Caregiver reported behavior, sleep and quality of life in children with Dravet syndrome: A population-based study

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Introduction
Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy with intractable seizures, usually starting in the first year of life, and with a high epilepsy related mortality, especially before the age of 10 years [1].Development, neurological examination, and EEG are normal at seizure onset and there are no preexisting cerebral lesions.However, developmental progress slows, and there is usually obvious developmental delay 12 to 60 months following seizure onset [2].Over 80 % of children with DS met the criteria for intellectual disability (ID) and the pooled prevalence of autism spectrum disorders (ASD) was 31 % in studies that used ASD-specific instruments [3].The syndrome is usually caused by a dominant pathogenic variant in the SCN1A gene [4].The incidence was calculated to 1:15,500 live births in a populationbased, prospective study [5], and between 1:16,000 and 1:46,000 live births in retrospective studies published after 2014 [6][7][8][9][10].
Individuals with DS have a higher frequency of behavioral problems compared with the general population and with individuals with a SCN1A variant who do not fulfil criteria for DS [11].There is an increased rate of externalizing problems such as aggression and hyperactivity in individuals with DS and internalizing problems like somatic complaints, withdrawn behavior, and anxious/depressed behavior.Attention problems are also common [3].Two-thirds of children with DS are reported to have problems with inattention or hyperactivity, three quarters with peer relations and one third with conduct [12].Sleep related problems or insomnia have been reported in 42-97 % of children with DS [13][14][15][16][17], and a significantly increased total sleep time has been observed in individuals with DS compared to healthy controls, possibly due to a lower quality of sleep [18].
Despite the extensive psychosocial impact of DS on affected children and their families, few studies have been focused on behavior, sleep, and quality of life (QoL).There is a need for population-based data on these areas, as previous studies mainly have been based on clinic-based participants.Studies investigating behavior have not used instruments validated for children with ID even though most children with DS fulfill the criteria for ID [3].Some of the items in behavior scales for children with normal cognitive abilities address behaviors that are not suitable for children with moderate/severe ID since they require certain verbal abilities.Many of the behaviors clinically observed in those with severe ID, such as autistic behavior, are not captured in scales adapted for use in children without ID [19,20].
In addition to describing behavior and sleep there is also a need to identify factors influencing behavior, sleep and QoL.Caregivers have reported a range of areas of concern in children with DS, that can significantly affect QoL, including problems with appetite, sleep, gait, seizures, and behaviour [13].In one study, health related quality of life (HRQoL), as measured by the PedsQL [21], in children with DS was reduced compared to healthy children, with other epilepsy syndromes, with and without learning difficulties [12].In this study the strongest predictor of lowered HRQoL was behavioral and emotional difficulties, as measured by the SDQ [22].In the broader pediatric epilepsy population, a number of studies have shown that behavioral and/or emotional difficulties, are often associated with reduced HRQoL [23,24].The relationship between sleep difficulties and QoL has not been comprehensively explored in children with Dravet syndrome.However, in children with epilepsy, sleep problems have been shown to be associated with lower QoL, although this relationship is mediated by the presence of neurodevelopmental problems, in that the relationship between sleep and HRQOL was no longer significant when the role of neurodevelopmental problems was considered [25].Regarding the relationship between behavior and sleep, and children with DS there is a lack of data.In children with epilepsy, a number of studies have shown that behavior problems are associated with a greater degree of sleep problems [26,27].
The aim of this population-based study was to investigate behavior, sleep, and QoL in Swedish children with Dravet syndrome.A second aim was to investigate factors associated with behavior, sleep, and QoL.

