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Sleep architecture in neonatal and infantile onset epilepsies in the first six months of life: A scoping review

Open AccessPublished:November 10, 2022DOI:https://doi.org/10.1016/j.ejpn.2022.11.004

      Highlights

      • Sleep is critical for brain development.
      • Complex relationship exists between sleep and epilepsy.
      • Scoping review of sleep architecture in infants with unprovoked seizures.
      • In self-limited epilepsy, sleep macrostructure was preserved.
      • In developmental and epileptic encephalopathies, sleep architecture was significantly disrupted.

      Abstract

      Aim

      Epilepsy occurs in approximately 80 per 100,000 infants in the first year of life, ranging in severity from self-limited and likely to spontaneously resolve, to severe developmental and epileptic encephalopathies. Sleep plays a key role in early brain development and the reciprocal relationship between sleep and seizures is not yet fully understood, particularly in young children. We conducted a Scoping Review to synthesise current knowledge of sleep architecture in neonates and infants with epilepsy.

      Method

      Peer-reviewed publications from 2005 to 2022 describing sleep architecture in infants up to six months of age with unprovoked seizures were included. The analysis set was derived from EMBASE, Web of Science and PubMED using key terms “sleep, epilepsy and infant” and related descriptors. Inclusion criteria were prospectively described in a Scoping Review protocol. Sleep architecture was assessed as macro- and micro-structural elements.

      Results

      21 publications were included in the qualitative analysis. In self-limited familial and genetic epilepsy, sleep macrostructure was generally preserved. In DEEs and in epileptic encephalopathies of genetic or structural aetiology, sleep architecture was significantly disrupted.

      Interpretation

      Early identification of infants with epilepsy is important to ensure early and effective treatment. In the DEE spectrum, sleep architecture is significantly impacted, and abnormal sleep architecture may be associated with compromised developmental outcome. Further research is needed to identify the sequence of events in abnormal brain development, epilepsy and sleep disruption and potentially help to predict the course of epilepsy towards a self-limited epilepsy versus a DEE.

      1. Introduction

      1.1 The structure and importance of sleep

      Sleep is a highly active process. The large amount of sleep during periods of rapid brain growth, connectivity and synaptic plasticity suggests an important role for sleep in early brain development [
      • Grigg-Damberger M.
      Ontogeny of sleep and its functions in infancy, childhood, and adolescence.
      ,
      • Knoop M.S.
      • de Groot E.R.
      • Dudink J.
      Current ideas about the roles of rapid eye movement and non-rapid eye movement sleep in brain development.
      ,
      • Bourel-Ponchel E.
      • Hasaerts D.
      • Challamel M.-J.
      • Lamblin M.-D.
      Behavioral-state development and sleep-state differentiation during early ontogenesis.
      ]. Changes in sleep architecture from pre-term infant to childhood, reflect the ongoing development of brain networks and the emergence of different sleep states is one of the most significant aspects of early brain maturation in infancy [
      • Mirmiran M.
      Development of fetal and neonatal sleep and circadian rhythms.
      ].
      Sleep occurs in cycles: in the first 3 months of life sleep cycles consist of active sleep, later developing to Rapid Eye Movement (REM) sleep, and quiet sleep, later NREM sleep [
      • Danker-Hopfe H.
      Growth and development of children with a special focus on sleep.
      ]. Onset of sleep occurs during active sleep. At term, in an ultradian rhythm of 3 h, these sleep cycles are interrupted by a wakefulness phase with feeding [
      • Bourel-Ponchel E.
      • Hasaerts D.
      • Challamel M.-J.
      • Lamblin M.-D.
      Behavioral-state development and sleep-state differentiation during early ontogenesis.
      ]. After 3 months of age, babies fall asleep in NREM sleep and end their sleep cycle during a REM period. Ultradian rhythm is progressively replaced by circadian rhythm [
      • Mirmiran M.
      Development of fetal and neonatal sleep and circadian rhythms.
      ,
      • Jiang F.
      Sleep and early brain development.
      ]. NREM is composed of sleep stages N1, N2 and N3 with progressive sleep depth characterised by increasing amounts of slow wave activity. REM sleep is faster, desynchronised activity, like wakefulness [
      • Moore J.L.
      • Carvalho D.Z.
      • St Louis E.K.
      • Bazil C.
      Sleep and epilepsy: a focused review of pathophysiology, clinical syndromes, Co-morbidities, and therapy.
      ]. Both NREM and REM are thought to play an important role in brain development [
      • Knoop M.S.
      • de Groot E.R.
      • Dudink J.
      Current ideas about the roles of rapid eye movement and non-rapid eye movement sleep in brain development.
      ,
      • Siegel J.M.
      Clues to the functions of mammalian sleep.
      ].
      Sleep architecture is composed of macro and microstructural elements, see Table 1.
      Table 1Composition of sleep architecture.
      Macrostructure [
      • Pereira A.M.
      • Bruni O.
      • Ferri R.
      • Palmini A.
      • Nunes M.L.
      The impact of epilepsy on sleep architecture during childhood.
      ,
      • Nunes F.
      Sleep organization in children with partial refractory epilepsy.
      ,
      • Chan M.
      Sleep macro-architecture and micro-architecture in children born preterm with sleep disordered breathing.
      ].
      Microstructure [
      • Borbély A.
      Sleep homeostasis and models of sleep regulation.
      ,
      • Bruni O.
      Cyclic alternating pattern: a window into pediatric sleep.
      ,
      • Guyer C.
      Brain maturation in the first 3 months of life, measured by electroencephalogram: a comparison between preterm and term-born infants.
      ]
      Total sleep timeDynamics of slow wave activity
      Proportion of REM and NREM sleepNumber and morphology of sleep spindles
      Wake after sleep onsetCyclic alternating pattern
      Number of completed sleep cycles
      Sleep latency
      Sleep efficiency
      Table 2Summarises epilepsies presenting in the first six months of life.
      EpilepsyIdentified genes and other aetiologies that have been implicated includeAge of onset of seizures and responsiveness to treatmentCharacteristic seizure typeDevelopment
      Self-limited (familial) neonatal epilepsyFamily history or de novo mutations in KCNQ2, KCNQ3Days 2–7, rarely after first 4 weeks (within days of being at term by corrected age for pre-term infants)Sequential seizures (focal clonic or tonic, often with apnoea and cyanosis)Normal
      Self-limited (familial) neonatal infantile epilepsyFamily history or de novo mutations SCN2A KCNQ2Day 1–23 months of life (mean 11 weeks, median 13 weeks)Initially focal tonic features with head and eye deviation, followed by other tonic and clonic features. Some have prominent apnea and staring. Seizures vary in duration from 20 s to 4 min. Seizures with fever are rare.Normal
      Self-limited (familial) infantile epilepsyPRRT2

      KCNQ2, KCNQ3

      SCN2A
      Infantile: 3–20 months of age, peak at 6 monthsBrief focal seizures, often occurring in clustersNormal
      Early infantile developmental and epileptic encephalopathy

      (previously early myoclonic encephalopathy and Ohtahara syndrome)
      PIGA, SETBP1, SIK1, SLC25A22, GLDC, AMT,

      Metabolic aetiologies, less often structural

      GNAO1, ARX, DOCK7, STXBP1, CDKL5, KCNQ2, KCNT1, NECAP1, PIGA, PIGQ, SCN2A, SCN8A, SIK1, SLC25A22, SCL35A2, STXBP1, UBA5, WWOX

      Structural aetiologies, less often metabolic
      First 2 months of life (more than half of cases have onset of seizures by 10 days of life)

      First month of life (range 1–3 months)
      Focal or multifocal myoclonus, focal seizures, spasms

      Tonic seizures, sequential seizures in neonates

      Tonic spasms and focal seizures
      Profoundly impaired

      Delay, often severe
      Genetic Epilepsy with febrile seizures + (GEFS+) spectrumSCN1A and SCN1B pathogenic variants

      Other gene variants encoding voltage-gated sodium, calcium, and potassium channels, and ligand-gated ion channels including nicotinic cholinergic receptor subunits, the γ-aminobutyric acid (GABA) A receptor subunits, and syntaxin 1B (STX1B) have also been linked to the syndrome
      Febrile seizures in GEFS + families may begin prior to 6 months of age unlike typical febrile seizures and persist beyond 6 years of age.

