Autonomic dysfunction and sudden death in patients with Rett syndrome: a systematic review

Abstract

Background: Rett syndrome (RTT), a debilitating neuropsychiatric disorder that begins in early childhood, is characterized by impairments in the autonomic nervous system that can lead to sudden unexpected death. This study explores the mechanisms of autonomic dysfunction to identify potential risk factors for sudden death in patients with RTT. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria, we undertook comprehensive systematic reviews using the PubMed, Scopus, Cochrane, PsycINFO, Embase and Web of Science databases. Results: We identified and critically appraised 39 articles for autonomic dysfunction and 5 for sudden death that satisfied the eligibility criteria. Following thematic analysis, we identified 7 themes: breathing irregularities, abnormal spontaneous brainstem activations, heart rate variability metrics, QTc changes, vagal imbalance, fluctuation in peptides and serotonergic neurotransmission. We grouped these 7 themes into 3 final themes: (A) brainstem modulation of breathing, (B) electrical instability of the cardiovascular system and (C) neurochemical changes contributing to autonomic decline. We described key evidence relating to each theme and identified important areas that could improve the clinical management of patients with RTT. Limitations: The heterogeneity of the methods used to assess autonomic function increased the difficulty of making inferences from the different studies. Conclusion: This study identified the important mediators of autonomic dysfunction and sudden death in patients with RTT. We proposed brainstem mechanisms and emphasized risk factors that increase brainstem vulnerability. We discussed clinical management to reduce sudden death and future directions for this vulnerable population.We performed 2 separate systematic reviews using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. 29 The first review examined autonomic dysfunction, and the second focused on the causes of sudden death in patients with RTT. Article selectionThe selection of articles for each systematic review was performed by the first (J.S.) and the second author (E.L.) independently. Database searches were done in a blinded manner using the same search terms. Once the eligible articles had been identified independently by J.S. and E.L., any doubts were resolved during a meeting to review the queried article(s) against the inclusion and exclusion criteria. The final selection of eligible articles included in the critical appraisals was made based on agreement between J.S. and E.L.

Movement disorders in patients with Rett syndrome: A systematic review of evidence and associated clinical considerations

“…To reduce search strategy bias, we used the principles adopted for our previous evidence synthesis 14 . First, both the first (J.S.)…”

Parent-Mediated Interventions for Infants under 24 Months at Risk for Autism Spectrum Disorder: A Systematic Review of Randomized Controlled Trials

“…Crucially, studies should fully disclose conflicts of interests due to the potential for these factors to influence the research process (Bekelman et al, 2003;Cortese et al, 2016). Disclosures may not necessarily lead to high risk of bias in studies (Singh et al, 2020), but it is important to assess disclosures collectively with the other Cochrane domains. Percentage agreement was 100% (κ = 1.00) for all seven studies in this domain.…”

Differentiating Females with Rett Syndrome and Those with Multi-Comorbid Autism Spectrum Disorder Using Physiological Biomarkers: A Novel Approach

“…The involvement of the autonomic nervous system (ANS) is pervasive, and a degree of autonomic dysregulation is present in the majority of RTT patients, to the extent that RTT can be considered a congenital form of dysautonomia [ 5 ]. Autonomic dysregulation manifests with a variety of emotional, behavioural, and autonomic symptoms, and it is linked with an increased risk of sudden death when compared to the general population [ 6 , 7 ]. Emotional, behavioural, and autonomic dysregulation (EBAD) is a term coined to describe the co-occurrence of dysautonomia in some children who display emotional and behavioural issues [ 8 ].…”

“…RTT patients with autonomic dysregulation typically present with signs of sympathetic over-activity such as anxiety/panic attacks, breathing dysrhythmia, temperature instability, peripheral vascular changes, gut dysmotility and cardiac abnormalities. Even if autonomic dysregulation tends to be a lifelong issue in RTT [ 7 , 9 ], few patients receive specific treatments for the autonomic dysregulation [ 10 ]. While certain mutations can offer some information on the clinical profiles of autonomic dysregulation in patients with RTT [ 10 , 11 ], in the majority of cases the genotype–phenotype relationship of autonomic dysregulation in RTT remains elusive.…”

“…Moreover, up to 90% of Rett patients have a risk of developing epilepsy [ 13 ] due to the brainstem immaturity. The clinical management of these and other symptoms can have a profound impact on the inherent cardiorespiratory vulnerability in RTT patients and if not managed appropriately may increase the risk of sudden cardiac death in this patient group [ 7 ].…”