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As a developmental and epileptic encephalopathy, DS is not limited to seizures.
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By middle childhood, cognitive, speech, gait, and behavioral symptoms are severe.
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Intensive medical and caregiver support for individuals with DS is required.
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Studies using standardized measures are needed to document outcomes over time.
Abstract
Dravet syndrome (DS) is a developmental and epileptic encephalopathy with evolving disease course as individuals age. In recent years, the treatment landscape of DS has changed considerably, and a comprehensive systematic review of the contemporary literature is lacking. Here we synthesized published evidence on the occurrence of clinical impacts by age, the economic and humanistic (health-related quality-of-life [HRQoL]) burden, and health state utility. We provide an evidence-based, contemporary visualization of the clinical manifestations, highlighting that DS is not limited to seizures; non-seizure manifestations appear early in life and increase over time, contributing significantly to the economic and humanistic burden of disease. The primary drivers of HRQoL in DS include seizure severity, cognition, and motor and behavioral problems; in turn, these directly affect caregivers through the extent of assistance required and consequent impact on activities of daily living. Unsurprisingly, costs are driven by seizure-related events, hospitalizations, and in-home medical care visits. This systematic review highlights a paucity of longitudinal data; most studies meeting inclusion criteria were cross-sectional or had short follow-up. Nonetheless, available data illustrate the substantial impact on individuals, their families, and healthcare systems and establish the need for novel therapies to address the complex spectrum of DS manifestations.
Dravet syndrome (DS) is a severe, life-long developmental and epileptic encephalopathy that begins in infancy and evolves with accumulating morbidity that significantly impacts individuals and their families [
]. More than 85% of people living with DS present with pathogenic variants in the SCN1A gene (SCN1A+ DS) encoding the α subunit of the NaV1.1 sodium channel, which is primarily expressed in GABAergic inhibitory interneurons [
]. Impairment of NaV1.1, results in a profound loss of GABAergic signaling, which is implicated in the pathogenesis of disease. Dravet syndrome is thus conceptualized as a channelopathy because the effects of the variants on the sodium channel appear to contribute to the disorder independent of the seizures [
The symptomatic expression of DS is complex due to its evolving heterogeneity as individuals age. People living with DS experience a high seizure burden in the first year of life with seizure types evolving over time [
]. Additional DS manifestations typically begin shortly after seizure onset, including neurodevelopmental stagnation or decline, behavioral and sleep difficulties, and motor impairment, which worsen and become more detectable throughout childhood [
Jansson JS, Hallbook T, Reilly C. Intellectual functioning and behavior in Dravet syndrome: A systematic review. Epilepsy Behav 2020;108 (no pagination).
Rampazzo ACM, Dos Santos RRP, Maluf FA, Simm RF, Marson FAL, Ortega MM, et al. Dravet syndrome and Dravet syndrome-like phenotype: a systematic review of the SCN1A and PCDH19 variants. Neurogenetics 2021: 1-11.
] makes characterizing the natural history and burden of disease challenging. In addition, the past few years have seen a rapidly changing treatment landscape with the approval of therapies such as fenfluramine, cannabidiol, and stiripentol, which have demonstrated efficacy in reducing the seizure burden in DS [
Improved everyday executive functioning following profound reduction in seizure frequency with fenfluramine: Analysis from a phase 3 long-term extension study in children/young adults with Dravet syndrome.
Jansson JS, Hallbook T, Reilly C. Intellectual functioning and behavior in Dravet syndrome: A systematic review. Epilepsy Behav 2020;108 (no pagination).
Rampazzo ACM, Dos Santos RRP, Maluf FA, Simm RF, Marson FAL, Ortega MM, et al. Dravet syndrome and Dravet syndrome-like phenotype: a systematic review of the SCN1A and PCDH19 variants. Neurogenetics 2021: 1-11.
Nabbout R, Dirani M, Teng T, Bianic F, Martin M, Holland R, et al. Impact of childhood Dravet syndrome on care givers of patients with DS, a major impact on mothers. Epilepsy Behav 2020;108 (no pagination).
]. While the detrimental effects of informal caregiving on caregivers’ mental health and HRQoL have been shown, no systematic review has summarized the substantial humanistic burden reported among those living with DS. Furthermore, a synthesis of the literature on direct and indirect cost impacts of DS is currently lacking.