Material and methods
We conducted a population-based study of Swedish children with DS between October 2018 and April 2020.Recruitment process is described in Supplement 1.As of December 31st, 2018, there were 55 known Swedish children with DS.Of those seven were deceased.Thus, there were 48 known children alive with DS in Sweden, corresponding to a prevalence of 1/45,000 (95 % CI 1/35,000-1/63,000) [6].Of those, 42/ 48 (88 %) were included in a clinical assessment where epilepsy and its treatment [6], intellectual function [28] and seizure precipitants and strategies to avoid seizures in DS [29] have been described.The recruitment process is described in Supplement 1. Clinical characteristics are presented in Table 1.The criteria for ID were met in 36/42 (86 %) children [28].All but two children (40/42, 95 %) had a variant in the SCN1A gene that could explain the syndrome and 19/42 (45 %) were females.The most common seizure types were focal to bilateral tonic clonic (n = 41/42, 98 %) and myoclonic (n = 35/42, 83 %) [6].
In the current study we analyzed behavior, insomnia and QoL in the 42 children who had been included in earlier assessments.Inclusion criteria in the study are the one used by Nabbout et al 2013: 1) no preexisting cerebral lesions and a normal EEG in a normal infant; 2) normal development until the first seizure occurring before one year of age; 3) refractory unilateral or bilateral clonic or tonic clonic seizures affecting one or both sides simultaneously or alternatively; 4) exclusion of any other epilepsy syndrome, including negative PDCH19 analysis in SCN1A negative children [30].

Assessment
Primary caregivers completed assessments of behavior, insomnia and QoL between October 2018 and April 2020.

Measure of behavior
The Developmental Behavior Checklist (DBC) is a measure of  [6,28].* Unless stated as median (range) for the variable. 1One child with the first seizure at 2.3 years who also had a benign infratentorial tumor was included in the study after discussion between pediatric neurologists Björn Bjurulf (BB) and Tove Hallböök (TH) since the phenotype was typical for DS. 2 ASD and ADHD diagnoses were diagnosed according to DSM-5 criteria based on an consensus by an experienced psychologist and neurologists. 3One child was not assessed for ASD due to age under two years. 4Five children were not assessed for ADHD due to age under four years. 5Based on clinical assessment by BB or TH. 6 Mild hemiparesis in one patient due to a benign infratentorial cerebral tumor and in another patient after a prolonged episode of convulsive status epilepticus. 7Other medications than Melatonin to treat problems falling asleep had been used in six children (alimemazine was presently used in three, and had previously been used in one, clonidine had previously been used in one and both these medications had been used in one).All these six children had also tried Melatonin. 8One child had previously been treated with atomoxetine.
behavioral and emotional difficulties in children and adolescents with ID, including those with co-occurring ASD [20,31,32].It consists of 96 descriptions of behavior and norms are available for mild, moderate, severe and profound ID and for the ID group as a whole.Each item is scored on a 3-point scale: Not true as far as you know (0), sometimes or somewhat true (1), often true or very true (2).All items are added to give a total behavior raw score.The raw scores can be converted to standardized T scores (DBC-T scores) which makes it possible to compare scores in the different subscales.We used the revised DBC-P (parent form) adapted for evaluation of children 4-18 years old.There are five subscales representing clinically relevant dimensions of behavior among children with ID: self-absorbed; disruptive; communication disturbance; anxiety and socially relating.The DBC subscales have been shown to be reliable and valid measures of caregivers' ratings of behavioral disturbances and the subscales have high factorial validity and internal consistency [20].

Measure of insomnia
The Insomnia Severity Index (ISI) is a questionnaire assessing the nature, severity and impact of sleep difficulties [33].It is composed of seven items, assessing recent problems with sleep onset, sleep maintenance, early morning awakening, sleep dissatisfaction, noticeability of sleep problems by others, interference of sleep difficulties with daily functioning, and distress caused by sleeping difficulties.The current severity (i.e., last two weeks) of each item is rated on a 5-point Likert scale: No problem (0); mild problem (1); moderate problem (2); severe problem (3) and very severe problem (4).This yields a total score ranging from 0 to 28.Total scores are interpreted as follows: absence of insomnia (0-7); sub-threshold insomnia (8)(9)(10)(11)(12)(13)(14); moderate insomnia (15)(16)(17)(18)(19)(20)(21); and severe insomnia (22)(23)(24)(25)(26)(27)(28).The questionnaire showed adequate concurrent validity with sleep diaries and polysomnography and adequate internal consistency and could detect changes in perceived sleep difficulties when used in adults [34].Although typically used as a self-report questionnaire it has also been used as a caregiver-reported questionnaire for children with cerebral palsy [35].In the current study we define "insomnia" as different types of sleep-related problems as scored with the Insomnia Severity Index.

