Top Caregiver Concerns in Classic RTT
The top five weighted concerns reported by caregivers for people with Classic RTT are 1) Lack of effective communication; 2) Seizures; 3) Lack of hand use; 4) Abnormal Walking/Balance; and 5) Constipation. Figure 1 displays the weighted concerns whose 95% CI are above zero, with the pairwise differences shown in the inset of Figure 1. The full rank list of weighted concerns is presented in Additional file 2: Table S2.
Higher caregiver concern regarding the lack of key functional skills such as communication, hand use, and effective ambulation is not surprising for Classic RTT given the marked deficiencies affected individuals have in these functional domains; however, high level of caregiver concern regarding common clinical problems such as seizures and constipation is also notable. Importantly, caregivers rank “Lack of effective communication” as the top concern, with a weighted score far higher than the other concerns. This is very understandable as effective communication is fundamental to establishing any consistent interaction with the affected individuals.
Variation in top caregiver concerns in Classic RTT between age groups
Viewing these concerns in Classic RTT according to the age of the individual provides a somewhat different picture (Fig. 2). Effective communication remains the top concerns until the oldest age group in which ambulation becomes paramount. Seizures, on the other hand are not a prominent concern until age 5, reaching a peak in the 15-20 year-old group and declining for the next four periods, consistent with the clinical observation of the peak period of seizure onset and severity [29]. Lack of hand use is the second highest concern until age 5, after which it declines steadily until it becomes much less important in the oldest group, despite the fact that hand function does not notably improve in the older age groups [30]. Constipation, a very common clinical problem [31], is a relatively steady concern throughout the first ten years, but then more than doubles in importance throughout the older age groups. Decreased mobility and ability to stand or walk individual could increase this issue. Rapid breathing or breath holding is non-existent as a concern until age 3, increases through age 15 and then declines to non-existent in the oldest group, following expected trends observed for the incidence of breathing abnormalities [32]. Concern regarding repetitive hand movements [30], is most significant during the first five years and then becomes less concerning for the remaining periods. Many of the less common concerns remain relatively constant with age, with notable exceptions that fit known age-dependent patterns of symptom onset and progression.
Caregiver concerns in Classic RTT based on MECP2 mutation
We compared variation in caregiver concerns for Classic RTT across the common, recurrent MECP2 mutations (R168X, R255X, R270X, R106W, T158M, R133C, R294X, R306C) as well as mutation groupings that cause similar molecular disruption of the MECP2 gene (Early Truncations, Large Deletions, C-terminal truncations [CTT]) compared to the combined concerns for people of all ages with Classic RTT (Figure 3). The overall pattern of top caregiver concerns was relatively consistent between mutation groups, although some differences were observed. Lack of effective communication remained the top concern across all mutation groups, although lack of hand use fell out of the top five concerns for R106W and R133C, gait problems for Large Deletions and R106W, and Constipation for R306C. In all these cases, these concerns remained within the top ten caregiver concerns, supporting the broad importance of these issues. Notably, while lack of effective chewing and swallowing ranked as the number 10 concern for all Classic RTT, for people with R106W this concern moved to the number 4 concern.
Broadly, the remaining top ten caregiver concerns remained consistent across the mutation groups, although some notable movement of specific concerns (as defined by a change of more than 50% of all Classic RTT percentages) was observed for some concerns. For example, repetitive hand movements were the number 6 concern for all Classic RTT but moved to number 19 concern for R294X. Similarly, air swallowing/bloating/excessive gas, the number 7 concern overall for all Classic RTT fell to number 20 for R270X and CTT. Notable movements into the top ten concerns include scoliosis/kyphosis for R168X, R255X and Early Truncations (all regarded as mutations associated with more severe clinical phenotypes), anxiety for R133C and R306C, and self-abuse for R294X. The increased rate of caregiver concerns for behavioral issues in mutations associated with less overall functional impairment (R133C, R294X, and R306C) is concordant with the clinically observed increased rates of behavioral problems in less severely affected individuals with Classic RTT [33].
Caregiver concerns in Classic RTT vary by clinical severity
We evaluated top caregiver concerns in relation to clinician assessed severity by using the Clinical Global Impression – Severity (CGI-S) and RTT Clinical Severity Score (CSS). For the CGI-S, Lack of effective communication remained the top concerns across all severity groups (Figure 4). Within the CGI-S range that encompasses the bulk of the people with Classic RTT (CGI-S=4-6, accounting for 90.3%), the top concerns remain grossly similar, with some exceptions such as Repetitive hand movements dropping from number 6 to number 15 for the Severely Impaired group (CGI-S=6). Caregiver concern for seizures is very low in the Mildly Impaired group (CGI-S=3) and rises steadily with increasing CGI-S severity. Lack of hand use is a constant concern throughout the severity range until reaching the Most Impaired group (CGI-S=7), when it drops out the top 10 concerns. This is interesting as people within this severity group have the most overall impaired hand function, suggesting that caregivers shift focus to other clinical concerns when functional skills are severely impaired. This pattern is also seen for Abnormal walking/Balance issues, which are the number 2 concern for the Markedly Impaired group (CGI-S=5) but drop in the more severely affected groups (CGI-S=6-7), despite overall worsening gait function in people in these severity groups. While the Mildly Impaired (CGI-S=3) and Most Impaired (CGI-S=7) represent small fractions of the overall population (5.8% and 3.9%, respectively), there are interesting patterns of the top concerns. In the Mildly Impaired group, clinical features such as seizures, constipation, and chewing and swallowing drop, but behavioral concerns such as screaming episodes, anxiety, self-abusive behaviors, and aggressiveness increase to be within the top 10 concerns. This is in concordance with the observation that behavioral issues are more prominent in less severely affected individuals [33]. In the Most Impaired group, concerns for Frequent Infections, Gastroesophageal reflux, Other GI, and Other Health issues rise in concern.
