Utilization of Non-pharmacological Interventions in Rett Syndrome: A Systematic Review of the Literature on Supportive Care Management

Abstract

Introduction

Rett syndrome (RTT) is a rare neurodevelopmental disorder characterized by early childhood loss of mobility, reduced verbal communication, and behavioral impairment. Although non-pharmacological supportive interventions are widely used, there is a need to better understand their role in RTT care globally.

Methods

Following PRISMA guidelines and a PICOST framework, a systematic review of white (PubMed, Embase, Cochrane) and gray literature was conducted. Non‑pharmacological interventions examined in the United States (US) and outside the US (OUS) settings included ancillary services (e.g., physical therapy [PT]), assistive devices (e.g., wheelchairs), surgical procedures (e.g., scoliosis correction), and assisted interventions (e.g., enteral feeding).

Results

Across 28 eligible studies, patient ages ranged from 1 to 66 years, and 71.4% focused exclusively on female patients with RTT. Approximately 25.0% of the studies were conducted in the US, while 75.0% were conducted in OUS. Six studies examined ancillary service use, where PT utilization ranged from 24.4% to 100.0% and occupational therapy (OT) ranged from 11.5% to 91.7%. Pediatric patients demonstrated a two- to fourfold higher utilization of PT and OT services compared to adults. Among six studies evaluating assistive devices, wheelchair use was reported in up to 90.0% of patients. Nine studies reported surgical procedures, with 1.2%–50.0% of patients requiring scoliosis surgery. Eighteen studies examined assisted interventions, showing enteral feeding utilization rates from 2.0% to 52.0%.

Conclusion

Despite the universal clinical reliance on non-pharmacological interventions in RTT, the evidence base quantifying their real-world utilization remains sparse. The wide variability in reported rates might be due to differences in data sources, geographic settings, and patient populations which underscores the need for standardized, prospective, longitudinal research. Age-related declines in ancillary service use and geographic gaps highlight systemic disparities that warrant further investigation. These findings provide a foundational evidence base to inform health resource planning and future research priorities in RTT.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40120-026-00962-8.

Key Summary Points

This systematic review of literature synthesizes global evidence related to the non-pharmacological best supportive care and management of Rett syndrome (RTT), a rare and progressive neurodevelopmental disorder primarily affecting women.

The review identified 28 eligible studies and found that, although multidisciplinary supportive care is widely recommended in RTT, published evidence describing the real-world utilization, frequency, and longitudinal delivery of non-pharmacological services remains limited.

Use of ancillary therapies such as physical, occupational, and speech therapy was generally higher in pediatric populations than in adults; however, because evidence-based standards for therapy intensity, frequency, and duration across the lifespan are lacking in RTT, these age-related differences should be interpreted descriptively rather than as evidence of underuse.

Regional variations were also observed in management of RTT; for example, scoliosis surgery and wheelchair use were studied more frequently outside of the United States.

The high reliance on enteral feeding (up to 52%) and expensive assistive technologies highlights a substantial, yet underquantified, economic and caregiver burden that persists throughout the RTT lifespan.

Introduction

Rett syndrome (RTT) is a rare, severe, and progressive neurodevelopmental disorder that primarily affects female patients [1]. It is caused by a genetic mutation in the methyl-CpG-binding protein 2 (MECP2) gene [1, 2]. The estimated incidence of RTT is 1 in 10,000 girls by 12 years of age in the United States (US) [3]. While the reported prevalence of RTT is 5.2 cases per 100,000 women in the US, the prevalence of RTT is 5 to 10 cases per 100,000 women globally. Men can also be diagnosed with RTT, and the prevalence of RTT among male patients is estimated to be 0.08 to 0.10 per 10,000 [4, 5]. RTT typically manifests between 6 and 18 months of age, with the core symptomatic features being loss of communication abilities and purposeful hand use, along with other motor skill issues such as gait abnormalities that vary significantly among affected patients [2, 3]. RTT also affects multiple organ systems leading to respiratory, gastrointestinal, orthopedic, and neurological comorbidities among others [6–8]. Furthermore, other complications like liver injury, urological dysfunction, and inflammatory response problems are also associated with RTT [9]. RTT management has primarily centered on multidisciplinary, symptom-directed supportive care for motor, respiratory, sleep, seizure, gastrointestinal, and cardiovascular manifestations [3, 10].

Given its complex and heterogeneous clinical presentation, RTT management has involved an integrated, multidisciplinary management paradigm comprising the pharmacological treatment of specific symptoms in conjunction with non-pharmacological interventions from allied health professionals and ancillary services [3]. Historically, non-pharmacological strategies have included a spectrum of ancillary services (e.g., physical therapy [PT], occupational therapy [OT]), critical surgical procedures (e.g., for scoliosis or hip dysplasia), and assisted interventions or devices (e.g., gastrostomy tubes, communication devices, wheelchairs) that are indispensable for improving an individual’s functioning and quality of life in RTT [11]. Despite the clinical necessity of these interventions, the resource burden of such lifelong, intensive support remains poorly understood.