Measure of QoL
To measure QoL we used a single question from the Epilepsy and Learning Disabilities Quality of Life (ELQoL) scale: "How would you describe the QoL of your child during the last four weeks?"This question is rated on a 5-point scale: "Very good" (1); "Good" (2); "Reasonably good" (3); "Bad" (4) and "Very bad" (5).A similar single question from the QOLCE-76 ("In the past 4 weeks, what has your child's QoL been?") has been validated for evaluation of QoL in children with focal, drugresistant epilepsy, and rated on a five-point Likert scale from excellent to poor [36].This global estimation of QoL, showed moderate to strong correlations (r ≥ 0.30-0.50)with the composite scores in QOLCE-76 and KIDscreen-27, and had moderate test-retest reliability and was able to detect clinically important change in patients' QoL.

Data analysis
A p-value of <0.05 was considered statistically significant in all the analyses.The IBM Statistics for Windows, ver.28 software (IBM Corporation, Armonk, NY, USA) was used for the statistical analyses.Wilcoxon signed rank test was used to compare T-scores between DBC subscales.Simple linear regression was done to identify if specific factors were significantly associated with the outcomes "Behavior" according to the composite DBC raw score, "Insomnia" according to ISI composite score and "QoL" according to global QoL question in ELDQoL.Factors associated at the p <0.20 level were included in multivariable modelling as previously described [37].The factors included as possible predictors were age at assessment, gender, epilepsy severity, previous use of contraindicated sodium channel inhibitors, age at first seizure, age at first episode of convulsive status epilepticus, adaptive behavior based on Vineland adaptive behavior score, second edition (VABS-2), severity of side effects associated with anti-seizure medications (ASMs) based on the ELDQoL subscale "Side effects", if the child had severe ID (yes or no) and autistic symptoms based on results of the Social Communication Questionnaire (SCQ) total score.Composite scores of DBC and ISI were included as possible predictors of QoL and composite score of DBC and ISI were included as possible predictors for each other.
Epilepsy severity was investigated based on five items from the ELDQoL scale [38], employed in previous studies of DS in the children in this study and by others [12,28,29].The VABS-2 is a measure of the child's adaptive behavior in four domains: communication, daily living skills, socialization and for children six years or younger, motor domains [39].The SCQ is a validated smeasure consisting of 40 yes/no items, related to symptoms of autism [40].The ELDQoL subscale "Side Effects" is a validated scale containing 19 items regarding side-effects of ASMs [38].In the linear regression analysis, we used the five items of epilepsy severity from the ELDQoL as a measure of epilepsy, the VABS-2 as a measure of adaptive behavior, the ELDQoL Side Effect subscale as a measure of ASM side effects and the SCQ as a measure of autism.
Cronbach's α was used to assess the internal consistency of ISI items, where α > 0.80 was considered adequate [41].

Ethics
The study was approved by the Ethical Review Committee of the University of Gothenburg (Sweden) and The Swedish Ethical Review Authority (Dnr 450-10, T672-18, and 2020-03783).Written informed consent was obtained from caregivers and from participants older than 15 years if they were developmentally able to understand information about the study.

Behavior
The median DBC-T score was 54.5.Twenty-nine out of 40 (72 %) children had a composite DBC-T score > 50 and thus scored in the range of 'serious' concern (Table 2).
Twenty-eight (70 %) children scored in the serious range of concern for the self-absorbed subscale of DBC, 25 (62 %) for the anxiety subscale, 24 (60 %) for the disruptive and communication disturbance subscales and 18 (45 %) for the social relating subscale (Table 2).As described in Table 2 and Supplement 2, the subscale social relating had significantly lower ranked values, indicating less serious problems, than all the other subscales; disruptive (Z = -3.0,p = 0.003), communication disturbance (Z = -3.1,p = 0.002), anxiety (Z = -3.0,p = 0.003) and self-absorbed (Z = -3.9,p < 0.001).The disruptive subscale had significantly lower ranked values than the subscale self-absorbed (Z = -2.5, p = 0.013).There were no other significant differences in ranks between the DBC-Tscores on the subscales or the total scale.The only factor significantly associated with the outcome "Behavior" in a multiple regression model was the SCQ total score (B = 1.3 (0.29-2.3), p = 0.013, R square = 0.21), indicating that children with more autistic symptoms had significantly more behavioral problems (Supplement 3).

