Autonomic breathing abnormalities in Rett syndrome: caregiver perspectives in an international database study

Breath-holding was reported by caregivers for approximately two thirds of the sample, whereas just under half were said to experience hyperventilation or abdominal bloating. Onset usually occurred during early childhood. The prevalence of irregular breathing and abdominal bloating were comparable between mutation groups, but hyperventilation and abdominal bloating were affected differently by age. Frequent breath-holding and hyperventilation became less evident while abdominal bloating became more evident with increasing age. More than four fifths of those with hyperventilation (88.3%) and those with abdominal bloating (81.7%) also experienced breath-holding. Approximately one quarter of the sample were reported to experience all three conditions. The impacts of breath-holding, hyperventilation and abdominal bloating were perceived as broadly similar across age and mutation groups, although those individuals with a p.Arg294* mutation were considered to be more impacted by all three conditions.

These prevalence data are consistent with proportions reported by smaller sample size (n = 53 [26], n = 143 [34], n = 145 [35]) parent-report studies for breath-holding. Slightly higher prevalences of breath-holding (76.9%) and hyperventilation (58.2%) were reported in a smaller (n = 91) and slightly older (4–47 years, mean 20.5 years) Italian population [28]. Conversely, parent-report studies with older (≥16 years, n = 53) [27] or exclusively adult populations (>18 years, n = 146) [7] reported lower prevalence of hyperventilation (49.3 and 39%, respectively) in their samples. The higher prevalence of abdominal bloating we found in older individuals was consistent with other studies with older populations [7, 27].

Direct measurement of respiratory function in individuals with Rett syndrome has suggested that all subjects experience breath-holding [9, 10, 15, 29] and hyperventilation [15, 29]. This differential between parent-report studies and clinical studies may in part result from the small sample size of the clinical studies (n < 48) [9, 10, 15, 29] or because some breathing irregularities are very subtle and thus not observable by family members or carers. By contrast, the proportion of patients with Rett syndrome reported with abdominal bloating in a small clinical study (n = 33, 61%) [31] was broadly comparable to the prevalence found in this parent-report study (42.2%). Ours is the largest genetically confirmed sample to compare the individual prevalences of breath-holding, hyperventilation and abdominal bloating across all age groups, giving strength to the findings.

We found that autonomic disturbances were first observed during early childhood for many individuals with earlier onset of breath-holding (occurring in half by age of 4 years) compared with hyperventilation (occurring in a half by age of 5 years). The mean age of regression in Rett syndrome has been reported as 19.3 months [36], and the median ages of loss of speech and hand function at 18 and 22 months, respectively [37]. Thus, in comparison, the onsets of breath-holding and hyperventilation, we identified, are occurring somewhat later, generally after the regression period. As with other clinical features [38], the age of regression also varies by genotype and is, for example, 10 months earlier in those with p.Arg106Trp than in those with C-terminal deletions [36]. Therefore, it is not possible to specify exactly the relationship between the stage of developmental regression as defined by Hagberg and Witt Engerstrom [39] 1986 and the onset of breathing irregularities. However, despite the known demonstrated effect of genotype on regression age [36], we did not find in this analysis that mutation type influenced the age of onset reported for autonomic disturbances, possibly because of the truncated sample used for the time-to-event analyses.

Daily episodes of breath-holding and hyperventilation were reported for almost a half and just over a quarter of the sample, respectively. Although we did not identify any relationship with mutation type, frequent hyperventilation declined with age. This may suggest that maturation leads to a real reduction in frequency of hyperventilation. Data from animal studies investigating potential mechanisms for respiratory irregularities suggest that respiratory control may be disturbed by a number of altered and interacting neuronal pathways that change with developmental age [17, 19]. These may contribute to multiple breathing rhythms being displayed by one individual over a lifetime [17, 29] and could potentially contribute to less frequent observation of irregular breathing with age as seen in our data. However, it is also possible that parents of older individuals may have become more familiar with daily episodes of hyperventilation or breath-holding and were therefore less likely to report their presence. Alternatively, these findings might result from a survival bias, whereby individuals with more severe and frequent irregular breathing have died. The latter hypothesis is supported by the parent-reported decline in breath-holding spells and hyperventilation in a 5-year longitudinal study of Dutch women with Rett syndrome [27]. Initially 73 and 39% of the cohort were reported to have breath-holding spells and hyperventilation, respectively. Five years later, seven women had died, and 60 and 26% of the smaller cohort (n = 37) were reported to experience breath-holding and hyperventilation, supporting the survival bias hypothesis. However, further longitudinal research that encompasses younger individuals with Rett syndrome is required to confirm these findings and the underlying mechanisms.