The objectives of this contemporary and comprehensive systematic review were two-fold (1) to characterize the spectrum and evolution of DS manifestations, and (2) to define the clinical, humanistic, and economic costs of living with, and caring for, DS.
2. Materials and methods
We conducted a systematic literature review following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines for designing, performing, and reporting systematic reviews to guide the conduct of this review [
The search was implemented on December 4, 2020, in MEDLINE (MEDLINE and MEDLINE in-process [OVID SP]) and EMBASE to identify published data on the clinical, economic, and humanistic burden of DS by age and genotype (where available) from database inception to December 3, 2020. To ensure the latest data available were captured (up to December 3, 2020), conference abstracts were screened for inclusion. In addition to the conference abstracts identified through MEDLINE and EMBASE, the search was supplemented by a search for abstracts from congresses – on or before December 3, 2020 – including the American Epilepsy Society (AES), European Paediatric Neurology Society (EPNS), and American Academy of Neurology (AAN). Conference abstracts published before 2018 were excluded.
2.2 Search strategy
An intentionally broad search strategy (Supplemental Table 1) was developed to comprehensively capture relevant literature. The search included medical subject headings for the population of interest (DS or DS+ SCN1A) and study design filters adapted from the National Institute for Health and Care Excellence (NICE) guidelines for developing literature search strategies [
]. The searches were restricted to English and also French, given the breadth of data published in these languages. There were no restrictions based on geographical region or publication date, but animal studies were excluded.
2.3 Study selection
Two researchers independently reviewed all abstracts identified by the search strategy against the study-specific PECOS (Population, Exposure, Comparator, Outcomes, Study design) criteria (Fig. 1). Exclusion of manuscripts based on study outcomes was performed during full text review. Full text of studies that met inclusion criteria during abstract screening were screened for inclusion by two reviewers using study-specific PECOS. If screening researchers differed when categorizing studies for inclusion/exclusion in either abstract or full-text review, a third researcher provided arbitration. In order to narrow the focus to contemporary studies describing individuals with DS based on current diagnosis criteria/language, we excluded older studies using terms such as Severe Myoclonic Epilepsy in infancy (SMEI) or borderline SMEI (SMEB) during full text screening. De-duplication, abstract screening, and full text screening were conducted using Microsoft Excel.
Fig. 1PECOS (Population, Exposures/Comparators, Outcomes, Study design) criteria.
Two researchers independently extracted all available data of interest from the eligible studies, including study author and year of publication; study design, period, location, and follow-up length; sponsor; baseline clinical and demographic characteristics; sample size; intervention, outcomes measured (including details on the outcome measures/assessment of the outcome and definitions, where available), and results. Mean, median, standard deviation, and range were extracted for continuous variables; number of individuals and the proportion were extracted for dichotomous and categorical variables. We also extracted patient-level data when available. Outcomes included those specified in the PECOS criteria, extracted by age and genotype (Fig. 1). Discrepancies between the data extracted by the two data reviewers were resolved through discussion with a third researcher until consensus was reached. Data extraction was completed in Microsoft Excel.
2.5 Quality assessment
The strength of the available evidence from publications included in the final analysis was assessed using the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) Statement for observational studies [
Data were stored in Microsoft Excel and synthesized using an iterative approach. The frequency of key study and patient characteristics were tabulated.
To synthesize data on the clinical burden, the occurrence of DS symptoms was summarized in narrative, according to genotype (if available) and age (in years [y] or by age category: onset/infancy [<2y], early childhood [2–4y], middle childhood [5–9y], adolescence [10–17y], and adulthood [>18y]). For seizure-related outcomes, occurrence was summarized according to type (motor [e.g. tonic, tonic-clonic (TC), focal clonic (FC), myoclonic], non-motor seizures [e.g. absences], and seizures arising during sleep) or duration (prolonged seizures and/or status epilepticus [SE; convulsive and non-convulsive]). Note that as epilepsy classifications/definitions have changed over time, we used current ILAE classification to group/synthesize seizure-related outcomes across the identified studies.