Insomnia
Cronbachs alpha was 0.89 for the ISI subscales and thus 'adequate'.According to the ISI scale 18/42 (43 %) children scored in the range of moderate to severe clinical insomnia (Table 3).The number of children who scored in different ranges of difficulties for the different ISI subscales are described in Table 3.The only factor significantly associated with the total score on the ISI in a multiple regression model was severity of ASM side effects according to the ELDQoL subscale "Side Effects" (B = -0.24(-0.46-− 0.014)), p = 0.032, R square = 0.19).More severe side effects were associated with more severe insomnia (Supplement 4).

Discussion
In this population-based study of 42 children with Dravet syndrome (DS), we used standardized questionnaires, answered by caregivers to evaluate behavioral problems, insomnia and QoL.We found indications of clinically significant behavioral problems in 70 % of children, moderate or severe clinical insomnia in 40 % and 'poor' or 'very poor' QoL in 17 %, as well as specific patterns regarding sleep and behavior.

Behavior
Seventy percent of children scored in the serious range of concern for the DBC-T score.In a Study by Sinoo et al. 40 % of individuals with DS scored in the clinical ranges of behavioral problems [11] as measured by the Child/ Adult Behavior Checklist (C/ABCL).One possible explanation to the higher scores in our study could be that we did not include adults, who had significantly fewer behavioral problems in their study.Another possible explanation could be that the C/ABCL used by Sinoo et al. to measure behavioral problems is less reliable for children with moderate and severe ID [19], which are common levels of intellectual functioning in children with DS.
We found significant less problems associated with the social relating subscale than with all other subscales.Children with DS, even those who fulfill criteria for autism, have been shown to display a relative preservation of social skills as measured by the Vineland Adaptive Behavior Scales [42].However, the surface preservation of social skills, masking a lack of social understanding, is a risk that autism diagnoses are underestimated in children with DS [43].We found significantly less problems associated with the disruptive behavior subscale than with the selfabsorbed subscale.Problems related to the self-absorbed subscale are more common in children with severe ID, while problems related to the disruptive subscale are more common in children with mild ID [44].However, there was a similar number of children with mild and severe ID in our study and thus differences might be due to a DS specific behavioral profile.There was a significant association between total behavioral problems and autistic symptoms.This might indicate that autistic symptoms can explain a significant proportion of behavioral problems in children with DS.Thus, it is possible that strategies used to treat behavioral problems in children with ASD can also be used to treat behavioral problems in children with DS.

