Dravet syndrome: A systematic literature review of the illness burden

Abstract

We performed a systematic literature review and narrative synthesis according to a pre-registered protocol (Prospero: CRD42022376561) to identify the evidence associated with the burden of illness in Dravet syndrome (DS), a developmental and epileptic encephalopathy characterized by drug-resistant epilepsy with neurocognitive and neurobehavioral impairment. We searched MEDLINE, Embase, and APA PsychInfo, Cochrane's database of systematic reviews, and Epistemonikos from inception to June 2022. Non-interventional studies reporting on epidemiology (incidence, prevalence, and mortality), patient and caregiver health-related quality of life (HRQoL), direct and indirect costs and healthcare resource utilization were eligible. Two reviewers independently carried out the screening. Pre-specified data were extracted and a narrative synthesis was conducted. Overall, 49 studies met the inclusion criteria. The incidence varied from 1:15 400-1:40 900, and the prevalence varied from 1.5 per 100 000 to 6.5 per 100 000. Mortality was reported in 3.7%-20.8% of DS patients, most commonly due to sudden unexpected death in epilepsy and status epilepticus. Patient HRQoL, assessed by caregivers, was lower than in non-DS epilepsy patients; mean scores (0 [worst] to 100/1 [best]) were 62.1 for the Kiddy KINDL/Kid-KINDL, 46.5-54.7 for the PedsQL and 0.42 for the EQ-5D-5L. Caregivers, especially mothers, were severely affected, with impacts on their time, energy, sleep, career, and finances, while siblings were also affected. Symptoms of depression were reported in 47%-70% of caregivers. Mean total direct costs were high across all studies, ranging from $11 048 to $77 914 per patient per year (PPPY), with inpatient admissions being a key cost driver across most studies. Mean costs related to lost productivity were only reported in three publications, ranging from approximately $19 000 to $20 000 PPPY ($17 596 for mothers vs $1564 for fathers). High seizure burden was associated with higher resource utilization, costs and poorer HRQoL. The burden of DS on patients, caregivers, the healthcare system, and society is profound, reflecting the severe nature of the syndrome. Future studies will be able to assess the impact that newly approved therapies have on reducing the burden of DS.

Keywords: caregiver burden; developmental and epileptic encephalopathy; direct costs; health-related quality of life; indirect costs.

FIGURE 1

PRISMA flow diagram. Adapted from Page et al.

FIGURE 2

HRQoL in patients with DS. Data are mean values. Higher values = better HRQoL. EQ‐5D‐5L population norm data are from Azzi 2020 for France, Grochtdreis 2019 for Germany, Scalone 2015 for Italy, and Hernandez 2018 for Spain. EQ‐5D‐5L population norm data are not available for the UK/England and data from a mixed disease population was used instead (Richardson ¹²⁹ ). *Statistically significant difference versus DS (where analyzed). Adapted from Brunklaus, Sinoo, Strzelczyk, Pagano, Strzelczyk, and Lagae.

FIGURE 3

Direct costs in patients with DS according to seizure burden. ADHD, attention deficit hyperactivity disorder; ASM, anti‐seizure medication; ED, emergency department; EU5, France, Germany, Italy, Spain, and the UK; OP, outpatient. Data are mean values per person per year. $1.00 = €1 (Google Finance 30th August 2022) i.e. US dollars and Euros were equivalent at the time of writing the narrative synthesis. Adapted from Lagae, Schubert‐Bast and Reaven.

FIGURE 4

Summary of the burden of illness in patients with DS. ADHD, attention deficit hyperactivity disorder; ASM, anti‐seizure medication; BDI, Beck's Depression Inventory; DRE, drug‐resistant epilepsy; DS, Dravet syndrome; HRQoL, health‐related quality of life; LOS, length of stay; PPPY, per person per year; SE, status epilepticus; SR, seizure remission; SUDEP, sudden unexpected death in epilepsy; VAS, visual analogue scale. *Data are mean values across studies; Euros (€) were converted to US dollars at a rate of €1 = $1.00 (Google Finance 30th August 2022) i.e. US dollars and Euros were equivalent at the time of writing the narrative synthesis.