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OBJECTIVE: Eyelid myoclonia with absences (EMA) is a syndrome characterized by eyelid myoclonia with or without absences, eye closure-induced generalized electroencephalographic (EEG) paroxysms and photosensitivity. Few data are available about the prognostic factors of this syndrome. The main objectives of our study were to describe the clinical and EEG features of a group of patients with EMA and to evaluate the presence of prognostic factors. METHODS: We retrospectively selected a cohort of patients with diagnosis of EMA evaluated in the epilepsy service of the Neurological Clinic of Catania, in the Neurology and Clinical Neurophysiopathology Unit of Oasi Research Institute, Troina and in the Regional Epilepsy Centre of Bianchi-Melacrino-Morelli Hospital of Reggio Calabria. We considered the features of the patients during the first year of disease, and at the last follow-up visit. We stratified the patients into two groups: "seizure-free", defined as the absence of seizures for at least 2 years, and "not seizure-free" and we evaluated the evolution of their characteristics and the presence of factors associated with outcome. RESULTS: We enrolled 51 patients (40 women (78%); mean age: 30.8 years ± 15.5 [range 10-79]). The mean follow-up time was 8.7 ± 5.8 years. Eleven patients (21.6%) achieved the condition of seizure-free. Family history of epilepsy was associated with the condition of seizure-free (P = 0.05). At the last follow-up visit, EEG photosensitivity and eye closure sensitivity were significantly associated with the condition of "not seizure-free". SIGNIFICANCE: The results of our study revealed that a positive family history of epilepsy might be associated with a better outcome in EMA. Furthermore, the persistence of photosensitivity and eye closure sensitivity might indicate persistence of seizures, offering an aid in therapeutic management.
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Epilepsias Mioclónicas/complicaciones , Epilepsias Mioclónicas/diagnóstico , Epilepsia Tipo Ausencia/complicaciones , Epilepsia Tipo Ausencia/diagnóstico , Enfermedades de los Párpados/complicaciones , Enfermedades de los Párpados/diagnóstico , Adolescente , Adulto , Anciano , Anticonvulsivantes/uso terapéutico , Niño , Estudios de Cohortes , Electrodiagnóstico , Electroencefalografía , Epilepsias Mioclónicas/tratamiento farmacológico , Epilepsia Tipo Ausencia/tratamiento farmacológico , Enfermedades de los Párpados/tratamiento farmacológico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: It is well known that sleep-related motor seizures can originate from the temporal lobe. However, little is known about the clinical features of minor motor manifestations during sleep in patients with temporal lobe epilepsy. The main objective of our study was to verify the existence of minor motor events during sleep in patients with mesial temporal lobe epilepsy (MTLE) and to define their clinical features and electroencephalography (EEG) correlations. METHODS: We enrolled in the study patients with diagnosis of symptomatic MTLE and a group of healthy controls. All patients and controls underwent long-term video -EEG monitoring, including at least one night of nocturnal sleep. We analyzed all the movements recorded during nocturnal sleep of patients and controls and their electroencephalographic correlations. RESULTS: We analyzed the nocturnal sleep of 15 patients with symptomatic MTLE (8 males and 7 females; mean age ± standard deviation [SD]31.8 ± 14.9 years) and of 15 healthy controls (6 males and 9 females; mean age ± SD 32.8 ± 11.2 years). The analysis of movements during sleep revealed significant differences between groups, with the patients presenting significantly more movements in sleep than healthy controls (56.7 ± 39.2 vs. 15 ± 6.1; p < 0.001) with significant differences regarding oroalimentary automatisms, limb dystonia, straightening movements and gestural automatisms. EEG analysis showed that the proportion of movements preceded by EEG abnormalities was significantly higher in patients than in controls (57.8 ± 35.9 movements vs. 16.6 ± 13.4 movements; p < 0.001). SIGNIFICANCE: The results of our study demonstrated the presence of minor motor events during sleep in patients with MTLE, suggesting an epileptic origin of these episodes. The study of nocturnal sleep in MTLE patients is useful in helping the clinicians in the diagnostic and therapeutic workup of these patients.