Insomnia
Moderate clinical insomnia was seen in 14/42 (33 %) children and severe insomnia in 4/42 (10 %), in line with results in another study using the Sleep Disturbance Scale [14] where 44 % of individuals with DS had an abnormal sleep score.In another study using the Sleep Behavior Questionnaire, severe insomnia was found in 28 % of individuals with DS [16].Thus, moderate or severe insomnia are common in DS, affecting between 40 and 50 % of all individuals.In our study one third of all children had severe or very severe problems of waking up at night and one third had severe or very severe disturbance of daily activities due to insomnia.In another study daytime sleepiness and mild night waking problems were more frequent in individuals with DS than in individuals with other types of epilepsy [16].
In the current study 17 % had a severe or very severe problem falling asleep, fewer than for all other insomnia related problems (Table 4).A possible explanation for the relatively low prevalence of difficulties falling asleep is that Melatonin had been used to treat problems falling  # ISI is a questionnaire for evaluation of perceived sleep difficulties, comprising seven items, each rated on a 0-4 scale.Total score ranges from 0 to 28.A higher score suggests more severe insomnia and a score at or above 15 indicates clinically significant insomnia.ISI for the child was scored by one or both caregivers.ISI has been validated for use in adults [34], but has also been used in children [35].Out of 48 known Swedish children with DS 42 participated in this study.
asleep in 45 % of the children in our study.Of the ones using Melatonin, 26 % were currently using this medication.Similar results were found in another study in which 39 % of children and adults with DS took medication to assist sleep, predominantly Melatonin [14].A previous study suggest that use of Melatonin in DS leads to improvements in sleep initiation and maintenance, cognitive function and QoL, but there was no difference in total sleep or wakefulness after sleep onset compared with placebo [18].Seizures were provoked by sleep in 56 % of children in the current study.In another study seizures disrupted sleep in 53 % of children with DS and in 48 % nocturnal seizures three or more nights per week were reported [45].Thus, seizures disturb sleep in children with DS, and strategies to reduce seizure frequency are important, also to improve insomnia.We found that sleep-associated problems were significantly associated with increased side effects of ASMs according to caregivers.ASMs have been identified as factors leading to day-time drowsiness and troubles falling asleep and staying asleep by caregivers [45].The results on sleep by single ASMs are conflicting [46].Clobazam might reduce sleep latency and improve sleep efficiency [47].Valproate and levetiracetam might increase daytime sleepiness, but not topiramate or zonisamide [46,48,49].Seizures, ASMs and comorbid sleep disorders such as sleep apnea can all affect architecture of sleep and promote sleep disruption or daytime sleepiness and it is often hard to know the cause of sleep associated problems [46,50].

Quality of life (QoL)
Most caregivers regarded QoL of their child as "good" or "very good", but 17 % considered QoL as "poor" or "very poor".In another study using a similar single question for evaluation of QoL in children with refractory epilepsy, only 2.5 % of caregivers considered QoL of their child as "poor" [36].In this study "very poor" was not an alternative.A study by Brunklaus et al. indicated that children with DS had a generally low HRQoL, that was lower compared to other children with epilepsy combined with mental, behavioral, or neurologic disability as well as normative data [12].Thus, children with DS might have worse QoL than other children with refractory epilepsy and with epileptic and developmental encephalopathy.Our study indicates that more severe insomnia is associated with reduced QoL, highlighting the need to support children with DS and sleep associated problems.In two studies, larger than ours, with 163 [12] respectively 85 participants [11], HRQoL was significantly related to cognitive and behavioral problems.In the largest study by Brunklaus et al. [12], there was also a significant relationship between HRQoL and different markers of increased seizure severity.Poorer QoL in our study was not related to any of the factors mentioned above, possibly due to fewer participants, leading to less Fig. 1.Quality of life of the child during the last four weeks according to caregivers.The figure is based on one question in the Epilepsy Learning Disabilities Quality of Life (ELDQoL) Scale [38]: "How would you describe the quality of life of your child during the last four weeks?".The question was answered by caregivers of 41/ 48 known Swedish children with Dravet Syndrome.One child, aged one year, was excluded from the ELDQoL questionnaire, due to young age and six children did not participate in the study.The question is rated on a 5-point scale from "Very good" to "Very poor".A similar question from the QOLCE-76 scale [53] has been validated for use in children with focal drug-resistant epilepsy and showed moderate correlation with the composite QOLCE-76 scale [36].

Table 4
The insomnia severity index (ISI) in 42/48 Swedish children with Dravet syndrome (scores for subscales) # .power, making it more difficult to find significant associations.However, these studies were not population-based, and the instruments employed differed to those of the current study, which may also explain the different findings.

Strengths and weaknesses of the study
Even though our sample size is relatively small, it is population based and the three questionnaires were answered by caregivers of more than 80 % of all known Swedish children with DS, reducing the risk for selection bias.This is to our knowledge the first study using an instrument validated for children with moderate to severe/profound ID (the DBC) when evaluating behavior in DS, increasing the possibility of capturing behaviors that are common in children with such types of intellectual disabilities.Other strengths are that we study a well-defined epilepsy syndrome, genetically verified in 40/42 (95 %) individuals and that all DS diagnoses have been verified by two experienced pediatric epileptologists.There are some weaknesses.We did not have a controlgroup of children with other epilepsy syndromes and QoL was measured by a single item.Thus, the measure lacks coverage of the subcomponents of QOL.The ISI is not well-validated for use in children.Additionally, it may not cover the full range of sleep difficulties experienced by children.But there were no other instruments available in Swedish at the time of the study.ISI has previously been used as a measure of sleep difficulties in children with cerebral palsy, and in the current study this single item showed good internal consistency.