      Other afebrile seizure types may develop at various ages.
      Febrile seizures, which may be generalized or focal, are mandatory for diagnosis. In addition, a variety of other generalized or focal afebrile seizures may be seenUsually normal
      Infantile epileptic spasms syndrome

      (previously West Syndrome and Infantile Spasms)
      CDKL5, STXBP1, ARX, ALG13, DOCK7, DNM1, FOXG1, GABRA1, GABRB1, GABRB3, GNAO1, GRIN1, GRIN2A, GRIN2B, IQSEC2, KCNT1, SCA2, SCN1A, SCN2A, SCN8A, SETBP1, SIK1, SLC25A22, SLC35A2, SPTAN1, ST3Gal3, STXBP1, TBC1D24, TCF4, WWOX

      Metabolic and structural aetiologies
      Between 3 and 12 months of age, although later onset may occurClusters of epileptic spasms at onsetNormal to severe delay at onset

      Over time, 70%–90% develop intellectual disability, often severe
      Myoclonic epilepsy in infancyUnknownBetween 4 months and 2 years of age, peak age of 6–18 monthsMyoclonic seizures, often activated by startle, noise, or touchDevelopment is normal at onset

      A minority develop cognitive delays over time
      Epilepsy of infancy with migrating focal seizuresKCNT1; SCN2A; PLCB1, QARS, SCN1A, SCN8A, SLC25A22, TBC1D24, SLC12A5, TBC1D24, CHD2First 6 months after birth (mean 3 months), later onset has been reportedMultifocal clonic or tonic seizures that are often subtle and associated with autonomic featuresSevere delay
      Terminology reflects updated 2022 ILAE Classification & Definition of Epilepsy Syndromes with Onset in Neonates and Infants [
      • Zuberi S.M.
      • Wirrell E.
      • Yozawitz E.
      • Wilmshurst J.M.
      • Specchio N.
      • Riney K.
      • et al.
      ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: position statement by the ILAE Task Force on Nosology and Definitions.
      ].
      Table 2 Epilepsies presenting in the first six months of life [
      • Zuberi S.M.
      • Wirrell E.
      • Yozawitz E.
      • Wilmshurst J.M.
      • Specchio N.
      • Riney K.
      • et al.
      ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: position statement by the ILAE Task Force on Nosology and Definitions.
      ,
      • McTague A.
      The genetic landscape of the epileptic encephalopathies of infancy and childhood.
      , ,
      • Fine A.
      Seizures in children.
      ,
      • Lee E.
      Epilepsy syndromes during the first year of life and the usefulness of an epilepsy gene panel.
      ,
      • Pavone P.
      Benign and severe early-life seizures: a round in the first year of life.
      ,
      • Koutroumanidis M.
      • Arzimanoglou A.
      • Caraballo R.
      • Goyal S.
      • Kaminska A.
      • Laoprasert P.
      • et al.
      The role of EEG in the diagnosis and classification of the epilepsy syndromes: a tool for clinical practice by the ILAE Neurophysiology Task Force (Part 2).
      ,
      • Specchio N.
      • Vigevano F.
      The spectrum of benign infantile seizures.
      ].
      Slow wave activity is a marker of homeostatic regulation, synaptic strength and drive for sleep [
      • Chan M.
      Sleep macro-architecture and micro-architecture in children born preterm with sleep disordered breathing.
      ,
      • Schoch S.
      Across-night dynamics in traveling sleep slow waves throughout childhood.
      ]. The morphology of slow waves provides information about nocturnal regeneration and cortical maturation [
      • Guyer C.
      Brain maturation in the first 3 months of life, measured by electroencephalogram: a comparison between preterm and term-born infants.
      ,
      • Schoch S.
      Across-night dynamics in traveling sleep slow waves throughout childhood.
      ,
      • Fattinger S.
      • Schmitt B.
      • Heinzle B.K.B.
      • Critelli H.
      • Jenni O.G.
      • Huber R.
      Impaired slow wave sleep downscaling in patients with infantile spasms.
      ] and slow wave sleep is suggested to be involved in nocturnal memory consolidation [
      • Bruni O.
      Cyclic alternating pattern: a window into pediatric sleep.
      ]. Decreased strength of cortical synapses during sleep due to pruning processes is represented by the declining slope of slow waves, and linked to neuronal recovery and learning capacity [
      • Tononi G.
      Sleep function and synaptic homeostasis.
      ].
      Cyclic alternating pattern (CAP) participates in the dynamic organisation of sleep. As a marker of sleep instability, build-up and maintenance of deep sleep, it is an important element of sleep microstructure [
      • Parrino L.
      Cyclic alternating pattern (CAP): the marker of sleep instability.
      ]. CAP is spontaneous periodic NREM sleep EEG activity, distinct from background EEG activity [
      • Terzano M.G.
      Atlas, rules, and recording techniques for the scoring of cyclic alternating pattern (CAP) in human sleep.
      ] which provides insights into the adaptive properties of the sleeping brain [
      • Bruni O.
      Cyclic alternating pattern: a window into pediatric sleep.
      ,
      • Terzano M.G.
      Atlas, rules, and recording techniques for the scoring of cyclic alternating pattern (CAP) in human sleep.
      ]. Age related changes in CAP reflect biological development through childhood and adolescence and CAP may be altered in epilepsy [
      • Parrino L.
      Cyclic alternating pattern (CAP): the marker of sleep instability.
      ,
      • Terzano M.G.
      • Mancia D.
      • Salati M.R.
      • Costani G.
      • Decembrino A.
      • Parrino L.
      The cyclic alternating pattern as a physiologic component of normal NREM sleep.
      ].
      Studies have shown an alteration of slow wave activity and CAP in association with epilepsy, and a corresponding impairment of sleep quality [
      • Bruni O.
      Cyclic alternating pattern: a window into pediatric sleep.
      ,
      • Fattinger S.
      • Schmitt B.
      • Heinzle B.K.B.
      • Critelli H.
      • Jenni O.G.
      • Huber R.
      Impaired slow wave sleep downscaling in patients with infantile spasms.
      ,
      • Tononi G.
      Sleep function and synaptic homeostasis.
      ,
      • Parisi P.
      • Bruni O.
      • Pia Villa M.
      • Verrotti A.
      • Miano S.
      • Luchetti A.
      • et al.
      The relationship between sleep and epilepsy: the effect on cognitive functioning in children.
      ].

      1.2 Seizures and epilepsy in infants

      Epilepsy occurs in approximately 80 per 100,000 infants in the first year of life [
      • Eltze C.M.
      • Chong W.K.
      • Cox T.
      • Whitney A.
      • Cortina-Borja M.
      • Chin R.F.
      • et al.
      A population-based study of newly diagnosed epilepsy in infants.
      ,
      • Shellhaas R.A.
      • Wusthoff C.J.
      • Tsuchida T.N.
      • Glass H.C.
      • Chu C.J.
      • Massey S.L.
      • et al.
      Profile of neonatal epilepsies, characteristics of a prospective US cohort.
      ,
      • Wilmshurst J.M.
      • Gaillard W.D.
      • Vinayan K.P.
      • Tsuchida T.N.
      • Plouin P.
      • Van Bogaert P.
      • et al.
      Summary of recommendations for the management of infantile seizures: task force report for the ILAE commission of pediatrics.
      ,
      • Gaily E.
      • Lommi M.
      • Lapatto R.
      • Lehesjoki A.-E.
      Incidence and outcome of epilepsy syndromes with onset in the first year of life: a retrospective population-based study.
      ], ranging in severity from self-limited and likely to spontaneously resolve, to developmental and epileptic encephalopathies (DEE). DEE represent a group of severe heterogeneous disorders with developmental consequences arising directly from the effect of the genetic mutation in addition to the effect of the frequent epileptic activity on development [
      • Scheffer I.
      ILAE classification of the epilepsies: position paper of the ILAE commission for classification and terminology.
      ].
      Seizures occur relatively frequently at neonatal age, in approximately 3/1000 live births [
      • Pressler R.L.L.
      Why we urgently need improved seizure and epilepsy therapies for children and neonates.
      ,
      • Pisani F.
      • Spagnoli C.
      • Falsaperla R.
      • Nagarajan L.
      • Ramantani G.
      Seizures in the neonate: a review of etiologies and outcomes.
      ]. Most neonatal seizures are acute provoked seizures, secondary to hypoxic ischaemic encephalopathy (HIE), stroke, haemorrhage, or acute metabolic derangements, however 10–15% of seizures are unprovoked, reflecting the onset of neonatal epilepsies [
      • Shellhaas R.A.
      • Wusthoff C.J.
      • Tsuchida T.N.
      • Glass H.C.
      • Chu C.J.
      • Massey S.L.
      • et al.
      Profile of neonatal epilepsies, characteristics of a prospective US cohort.
      ,
      • Pisani F.
      • Spagnoli C.
      • Falsaperla R.
      • Nagarajan L.
      • Ramantani G.
      Seizures in the neonate: a review of etiologies and outcomes.
      ,
      • Cornet M.C.
      • Morabito V.
      • Lederer D.
      • Glass H.C.
      • Ferrao Santos S.
      • Numis A.L.
      • et al.
      Neonatal presentation of genetic epilepsies: early differentiation from acute provoked seizures.
      ]. Only 15% of babies with neonatal seizures develop epilepsy [
      • Pisani F.
      • Spagnoli C.
      • Falsaperla R.
      • Nagarajan L.
      • Ramantani G.
      Seizures in the neonate: a review of etiologies and outcomes.
      ], 68% of them appearing in the first year of life [
      • Pisani F.
      • Facini C.
      • Pavlidis E.
      • Spagnoli C.
      • Boylan G.
      Epilepsy after neonatal seizures: literature review.
      ].
      The aetiology of epilepsy is primarily genetic (42%), structural (41%) due to congenital malformations, overlapping structural and genetic (9%), or rarely due to inborn errors of metabolism [
      • Shellhaas R.A.
      • Wusthoff C.J.
      • Tsuchida T.N.
      • Glass H.C.
      • Chu C.J.
      • Massey S.L.
      • et al.
      Profile of neonatal epilepsies, characteristics of a prospective US cohort.
      ,
      • Pisani F.
      • Spagnoli C.
      • Falsaperla R.
      • Nagarajan L.
      • Ramantani G.
      Seizures in the neonate: a review of etiologies and outcomes.
      ,
      • McTague A.
      The genetic landscape of the epileptic encephalopathies of infancy and childhood.
      ].
      Approximately one-third of newborns with brain malformations as their primary seizure aetiology also have co-existing precipitators of symptomatic seizures, eg HIE and infection [
      • Shellhaas R.A.
      • Wusthoff C.J.
      • Tsuchida T.N.
      • Glass H.C.
      • Chu C.J.
      • Massey S.L.
      • et al.
      Profile of neonatal epilepsies, characteristics of a prospective US cohort.
      ].