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Electroencefalografía , Epilepsia del Lóbulo Temporal/diagnóstico , Epilepsia del Lóbulo Temporal/fisiopatología , Polisomnografía , Procesamiento de Señales Asistido por Computador , Grabación en Video , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Adolescente , Adulto , Anticonvulsivantes/uso terapéutico , Automatismo/diagnóstico , Automatismo/tratamiento farmacológico , Automatismo/fisiopatología , Mapeo Encefálico , Dominancia Cerebral/efectos de los fármacos , Dominancia Cerebral/fisiología , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Lóbulo Temporal/efectos de los fármacos , Lóbulo Temporal/fisiopatología , Adulto JovenAsunto(s)
Epilepsia Refractaria/patología , Síndromes Epilépticos/patología , Convulsiones Febriles/patología , Adulto , Epilepsia Refractaria/diagnóstico por imagen , Epilepsia Refractaria/fisiopatología , Síndromes Epilépticos/diagnóstico por imagen , Síndromes Epilépticos/fisiopatología , Humanos , Imagen por Resonancia Magnética , Masculino , Convulsiones Febriles/diagnóstico por imagen , Convulsiones Febriles/fisiopatología , Estado Epiléptico/diagnóstico por imagen , Estado Epiléptico/patología , Estado Epiléptico/fisiopatologíaRESUMEN
The association between hereditary myotonic disorders and epilepsy is seldom described in the literature. To date, few reports have dealt with dystrophic myotonias, whereas a single case demonstrating an association between sporadic congenital myotonia and epilepsy was recently reported in a patient carrying a de novo mutation of the CLCN1 gene. Additional evidence for a role of CLCN1 in the pathogenesis of epilepsy is derived from large-scale exome analysis of ion channel variants and expression studies. Here, we describe the first case of association between familial Thomsen myotonia and epilepsy. All the affected members of a two-generation family presented myotonia and disclosed a pathogenic mutation in CLCN1. In addition, one individual experienced epileptic seizures due to limbic encephalitis (LE) with anti-GAD antibodies. The occurrence of the two diseases in this patient could be a chance association, however, CLCN1 mutation, as a susceptibility factor for epilepsy through dysfunction of GABAA inhibitory signalling, cannot be ruled out as a possible influence.
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Glutamato Descarboxilasa/inmunología , Encefalitis Límbica/inmunología , Miotonía Congénita/inmunología , Adolescente , Canales de Cloruro/genética , Glutamato Descarboxilasa/genética , Humanos , Encefalitis Límbica/complicaciones , Encefalitis Límbica/genética , Masculino , Mutación , Miotonía Congénita/complicaciones , Miotonía Congénita/genética , LinajeRESUMEN
COVID-19 had a massive impact on sleep, resulting in overall increase of sleep disturbances. During lockdown many factors contributed to sleep disturbances, in particular changes in sleep-wake habits and stress. This article will describe the frequency and features of the principal parasomnias and the impact of the pandemic and the government restriction measures on sleep. Among different pathophysiological hypotheses, we will discuss the role of stress, considered as an expression of the allostatic load. Finally, during the pandemic, parasomnias were mainly investigated by questionnaires, with controversial results; video-polysomnographic studies are crucial to obtain a definitive diagnosis, even in critical conditions.
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COVID-19 , Parasomnias , Trastornos del Sueño-Vigilia , Humanos , COVID-19/epidemiología , Pandemias , Control de Enfermedades Transmisibles , Parasomnias/diagnóstico , Parasomnias/epidemiologíaRESUMEN
STUDY OBJECTIVES: to define sleep-related movements in healthy adults according to sex and age. METHODS: sleep-related movements from 50 video-polysomnography (vPSG) recordings of 27 men and 23 women, from 20 to 70 years old, were classified according to ICDS-3-TR and AASM criteria (codified movements); the remaining movements (non-codified movements) were described according to type (elementary movements-EMs or complex movements-CMs), topography (focal, segmental, multifocal or generalized) and, if present, were assigned to motor patterns (MPs). RESULTS: of 4057 movements analyzed, 54.6% (2216/4057) were non-codified (1861 CMs, 355 EMs) and 1841 were codified. CMs were mainly generalized (70%) while EMs were multifocal (40%) or focal (30%). The median movement index (MI; movement/hour) was 11 and the median duration was 4 s. MI decreased from stages N1/REM>N2>N3; men showed a higher MI. An MP was assigned to 2204 codified and non-codified movements, mainly stretching (50%) and scratching (30%). Stretching increased in REM sleep while food-carrying behaviors increased in N2. Men showed more food-carrying behaviors, changes of body positions and comfort movements while stretching was more common in women. Younger subjects exhibited more food-carrying behaviors, while scratching and stretching were more prevalent in the middle-aged group. Older subjects showed more changes in body positions and comfort movements. CONCLUSIONS: 54.6% of sleep-related movements in healthy subjects were non-codified and characterized by motor sequences that can configure MPs. Our comprehensive classification method allows a detailed description of the physiological movements underlying differential motor control during sleep stages influenced by age and sex.