The comparison of concerns with CSS revealed a slightly different picture (Figure 5). Effective communication remained the top concern up to CSS of 36-40 where it was tied with seizures. At CSS >40 (most severe), effective communication concerns fell well below that for seizures. Seizures were not a concern at CSS 6-10 (least severe) but increased steadily from being relatively low in CSS 11-15 and 16-20 and then becoming increasingly prominent at higher scores. Walking/balance issues were modest at CSS 6-10 but increased through CSS 26-30 before falling dramatically at higher scores until not being a factor at CSS >40. Lack of hand use was of modest concern at CSS 6-10, was most prominent at CSS 11-15 and 16-20, and then declined thereafter. This pattern matched that seen using CGI-S as a measure of severity (especially since CSS and CGI-S are concordant [17]), with caregivers expressing less concern for functional hand use and gait for the most severely impaired individuals, despite these individuals being markedly impaired in these functional domains. In the most severely affected CSS groups, Frequent infections and GU issues concerns rise. Also as seen in the CGI-S analysis, behavioral concerns (Anxiety, Screaming episodes, Aggressiveness) are increased in the lowest severity groups and drop rapidly with increasing severity to being essentially nonexistent. Broadly summarizing the evaluation of top caregiver concerns, concern for problems with functional skills such as hand use and walking are most prominent in the middle severity groups (CGI-S=4-6, CSS=11-35); Seizures, GI problems, Scoliosis, and Frequent infection concerns becoming more important concerns in the most severely affected groups (CGI-S=7, CSS>36); and behavioral problems showing increased caregiver concern for the least affected groups (CGI-S=3, CSS<10).
To evaluate the relationship of the First Caregiver Concern (not weighted) for an individual to clinical features, we compared the Number 1 listed caregiver concern to individual CSS item scores related to language, seizures, and hand use (Table 3). The percentage of caregivers who listed Lack of Effective Communication (Communication), Seizures, and Lack of hand use (Hand Use) for each item score for CSS Language, CSS Seizure, and CSS Hand Use score is presented. Broadly, increasing severity in a domain on the CSS (higher score) is associated with increased percentage of that domain being ranked First concern, however this increase is not linear or completely consistent. Interestingly, while concern for Effective communication rises and peaks with a CSS Language score = 3 (vocalization, babbling), the percentage drops at the most severe CSS Language score = 4 (screaming, no utterances). A similar pattern is observed for the top concern Lack of hand use and the CSS Hand Use score, with the concern for hand use dropping at the highest CSS Hand Use score. These results are consistent with the finding that the caregiver concern for these functional skills declines in the highest severity groups of the global measures of severity, CGI-S and CSS.
Seizures are infrequently the top concern when seizures are absent (CSS Seizure = 0) and have the highest percentage as the top concern for the most severe CSS Seizure category (daily, intractable). An increase in seizures occurs as the top concern occurs for people with weekly seizures. A large percentage of caregivers of individuals without seizures (CSS Seizure = 0) ranked Lack of communication as the top concern (55.8%), which dropped rapidly as seizure burden increased. This pattern was also present for Lack of hand use, which dropped as the top concern rapidly as seizure burden increased. Overall, a pattern emerges that increasing seizure burden changes the frequency at which caregivers select the top concern, with decline in concern for functional skills and increase in seizures as the number one concern.
Table 3: Comparison of individual CSS item scores to number one caregiver concern.
|
Number 1 concern
|
CSS Language
|
Communication
|
Seizures
|
Hand Use
|
0 - Preserved, contextual
|
0.0%
|
0.0%
|
1.2%
|
1 - Short phrases only
|
0.9%
|
0.0%
|
1.2%
|
2 - Single words
|
11.5%
|
0.0%
|
6.2%
|
3 - Vocalization, babbling
|
61.9%
|
77.1%
|
50.6%
|
4 - Screaming, no utterances
|
25.7%
|
22.9%
|
40.7%
|
CSS Seizures
|
Communication
|
Seizures
|
Hand Use
|
0 - Absent
|
55.8%
|
1.2%
|
65.7%
|
1 - <Monthly
|
18.6%
|
12.3%
|
11.4%
|
2 - >Weekly to monthly
|
9.3%
|
12.3%
|
11.4%
|
3 - Weekly
|
6.6%
|
27.2%
|
5.7%
|
4 - More than weekly
|
4.4%
|
12.3%
|
2.9%
|
5 - Daily (intractable)
|
5.3%
|
34.6%
|
2.9%
|
CSS Hand Use
|
Communication
|
Seizures
|
Hand Use
|
0 - Conserved
|
12.8%
|
3.7%
|
11.4%
|
1 - Acquired on time, partially conserved
|
16.4%
|
8.6%
|
20.0%
|
2 - Acquired late, partially conserved
|
11.1%
|
8.6%
|
2.9%
|
3 - Acquired and lost
|
53.1%
|
69.1%
|
57.1%
|
4 - Never acquired
|
6.6%
|
9.9%
|
8.6%
|
The top three weighted concerns for all Classic RTT is shown along the top, and the percentage of caregivers who indicated this being the first problem (Number 1 concern) for each of the CSS item scores is indicated in the cells. Percentages sum within column for each CSS item.
