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

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

J Psychiatry Neurosci 2020;45(3):150-181 | PDF | Appendix

Jatinder Singh, MSc, PhD; Evamaria Lanzarini, MD; Paramala Santosh, MBBS, MD, PhD

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.


Submitted Feb. 16, 2019; Revised May 23, 2019; Revised Jun. 27, 2019; Accepted Jul. 3, 2019; Published online Nov. 8, 2019

Acknowledgements: The authors thank Ludovica Gualniera for administrative assistance with the drawings in Figure 3 and Leighton McFadden for reading the manuscript.

Affiliations: From the Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK (Singh, Santosh); the Centre for Interventional Paediatric Psychopharmacology and Rare Diseases, South London, and Maudsley NHS Foundation Trust, London, UK (Singh, Lanzarini, Santosh); and the Child and Adolescent Neuropsychiatry Unit, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy (Lanzarini).

Competing interests: J. Singh is a member of the professional advisory board for Reverse Rett and a trial research methodologist on the sarizotan clinical trial (protocol number sarizotan/001/II/2015; Clinical-Trials.gov identifier: NCT02790034). P. Santosh is the co-inventor of the HealthTracker and is the chief executive officer and shareholder in HealthTracker. He is the principal investigator (PI) on the sarizotan clinical trial (protocol number sarizotan/001/II/2015; ClinicalTrials. gov identifier: NCT02790034), and the PI on the GW Pharma clinical trial in RTT. E. Lanzarini has no competing interests to declare.

Contributors: J. Singh conceptualized the systematic review. J. Singh and E. Lanzarini independently performed the search process and information gathering. All authors were involved in the critical appraisal of the articles and the thematic analysis. J. Singh wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.

DOI: 10.1503/jpn.190033

Correspondence to: P. Santosh, Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD) Research Team, Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London; paramala.1.santosh@kcl.ac.uk