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Disorders of arousal (DoA) are NREM parasomnias characterized by motor and emotional behaviors emerging from incomplete arousals from deep sleep. DoA are largely present in pediatric populations, a period during which they are labeled as self-limited manifestations. However, an extensive literature has shown that DoA can persist in adulthood, with different characteristics from childhood DoA. Adult DoA patients usually report excessive daily sleepiness, sleep-related violence during DoA episodes or potentially harmful behaviors, which are rare in childhood. The semeiological features of DoA episodes in adulthood may complicate differential diagnoses with other motor manifestations during sleep, in particular sleep-related hypermotor epilepsy. However, it cannot be excluded that adults with DoA attending sleep centers constitute a more severe phenotype, thus not being representative of adult DoA in the general population. Video-polysomnographic studies of DoA document a spectrum of motor patterns of different complexities, the simplest of which may often go unnoticed. Despite the different complexities of the episodes, neurophysiologic studies showed the co-existence of deep sleep and wakefulness during DoA episodes or even before their onset. These aspects make DoA an ideal model to investigate the mechanisms regulating local sleep, sleep arousal and cognitive functions including spatial and temporal orientation, attention or memory.
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Non-rapid eye movement (NREM) sleep parasomnias are recurrent abnormal behaviors emerging as incomplete arousals out of NREM sleep. Mounting evidence on NREM sleep parasomnias calls for an update of clinical and therapeutical strategies. In the current review, we summarize the state of the art and provide the necessary background to stimulate a critical revision of diagnostic criteria of disorders of arousal (DoA), the most common NREM sleep parasomnia. In particular, we highlight the poor sensitivity of the diagnostic items related to amnesia and absence of conscious experiences during DoA episodes, encourage the role of video-polysomnography and home-video recordings in the diagnostic and treatment work-up, and suggest three levels of diagnostic certainty based on clinical and objective findings. Furthermore, we highlight current gaps of knowledge that prevent the definition of standard guidelines and future research avenues.
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Epilepsia/fisiopatología , Movimiento , Trastorno de la Conducta del Sueño REM/fisiopatología , Sueño , Anciano , Epilepsia/complicaciones , Epilepsia/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Movimiento/fisiología , Trastornos Parkinsonianos/complicaciones , Trastornos Parkinsonianos/diagnóstico , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/fisiopatología , Trastorno de la Conducta del Sueño REM/complicaciones , Trastorno de la Conducta del Sueño REM/diagnóstico , Sueño/fisiología , Grabación en VideoRESUMEN
Purpose: Disorders of arousal (DoA) are characterized by incomplete awakening from NREM sleep, with the admixture of both deep sleep and wake EEG activity. Previous observations suggested that changes in EEG activity could be detected in the seconds preceding DoA episodes. The aims of this work were to characterize the topography of EEG spectral changes prior to DoA episodes and to investigate whether or not behavioral complexity could be predicted by changes in EEG immediately preceding behavioral onsets. Patients and Methods: We collected 103 consecutive video-polysomnographic recordings of 53 DoA adult patients and classified all episodes as simple, rising and complex arousal movements. For each episode, a 5-second window preceding its motor onset ("pre-event") and a 60-second window from 2 to 3 minutes before the episodes ("baseline") were compared. Subsequently, a between-group comparison was performed for the pre-event of simpler versus the more complex episodes. Results: Spectral analysis over 325 DoA episodes showed an absolute significant increase prior to DoA episodes in all frequency bands excluding sigma, which displayed the opposite effect. In normalized maps, the increase was relatively higher over the central/anterior areas for both slow and fast frequency bands. No significant differences emerged from the comparison between simpler and more complex episodes. Conclusion: Taken together, these results show that deep sleep and wake-like EEG rhythms coexist over overlapping areas before DoA episodes, suggesting an alteration of local sleep mechanisms. Episodes of different complexity are preceded by a similar EEG activation, implying that they possibly share a similar pathophysiology.