Other non-seizure-related outcomes of interest included the occurrence of developmental delays, intellectual disability (ID), communication/speech impairments, autism spectrum disorder (ASD) diagnosis or traits, attention-deficit hyperactivity disorder (ADHD) diagnosis or traits, delay in achieving motor milestones, ataxia, and crouch gait. Intellectual disability data were summarized based on intellectual/cognitive and adaptive functioning outcomes where available; or scores on measures of intellectual/cognitive development, adaptive functioning, or development along with intelligence quotient (IQ), development quotient (DQ), and global quotient (GQ) scores. Communication and speech impairment were summarized by the prevalence of speech motor impairment, as well as expressive and receptive communication impairments. Additionally, causes of mortality (e.g., SUDEP), where reported, were tabulated.
Patterns of the timing of clinical events were described using the age at first occurrence, age-specific rates, and/or scores on relevant outcome measures by age, as published in the original studies. We developed a visualization to display the occurrence (the percentage of patients with the outcome by age) and age at onset of seizure- and non-seizure-related outcomes. Estimates from the largest and/or most robust studies (e.g., from longitudinal studies, or from large cross-sectional studies reporting events by age strata) were plotted for each outcome.
Estimates of the economic, patient and caregiver burden of DS, as well as any reported health effects among caregivers were summarized by age, genotype, seizure severity, and level of neurodevelopmental impairment. For the economic burden, costs related to DS-specific healthcare resource use (seizure-related costs, e.g., costs for medical claims with a diagnosis code for epilepsy or seizures, and pharmacy costs for antiseizure medications [ASMs], etc.; non-seizure-related costs, e.g. costs for speech therapist appointment, etc.), as well as all-cause costs (i.e. both DS-specific and non-DS-related healthcare resource use) were considered. Indirect costs (e.g. costs due to lost caregiver time) were also captured. Costs were presented as reported in the studies. For ease of comparison, annualized costs were presented in a common currency (USD; conversion rates 2021-03-25) and inflated to 2020 values (using country specific annual consumer price indices [CPIs]; direct costs were inflated using CPI for health; indirect costs were inflated using CPI overall). Drivers of costs as reported in the original articles were described.
To summarize the impact of DS on quality of life on individuals living with DS and their caregivers, scores on relevant HRQoL instruments were reported. Trends in HRQoL over time and by age were reviewed. Qualitative data on caregiver burden were summarized descriptively. Factors reported to be key drivers of symptom progression and burden were collated across studies.
Finally, data on health state utility values were reviewed. Health state utility values quantify how strongly a person values, or prefers being in, a particular health state associated with a given health condition. Health state utility values are measured on a scale between 0 and 1. These were presented according to respondent type (patient vs. proxy vs. caregiver), instrument, and other patient and caregiver characteristics, as available.
3. Results
3.1 Studies identified
The database search yielded 3824 records, of which 3084 (80.6%) were excluded during abstract review and 644 (16.8%) during full-text review – the majority of these did not meet population and study design criteria. Seven additional abstracts from conference proceedings were included to the 90 manuscripts and 6 conference abstracts identified through MEDLINE and EMBASE, totaling 103 studies eligible for review (Fig. 2). Publication dates ranged from 2006 to 2020. Sixty-five percent (n = 67) of identified studies were published in the last 5 years of search implementation (2016–2020; Supplemental Fig. 1). Major themes reported in the studies included the natural history of DS (n = 8); the burden of DS (n = 24; comorbidities, economic and/or humanistic burden); frequency and semiology of seizures (n = 18); neurodevelopmental progression (n = 20); and other outcomes (n = 33; e.g., including mortality, gait, genetic sequencing, and incidence). Most studies were European (n = 51), followed by 18 from the USA, 7 with international samples, and 27 from other countries (e.g. Australia, China). Study characteristics, baseline demographics, and clinical characteristics are summarized in Supplemental Table 2, and a summary of the outcomes reported on each study in Supplemental Table 3. While conference abstracts may not include detailed information, they offer the most up-to-date primary findings of a study and were therefore screened for inclusion, resulting in 13 conference abstracts eligible for review [
Golbeck E. Nocturnal seizures and sleep variability in children and young adults with dravet syndrome. In: Poster presented at: American Epilepsy Society. New Orleans, USA; 2018.
Pnd34 economic burden of probable Lennox-Gastaut syndrome, probable Dravet syndrome, and other refractory epilepsies for United States medicaid health plans.
Li W, Schneider AL, Scheffer IE. 116 - Delineating the phenotypic limits of Dravet syndrome due to SCN1A pathogenic variants. In: Presented at: Dravet Syndrome Foundation Roundtable. Baltimore, USA; 2019.
