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 Reporting Items for Systematic Review 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.

Fig. 1

Identification of themes. ASBA = abnormal spontaneous brainstem activation; CSB = cardiac sensitivity to baroreflex; CVT = cardiac vagal tone; HF = high frequency; HRV = heart rate variability; LF = low frequency; MAP = mean arterial pressure; QT = Q and T waves on electrocardiogram; QTc = corrected QT.

Fig. 2

Frequency of themes identified from key findings of eligible studies. *Information relating to breathing irregularities emerged from 13 studies with a total of 2120 participants (questionnaires not counted as patient studies): Tarquinio et al. (2018), 1185 participants with RTT; Mackay et al. (2017), 413 families returned questionnaires; Pini et al. (2016), 151 participants with a clinical diagnosis of RTT; Anderson et al. (2014), 423 participants with RTT; Halbach et al. (2012), 137 participants with RTT; Vignoli et al. (2012), 84 families returned questionnaires; Weese-Mayer et al. (2008) and Weese-Mayer et al. (2006), 47 participants with RTT; Halbach et al. (2008), 70 postal questionnaires; Rohdin et al. (2007), 12 participants with RTT; Larsson et al. (2005), 125 questionnaires; Cass et al. (2003), 87 participants with RTT; Amir et al. (2000), 78 participants with RTT. ^†ASBAs were observed in 5 studies including 56 participants. Larsson et al. (2018) and Larsson et al. (2013), 21 participants with RTT; Bergström-Isacsson et al. (2013), 29 participants with RTT; Julu and Witt-Engerström (2005), 1 participant with RTT; Julu et al. (2001), 5 participants with RTT. ^‡Heart rate metrics such as CSB, MAP and/or CVT emerged from 7 studies including 461 participants. Larsson et al. (2018) and Larsson et al. (2013), 21 participants with RTT; Pini et al. (2016), 151 participants with a clinical diagnosis of RTT; Halbach et al. (2016), 132 participants with RTT; Bergström-Isacsson et al. (2014), 29 participants with RTT; Julu and Witt-Engerström (2005), 72 participants with RTT; Julu et al. (2001), 56 participants with RTT. ^§QTc changes, whether no change or prolongations, emerged from 6 studies including 286 participants. Crosson et al. (2017), 100 participants with RTT; Kumar et al. (2017), 23 participants with RTT; Guideri et al. (2005), 22 participants with RTT; Dotti et al. (2004), 3 participants with MECP2 mutation and X-linked intellectual disability; Guideri et al. (2001), 84 participants with RTT (74 with RTT and 10 with RTT preserved speech variant); Guideri et al. (1999), 54 participants with RTT. ^¶Vagal imbalance (LF/HF) ratio was explored in 7 studies including 246 participants. Kumar et al. (2017), 23 participants with RTT; Acampa et al. (2008), 32 participants with RTT; Guideri et al. (2005), 22 participants with RTT; Dotti et al. (2004), 3 participants with MECP2 mutation and X-linked intellectual disability; Guideri et al. (2004), 28 participants with RTT; Guideri et al. (2001), 84 participants with RTT (74 with RTT and 10 with RTT preserved speech variant); Guideri et al. (1999), 54 participants with RTT. **Fluctuations of peptides were explored in 6 studies including 111 participants. Substance P came from RTT autopsy tissue samples, and cerebrospinal fluid. Ghrelin: Yuge et al. (2017), 4 participants with RTT; Hara et al. (2011), 27 participants with RTT. Leptin: Acampa et al. (2008), 32 participants with RTT. Substance P: Deguchi et al. (2000), 14 participants with RTT; Deguchi et al. (2001), 14 participants with RTT; Matsuishi et al. (1997), 20 participants with RTT. ^††Serotonin or serotoninergic neurotransmission emerged in 2 studies including 39 participants. Guideri et al. (2004), 28 participants with RTT; Paterson et al. (2005), 11 brainstem tissue samples from participants with RTT. ASBA = abnormal spontaneous brainstem activation; CSB = cardiac sensitivity to baroreflex; CVT = cardiac vagal tone; HF = high frequency; HRV = heart rate variability; LF = low frequency; MAP = mean arterial pressure; QT = Q and T waves on electrocardiogram; QTc = corrected QT; RTT = Rett syndrome.

Fig. 3

Potentiation of brainstem vulnerability in RTT. Brainstem vulnerability in RTT leads to impaired cardiorespiratory autonomic control that presents with irregular breathing and modulations in the sympathovagal imbalance. Both hyperventilation and breath-holding shift the equilibrium, which is not sufficiently compensated for by an appropriate increase in vagal tone. These abnormalities result in heightened cardiac electrical instability and increased susceptibility to arrhythmias, represented by reduced heart rate variability and ECG abnormalities (prolonged QTc, T-wave abnormalities). In patients with Rett syndrome, intervening events such as epileptic seizures and infections/sepsis might enhance this underlying autonomic impairment and precipitate an acute cardiorespiratory dysfunction that can occasionally result in sudden death. For the same reasons, pro-arrhythmic medications and those that induce central respiratory depression (e.g., benzodiazepines) must be used with extreme caution in these patients, because they could worsen the underlying autonomic instability. Patients who present with a combination of potentiating factors such as those with significant breathing abnormalities (hyperventilation/breath-holding), uncontrolled generalized epileptic seizures and QT prolongation might be at increased risk for sudden death. A formal cardiac assessment would be warranted in people with suspected QT prolongation to evaluate the use of β-adrenergic blockers, even though their efficacy in reducing cardiac mortality in people without definite long QT syndrome has not yet been demonstrated. Other factors that can increase the risk of sudden cardiac death include structural and functional heart defects, transient systemic factors such as metabolic or hemodynamic abnormalities, and genetic predisposition to fatal arrhythmias. These factors may act individually or in combination. ECG = electrocardiogram; QT = Q and T waves on electrocardiogram; QTc = corrected QT; RTT = Rett syndrome.