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STUDY OBJECTIVES: To describe clinical and video-polysomnographic features of disorders of arousal (DoA) in older adults. METHODS: Four consecutive male patients with nocturnal motor behaviors underwent a clinical interview, neurologic examination, laboratory tests, brain magnetic resonance imaging, and nocturnal in-laboratory or 24- to 48-hour home video polysomnography. The patients repeated an evaluation after 6 months of follow-up, including a 48-hour home video polysomnography in 2 patients. RESULTS: The patients were aged 65-72 years, and 1 patient has Parkinson disease. Sleep-related behavioral episodes had begun from 12-55 years before our observation. Three patients presented with a positive family history for DoA. Sleep motor episodes were described as suddenly raising the head or trunk, sitting in bed, screaming, speaking, gesturing, and sleepwalking (in 1 patient). When questioned, all patients seemed confused, rarely reporting any dream-like content. We recorded 25 DoA episodes of different intensity and complexity arising from nonrapid eye movement sleep. The semiology of the episodes was similar to that described in younger patients, consisting of sleep terrors and confusional arousals. All patients presented with physiological rapid eye movement sleep muscle atonia. Medication therapy reduced the frequency of the episodes in 2/4 patients. CONCLUSIONS: DoA may begin in adulthood and persist or arise in older adults, sometimes causing sleep-related injuries. Motor patterns of DoA in older adults are similar to those of younger patients. A combined clinical examination and video polysomnography recording are crucial in establishing a definitive diagnosis of nocturnal motor behavior in all older adults and especially in those affected by neurodegenerative diseases. CITATION: Loddo G, Fragiacomo F, Mainieri G, et al. Disorders of arousal in 4 older men: evidence from clinical practice. J Clin Sleep Med. 2022;18(1):129-136.
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Terrores Nocturnos , Trastornos del Despertar del Sueño , Sonambulismo , Adulto , Anciano , Nivel de Alerta , Humanos , Masculino , Polisomnografía , Sonambulismo/diagnósticoRESUMEN
Non-rapid eye movement (NREM) sleep parasomnias are characterized by motor and emotional behaviors emerging from incomplete arousals from NREM sleep and they are currently referred to as disorders of arousal (DoA). Three main clinical entities are recognized, namely confusional arousal, sleep terror and sleepwalking. DoA are largely present in pediatric populations, an age in which they are considered as transitory, unhabitual physiological events. The literature background in the last twenty years has extensively shown that DoA can persist in adulthood in predisposed individuals or even appear de novo in some cases. Even though some episodes may arise from stage 2 of sleep, most DoA occur during slow wave sleep (SWS), and particularly during the first two sleep cycles. The reasons for this timing are linked to the intrinsic structure of SWS and with the possible influence on this sleep phase of predisposing, priming and precipitating factors for DoA episodes. The objective of this paper is to review the intrinsic sleep-related features and chronobiological aspects affecting SWS, responsible for the occurrence of the majority of DoA episodes during the first part of the night.
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Sleep is a universal, highly preserved process, essential for human and animal life, whose complete functions are yet to be unravelled. Familial recurrence is acknowledged for some sleep disorders, but definite data are lacking for many of them. Genetic studies on sleep disorders have progressed from twin and family studies to candidate gene approaches to culminate in genome-wide association studies (GWAS). Several works disclosed that sleep-wake characteristics, in addition to electroencephalographic (EEG) sleep patterns, have a certain degree of heritability. Notwithstanding, it is rare for sleep disorders to be attributed to single gene defects because of the complexity of the brain network/pathways involved. Besides, the advancing insights in epigenetic gene-environment interactions add further complexity to understanding the genetic control of sleep and its disorders. This narrative review explores the current genetic knowledge in sleep disorders in children, following the International Classification of Sleep Disorders-Third Edition (ICSD-3) categorisation.