The presence of one autonomic disturbance was associated with an increased risk of having either of the other two autonomic disturbances, with the strongest of these relationships being the association between breath-holding and hyperventilation. This relationship is consistent with earlier studies where it was hypothesized that either hyperventilation induced breath-holding [12] or that breath-holding induced hyperventilation [40]. More recent physiological studies suggest that there is no single relationship between these two types of irregular breathing and that several irregular breathing patterns that include breath-holding and hyperventilation exist in Rett syndrome [8, 29]. One study measuring respiratory function in 12 subjects with Rett syndrome using remote cardio-respiratory event monitoring in the home environment found that no dominant pattern emerged, but each individual demonstrated their own unique dominant pattern that included shallow breathing, hypoventilation and/or apnoea [29]. We also found that abdominal bloating commonly co-occurred with both hyperventilation and breath-holding. Consistently, a study (n = 33) monitoring respiration and swallowing at rest determined that air swallowing could occur concurrently with both breath-holding and hyperventilation [31]. Of the 20 individuals with abdominal bloating, 17 swallowed air during breath-holding and the remaining three “gulped” air during hyperventilation. It is possible that breath-holding is more likely to result in swallowed air, whereas hyperventilation is not as likely to lead to swallowed air, but those who do concurrently hyperventilate and swallow air take in more air through “gulping” and are therefore at a greater risk of developing abdominal bloating.

Caregivers perceived considerable impacts on daily life for almost half of those with abdominal bloating and just over a third of those with breath-holding or hyperventilation. In a population-based study on outcomes following gastrostomy, 39 of 66 with a gastrostomy also experienced abdominal bloating and 55% of those caregivers observed reduced impact following gastrostomy [41]. Abdominal bloating can be extremely uncomfortable, and gastrostomy has also been recommended in individual cases for venting and relief of pain [31, 32, 41]. Girls and women with a p.Arg294* mutation were perceived to be substantially affected by autonomic disturbances more often than girls and women in any other mutation group. Serotonin neurotransmitters are important regulators of respiratory patterns and mood [25], and in an Australian population-based study, individuals with a p.Arg294* mutation were also more likely to experience mood disturbance in comparison to those with other mutations [35]. The mutation p.Arg294* is usually associated with a mild overall phenotype and less severe clinical features [42‐45]. However, it is possible that the deficits of serotonergic neurotransmission in Rett syndrome [25, 46] are greater for individuals with a p.Arg294* mutation, and therefore, the regulation of breathing and mood in these individuals is more affected than those with other mutation types.

The minority of those with autonomic dysfunction and moderate to severe impact on daily life received a medically prescribed treatment, not surprising given that available literature is limited mainly to case studies [47‐51] and two case series (n = 7 [52] and 8 [53]). Interestingly, six caregivers in our study observed mixed effects in relation to the use of buspirone in contrast to positive effects described in two case studies [47, 49], and only a minority of those prescribed SSRI medications appeared to respond favourably in contrast with the positive effect seen in one case study [49]. Two individuals in our sample had been prescribed naltrexone which has been found associated with adverse effects in a previous clinical trial [54]. The use of topiramate and acetazolamide were each associated with benefits for a small number of individuals in our study, consistent with observations for nine of 10 patients [51, 53] and one of two patients [51], respectively. A previous case series reported reduced autonomic breathing disturbances following prescribed magnesium citrate [52], but this had not been prescribed for autonomic disturbances in our sample although we did observe that those taking magnesium for constipation were not severely impacted by their breathing disturbances. Supported respiration with CPAP or BIPAP was useful for some [48], and no individual had been prescribed carbogen [50]. Further trials are desperately needed to delineate evidence-based management pathways, and our data suggests that topiramate and magnesium citrate could be worthy of further investigation.

Parents were asked to provide information regarding the onset of conditions that typically appear during early childhood. Length of recall and the related effects of memory lapse, whereby the ability to remember events declines over time, and telescoping, where past events are recalled as happening more recently [55], are therefore issues which have to be considered in studies such as ours. In such studies, increased salience of symptoms may influence recall positively while mild symptoms may be under-reported because of memory lapse for less significant events [56‐58]. We acknowledge that recall for age at onset of breath-holding may be better than for hyperventilation because it is likely to be of more concern to parents. Our study therefore sought to balance the risk of recall bias with the need for an adequate sample size by asking parents targeted questions about the time period around the event and by limiting the time-to-event analyses to those under 10 years of age. However, our conclusions should still be tempered by the potential for some recall bias.

We acknowledge that our study has other limitations. Chance associations are possible due to the multiple comparisons made in our paper. We also recognize that these data are parent-reported and that differences from clinical estimates may arise from difficulties observing the potentially subtle nature of autonomic disturbances. Future research could undertake direct physiological assessment using a large representative sample and correlate these data with parent observation of autonomic abnormalities.