Patel A, Reaven NL, Funk SE, Story TJ, Chez M. The direct cost burden of illness (BOI) of Dravet syndrome (DS) in the US (P6.290). In: Poster presented at: American Academy of Neurology. Los Angeles, USA; 2018.
Pro58 quality of life in patients with Dravet syndrome or Lennox Gastaut syndrome in the UK: higher seizure frequency has a substantial negative impact on quality of life.
Inpatient hospitalizations and readmissions among patients with probable lennox-gastaut syndrome, dravet syndrome, tuberous sclerosis complex, and other refractory epilepsies.
Sullivan J, Zafar M, Flamini R, Knupp K, Ziobro J, Perry S, et al. 81 - Observational study to investigate cognition and other non-seizure comorbidities in children and adolescents with Dravet syndrome: patient analysis of the BUTTERFLY study. In: Poster presented at: American Epilepsy Society. Virtual Meeting; 2020.
Epidemiology, healthcare resource use, and mortality in patients with probable dravet syndrome: A population-based study on German health insurance data.
3.2 Evolution and presentation of clinical semiology
Of the studies identified (n = 103), 94 included estimates on the patterns of timing of clinical events. While several of these were prospective studies (n = 14), most were small cross-sectional studies, had a short follow-up period, or were chart reviews of adults (Supplemental Tables 2 and 3) [
Nabbout R, Dirani M, Teng T, Bianic F, Martin M, Holland R, et al. Impact of childhood Dravet syndrome on care givers of patients with DS, a major impact on mothers. Epilepsy Behav 2020;108 (no pagination).
Golbeck E. Nocturnal seizures and sleep variability in children and young adults with dravet syndrome. In: Poster presented at: American Epilepsy Society. New Orleans, USA; 2018.
Pnd34 economic burden of probable Lennox-Gastaut syndrome, probable Dravet syndrome, and other refractory epilepsies for United States medicaid health plans.
Li W, Schneider AL, Scheffer IE. 116 - Delineating the phenotypic limits of Dravet syndrome due to SCN1A pathogenic variants. In: Presented at: Dravet Syndrome Foundation Roundtable. Baltimore, USA; 2019.
Patel A, Reaven NL, Funk SE, Story TJ, Chez M. The direct cost burden of illness (BOI) of Dravet syndrome (DS) in the US (P6.290). In: Poster presented at: American Academy of Neurology. Los Angeles, USA; 2018.
Pro58 quality of life in patients with Dravet syndrome or Lennox Gastaut syndrome in the UK: higher seizure frequency has a substantial negative impact on quality of life.
Inpatient hospitalizations and readmissions among patients with probable lennox-gastaut syndrome, dravet syndrome, tuberous sclerosis complex, and other refractory epilepsies.
Sullivan J, Zafar M, Flamini R, Knupp K, Ziobro J, Perry S, et al. 81 - Observational study to investigate cognition and other non-seizure comorbidities in children and adolescents with Dravet syndrome: patient analysis of the BUTTERFLY study. In: Poster presented at: American Epilepsy Society. Virtual Meeting; 2020.
Epidemiology, healthcare resource use, and mortality in patients with probable dravet syndrome: A population-based study on German health insurance data.
Influence of contraindicated medication use on cognitive outcome in Dravet syndrome and age at first afebrile seizure as a clinical predictor in SCN1A-related seizure phenotypes.
Juanes M, Veneruzzo G, Loos M, Reyes G, Araoz HV, Garcia FM, et al. Molecular diagnosis of epileptic encephalopathy of the first year of life applying a customized gene panel in a group of Argentinean patients. Epilepsy Behav 2020;111.
Jiang T, Shen Y, Chen H, Yuan Z, Mao S, Gao F. Clinical and molecular analysis of epilepsy-related genes in patients with Dravet syndrome. Medicine (United States) 2018;97 (50) (no pagination).
Brown A, Arpone M, Schneider AL, Micallef S, Anderson VA, Scheffer IE. Cognitive, behavioral, and social functioning in children and adults with Dravet syndrome. Epilepsy Behav 2020;112 (no pagination).
A multicenter, matched case-control analysis comparing burden-of-illness in Dravet syndrome to refractory epilepsy and seizure remission in patients and caregivers in Germany.
Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30: 389-399.