      1.3 The complex and reciprocal relationship between sleep and epilepsy

      Frequent seizures and high intensity of epileptic activity can disrupt sleep regulation and circadian rhythms and fragment sleep [
      • Vaughn B.
      Sleep and epilepsy.
      ]. Sleep disruption, in turn, may interfere with seizure control [
      • Pereira A.M.
      • Bruni O.
      • Ferri R.
      • Palmini A.
      • Nunes M.L.
      The impact of epilepsy on sleep architecture during childhood.
      ]. Antiepileptic therapy can also contribute to sleep architecture disturbance [
      • Chan S.Y.S.
      Sleep architecture and homeostasis in children with epilepsy: a neurodevelopmental perspective.
      ].
      Seizures are associated with adverse neurodevelopmental outcomes [
      • Zhou K.Q.
      • McDouall A.
      • Drury P.P.
      • Lear C.A.
      • Cho K.H.T.
      • Bennet L.
      • et al.
      Treating seizures after hypoxic-ischemic encephalopathy-current controversies and future directions.
      ], however, it has yet to be established whether abnormal sleep reflects abnormal brain development, or whether abnormal sleep exacerbates pre-existing abnormal neurodevelopment [
      • Parisi P.
      The relationship between sleep and epilepsy: the effect on cognitive functioning in children.
      ].
      We conducted a scoping review to systematically map research in this sensitive period of development and to help identify potential knowledge gaps and topics for further research. The more we understand about this complex interplay between sleep and epilepsy, the more precisely we can intervene to improve the lives of young children.

      2. Material and methods

      This paper adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews [
      • Tricco A.
      PRISMA extension for scoping reviews (PRISMA-ScR): checklist and explanation.
      ]. A scoping review protocol was created a priori (Appendix 1).
      To identify relevant publications we searched MEDLINE, EMBASE and Web of Science databases with a search strategy of keywords. The main search concept combined the terms “epilepsy” AND “infant” AND “sleep” with related descriptors for each of these elements. "Epilepsy” included epilepsy, epilepsies, epileptic seizure and encephalopathy, “infant” included infant, baby, babies, child∗, neonate, newborn, month-old, months-old and “sleep” included sleep, wakefulness, bed, cyclic alternating pattern and polysomnography. Additional searches included the combination of “epilepsy” OR “seizure” AND “sleep” AND individual aetiologies “metabolic”, “genetic”, “infectious”, “structural”, “immune”, “porencephalic”, “tumour”, “DNET”, “ganglioma” (Appendix 2).
      The original database searches were conducted on 11/5/20 and re-run on 19/12/21 to identify more recent sources.
      We included case reports, case-control studies, other types of studies and reviews published from 2005 to date, meeting the following eligibility criteria: 1) Original research published in peer-reviewed journals; 2) Population with unprovoked seizures and onset of epilepsy in the first six months of life; 3) Publications providing data on sleep architecture if they gave information for at least one data variable on microstructure/microstructure of sleep as described in Table 2, even if the primary intent of the study was not focused on sleep architecture.
      We excluded studies if 1) no full text study was published; 2) the publication language was not English; 3) the publication only described seizure semiology or sleep quality; 4) the primary focus was Dravet Syndrome.
      The rationale for selecting the 6 month cut-off is pathophysiological and sleep related, based on the expected peak impact of the underlying condition on sleep architecture.
      Epilepsies within the first six months of life were defined according to the ILAE 2017 classification [
      • Scheffer I.
      ILAE classification of the epilepsies: position paper of the ILAE commission for classification and terminology.
      ]. We excluded papers exclusively describing seizure semiology and also those focused on Dravet Syndrome, because the highest seizure burden and its impact on sleep and development of patients with Dravet syndrome is after the first 6 months of life [
      • McTague A.
      The genetic landscape of the epileptic encephalopathies of infancy and childhood.
      ,].
      Title, abstract and full-text searches were screened against the inclusion criteria by one reviewer. We also hand searched grey literature and scanned relevant review articles and journal tables of content for additional references.
      Final search results were exported into EndNote and duplicates manually removed. To increase consistency, two reviewers (SJ and AD) discussed the final list of publications to agree on study selection and amended the screening and data extraction plan. Disagreements were resolved through discussion.
      We grouped publications by aetiology and epilepsy type. Two reviewers (SJ and AD) agreed the fields for data charting. One reviewer (SJ) extracted the data, which was then cross-checked by a second reviewer (DK), see Supplementary Information.
      In line with accepted scoping review methodology [
      • Tricco A.
      PRISMA extension for scoping reviews (PRISMA-ScR): checklist and explanation.
      ], a formal risk of bias and methodological quality of data was not conducted, however, a level of evidence from 1 to 5 (1 being the highest) was assigned to each manuscript, according to the Joanna Briggs Institute recommendation [
      The Joanna Briggs Institute levels of evidence and grades of recommendation working party∗. SupportingDocumentfortheJoannaBriggsInstituteLevelsofEvidence andGradesof recommendation, 2014 recommendation.
      ] (Table 3).
      Table 3Level of evidence framework.
      Level of evidence
      1Inception cohort studies
      1aSystematic review of inception cohort studies
      1bInception cohort study
      2Studies of all or none
      2aSystematic review of all or none studies
      2bAll or none studies
      3Cohort studies
      3aSystematic review of cohort studies (or control arm of Randomised Controlled Trial (RCT))
      3bCohort study (or control arm of RCT)
      4Case series/Case Controlled/Historically Controlled studies
      4aSystematic review of Case series/Case Controlled/Historically Controlled studies
      4bIndividual Case series/Case Controlled/Historically Controlled study
      5Expert Opinion and Bench Research
      5aSystematic review of expert opinion
      5bExpert consensus
      5cBench research/single expert opinion
      During the conduct of the review, we noted that the protocol was not specific enough. A post-hoc modification was made specifying that infants with provoked seizures were excluded.

      3. Results

      We reviewed 7237 abstracts and 561 full-text articles, duplicates were manually removed and 540 publications were excluded (Fig. 1). 21 publications were included in the final analysis (Table 4).
      Table 4Overview of publications included in qualitative analysis.
      Data sourcesType of epilepsy described
      ManuscriptDescriptionLevel of evidenceSelf-limitedEarly infantile developmental and epileptic EncephalopathyAetiology specific
      West Syndrome and infantile spasmsEarly infantile epileptic encephalopathyEarly myoclonic epilepsyEpilepsy of infancy with migrating focal seizuresStructuralGeneticMetabolic
      Nunes, 2010 [
      • Nunes M.L.
      • Costa J.C.D.
      Sleep and epilepsy in neonates.
      ]
      Review article of sleep and epilepsy in neonates.

