The burden of illness in Lennox-Gastaut syndrome: a systematic literature review

Abstract

Background: Lennox-Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy characterized by drug-resistant epilepsy with multiple seizure types starting in childhood, a typical slow spike-wave pattern on electroencephalogram, and cognitive dysfunction.

Methods: We performed a systematic literature review according to the PRISMA guidelines to identify, synthesize and appraise the burden of illness in LGS (including "probable" LGS). Studies were identified by searching MEDLINE, Embase and APA PsychInfo, Cochrane's database of systematic reviews, and Epistemonikos. The outcomes were epidemiology (incidence, prevalence or mortality), direct and indirect costs, healthcare resource utilization, and patient and caregiver health-related quality of life (HRQoL).

Results: The search identified 22 publications evaluating the epidemiology (n = 10), direct costs and resource (n = 10) and/or HRQoL (n = 5). No studies reporting on indirect costs were identified. With no specific ICD code for LGS in many regions, several studies had to rely upon indirect methods to identify their patient populations (e.g., algorithms to search insurance claims databases to identify "probable" LGS). There was heterogeneity between studies in how LGS was defined, the size of the populations, ages of the patients and length of the follow-up period. The prevalence varied from 4.2 to 60.8 per 100,000 people across studies for probable LGS and 2.9-28 per 100,000 for a confirmed/narrow definition of LGS. LGS was associated with high mortality rates compared to the general population and epilepsy population. Healthcare resource utilization and direct costs were substantial across all studies. Mean annual direct costs per person varied from $24,048 to $80,545 across studies, and home-based care and inpatient care were significant cost drivers. Studies showed that the HRQoL of patients and caregivers was adversely affected, although only a few studies were identified. In addition, studies suggested that seizure events were associated with higher costs and worse HRQoL. The risk of bias was low or moderate in most studies.

Conclusions: LGS is associated with a significant burden of illness featuring resistant seizures associated with higher costs and worse HRQoL. More research is needed, especially in evaluating indirect costs and caregiver burden, where there is a notable lack of studies.

Keywords: Burden of illness; Caregiver burden; Developmental and epileptic encephalopathy; Direct costs; Epilepsy; Health-related quality of life; Indirect costs; Lennox–Gastaut syndrome; Seizures.

Fig 1

Timeline to show A the history of the characterization and treatment of LGS B the triad of symptoms characteristic of LGS and the clinical implications of the characterization of the syndrome. From: Lennox et al (1950) [1], Gastraut et al (1966) [2], Niedermeyer (1969) [90], Beaumanoir (1985) [91], ILAE 1989 [92], Engel (2001) [93], Arzimanoglou et al (2009) [3], Scheffer (2017) [94], World Health Organization (ICD-11) (2022) [64]. CLB, clobazam; CBD, cannabidiol; EEG, electroencephalogram; FFA, fenfluramine; FLB, felbamate; ILAE, International League Against Epilepsy; LGS, Lennox–Gastaut syndrome; LTG, lamotrigine; RUF, rufinamide; TPM, topiramate

Fig 2

PRISMA flow diagram. Adapted from Page et al (2021) [95]

Fig 3

A Total direct costs in LGS patients (blue) versus control patients (grey), patients with other epilepsies (lilac), and in LGS patients with seizure events vs without seizure events and LGS patients in years where patients were prescribed with rescue medication vs years where patients were not prescribed rescue medication (blue) B resource utilization and costs in LGS patients vs controls; C resource utilization and costs in LGS patients with seizure events vs without seizure events. Adapted from: Reaven et al (2018) [54], Piña-Garza et al (2017) [46], Stockl et al (2019) [55], Hollenack et al (2019) [52], Reaven et al (2019) [53] and Strzelczyk et al (2021) [47] .* Costs were converted from Euros to US dollars on 21^st June 2022 (exchange rate 1.00 Euro =1.06 US Dollars [xe.com]). ASM, anti-seizure medication; DS, Dravet syndrome; ED, emergency department; LGS, Lennox–Gastaut syndrome; PPPY, per person per year; OP, outpatient; TSC, tuberous sclerosis complex

Fig 4

A Cost drivers according to inpatient and emergency department admissions (red), outpatient visits (orange), home health (home nursing and physiotherapy; blue), equipment (yellow) and medication (green) costs (where reported) B Patient and caregiver HRQoL according to number of drop seizures per month and number of seizure-free days in the UK and France. Mean health state utility scores for a hypothetical patient with LGS and a hypothetical caregiver of a patient with LGS. A Adapted from: Strzelczyk et al (2021) [47] and Reaven et al (2018) [54]. Home health= home-based nursing, personal care, and residential habilitation services. B Adapted from Auvin et al (2021) [61]. ASM, anti-seizure medication; ED, emergency department; HRQoL, health-related quality of life; OP, outpatient