Dravet C BM, Guerrini R, Giraud N, Roger J, Severe myoclonic epilepsy. In: Roger J, Bureau M, Dravet C, Dreifuss FE, Perret A, Wolf P, editors. Epileptic syndromes in infancy, childhood and adolescence. 2nd ed. London: John Libbey; 1992. p. 75–88. . 1992.
Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, Engel J, French J, Glauser TA, Mathern GW. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. In: Wiley Online Library; 2010.
Commission. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1981;22: 489-501.
Mitta N, Menon RN, McTague A, Radhakrishnan A, Sundaram S, Cherian A, Madhavilatha GK, Mannan AU, Nampoothiri S, Thomas SV. Genotype-phenotype correlates of infantile-onset developmental & epileptic encephalopathy syndromes in South India: A single centre experience. Epilepsy Res 2020;166 (no pagination).
Development and content validation of a preliminary core set of patient- and caregiver-relevant outcomes for inclusion in a potential composite endpoint for Dravet Syndrome.
Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology.
Wu YW, McDaniel SS, Sullivan J, Meisler MH, Walsh EM, Li S, Kuzniewicz MW, Xu S. Incidence of Dravet syndrome in a U.S. population. Ann Neurol 2015;19: S155.
]. The contemporary published data highlight the dramatic clinical impact of DS attributable to seizure- and non-seizure-related manifestations. Fig. 3, Fig. 4 illustrate the age-specific evolution of clinical manifestations of DS using evidence from longitudinal studies (n = 11) [
Influence of contraindicated medication use on cognitive outcome in Dravet syndrome and age at first afebrile seizure as a clinical predictor in SCN1A-related seizure phenotypes.
Golbeck E. Nocturnal seizures and sleep variability in children and young adults with dravet syndrome. In: Poster presented at: American Epilepsy Society. New Orleans, USA; 2018.
] reporting events by age. Comparison between studies was hampered by differing patient ages, definitions, outcome measures, and duration of follow-up.
Fig. 3Clinical evolution of seizure-related manifestations and mortality in DS: Data from 8 longitudinal studies and 6 large (n > 50) cross-sectional studies.
While the early occurrence of seizures is a defining feature of DS, seizure types evolve over time, and importantly, persist into adulthood. Seizures typically shift from prolonged, provoked, focal seizures occurring while awake during childhood, to short generalized onset seizures occurring in sleep during adolescence and adulthood. Generally, the frequency and severity of seizures decreases from later childhood/adolescence to adulthood yet prolonged periods of seizure freedom remain uncommon. Most studies reporting on seizure-related outcomes described the percentage of patients with seizures, or age at first seizure, rather than seizure rates by age. The age-specific evolution of seizures over time is depicted in Fig. 3.
SE (defined as one seizure or sequential seizures without return to baseline level of consciousness lasting ≥ 30 min) was described in 40 studies (Supplemental Table 3). Only 13 studies assessed SE longitudinally and the remaining 27 had a cross-sectional design. SE is common in infancy [
Juanes M, Veneruzzo G, Loos M, Reyes G, Araoz HV, Garcia FM, et al. Molecular diagnosis of epileptic encephalopathy of the first year of life applying a customized gene panel in a group of Argentinean patients. Epilepsy Behav 2020;111.
Juanes M, Veneruzzo G, Loos M, Reyes G, Araoz HV, Garcia FM, et al. Molecular diagnosis of epileptic encephalopathy of the first year of life applying a customized gene panel in a group of Argentinean patients. Epilepsy Behav 2020;111.
Prolonged seizures (defined at a minimum as seizures lasting ≥5 min) were described in only 19 studies, and only 2 were longitudinal (Supplemental Table 3). The mean age at onset ranged from 5 to 8.5 months [
], and while they appear to decline with age, supportive data on the occurrence of prolonged seizures after childhood are scarce.
The most commonly described seizure types were TC, FC, absence, and myoclonic seizures. Tonic-clonic (generalized or unspecified) seizures were described in 48 studies (Supplemental Table 3), with a mean age at onset ranging from 5 to 9 months [
Jiang T, Shen Y, Chen H, Yuan Z, Mao S, Gao F. Clinical and molecular analysis of epilepsy-related genes in patients with Dravet syndrome. Medicine (United States) 2018;97 (50) (no pagination).