      Literature review with search of PubMed database using key words “neonatal seizures” and “sleep”
      4+++
      Caraballo, 2013 [
      • Caraballo R.
      Myoclonic epilepsy in infancy: an electroclinical study and long-term follow-up of 38 patients.
      ]
      Retrospective chart review of 38 patients with myoclonic epilepsy in infancy4+
      Koutromanidis, 2017 [
      • Koutroumanidis M.
      • Arzimanoglou A.
      • Caraballo R.
      • Goyal S.
      • Kaminska A.
      • Laoprasert P.
      • et al.
      The role of EEG in the diagnosis and classification of the epilepsy syndromes: a tool for clinical practice by the ILAE Neurophysiology Task Force (Part 2).
      ]
      Review article by the ILAE Neurophysiology Task Force on the role of EEG in diagnosis and classification of the main neonatal and paediatric epilepsy syndromes5+++++
      Lee, 2015 [
      • Lee Y.J.
      • Yeon G.M.
      • Kim Y.M.
      • Nam S.O.
      Relationship between initial electroencephalographic characteristics and seizure outcomes in children with non-lesional West syndrome.
      ]
      Retrospective review of 66 children with non-lesional West Syndrome, comparing those with and without seizure free outcomes4+
      Fois, 2010 [
      • Fois A.
      Infantile spasms: review of the literature and personal experience.
      ]
      Literature review and personal experience of infantile spasms5+
      Guzzetta, 2008 [
      • Guzzetta F.
      • Cioni G.
      • Mercuri E.
      • Fazzi E.
      • Biagioni E.
      • Veggiotti P.
      • et al.
      Neurodevelopmental evolution of West syndrome: a 2-year prospective study.
      ]
      2 year prospective study of 21 infants with West Syndrome3+
      Fattinger, 2015 [
      • Fattinger S.
      • Schmitt B.
      • Heinzle B.K.B.
      • Critelli H.
      • Jenni O.G.
      • Huber R.
      Impaired slow wave sleep downscaling in patients with infantile spasms.
      ]
      Retrospective case-controlled study in 14 infants diagnosed with West syndrome, assessing slow wave sleep4+
      Muzykewicz, 2009 [
      • Muzykewicz D.A.
      • Costello D.J.
      • Halpern E.F.
      • Thiele E.A.
      Infantile spasms in tuberous sclerosis complex: prognostic utility of EEG.
      ]
      Retrospective chart review of 45 children with tuberous sclerosis and a history of Infantile Spasms4+
      Spenner, 2019 [
      • Spenner B.
      • Krois-Neudenberger J.
      • Kurlemann G.
      • Althaus J.
      • Schwartz O.
      • Fiedler B.
      The prognostic value of sleep spindles in long-term outcome of West Syndrome.
      ]
      Retrospective single observer review of 448 sleep EEGs recorded during first two years of life in 44 patients with West syndrome4+
      Fusco, 2020 [
      • Fusco L.
      • Serino D.
      • Santarone M.E.
      Three different scenarios for epileptic spasms.
      ]
      Review article summarising three different scenarios in which epileptic spasms (ES) may occur5++
      Heinrich, 2021 [
      • Heinrich B.
      • Schmitt B.
      • Bölsterli B.K.
      • Critelli H.
      • Huber R.
      • Fattinger S.
      Disparate effects of hormones and vigabatrin on sleep slow waves in patients with West syndrome - an indication of their mode of action?.
      ]
      Retrospective case-controlled analysis of 61 infants with onset of West Syndrome between 2 and 24 months of age, treated with vigabatrin (VGB) or hormones, or both.4+
      Gofschteyn, 2021 [
      • Gofshteyn Js K.K.G.
      • Marquis B.O.J.J.L.
      • Gourley D.
      • Grinspan Z.
      • et al.
      Measurable outcomes for pediatric epileptic encephalopathy: a single-center experience with corticosteroid therapy.
      ]
      Retrospective single-centre cohort study including 35 children with epileptic encephalopathy (excluding infantile spasms). Age range at onset of epilepsy ranged from 0 to 3years3+
      Liu, 2017 [
      • Liu L.L.
      • Hou X.L.
      • Zhang D.D.
      • Sun G.Y.
      • Zhou C.L.
      • Jiang Y.
      • et al.
      Clinical manifestations and amplitude-integrated encephalogram in neonates with early-onset epileptic encephalopathy.
      ]
      128 term neonates with neonatal seizures followed up until 1 year old. 66 neonates evolved into EOEE (Early onset epileptic encephalopathy) the other 62 served as the non-EOEE (nEOEE = control) group.

      Primary causes of seizures were severe perinatal cerebral injury, congenital encephalodysplasia, and congenital metabolic diseases. Aetiology unclear in 72.4% of infants.
      3++
      Khan, 2008 [
      • Khan R.L.
      • Nunes M.L.
      • Garcias da Silva L.F.
      • da Costa J.C.
      Predictive value of sequential electroencephalogram (EEG) in neonates with seizures and its relation to neurological outcome.
      ]
      Retrospective analysis of 58 pairs of sequential EEGs from newborns with seizures belonging to 2 historical cohorts of infants admitted to NICU. Mix of provoked and unprovoked seizures.3+
      Carvalho, 2017 [
      • Carvalho M.
      • Miranda D.D.
      • van der Linden V.
      • Sobral P.F.
      • Ramos R.C.F.
      • Rocha M.A.W.
      • et al.
      Sleep EEG patterns in infants with congenital Zika virus syndrome.
      ]
      Case series including sleep EEG patterns in 37 infants aged <6 months with microcephaly diagnosed with congenital Zika virus infection4+
      Kanda, 2018 [
      • Kanda P.A.M.
      Sleep EEG of microcephaly in zika outbreak.
      ]
      Retrospective review of sleep EEGs in 10 patients with microcephaly associated with Zika virus infection4+
      Aravindhan, 2018 [
      • Aravindhan A.
      • Shah K.
      • Pak J.
      • Veerapandiyan A.
      Early-onset epileptic encephalopathy with myoclonic seizures related to 9q33.3-q34.11 deletion involving STXBP1 and SPTAN1 genes.
      ]
      Case report of a 10-month-old with early-onset epileptic encephalopathy due to hemizygous deletion 9q33.3q34.11 involving STXBP1 and SPTAN1 genes4+
      Serino, 2013 [
      • Serino D.
      • Specchio N.
      • Pontrelli G.
      • Vigevano F.
      • Fusco L.
      Video/EEG findings in a KCNQ2 epileptic encephalopathy: a case report and revision of literature data.
      ]
      Case report of an infant with genetic variant of KCNQ2 gene and review of 15 cases from literature4+
      Alsaleem, 2019 [
      • Alsaleem M.
      • Carrion V.
      • Weinstock A.
      • Chandrasekharan P.
      Infantile refractory seizures due to de novo KCNT 1 mutation.
      ]
      Case report of a term infant with genetic variant of KCN, multiple seizures refractory to anti-seizure medication4+
      Bozarth, 2018 [
      • Bozarth X.
      • Dines J.N.
      • Cong Q.
      • Mirzaa G.M.
      • Foss K.
      • Lawrence Merritt J.
      • et al.
      Expanding clinical phenotype in CACNA1C related disorders: from neonatal onset severe epileptic encephalopathy to late-onset epilepsy.
      ]
      Case report of one infant who presented with neonatal onset epileptic encephalopathy with de novo missense variant in CACNA1C (c.4087G > A (p.V1363 M))4+
      Olson, 2012 [
      • Olson H.E.
      • Poduri A.
      CDKL5 mutations in early onset epilepsy: case report and review of the literature.
      ]
      Case report and review of the literature (29 publications) of CDKL5 mutations in early onset epilepsy4+
      Olischar, 2012 [
      • Olischar M.
      • Shany E.
      • Aygün C.
      • Azzopardi D.
      • Hunt R.W.
      • Toet M.C.
      • et al.
      Amplitude-integrated electroencephalography in newborns with inborn errors of metabolism.
      ]
      aEEG tracings of 30 neonates with metabolic disorders from an international registry4+
      Guerriero, 2017 [
      • Guerriero R.M.
      • Patel A.A.
      • Walsh B.
      • Baumer F.M.
      • Shah A.S.
      • Peters J.M.
      • et al.
      Systemic manifestations in pyridox(am)ine 5′-phosphate oxidase deficiency.
      ]
      Case series of 6 infants from one centre with PNPO deficiency, neonatal-onset epileptic encephalopathy with developmental delay and seizures4+
      Schmitt, 2010 [
      • Schmitt B.
      Seizures and paroxysmal events: symptoms pointing to the diagnosis of pyridoxine-dependent epilepsy and pyridoxine phosphate oxidase deficiency.
      ]
      Retrospective case review of four patients with PDE and one patient with PNPO4+
      Melikishvili, 2020 [
      • Melikishvili G.
      • Dulac O.
      • Gataullina S.
      Neonatal SCN2A encephalopathy: a peculiar recognizable electroclinical sequence.
      ]
      Retrospective case review of three patients with de novo SCN2A mutations4+

      3.1 Results: summary of findings

      We identified 21 publications providing data relating to sleep architecture in our target population. We found no data relating to sleep architecture in non-familial self-limited neonatal epilepsy or in structural epilepsies due to paediatric tumours.
      In self-limited familial and genetic epilepsy, sleep macrostructure was generally preserved. In DEEs and in epileptic encephalopathies of genetic or structural aetiology, sleep architecture was significantly disrupted.