Caregiver concerns in Atypical RTT
The top concerns for caregivers of individuals with Atypical RTT were generally similar to those reported in Classic RTT, with lack of effective communication being greatest and lack of hand use, walking/balance issues, and constipation each being less concerning, but similar (Figure 6). Seizures, however, were less concerning for parents or caregivers whose daughter was regarded as Atypical RTT. Based on the CSS scores, Atypical RTT has a binomial distribution above and below a CSS score of 18 [28]. When viewed as mild or severe Atypical RTT, several differences stand out. Among people with mild Atypical RTT, seizures were much less concerning, and lack of hand use and anxiety were of somewhat greater concern. Behavioral concerns such as screaming, anxiety, and other behavioral problems were increased in mild Atypical RTT. For people with severe Atypical RTT, seizures became the top weighted concern, with lack of effective communication, walking/balance, and hand use dropping. Other features such as GI issues (gastroesophageal reflux, poor weight gain) become more prominent.
Comparison of caregiver concerns between Classic RTT and other RTT-related disorders
Top concerns were compared across the different RTT-related disorders including MDS, CDD, and FS (Figure 6). Lack of effective communication remained the top weighted concern for both MDS and FS, but for CDD seizures become the top weighted concern, with more than 20% higher than for Classic RTT. This reiterates the known increase in overall seizure burden in people with CDD [34, 35]. Lack of hand use remained a significant concern in CDD and FS, but dropped markedly for MDS, but walking/balance concerns increased in MDS. Constipation was less of a concern for CDD, and repetitive hand movements was not a concern for FS. Notably, MDS has increased concern for chewing/swallowing and increased infections, the latter a noted problem in MDS [36-38]. Concerns about vision are present in people with CDD and FS, both of which have reported issues with cortical visual impairment [34, 39, 40].
Caregiver impression of improvement
At each visit, caregivers provided a global impression of whether the overall condition of their child had improved, worsened, or remained unchanged. They were also asked to indicate the main reason for their overall global impression. The percentage of responses for each category for Classic RTT, MDS, CDD, and FS is provided in Table 4. For all the disorders, the number one reason listed for improvement was communication ability, with a wide range from 18% for FS to 37% for Classic RTT. The top caregiver reported reason for worsening in all disorders was seizures, ranging from 19% for Classic RTT to 63% for CDD. During visits in which the caregiver reported overall improvement, the first listed top concern for Classic RTT, MDS, and FS was lack of effective communication; however, for CDD the most frequent top concern was seizures (79%), although lack of effective communication in CDD remained the second most common concern when improvement was noted (33%). While there was relative commonality amongst the disorders regarding the most frequent first listed top concern in relation to caregiver impression of improvement or worsening, variation between the disorders was apparent for the second most frequently identified number one caregiver concern. For visits with caregiver noted improvement: Classic RTT, the next most frequently identified number one concern was hand use (10%); MDS, gait (17%), CDD, communication (33%); and FS, seizures (18%). In visits where the caregiver indicated clinical worsening: Classic RTT, communication (18%), MDS, tie between gait and frequent infections (both 9%), CDD, tie between communication, frequent infections, teeth grinding, and poor weight gain (all 5%); and for FS, lack of effective chewing and swallowing (22%). In conclusion, the main driver of improvement and worsening for all these disorders is communication ability and seizures (respectively) and the first caregiver listed concerns are similar between disorders; however, differences emerge between the disorders especially when less frequently observed first listed concerns are evaluated.
Table 4: Caregiver Impression of Improvement
Caregiver Impression
|
Classic RTT
|
MDS
|
CDD
|
FS
|
Unchanged
|
52%
|
33%
|
38%
|
43%
|
Improved
|
27%
|
47%
|
49%
|
44%
|
Top Caregiver Reason
|
Communication
|
37%
|
30%
|
29%
|
18%
|
First Concern
|
Communication
|
30%
|
42%
|
33%
|
27%
|
First Concern
|
Seizures
|
8%
|
10%
|
47%
|
18%
|
Worsening
|
21%
|
20%
|
13%
|
13%
|
Top Caregiver Reason
|
Seizures
|
19%
|
42%
|
63%
|
22%
|
First Concern
|
Seizures
|
21%
|
55%
|
79%
|
39%
|
First Concern
|
Communication
|
18%
|
3%
|
5%
|
6%
|