequently, 5 patients were randomly selected among those with Epilepsy who had a PLMS index > 5. All 5 patients underwent other two nocturnal video-polisomnographic recordings (before and after administration of a dopamine agonist drug, Pramipexole 0.18 mg). In both recordings, PLMS and epileptiform discharges were also counted and analysed. RESULTS: Eighty-five patients who had been previously diagnosed with Epilepsy met the inclusion criteria for this study. Of these, 17/85 (20%) patients had a pathological PLM index (> 5). Of the 85 patients in our sample, 12/17 (70.6%), were diagnosed with Temporal Lobe Epilepsy, 2/17 (11.8%) with Frontal Lobe Epilepsy and 3/17 (17.6%) with Juvenile Myoclonic Epilepsy. PLMS registered in all 17 patients exhibited a mean PLMS index of 18.78 corresponding to the presence of a periodic nocturnal myoclonus of medium entity. In 58.8% PLMS appeared to be mainly distributed during the first half of the night and in 66.7% PLMS occurred during N2. The analysis of the 5 patients who underwent two VPSG (before and after administration of a dopamine agonist drug) showed a close to 50% reduction of epileptiform discharges in patients with PLMS and Epilepsy after administration of a dopamine agonist, namely Pramipexole. CONCLUSIONS: The study confirms the presence of PLMS in patients with Epilepsy. In our sample, the frequency of PLMS episodes stood at 23%. These movements mainly occurred during the first half of the night, in connection with the N2 stage, with a severity ranging from mild to moderate. They therefore had characteristics and distributions which made them more similar to the PLMS described during RLS than to those associated to neurodegenerative conditions. In addition, the PLMS in our sample were more frequent in patients with Temporal Lobe Epilepsy. Finally, considering the dopaminergic nature of PLMS, their occurrence in association with Epilepsy may serve to strengthen the role of dopamine in the pathophysiology of this disorder. This could have significant repercussions even in the therapeutic field, opening up new possibilities through the employment of dopamine agonists which may well find use in the treatment of some forms of Epilepsy.

Good quality sleep is essential for mental and physical health. Inadequate sleep impacts memory consolidation, learning and cognition, immune function, autonomic regulation, physical performance, and other vital functions. In many neurological disorders that are associated with sleep problems such as epilepsy and Alzheimer’s disease, changes in brain circuitry affect sleep-wake regulation mechanisms; this is reflected in anomalous sleep-wake architecture and usually accompanied by poor sleep depth. Thus, over many years, many approaches have been tried in humans and animal models with the goal of improving sleep quality. Unfortunately, each of those approaches comes with limitations or side effects. Thus, there is a need for a natural, safe, and low cost approach that overcomes many limitations to improve sleep and eventually the lives of individuals with sleep problems. Environmental temperature is one of the most important factors that affect sleep in humans and other animals. Studies have shown that the part of the brain governing thermoregulation is also involved in sleep-wake regulation. Even a mild change in environmental temperature can produce a significant effect on sleep. Thus, a better understanding of the sleep-thermoregulation interaction could lead to novel ways for treating many sleep disorders. As a first step on the translational pathway, experiments in animal models of disease conditions with disordered sleep are needed for investigating sleep–thermoregulation interactions and for devising and validating related approaches to enhance sleep quality before conducting them on humans. This dissertation explores and assesses the effect of changes in ambient temperature on sleep-wake architecture in control mice and epileptic mice, the latter from a model of temporal lobe epilepsy as an example of a disease model with disordered sleep. Then, based on the results of temperature effects on sleep in control and epileptic mice, different strategies are proposed and tested to modulate sleep through ambient temperature regulation in closed loop to improve sleep depth and regulate the timing of the sleep-wake cycle. The results presented in this dissertation demonstrate the feasibility of sleep enhancement and regulation of its timing and duration through manipulation of ambient temperature using closed-loop control systems. Similar approaches could foreseeably be used as more natural means for enhancing deep sleep in patients with epilepsy, Alzheimer’s, or Parkinson’s disease in which poor sleep is common and associated with adverse outcomes.