      4. Discussion

      In self-limited familial and genetic epilepsy, sleep macrostructure was generally preserved. In DEEs and in epileptic encephalopathies of genetic or structural aetiology, sleep architecture was significantly disrupted. More macrostructural than microstructural elements were reported in the articles included (Table 5).
      Table 5Summarises the key findings from our data analysis.
      Type of epilepsySummary of evidenceMacrostructureMicrostructureOther
      Self-limited epilepsyLevel 4 and 5 evidence from 2 review articles describing self-limited familial neonatal seizures, self-limited infantile epilepsy, myoclonic epilepsy of infancy [
      • Koutroumanidis M.
      • Arzimanoglou A.
      • Caraballo R.
      • Goyal S.
      • Kaminska A.
      • Laoprasert P.
      • et al.
      The role of EEG in the diagnosis and classification of the epilepsy syndromes: a tool for clinical practice by the ILAE Neurophysiology Task Force (Part 2).
      ,
      • Nunes M.L.
      • Costa J.C.D.
      Sleep and epilepsy in neonates.
      ] and 1 retrospective chart review of myoclonic epilepsy of infancy [
      • Caraballo R.
      Myoclonic epilepsy in infancy: an electroclinical study and long-term follow-up of 38 patients.
      ].
      Self-limited familial neonatal seizures: sleep features do not seem to be disrupted [
      • Nunes M.L.
      • Costa J.C.D.
      Sleep and epilepsy in neonates.
      ].

      Self-limited infantile epilepsy and myoclonic epilepsy of infancy: preserved sleep architecture [
      • Koutroumanidis M.
      • Arzimanoglou A.
      • Caraballo R.
      • Goyal S.
      • Kaminska A.
      • Laoprasert P.
      • et al.
      The role of EEG in the diagnosis and classification of the epilepsy syndromes: a tool for clinical practice by the ILAE Neurophysiology Task Force (Part 2).
      ,
      • Caraballo R.
      Myoclonic epilepsy in infancy: an electroclinical study and long-term follow-up of 38 patients.
      ].
      Early infantile development and epileptic encephalopathy (EIDEE)West Syndrome9 publications, primarily level 4 and 5 evidence [
      • Fattinger S.
      • Schmitt B.
      • Heinzle B.K.B.
      • Critelli H.
      • Jenni O.G.
      • Huber R.
      Impaired slow wave sleep downscaling in patients with infantile spasms.
      ,
      • Koutroumanidis M.
      • Arzimanoglou A.
      • Caraballo R.
      • Goyal S.
      • Kaminska A.
      • Laoprasert P.
      • et al.
      The role of EEG in the diagnosis and classification of the epilepsy syndromes: a tool for clinical practice by the ILAE Neurophysiology Task Force (Part 2).
      ,
      • Lee Y.J.
      • Yeon G.M.
      • Kim Y.M.
      • Nam S.O.
      Relationship between initial electroencephalographic characteristics and seizure outcomes in children with non-lesional West syndrome.
      ,
      • Fois A.
      Infantile spasms: review of the literature and personal experience.
      ,
      • Muzykewicz D.A.
      • Costello D.J.
      • Halpern E.F.
      • Thiele E.A.
      Infantile spasms in tuberous sclerosis complex: prognostic utility of EEG.
      ,
      • Spenner B.
      • Krois-Neudenberger J.
      • Kurlemann G.
      • Althaus J.
      • Schwartz O.
      • Fiedler B.
      The prognostic value of sleep spindles in long-term outcome of West Syndrome.
      ,
      • Fusco L.
      • Serino D.
      • Santarone M.E.
      Three different scenarios for epileptic spasms.
      ,
      • Heinrich B.
      • Schmitt B.
      • Bölsterli B.K.
      • Critelli H.
      • Huber R.
      • Fattinger S.
      Disparate effects of hormones and vigabatrin on sleep slow waves in patients with West syndrome - an indication of their mode of action?.
      ], with one level 3 evidence source, a prospective cohort study [
      • Guzzetta F.
      • Cioni G.
      • Mercuri E.
      • Fazzi E.
      • Biagioni E.
      • Veggiotti P.
      • et al.
      Neurodevelopmental evolution of West syndrome: a 2-year prospective study.
      ].
      Normal sleep patterns are absent, background is abnormal [
      • Fattinger S.
      • Schmitt B.
      • Heinzle B.K.B.
      • Critelli H.
      • Jenni O.G.
      • Huber R.
      Impaired slow wave sleep downscaling in patients with infantile spasms.
      ,
      • Fois A.
      Infantile spasms: review of the literature and personal experience.
      ,
      • Guzzetta F.
      • Cioni G.
      • Mercuri E.
      • Fazzi E.
      • Biagioni E.
      • Veggiotti P.
      • et al.
      Neurodevelopmental evolution of West syndrome: a 2-year prospective study.
      ,
      • Muzykewicz D.A.
      • Costello D.J.
      • Halpern E.F.
      • Thiele E.A.
      Infantile spasms in tuberous sclerosis complex: prognostic utility of EEG.
      ,
      • Fusco L.
      • Serino D.
      • Santarone M.E.
      Three different scenarios for epileptic spasms.
      ].

      One study demonstrated comparable total sleep time and sleep quality in overnight recordings [
      • Fattinger S.
      • Schmitt B.
      • Heinzle B.K.B.
      • Critelli H.
      • Jenni O.G.
      • Huber R.
      Impaired slow wave sleep downscaling in patients with infantile spasms.
      ] compared with healthy controls.

      Reduced REM sleep reported, although no significant difference was observed in REM amount in nap recordings [
      • Fattinger S.
      • Schmitt B.
      • Heinzle B.K.B.
      • Critelli H.
      • Jenni O.G.
      • Huber R.
      Impaired slow wave sleep downscaling in patients with infantile spasms.
      ]

      Sleep latency is comparable between control and treated infants [
      • Heinrich B.
      • Schmitt B.
      • Bölsterli B.K.
      • Critelli H.
      • Huber R.
      • Fattinger S.
      Disparate effects of hormones and vigabatrin on sleep slow waves in patients with West syndrome - an indication of their mode of action?.
      ]
      Physiological grapho-elements of sleep (vertex waves, spindles, and K-complexes) are usually absent [
      • Koutroumanidis M.
      • Arzimanoglou A.
      • Caraballo R.
      • Goyal S.
      • Kaminska A.
      • Laoprasert P.
      • et al.
      The role of EEG in the diagnosis and classification of the epilepsy syndromes: a tool for clinical practice by the ILAE Neurophysiology Task Force (Part 2).
      ,
      • Fusco L.
      • Serino D.
      • Santarone M.E.
      Three different scenarios for epileptic spasms.
      ].

      Emergence of sleep spindles may be disturbed, although retention of sleep spindles from disease onset has been described, as well as recurrence of sleep spindles after initiation of anti-convulsive treatment [
      • Spenner B.
      • Krois-Neudenberger J.
      • Kurlemann G.
      • Althaus J.
      • Schwartz O.
      • Fiedler B.
      The prognostic value of sleep spindles in long-term outcome of West Syndrome.
      ].

      Normal to borderline features of the sleep-spindle were reported to be more significantly and commonly maintained in seizure-free infants [
      • Lee Y.J.
      • Yeon G.M.
      • Kim Y.M.
      • Nam S.O.
      Relationship between initial electroencephalographic characteristics and seizure outcomes in children with non-lesional West syndrome.
      ].

      The physiological decrease of the slope of slow waves across the night during NREM sleep was reduced in infants with West Syndrome compared to controls [
      • Fattinger S.
      • Schmitt B.
      • Heinzle B.K.B.
      • Critelli H.
      • Jenni O.G.
      • Huber R.
      Impaired slow wave sleep downscaling in patients with infantile spasms.
      ].
      Among the sleep activities, the normal to borderline features of the sleep-spindle were more significantly and commonly maintained in the SF group [
      • Lee Y.J.
      • Yeon G.M.
      • Kim Y.M.
      • Nam S.O.
      Relationship between initial electroencephalographic characteristics and seizure outcomes in children with non-lesional West syndrome.
      ].