Implications for further research
With respect to future research, there is a need to further investigate insomnia, QoL, behavior and in children with DS in larger studies.Regarding interventions for children with Dravet syndrome who have sleep problems, it will be important to consider the impact on behavior and QoL.There is evidence that a behavioral-educational sleep intervention for toddlers and preschool children with epilepsy results in significant, measurable, and sustained benefits in sleep quality and quantity [51].These approaches should be tried in children with DS.The current study suggests an impact of side-effects of ASMs on sleep, and thus there is a need to consider how to minimize the potential effects of ASMs in any interventions.Regarding interventions to improve behavior, there is a need to consider the role of symptoms of ASD, and adapt materials and approaches to reflect that many children with DS have both ID and ASD.Again, outcomes of interventions need to include a consideration of impact on QoL and sleep.There is also a need for studies of newer ASMs to consider not only effects of seizures but also sleep, behavior and QoL.It has been shown that Fenfluramine has shown promise, with respect to seizure frequency and executive functioning in DS [52], and it is conceivable that newer ASMs may have impact beyond seizure control.
There is also a need to explore the frequency of non-seizure events associated with sleep such as obstructive and central sleep apnea in children with DS and to find effective treatments for those difficulties and to evaluate the effect of cognitive difficulties on behavior, sleep and QoL.Asking about and trying to minimize side effects of ASMs in children with DS might improve behavior, sleep and QoL.

Conclusion
Behavior and sleep are significantly negatively affected in children with DS and should routinely be investigated in all children with this diagnosis.There is a need to find successful interventions for these difficulties to optimize outcomes.

Declaration of competing interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [This study was supported by grants from the Swedish state under the agreement between the Swedish Government and the county councils, the ALF-agreement 956787, the Margarethahemmet, the Linnea and Josef Carlsson and Petter Silverskiöld foundations, Dravet Syndrome Association Sweden, and the National Center for Rare Diseases West.The funders had no role in the writing of the article.The authors have no declarations of competing interest.].

Use of medications to treat sleep problems 7
The total score has high validity shown by correlations between the scale and psychiatrists' classification and with other valid instruments assessing behavioral disorders in children with ID.There are three ranges of concern displayed for the total score and for the sub- [32]es.A T-score < 40 indicates a range of 'little' concern, a T-score of 40-50 indicates a range of 'moderate' concern and a T-score >50 indicates a range of 'serious' concern.An overall score that falls into the range of 'serious' concern indicates behavioral and emotional problems that require management or treatment and further assessment[32].Individuals with an overall range of 'serious' concern are more likely to meet the criteria for a mental health diagnosis.A score of 'moderate' concern might indicate problems that require management or treatment and meet the criteria for a mental health diagnosis.

Table 2
The Developmental Behavior Checklist-Parent Version (DBC-P) composite Tscore and T-scores of subscales in 40/48 known Swedish children with Dravet syndrome # .The Developmental Behavior Checklist (DBC) is a measure of behavioral and emotional disturbances in children and adolescents with intellectual disability (ID).There are five subscales representing clinically relevant dimensions of behavior among children with ID: self-absorbed; anxiety; communication disturbance; disruptive and socially relating.The raw scores are converted to standardized T scores which makes it possible to compare scores between the different subscales and with the total scale.A T-score < 40 indicates a range of little concern, a T-score of 40-50 indicates a range of moderate concern and a Tscore > 50 indicates a range of serious concern.Two children, one, respectively two years old could not be included due to young age, and six did not participate in this study. #

Table 3
The insomnia severity index (ISI) in 42/48 known Swedish children with Dravet syndrome (scores for total scale) # .