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Seizures are the most frequent neurological clinical symptoms of the central nervous system (CNS) during the neonatal period. Neonatal seizures may be ascribed to an acute event or symptomatic conditions determined by genetic, metabolic or structural causes, outlining the so-called 'Neonatal Epilepsies'. To date, three main groups of neonatal epilepsies are recognised during the neonatal period: benign familial neonatal epilepsy (BFNE), early myoclonic encephalopathy (EME) and 'Ohtahara syndrome' (OS). Recent advances showed the role of several genes in the pathogenesis of these conditions, such as KCNQ2, KCNQ3, ARX, STXBP1, SLC25A22, CDKL5, KCNT1, SCN2A and SCN8A. Herein, we reviewed the current knowledge regarding the pathogenic variants most frequently associated with neonatal seizures, which should be considered when approaching newborns affected by these disorders. In addition, we considered the new possible therapeutic strategies reported in these conditions.
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STUDY OBJECTIVES: To determine the polysomnography characteristics during sleep paralysis, false awakenings, and lucid dreaming (which are states intermediate to rapid eye movement [REM] sleep and wake but exceptionally observed in sleep laboratory). METHODS: In 5 participants, we captured 5 episodes of sleep paralysis (2 time marked with the ocular left-right-left-right code normally used to signal lucid dreaming, 1 time marked by an external noise, and 2 retrospectively reported) and 2 episodes of false awakening. The sleep coding (using 3-second mini-epochs) and spectral electroencephalography analysis were compared during these episodes and normal REM sleep as well as wakefulness in the same 4 of 5 participants and vs lucid REM sleep in 4 other patients with narcolepsy. RESULTS: During episodes of sleep paralysis, 70.8% of mini-epochs contained theta electroencephalography rhythm (vs 89.7% in REM sleep and 21.2% in wakefulness), 93.8% contained chin muscle atonia (vs 89.7% in REM sleep and 33.3% in wakefulness), and 6.9% contained rapid eye movements (vs 11.9% in REM sleep and 8.1% in wakefulness). The electroencephalography spectrum during sleep paralysis was intermediate between wakefulness and REM sleep in the alpha, theta, and delta frequencies, whereas the beta frequencies were not different between sleep paralysis and normal REM sleep. The power spectrum during false awakening followed the same profile as in sleep paralysis. CONCLUSIONS: The predominant theta electroencephalography rhythm during sleep paralysis and false awakenings (with rare and lower alpha rhythm) suggests that the brain during sleep paralysis is not in an awake but in a dreaming state.
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Parálisis del Sueño , Sueño REM , Sueños , Electroencefalografía , Humanos , Estudios Retrospectivos , VigiliaRESUMEN
Objectives: Pallister-Killian syndrome (PKS) is a rare genetic disorder with multi-organ involvement caused by mosaic tetrasomy of chromosome 12p. Although many caregivers report the presence of impaired sleep in their children, there are no clear data in the literature on this issue and no systematic study has ever been performed. With this study, we aimed to characterize the features of sleep in Pallister-Killian syndrome and identify the possible influence of clinical and demographic features. Moreover, our aim was to verify the effectiveness of conventional screening questionnaires in this particular group of patients. Methods: We prospectively enrolled 14 patients aged 1-17 years in collaboration with PKS Kids Italia ONLUS. The Sleep Disturbance Scale for Children (SDSC) questionnaire was administered to caregivers. Then, video polysomnography (VPSG) of at least 24 h was performed and results were compared with a same-aged control group. Results: A total of 92% of patients had abnormal SDSC scores, extremely high in the "disorder of initiating and maintaining sleep" (DIMS) and "sleep breathing disorders" (SBD) subscales. VPSG showed a significantly impaired macrostructure in PKS patients, with a higher Arousal Index (p < 0.00001) and percentage of time spent in N3 (p < 0.00001), and reduced Sleep Efficiency (p = 0.0006). After dividing both PKS and controls into two groups based on median age, some peculiarities emerged: the younger group had higher Awakenings Index (p = 0.0207) and percentage of time spent in N1 (p = 0.015) while the older group showed higher time in bed (TIB) (p = 0.0485), compared with controls. Due to poor compliance, the Apnea-Hypopnea Index (AHI) was evaluated only for 10 PKS children, being significantly increased (p = 0.0427) compared with controls. SBD subscale scores in SDSC were significantly related to AHI values in VPSG (p = 0.0099). Conclusions: This study constitutes the first attempt to describe the sleep pattern in PKS. Despite small numbers due to the rarity of the syndrome, our VPSG results confirm the high prevalence of sleep disorders (SDs) in these patients. It is therefore essential to investigate and treat them. The SDSC scale is a good screening tool for early detection also in these patients, with particular sensitivity in detecting breathing disorders.