      More typical hypsarrhythmia and loss of sleep-spindles may suggest a more severe phenotype with more affected normal cortical functions [
      • Lee Y.J.
      • Yeon G.M.
      • Kim Y.M.
      • Nam S.O.
      Relationship between initial electroencephalographic characteristics and seizure outcomes in children with non-lesional West syndrome.
      ].

      Disorganisation of slow wave sleep (NREM N3) was an unfavourable prognostic factor for neurosensory and developmental outcome [
      • Fattinger S.
      • Schmitt B.
      • Heinzle B.K.B.
      • Critelli H.
      • Jenni O.G.
      • Huber R.
      Impaired slow wave sleep downscaling in patients with infantile spasms.
      ,
      • Guzzetta F.
      • Cioni G.
      • Mercuri E.
      • Fazzi E.
      • Biagioni E.
      • Veggiotti P.
      • et al.
      Neurodevelopmental evolution of West syndrome: a 2-year prospective study.
      ,
      • Spenner B.
      • Krois-Neudenberger J.
      • Kurlemann G.
      • Althaus J.
      • Schwartz O.
      • Fiedler B.
      The prognostic value of sleep spindles in long-term outcome of West Syndrome.
      ] and associated with lower follow-up Intelligent

      Quotient (or equivalent measure) [
      • Muzykewicz D.A.
      • Costello D.J.
      • Halpern E.F.
      • Thiele E.A.
      Infantile spasms in tuberous sclerosis complex: prognostic utility of EEG.
      ].

      Significant but disparate effects of treatment on sleep slow waves54.
      Early infantile epileptic encephalopathySleep stages are unclassified and REM sleep is not detectable [
      • Nunes M.L.
      • Costa J.C.D.
      Sleep and epilepsy in neonates.
      ].

      Suppression burst is associated with impaired sleep quality and lack of physiological sleep elements including sleep cycles [
      • Koutroumanidis M.
      • Arzimanoglou A.
      • Caraballo R.
      • Goyal S.
      • Kaminska A.
      • Laoprasert P.
      • et al.
      The role of EEG in the diagnosis and classification of the epilepsy syndromes: a tool for clinical practice by the ILAE Neurophysiology Task Force (Part 2).
      ].
      Lack of sleep spindles which may reappear transiently with treatment [
      • Gofshteyn Js K.K.G.
      • Marquis B.O.J.J.L.
      • Gourley D.
      • Grinspan Z.
      • et al.
      Measurable outcomes for pediatric epileptic encephalopathy: a single-center experience with corticosteroid therapy.
      ]
      Suppression burst pattern occurs in both wakefulness and sleep, in contrast to early myoclonic encephalopathy, where it can be present only during sleep or enhanced by sleep [
      • Koutroumanidis M.
      • Arzimanoglou A.
      • Caraballo R.
      • Goyal S.
      • Kaminska A.
      • Laoprasert P.
      • et al.
      The role of EEG in the diagnosis and classification of the epilepsy syndromes: a tool for clinical practice by the ILAE Neurophysiology Task Force (Part 2).
      ].
      Early myoclonic epilepsyMay have preserved sleep background rhythms at complete presentation [
      • Koutroumanidis M.
      • Arzimanoglou A.
      • Caraballo R.
      • Goyal S.
      • Kaminska A.
      • Laoprasert P.
      • et al.
      The role of EEG in the diagnosis and classification of the epilepsy syndromes: a tool for clinical practice by the ILAE Neurophysiology Task Force (Part 2).
      ].
      Consistent suppression-burst pattern during sleep has been described in early myoclonic encephalopathy [
      • Nunes M.L.
      • Costa J.C.D.
      Sleep and epilepsy in neonates.
      ].
      Epilepsy of infancy with migrating focal seizuresDuring seizure-free periods, sleep and wakefulness are clearly differentiated [
      • Koutroumanidis M.
      • Arzimanoglou A.
      • Caraballo R.
      • Goyal S.
      • Kaminska A.
      • Laoprasert P.
      • et al.
      The role of EEG in the diagnosis and classification of the epilepsy syndromes: a tool for clinical practice by the ILAE Neurophysiology Task Force (Part 2).
      ].
      Sleep spindles are rare, asynchronous, and asymmetric [
      • Koutroumanidis M.
      • Arzimanoglou A.
      • Caraballo R.
      • Goyal S.
      • Kaminska A.
      • Laoprasert P.
      • et al.
      The role of EEG in the diagnosis and classification of the epilepsy syndromes: a tool for clinical practice by the ILAE Neurophysiology Task Force (Part 2).
      ]
      Genetic (overlaps with EIDEE)Level 4 evidence from six case reports, often including associated literature reviews [
      • Aravindhan A.
      • Shah K.
      • Pak J.
      • Veerapandiyan A.
      Early-onset epileptic encephalopathy with myoclonic seizures related to 9q33.3-q34.11 deletion involving STXBP1 and SPTAN1 genes.
      ,
      • Serino D.
      • Specchio N.
      • Pontrelli G.
      • Vigevano F.
      • Fusco L.
      Video/EEG findings in a KCNQ2 epileptic encephalopathy: a case report and revision of literature data.
      ,
      • Alsaleem M.
      • Carrion V.
      • Weinstock A.
      • Chandrasekharan P.
      Infantile refractory seizures due to de novo KCNT 1 mutation.
      ,
      • Bozarth X.
      • Dines J.N.
      • Cong Q.
      • Mirzaa G.M.
      • Foss K.
      • Lawrence Merritt J.
      • et al.
      Expanding clinical phenotype in CACNA1C related disorders: from neonatal onset severe epileptic encephalopathy to late-onset epilepsy.
      ,
      • Olson H.E.
      • Poduri A.
      CDKL5 mutations in early onset epilepsy: case report and review of the literature.
      ,
      • Melikishvili G.
      • Dulac O.
      • Gataullina S.
      Neonatal SCN2A encephalopathy: a peculiar recognizable electroclinical sequence.
      ] of CDKL5 deficiency disorder [
      • Olson H.E.
      • Poduri A.
      CDKL5 mutations in early onset epilepsy: case report and review of the literature.
      ] pathogenic variants of KCNT1 [
      • Alsaleem M.
      • Carrion V.
      • Weinstock A.
      • Chandrasekharan P.
      Infantile refractory seizures due to de novo KCNT 1 mutation.
      ] and KCNQ2 [
      • Serino D.
      • Specchio N.
      • Pontrelli G.
      • Vigevano F.
      • Fusco L.
      Video/EEG findings in a KCNQ2 epileptic encephalopathy: a case report and revision of literature data.
      ], STXBP1 and SPTAN1 deletion [
      • Aravindhan A.
      • Shah K.
      • Pak J.
      • Veerapandiyan A.
      Early-onset epileptic encephalopathy with myoclonic seizures related to 9q33.3-q34.11 deletion involving STXBP1 and SPTAN1 genes.
      ], SCN2A [
      • Melikishvili G.
      • Dulac O.
      • Gataullina S.
      Neonatal SCN2A encephalopathy: a peculiar recognizable electroclinical sequence.
      ] and CACNA1C pathogenic variant [
      • Bozarth X.
      • Dines J.N.
      • Cong Q.
      • Mirzaa G.M.
      • Foss K.
      • Lawrence Merritt J.
      • et al.
      Expanding clinical phenotype in CACNA1C related disorders: from neonatal onset severe epileptic encephalopathy to late-onset epilepsy.
      ].
      Poor wake-sleep transitions in KCNT1 [
      • Alsaleem M.
      • Carrion V.
      • Weinstock A.
      • Chandrasekharan P.
      Infantile refractory seizures due to de novo KCNT 1 mutation.
      ] and general disturbance of the sleep/wake cycle with CACNA1C mutation [
      • Bozarth X.
      • Dines J.N.
      • Cong Q.
      • Mirzaa G.M.
      • Foss K.
      • Lawrence Merritt J.
      • et al.
      Expanding clinical phenotype in CACNA1C related disorders: from neonatal onset severe epileptic encephalopathy to late-onset epilepsy.
      ].

      In CDKL5 deficiency disorder, EEG at onset can be normal with background slowing and preserved sleep features [
      • Olson H.E.
      • Poduri A.
      CDKL5 mutations in early onset epilepsy: case report and review of the literature.
      ].

