Treatment guidelines for rare, early-onset conditions associated with epileptic seizures: a literature review on Rett syndrome and tuberous sclerosis complex

Abstract

Background: Rett syndrome (RTT) and tuberous sclerosis complex (TSC) are two rare disorders presenting with a range of different epileptic seizures. Seizure management requires careful therapy selection, thereby necessitating development of high-quality treatment guidelines. This targeted literature review (TLR) aimed to characterise country-specific and international treatment guidelines available for pharmacological management of seizures in RTT and TSC.

Methods: A TLR was performed between 25-Jan and 11-Mar 2021. Manual searches of online rare disease and guideline databases, and websites of national heath technology assessment bodies were conducted for the following countries: Australia, Canada, France, Germany, Israel, Italy, Japan, Spain, Switzerland, UK, and US as defined by pre-specified eligibility criteria. Search terms were developed for each condition and translated into local languages where appropriate. Eligible publications were defined as guidelines/guidance reporting pharmacological management of seizures in patients with RTT and TSC. Guideline development methodology, geographical focus, author information and treatment recommendations were extracted from guidelines. An author map was generated using R version 3.5.1 to visualise extent of collaboration between authors.

Results: 24 total guidelines were included, of which three and six contained only recommendations for RTT and TSC, respectively (some provided recommendations for ≥ 1 condition). Guideline development processes were poorly described (50% [12 guidelines] had unclear/absent literature review methodologies); reported methodologies were variable, including systematic literature reviews (SLRs)/TLRs and varying levels of expert consultation. Most (83% [20/24]) were country-specific, with guideline authors predominantly publishing in contained national groups; four guidelines were classified as 'International,' linking author groups in the US, UK, Italy and France. High levels of heterogeneity were observed in the availability of treatment recommendations across indications, with 13 and 67 recommendations found for RTT and TSC, respectively. For RTT, all treatment recommendations were positive and sodium valproate had the highest number of positive recommendations (Khwaja, Sahin (2011) Curr Opin Pediatr 23(6):633-9). All TSC treatments (21 medications) received either exclusively negative (National Organization for Rare Disorders (2019)) or positive (Chu-Shore et al. (2010) Epilepsia 51(7):1236-41) recommendations; vigabatrin received the highest number of positive recommendations (Kaur, Christodoulou (2019)).

Conclusions: This review highlights the need for the development of international high-quality and comprehensive consensus-based guidance for the management of seizures with pharmacological therapy in RTT and TSC.

Trial registration: Not applicable.

Keywords: Guidelines; Literature review; Rare diseases; Rett syndrome; Seizures; Treatment; Tuberous sclerosis complex.

Fig. 1

Literature review flowchart. *Online information sources included: Guideline Central, National Organization for Rare Disorders (NORD), American Academy of Neurology (AAN), American Epilepsy Society (AES), International League Against Epilepsy (ILAE), Orphanet, Google, National Institute for Health and Care Excellence (NICE), Pharmaceutical Benefits Scheme (PBS), Canadian Agency for Drugs and Technologies in Health (CADTH), Ministerio de Sanidad, Consumo y Bienestar Social (MSCBS), Agenzia Italiana del Farmaco (AIFA), Haute Autorité de Santé (HAS), Gemeinsamer Bundesausschuss (G-BA), Bundesamt für Gesundheit (BAG), State of Israel – Ministry of Health, Ministry of Health, Labour and Welfare (MHLW)

Fig. 2

Geographies of identified guidelines. *No guidelines were identified for use in Israel, Switzerland, Germany or Australia. The geography of guideline use refers to the country for which the guidance was specifically developed. UK, United Kingdom; US, United States

Fig. 3

Types of literature review performed to inform guideline development. ‘None’ refers to guidelines in which a literature review was explicitly not used. NR, not reported; SLR, systematic literature review; TLR, targeted literature review

Fig. 4

Types of expert consultation performed to inform guideline development. ‘None’ refers to guidelines in which expert consultation was explicitly not used; ‘Other’ refers to working groups or targeted expert interviews. NR, not reported

Fig. 5

Guideline cross-referencing to other treatment guidelines and regulatory/HTA recommendations. Cross-referencing refers to the number of different treatment guidelines, regulatory body recommendations, HTA body recommendations or other references that were cited within the guidelines identified in this study, either in the body of the guideline text or in accompanying reference lists. ’Other’ references included a Cochrane systematic literature review, and informational websites about RTT or TSC. HTA, health technology assessment; RTT, Rett syndrome; TSC, Tuberous sclerosis complex

Fig. 6

Map of collaboration between the author groups of included guidelines. Each individual circle represents one author of a guideline. Each ‘cluster’ represents the group of authors that developed one guideline. Each cluster is labelled with the names of its respective first author(s). Guidelines which share one or more authors between them are connected by grey lines, with single circles between guideline clusters representing the individuals who authored both guidelines in question. Guidelines were classified as “International” if they were developed either for multiple countries or did not specify to which countries they pertained. Guidelines for which author names were not reported have not been included in this figure. NICE, National Institute for Health and Clinical Excellence; SIGN, Scottish Intercollegiate Guidelines Network

Fig. 7

Treatment recommendations for Rett syndrome. N = 13 (13 positive and 0 negative recommendations) from three guidelines. Positive recommendation: use of an individual ASM treatment that was recommended for use in a specific indication, irrespective of the line of treatment (e.g. first line) or whether the treatment was adjunctive; Negative recommendation: an individual ASM treatment that was highlighted as a potential option by a guideline but not recommended by a guideline for use (for any reason) in a specific indication, irrespective of the line of treatment or whether the treatment was adjunctive

Fig. 8

Treatment recommendations for tuberous sclerosis complex. N=67 (65 positive and two negative treatment recommendations) from 22 guidelines. Positive recommendation: use of an individual ASM treatment that was recommended for use in a specific indication, irrespective of the line of treatment (e.g. first line) or whether the treatment was adjunctive; Negative recommendation: an individual ASM treatment that was highlighted as a potential option by a guideline but not recommended by a guideline for use (for any reason) in a specific indication, irrespective of the line of treatment or whether the treatment was adjunctive. ACTH, adrenocorticotropic hormone