], but tend to decrease in adulthood. Focal clonic seizures, described in 17 studies, occur most commonly at onset and in early childhood then diminish with age. Generalized TC seizures are more common than FC seizures. In one study, at onset, generalized TC and FC seizures were reported in 54% and 32% of infants with DS, respectively [
Li W, Schneider AL, Scheffer IE. 116 - Delineating the phenotypic limits of Dravet syndrome due to SCN1A pathogenic variants. In: Presented at: Dravet Syndrome Foundation Roundtable. Baltimore, USA; 2019.
]. Absence seizures (atypical or unspecified) were described in 35 studies, and myoclonic seizures, in 43 studies (Supplemental Tables 2 and 3); these seizures appear to be less common than TC seizures, with occurrence peaking in childhood, diminishing by adolescence, and few reports in adulthood.
Seizures arising during sleep were described in 14 studies (3 of which were longitudinal; Supplemental Table 3). These begin on average at 7 years of age and appear to occur in up to 50% of children and almost 90% of adults living with DS. They tend to be brief, most commonly TC or tonic, and occur in clusters.
3.4 Non-seizure-related outcomes
Contemporary data on non-seizure-related outcomes highlight that the clinical burden of DS is not limited to seizures. Most patients have developmental delays [
Influence of contra-indicated medication use on cognitive outcomes in dravet syndrome and age at first afebrile seizure as clinical predictor in SCN1A-related seizure phenotypes.
] observed by middle childhood and adulthood (Fig. 4). Most children with DS attend special schools and most adults live with their parents or in specialized facilities [
Brown A, Arpone M, Schneider AL, Micallef S, Anderson VA, Scheffer IE. Cognitive, behavioral, and social functioning in children and adults with Dravet syndrome. Epilepsy Behav 2020;112 (no pagination).
]. The majority of studies of non-seizure-related manifestations reported on frequency by age, rather than mean age at occurrence, and definitions and measures varied greatly.
Twenty studies that focused on characterizing neurodevelopmental progression reported the age at or frequency of ID and/or developmental delays, and only 9 studies were longitudinal (Supplemental Table 3). Developmental delays frequently present in the first 2 years of life [
Influence of contra-indicated medication use on cognitive outcomes in dravet syndrome and age at first afebrile seizure as clinical predictor in SCN1A-related seizure phenotypes.
]. Deficits in cognitive scores (IQ, DQ, and GQ scores) – as commonly measured by the Wechsler Intelligence Scale for Children, clinician-reported Likert scale, Vineland Adaptive Behavior Scales, Griffiths Mental Development Scale, and Brunet-Lezine scales – become apparent in early childhood and are profoundly impacted by adulthood. In one study, approximately 50% of adolescents (mean age of patients 11 years) had a severe ID (based on an IQ/DQ score of ≤24) [
]. In another, more than 80% of those >15 years of age had a severe/profound learning disability (based on a 5-point Likert scale rated by clinicians) [
Influence of contra-indicated medication use on cognitive outcomes in dravet syndrome and age at first afebrile seizure as clinical predictor in SCN1A-related seizure phenotypes.
Influence of contra-indicated medication use on cognitive outcomes in dravet syndrome and age at first afebrile seizure as clinical predictor in SCN1A-related seizure phenotypes.
], and more impaired verbal skills when compared with other individuals with DS. Additionally, a recent cross-sectional study found that individuals with DS with ASD diagnosis had greater decline in intellectual and adaptive functioning than those individuals with DS without ASD diagnosis [
Speech or communication impairments, described in 31 studies (four longitudinal; Supplemental Table 3), are common and occur in 80% of individuals with DS [
ASD and ADHD diagnoses or traits were described in 23 studies (Supplemental Tables 2 and 3). While the prevalence of ASD and ADHD diagnosis was infrequently described, 20% of those with DS are diagnosed with ADHD, and up to 40% of children and 62% of adults with DS are diagnosed with ASD. In one study, autistic features were observed in 69% of individuals with DS overall, and in up to 28% of those younger than 5 years [
]. The proportion of individuals with ASD and ADHD diagnoses or traits appears to increase with age, peaking in middle childhood, and plateauing or decreasing in adulthood [
Sixteen studies reported the frequency of delayed achievement of motor milestones and 24 studies reported on ataxia or crouch gait (Supplemental Tables 2 and 3). By 2 years of age, up to 50% of children with DS have delays in fine (e.g., hand-eye coordination) and gross (e.g., sitting and walking independently) motor development [
]. Use of ambulatory devices are common, with up to half of adolescents requiring a wheelchair to cover distances of 500 m or more [as assessed using the functional mobility scale (FMS) scale] [
Twenty studies reported on mortality (Supplemental Table 3), 4 of which were large generalizable studies specifically focused on estimating mortality in DS [
Epidemiology, healthcare resource use, and mortality in patients with probable dravet syndrome: A population-based study on German health insurance data.