      One infant who presented with neonatal onset epileptic encephalopathy and CACNA1C variant had a severe disturbance of sleep/wake cycle, however, normal sleep architecture at 5 months of age on polysomnography [
      • Bozarth X.
      • Dines J.N.
      • Cong Q.
      • Mirzaa G.M.
      • Foss K.
      • Lawrence Merritt J.
      • et al.
      Expanding clinical phenotype in CACNA1C related disorders: from neonatal onset severe epileptic encephalopathy to late-onset epilepsy.
      ].
      STXBP1 and SPTAN1 variant:

      Interictal EEG showed a lack of normal organisation and complexity, and multifocal polyspike-wave during wakefulness and sleep [
      • Aravindhan A.
      • Shah K.
      • Pak J.
      • Veerapandiyan A.
      Early-onset epileptic encephalopathy with myoclonic seizures related to 9q33.3-q34.11 deletion involving STXBP1 and SPTAN1 genes.
      ].

      Following seizure cessation, improvement of sleep activity organisation and normalisation of architecture with improved continuity of background and resolution of suppression-burst pattern was reported in KCNQ2 and CACNA1C variant [
      • Serino D.
      • Specchio N.
      • Pontrelli G.
      • Vigevano F.
      • Fusco L.
      Video/EEG findings in a KCNQ2 epileptic encephalopathy: a case report and revision of literature data.
      ,
      • Bozarth X.
      • Dines J.N.
      • Cong Q.
      • Mirzaa G.M.
      • Foss K.
      • Lawrence Merritt J.
      • et al.
      Expanding clinical phenotype in CACNA1C related disorders: from neonatal onset severe epileptic encephalopathy to late-onset epilepsy.
      ].
      A very discontinuous pattern during sleep evolves towards a defined burst-suppression pattern in KCNQ2 [
      • Serino D.
      • Specchio N.
      • Pontrelli G.
      • Vigevano F.
      • Fusco L.
      Video/EEG findings in a KCNQ2 epileptic encephalopathy: a case report and revision of literature data.
      ].

      A very discontinuous pattern during sleep remains distinct from burst-suppression in SCN2A [
      • Melikishvili G.
      • Dulac O.
      • Gataullina S.
      Neonatal SCN2A encephalopathy: a peculiar recognizable electroclinical sequence.
      ].
      StructuralLevel 3 evidence from two cohort studiesSeverely abnormal background pattern and absence of sleep wake cycling in the encephalopathic group of infants [
      • Liu L.L.
      • Hou X.L.
      • Zhang D.D.
      • Sun G.Y.
      • Zhou C.L.
      • Jiang Y.
      • et al.
      Clinical manifestations and amplitude-integrated encephalogram in neonates with early-onset epileptic encephalopathy.
      ]
      A correlation with probable HIE and neurodevelopmental delay was also observed [
      • Khan R.L.
      • Nunes M.L.
      • Garcias da Silva L.F.
      • da Costa J.C.
      Predictive value of sequential electroencephalogram (EEG) in neonates with seizures and its relation to neurological outcome.
      ].
      Structural: Congenital Zika VirusLevel 4 evidence from two case seriesAbnormal background activity and abnormal sleep architecture, even in infants who had not yet developed epilepsy [
      • Carvalho M.
      • Miranda D.D.
      • van der Linden V.
      • Sobral P.F.
      • Ramos R.C.F.
      • Rocha M.A.W.
      • et al.
      Sleep EEG patterns in infants with congenital Zika virus syndrome.
      ]
      Lack of sleep spindles [
      • Carvalho M.
      • Miranda D.D.
      • van der Linden V.
      • Sobral P.F.
      • Ramos R.C.F.
      • Rocha M.A.W.
      • et al.
      Sleep EEG patterns in infants with congenital Zika virus syndrome.
      ,
      • Kanda P.A.M.
      Sleep EEG of microcephaly in zika outbreak.
      ]
      Modified hypsarrhythmia with or without burst suppression [
      • Carvalho M.
      • Miranda D.D.
      • van der Linden V.
      • Sobral P.F.
      • Ramos R.C.F.
      • Rocha M.A.W.
      • et al.
      Sleep EEG patterns in infants with congenital Zika virus syndrome.
      ,
      • Kanda P.A.M.
      Sleep EEG of microcephaly in zika outbreak.
      ]
      Inborn errors of metabolismLevel 3 and 4 evidence, composed of the following:

      1. Review of aEEG tracings of 30 neonates from an International Registry of metabolic disorders and congenital malformations [
      • Olischar M.
      • Shany E.
      • Aygün C.
      • Azzopardi D.
      • Hunt R.W.
      • Toet M.C.
      • et al.
      Amplitude-integrated electroencephalography in newborns with inborn errors of metabolism.
      ]. Specific metabolic disorders include inborn errors of energy metabolism, hyperammonaemia, amino and organic amino acid acidaemias, peroxisomal disorders or non-ketotic hyperglycinaemia [
      • Olischar M.
      • Shany E.
      • Aygün C.
      • Azzopardi D.
      • Hunt R.W.
      • Toet M.C.
      • et al.
      Amplitude-integrated electroencephalography in newborns with inborn errors of metabolism.
      ].

      2. A case series of six neonates, including five pre-term, with Pyridox(am)ine 5′-Phosphate Oxidase Deficiency (PNPO) deficiency, neonatal-onset epileptic encephalopathy, developmental delay and seizures [
      • Guerriero R.M.
      • Patel A.A.
      • Walsh B.
      • Baumer F.M.
      • Shah A.S.
      • Peters J.M.
      • et al.
      Systemic manifestations in pyridox(am)ine 5′-phosphate oxidase deficiency.
      ].