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PURPOSE: Juvenile myoclonic epilepsy (JME), like other forms of idiopathic generalized epilepsy, shows a marked female predominance. However, few studies have specifically addressed the role of sex in its long-term prognosis. We performed a systematic review of the literature relevant to JME prognosis, focusing on sex-based differences in prognostic factors and outcome. METHODS: A comprehensive literature search of the PubMed and Scopus databases was performed, considering all articles up to April 2020 in which long-term prognosis in JME had been explored and sex differences in outcome or prognostic factors were specified. RESULTS: We included 25 articles published between 1984 and 2020. Sex differences in epilepsy outcome were explored by 21 of the 25 studies, but only three reported different outcomes in male vs female patients. All three found female sex to be associated with a later response to antiseizure medications, worse seizure control, and a higher risk of relapse in their entire study samples, which included JME patients. Eight studies found sex-based differences in possible predictors of long-term outcome: prolonged epileptiform EEG runs and the presence of eye closure sensitivity, both more frequent in women, were factors possibly linked to a poorer prognosis, as were praxis induction and generalized EEG asymmetric changes, which instead were more common in men. Valproate use, more frequent in men, was associated with a better outcome. CONCLUSION: Most studies do not highlight sex differences in JME prognosis. However, some sex specificities do emerge, especially with regard to particular reflex traits and EEG abnormalities. Finally, sex may condition therapeutic choices, and thus have a possible impact on long-term outcome.
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Epilepsia Mioclónica Juvenil , Electroencefalografía , Femenino , Humanos , Masculino , Epilepsia Mioclónica Juvenil/diagnóstico , Epilepsia Mioclónica Juvenil/tratamiento farmacológico , Epilepsia Mioclónica Juvenil/epidemiología , Pronóstico , Convulsiones , Caracteres SexualesRESUMEN
PURPOSE: The link existing between epilepsy and sleep is widely recognized. However, little is known about the prevalence and the clinical consequences of the comorbidity between focal epilepsy and sleep disorders, especially those sleep phenomena classified as isolated symptoms or normal variants. Objective of the study was to evaluate the frequency of sleep disorders and physiological sleep variants in a group of adult patients with focal epilepsy as compared to healthy controls by means of nocturnal polysomnography. METHODS: We performed a retrospective observational study in the Neurological Clinic of the University of Catania in adult patients with a diagnosis of focal epilepsy and in a group of control subjects. All subjects underwent an overnight polysomnography. The following sleep disorders were considered: NREM-related parasomnias; REM-related parasomnias; sleep-related movement disorders; isolated symptoms or normal variants. RESULTS: 100 patients [mean age 30.3⯱â¯14.7 years, 40 men] and 62 controls [mean age 36.4⯱â¯15.9, 20 men] were studied. A significant higher percentage of sleep disorders was recorded in patients as compared to controls (73 % vs 48.4 %; pâ¯=â¯0.002). In particular, we found a higher frequency of periodic limb movements (PLM) (20 % vs 4.8 %; pâ¯=â¯0.007), bruxism (20 % vs 4.8 %; pâ¯=â¯0.007) and neck myoclonus (22 % vs 4.8 %; pâ¯=â¯0.003). Moreover, alternating limb muscle activation was associated with sleep-related hypermotor epilepsy (ORâ¯=â¯7.9; pâ¯=â¯0.01). CONCLUSION: Sleep disorders and physiological sleep variants are common in adult patients with focal epilepsy.