Epidemiology, healthcare resource use, and mortality in patients with probable dravet syndrome: A population-based study on German health insurance data.
], increasing to 18% by 40 years of age among those who survive to adulthood. Fig. 3 illustrates the evolution of all-cause mortality in DS and the risk of SUDEP alone, both of which persist into adulthood [
Epidemiology, healthcare resource use, and mortality in patients with probable dravet syndrome: A population-based study on German health insurance data.
The economic burden of DS was reported in 11 studies (Supplemental Table 3, Supplemental Fig. 2), 8 of which described direct costs. Five studies from the US focused primarily on all-cause costs [
Pnd34 economic burden of probable Lennox-Gastaut syndrome, probable Dravet syndrome, and other refractory epilepsies for United States medicaid health plans.
Patel A, Reaven NL, Funk SE, Story TJ, Chez M. The direct cost burden of illness (BOI) of Dravet syndrome (DS) in the US (P6.290). In: Poster presented at: American Academy of Neurology. Los Angeles, USA; 2018.
Inpatient hospitalizations and readmissions among patients with probable lennox-gastaut syndrome, dravet syndrome, tuberous sclerosis complex, and other refractory epilepsies.
Epidemiology, healthcare resource use, and mortality in patients with probable dravet syndrome: A population-based study on German health insurance data.
A multicenter, matched case-control analysis comparing burden-of-illness in Dravet syndrome to refractory epilepsy and seizure remission in patients and caregivers in Germany.
]. Publication dates ranged from 2018 to 2019 and reported on studies conducted between 2010 and 2018. Drivers of direct costs included medically treated seizure events, emergency medication, seizure frequency, level of disability, history of SE, nursing care level, number of non-seizure manifestations, and caregiver depression. The published mean annual all-cause costs ranged from $31,433 (in a US commercially insured population with a mean age of patients 12 years) [
Inpatient hospitalizations and readmissions among patients with probable lennox-gastaut syndrome, dravet syndrome, tuberous sclerosis complex, and other refractory epilepsies.
]. All-cause costs varied depending on insurance type (e.g., Medicaid coverage vs. commercial coverage), as well as the age and severity of the sample at the time of study. Across studies, seizure-related costs contributed to a large proportion of all-cause costs. All-cause medical costs for individuals living with DS were nearly 12 times greater than for age-matched members of the general population [
Patel A, Reaven NL, Funk SE, Story TJ, Chez M. The direct cost burden of illness (BOI) of Dravet syndrome (DS) in the US (P6.290). In: Poster presented at: American Academy of Neurology. Los Angeles, USA; 2018.
Pnd34 economic burden of probable Lennox-Gastaut syndrome, probable Dravet syndrome, and other refractory epilepsies for United States medicaid health plans.
Inpatient hospitalizations and readmissions among patients with probable lennox-gastaut syndrome, dravet syndrome, tuberous sclerosis complex, and other refractory epilepsies.
]. Mean annual DS-specific costs ranged from $15,885 (among the European subset of the international DISCUSS survey; mean age of DISCUSS cohort, 10.6 years) [
]. Dravet syndrome-specific costs varied based on the extent of informal care/home health data represented in the total estimate. One study reported on the percentage of costs attributable to seizure- vs. non-seizure-related care, with approximately 50% of DS-specific costs attributed to non-seizure-related healthcare resource use [
]. Dravet syndrome-specific costs were 1.5-fold higher among those with DS compared with drug-resistant epilepsy (e.g. individuals with recurrent seizures for whom physicians reported a lack of response to treatment changes) and 5-fold higher than patients with seizures in remission (e.g. individuals with complete seizure control for ≥1 year at the time of study entry) [
A multicenter, matched case-control analysis comparing burden-of-illness in Dravet syndrome to refractory epilepsy and seizure remission in patients and caregivers in Germany.