      3. A case series of five infants, four of whom have pyridoxine dependent epilepsy and one with PNPO [
      • Schmitt B.
      Seizures and paroxysmal events: symptoms pointing to the diagnosis of pyridoxine-dependent epilepsy and pyridoxine phosphate oxidase deficiency.
      ].
      More infants with inborn errors of energy metabolism and peroxisomal disorders retained SWC compared with other groups [
      • Olischar M.
      • Shany E.
      • Aygün C.
      • Azzopardi D.
      • Hunt R.W.
      • Toet M.C.
      • et al.
      Amplitude-integrated electroencephalography in newborns with inborn errors of metabolism.
      ,
      • Guerriero R.M.
      • Patel A.A.
      • Walsh B.
      • Baumer F.M.
      • Shah A.S.
      • Peters J.M.
      • et al.
      Systemic manifestations in pyridox(am)ine 5′-phosphate oxidase deficiency.
      ].
      In one infant with pyridoxine dependent epilepsy, interictal EEG demonstrated trace alternant in sleep and a few sharp waves in the neonatal period.‘Sleep disturbance’ without specification was also reported [
      • Schmitt B.
      Seizures and paroxysmal events: symptoms pointing to the diagnosis of pyridoxine-dependent epilepsy and pyridoxine phosphate oxidase deficiency.
      ].
      The early identification of infants with epilepsy, is important, to ensure early and effective treatment, however the evolution from seizures to a non-reversible encephalopathy cannot be predicted [
      • Pressler R.L.L.
      Why we urgently need improved seizure and epilepsy therapies for children and neonates.
      ]. Development of children with self-limited epilepsies is usually normal (Table 2), while developmental outcomes are impaired in other forms of epilepsy. The following questions need to be addressed:Is disturbed sleep architecture a marker of abnormal brain development, or does abnormal sleep contribute to pre-existing abnormal neurodevelopment? If sleep architecture is conserved in self-limited epilepsy, how could the study of sleep play a role in helping to predict the evolution of epilepsy early in the disease process?
      From the data analysed, it is not possible to infer whether sleep architecture disruption precedes epilepsy in this population, or vice versa. One could hypothesise that alterations in sleep arise rather secondary to encephalopathy, but this assumption requires additional exploration.
      As a disorder of cortical network organisation [
      • Ma K.
      Epilepsy as a disorder of cortical network organization.
      ] epilepsy affects brain structures involved in sleep plastic functions, such as the cortico-thalamic and hippocampal systems [
      • Halascz P.
      Sleep and epilepsy link by plasticity.
      ]. Seizures or high intensity of epileptiform discharges occurring early in life do so during a critical period of activity-dependent synaptogenesis (blooming) and its regulation by elimination of extra synapses (pruning), a sign of plasticity [
      • Tononi G.
      Sleep function and synaptic homeostasis.
      ,
      • Rakhade S.
      Epileptogenesis in the immature brain: emerging mechanisms.
      ]. Early alterations of sleep could have a lasting impact on the maturation of neural networks, resulting in functional disorders [
      • Bourel-Ponchel E.
      • Hasaerts D.
      • Challamel M.-J.
      • Lamblin M.-D.
      Behavioral-state development and sleep-state differentiation during early ontogenesis.
      ,
      • El-Dib M.
      Sleep wake cycling and neurodevelopmental outcome in very low birth weight infants.
      ]. The disappearance of physiological sleep elements may reflect dysfunctional networks, particularly in structures such as the thalamus, hypothalamus and brain stem. One could envisage a ‘tipping point’ of pathophysiologic events and remodelling, beyond which the developing brain is unable to compensate. These manifest either simultaneously, or sequentially, as disruption of sleep architecture and an epilepsy that cannot spontaneously resolve.
      Genetics may also influence the magnitude and appearance of sleep disruption. A genetic epilepsy either directly or through seizure activity or neurodevelopmental impact, could also impact genes involved in regulation of sleep, such as clock genes [
      • Borbely A.
      The two-process model of sleep regulation: a reappraisal.
      ].
      Sleep homeostasis and circadian regulation interact on a molecular/genetic level [
      • Borbely A.
      The two-process model of sleep regulation: a reappraisal.
      ]. A high seizure or epileptic activity burden would also disrupt circadian regulation [
      • Chan S.Y.S.
      Sleep architecture and homeostasis in children with epilepsy: a neurodevelopmental perspective.
      ]. In the popualation we analysed, it would be interesting to explore how the underlying pathophysiology of epilepsy impacts the evolution of ultradian to circadian rhythm, further confounding sleep changes. In infants with DEE, even with good seizure control, there is an underlying development delay due to the genetic component, which may also lead to further changes.
      Cellular mechanisms that underlie the vicious cycle of sleep disturbance and seizures are yet to be fully elucidated [
      • Reddy S.
      Neuroendocrine aspects of improving sleep in epilepsy.
      ] and the aetiology of disrupted sleep architecture is likely to be multifactorial. Epilepsy per se, through seizure activity, interictal discharges and ASM may play a role [
      • Chan S.Y.S.
      Sleep architecture and homeostasis in children with epilepsy: a neurodevelopmental perspective.
      ,
      • Parisi P.
      The relationship between sleep and epilepsy: the effect on cognitive functioning in children.
      ,
      • Racaru V.M.
      • Cheliout-Heraut F.
      • Azabou E.
      • Essid N.
      • Brami M.
      • Benga I.
      • et al.
      Sleep architecture impairment in epileptic children and putative role of anti epileptic drugs.
      ]. Specific seizure characteristics, in terms of frequency, type and diurnal distribution have been described in association with sleep disturbance in older children and mostly adult patients [
      • Crespel A.
      • Coubes P.
      • Baldy-Moulinier M.
      Sleep influence on seizures and epilepsy effects on sleep in partial frontal and temporal lobe epilepsies.
      ,
      • Matos G.
      • Andersen M.L.
      • do Valle A.C.
      • Tufik S.
      The relationship between sleep and epilepsy: evidence from clinical trials and animal models.
      ], however this information was not readily available from the publications included in the qualitative analysis.
      Change of the slope of slow waves and alteration of cyclic alternating pattern, an important element of microstructure, represent biomarkers of physiological sleep and sleep protection, although we found no data relating to CAP in our population. The physiological decrease of the slope of slow waves across the night during NREM sleep was reduced in infants with West Syndrome compared to controls [
      • Fattinger S.
      • Schmitt B.
      • Heinzle B.K.B.
      • Critelli H.
      • Jenni O.G.
      • Huber R.
      Impaired slow wave sleep downscaling in patients with infantile spasms.
      ]. This reflects hypsarrhythmia, a loss of organised brain activity, which impairs brain development. If brain activity is disorganised, then sleep is also disorganised and nocturnal regenerative processes will be impacted. Together with sleep spindle frequency, these elements allow a quantification of the integrity of sleep. In our analysis, sleep spindles were disturbed, reduced, asynchronous or absent in infants with DEE.
      Anti-seizure medication (ASM) can affect REM and NREM sleep, in particular slow wave sleep, NREM N3, both beneficially and detrimentally [
      • Kothare S.
      Sleep and epilepsy in children and adolescents.
      ]. Very few drugs are licensed for use in neonates and most data relating to ASM and sleep originate from adult studies [
      • Pressler R.L.L.
      Why we urgently need improved seizure and epilepsy therapies for children and neonates.
      ]. ASMs affect sleep architecture, some positively. Valproate may increase daytime sleepiness and slow wave sleep and decrease REM [
      • Kothare S.
      Sleep and epilepsy in children and adolescents.
      ]. Levetiracetam can also enhance daytime sleepiness, but decreases slow wave sleep and REM [
      • Jain S.
      Effects of epilepsy treatments on sleep architecture and daytime sleepiness: an evidence-based review of objective sleep metrics.
      ]. Phenobarbitone also reduces REM sleep. Carbamazepine increases slow wave sleep and decreases REM sleep [
      • Jain S.
      Effects of epilepsy treatments on sleep architecture and daytime sleepiness: an evidence-based review of objective sleep metrics.
      ]. These effects appear independent of their anticonvulsant actions [
      • Kothare S.
      Sleep and epilepsy in children and adolescents.
      ]. Data from adult studies with perampanel suggest an decrease in wake after sleep onset (WASO), increase of total sleep time, sleep maintenance index, duration of N3, a decrease of wake time, sleep latency and WASO, but no effect on micro-awakenings [
      • Liguori C.
      • Toledo M.
      • Kothare S.
      Effects of anti-seizure medications on sleep architecture and daytime sleepiness in patients with epilepsy: a literature review.
      ,
      • Rocamora R.
      • Álvarez I.
      • Chavarría B.
      • Principe A.
      Perampanel effect on sleep architecture in patients with epilepsy.
      ].
      In our analysis, there were insufficient data to provide meaningful observations related to the impact of ASM on sleep architecture.

      4.1 Limitations

      Our scoping review was conducted according to accepted scoping review methodology, however there are some inherent limitations.
      To maximise feasibility of the review, we limited publications to the last fifteen years, accepting the possibility of excluding older publications that might yield informative data.
      We assigned a level of evidence to each publication, however, in line with accepted scoping review methodology, we did not conduct a formal quality and risk of bias analysis of individual manuscripts. The level of evidence ranged from 3 to 5, reflecting the absence of randomised or even longitudinal controlled trials in this area. This may impact the robustness of conclusions from the data.
      Many of the studies were not designed or focused to study sleep architecture and there is variability in the parameters used to assess sleep architecture. In some publications only aEEG was used and no polysomnography was conducted. In others only sleep wake cycling is mentioned, with few additional elements of sleep architecture (Table 1) considered.
      Categorising publications by epilepsy type and aetiology allowed us to manage the data, although it is well recognised that aetiology of epilepsy may be multi-factorial [
      • Scheffer I.
      ILAE classification of the epilepsies: position paper of the ILAE commission for classification and terminology.
      ].
      We noted that our protocol was not specific enough at the outset. One post-hoc modification was to specify that infants with provoked seizures were excluded.

      5. Conclusions

      Sleep macrostructure is generally preserved in self-limited genetic epilepsy in the first 6 months of age. In infants with epilepsies in the DEE spectrum, sleep architecture is significantly impacted. Infants with abnormal sleep architecture may also experience compromised developmental outcomes, however a direct association is hypothetical and more likely to be multi-factorial, reflecting underlying aetiology, evolution of the disease and seizure burden. The relative contribution of each factor is difficult to tease out.
      More longitudinal and well-controlled studies are needed to assess and quantify the changes in sleep architecture in this population and to characterise the individual contribution of sleep, epilepsy and ASM in this vicious cycle of disruption. Additional insights may also provide opportunities for biomarkers, enabling earlier interventions and therapeutic progress for this patient population.
      Further research could also help in elucidating the sequence of events of abnormal brain development, epilepsy and sleep disruption and potentially contribute to understanding the likelihood of epilepsy evolution towards a self-limited condition, or a DEE.

      Funding source

      None.

      Author contributions

      Dr Jethwa designed the scoping review protocol, conducted literature searches, reviewed publications, extracted data, prepared the qualitative analysis and drafted the initial manuscript.
      Dr Datta conceptualised and designed the scoping review, reviewed the final list of publications for analysis and reviewed and revised the manuscript.
      Didem Kaya cross-checked the extracted data.
      Dr Pressler reviewed and revised the manuscript and provided helpful input to the concept and data analysis.

      Declaration of competing interest

      R.P. is an investigator for studies with UCB and Johnson & Johnson. She served as a consultant, speaker and on Advisory Boards for Natus, Persyst, GW and UCB. Her research is supported by the National Institute of Health Research (NIHR) Biomedical Research Centre at Great Ormond Street Hospital and Cambridge University Hospital, NIHR and Evelina Charity. She is on the editorial board of Journal of Clinical Neurophysiology, Neurophysiologie Clinique and European Journal of Paediatric Neurology as well an Associated editor for Epilepsia Open.
      A.D. is an investigator for studies with Neurocrine and Idorsia. He serves as a consultant, speaker and on Advisory Boards for Neurocrine, Idorsia, Epilog, Eisai, Jazz Pharmaceuticals.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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