], reported on indirect costs associated with DS. The drivers included seizure frequency, level of disability, and number of additional symptoms. Mean annual indirect costs ranged from €19,160 (from a German multicenter survey in which 40% of mothers reported missing >37 days of work per year due to DS (mean age of patients 10.1 years) [
] to $81,582 (from a US survey where all caregivers experienced lost leisure time and missed a mean of 48 days of work per year due to DS, mean age of patients 11.7 years) [
Estimates of direct and indirect costs were highly variable due to differences in population, study designs, and the structure of the healthcare systems included.
3.7 HRQoL
Nine studies described the HRQoL among people with DS (Supplemental Tables 3 and 6), only one of which was longitudinal. In every study, HRQoL was assessed by caregiver proxy. Overall, HRQoL deficits occur when children are young (<5 years), increase with age, and persist through life. Available HRQoL data show that impairments experienced by those living with DS appear to be greater than those experienced by other individuals with epilepsy, and children in the general population [
A multicenter, matched case-control analysis comparing burden-of-illness in Dravet syndrome to refractory epilepsy and seizure remission in patients and caregivers in Germany.
] are presented in Supplemental Table 6. Total PedsQL scores decrease with age, with the largest declines observed in scores of physical, cognitive, and social functioning domains [
Thirteen studies (11 of which were qualitative) reported the burden of DS on caregivers (Supplemental Tables 3 and 7). As most people with DS require 24-h care, the impact on caregivers is substantial [
Nabbout R, Dirani M, Teng T, Bianic F, Martin M, Holland R, et al. Impact of childhood Dravet syndrome on care givers of patients with DS, a major impact on mothers. Epilepsy Behav 2020;108 (no pagination).
]. One study reported that, across the age-span of people living with DS, the most difficult aspects of caregiving include the impact on other siblings, dealing with cognitive and developmental delays, arranging for alternative care, communication challenges, coordinating medical and ancillary care, managing behavior problems, and tending to the personal care of the individual living with DS [
]. Another study described the most difficult aspects of caregiving by disease stages or phases (defined by both age of the individual living with DS and seizure severity) [
]. The first stage begins in the first year of life with the onset of prolonged seizures and the most difficult aspects of caregiving include seizure control and uncertainty about diagnosis [
]. After approximately 1 year of age, the second phase emerges with other seizure types along with developmental, behavioral, and sleep issues. During the third stage in early adolescence, better seizure control is achieved but increased intellectual disability and behavioral problems drive caregivers’ social isolation from family and friends [
Nabbout R, Dirani M, Teng T, Bianic F, Martin M, Holland R, et al. Impact of childhood Dravet syndrome on care givers of patients with DS, a major impact on mothers. Epilepsy Behav 2020;108 (no pagination).
A multicenter, matched case-control analysis comparing burden-of-illness in Dravet syndrome to refractory epilepsy and seizure remission in patients and caregivers in Germany.
Nabbout R, Dirani M, Teng T, Bianic F, Martin M, Holland R, et al. Impact of childhood Dravet syndrome on care givers of patients with DS, a major impact on mothers. Epilepsy Behav 2020;108 (no pagination).
Nabbout R, Dirani M, Teng T, Bianic F, Martin M, Holland R, et al. Impact of childhood Dravet syndrome on care givers of patients with DS, a major impact on mothers. Epilepsy Behav 2020;108 (no pagination).
]. Mothers, in particular seem to be impacted both personally and professionally; compared with fathers, they report a greater impact of caregiving on their social life, relationships with family and friends, time and energy, professional life, and health [
Nabbout R, Dirani M, Teng T, Bianic F, Martin M, Holland R, et al. Impact of childhood Dravet syndrome on care givers of patients with DS, a major impact on mothers. Epilepsy Behav 2020;108 (no pagination).
Nabbout R, Dirani M, Teng T, Bianic F, Martin M, Holland R, et al. Impact of childhood Dravet syndrome on care givers of patients with DS, a major impact on mothers. Epilepsy Behav 2020;108 (no pagination).
Pro58 quality of life in patients with Dravet syndrome or Lennox Gastaut syndrome in the UK: higher seizure frequency has a substantial negative impact on quality of life.
A multicenter, matched case-control analysis comparing burden-of-illness in Dravet syndrome to refractory epilepsy and seizure remission in patients and caregivers in Germany.
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