Consensus guidelines for RTT management recommend the early integration of ancillary health services such as physical, occupational, and speech-language therapies; however, the real-world utilization patterns of these services are relatively unknown [12]. To our knowledge, only one recent study examining the natural history of patients with RTT has contextualized the use of pharmacological and non-pharmacological interventions for RTT management, which may consequently impose a significant economic burden on patients, caregivers, providers, and the healthcare system in the US [11]. Nevertheless, the extent to which existing literature has examined the prevalence and patterns of non-pharmacological interventions across different regions remains unclear. Therefore, this review was conducted to provide a global perspective on the non-pharmacological management of RTT, encompassing both US and outside of the US (OUS) settings. This review aims to provide the RTT community, including clinicians, key opinion leaders, and caregivers, with vital insights into the diverse spectrum of supportive services, therapies, and assistive devices currently utilized in real-world practice. By synthesizing the reported patterns and use of such interventions, this research offers a foundational understanding of how RTT is managed through non-pharmacological means across different regions.

Methods

A global review of white literature comprising peer-reviewed publications (PubMed, Embase, Cochrane) was conducted using the methodology outlined in Cochrane Handbook for Systematic Reviews of Interventions (CHSRI, version 6.3.0) and following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). To complement white literature, a review of gray literature comprising non-traditional publication sources (i.e., clinical trial registries/websites, manually screened reference lists and citations from included articles to identify potentially relevant studies not captured by the database search, etc.) was also conducted to examine information that was missed by conventional academic methods. The methodological approach for the literature review is explained in the following sections.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. As a literature review of secondary, published data, ethics committee approval was not required.

Search Strategy and Data Sources

A systematic search of the global literature was performed across different data sources to identify relevant English language studies published between January 01, 2000 and July 31, 2025. A combination of MeSH (Medical Subject Headings) and Emtree (i.e., Elsevier’s authoritative life science thesaurus) terms, as well as free-text words were used to identify studies related to the use of non-pharmacological and ancillary services. For example, the research included a combination of “Rett syndrome” with the following keywords such as: “augmentative therapy”, “bath aid”, “brace”, “communication”, “communication therapy”, “education”, “feeding therapy”, “hand splint”, “hippo therapy”, “hydrotherapy”, “language therapy”, “occupational therapy”, “physical therapy”, “pool therapy”, “speech generative device”, “speech therapy”, “swim therapy”, “vision therapy”, “walker”, “wheelchair” to include a variety of results. The full list of keywords and the search strategy are provided in Supplementary Tables 1 & 2. Additional research included manual examination of bibliography lists from recent systematic literature reviews and meta-analyses (published within the past 5 years), and searches of clinical trial registries (e.g., clinicaltrials.gov, clinicaltrialsregister.eu, International Clinical Trials Registry Platform). To ensure the comprehensiveness of this review, no age and gender restrictions were applied to the patient population. The PRISMA checklist is provided in Supplementary Table 3.

Study Selection Criteria

A predefined PICOST (Population, Interventions, Comparison, Outcomes, Study Design, and Timeframe) framework guided the eligibility criteria for study selection (Fig. 1). Studies were included if they involved patients with RTT without applying restrictions on the type of interventions or comparisons, to ensure a comprehensive and broad capture of potentially diverse non-pharmacological intervention strategies used in managing RTT symptoms. The review also incorporated published studies regardless of the differences in study designs and data sources such as clinical trials, real-world studies, case series, registries, and observational studies. Studies were excluded if they lacked extractable data such as letters to the editor, commentaries, editorials, reviews, study protocols, or were case reports or case series that had a sample size of less than 10 patients, and those not published in English. Additionally, animal studies, in vitro studies, or pharmacokinetic studies were excluded.

Fig. 1.

PICOST criteria. OUS outside of the United States, PICOST Population, Intervention, Control, Outcomes, Study design and Timeframe, US United States

Study Selection and Data Extraction

Published studies were screened against predefined eligibility criteria in two phases: title/abstract screening (phase 1) and full-text screening (phase 2). Investigators independently screened titles and abstracts, evaluated full texts, and resolved any disagreements through discussion. Data were subsequently extracted from all eligible studies using a priori standardized data extraction form designed to capture variables of interest, including patient demographics (e.g., sample size, age, gender) and study characteristics (e.g., publication year, country, study design, setting). Additionally, studies were classified based on their country or region-specific geographic origin (e.g., US, OUS, and multinational [two or more countries including US]). Eligible studies were stratified into two groups based on geography to examine those conducted in the US vs. OUS. This is due to the inherent and substantial differences in public vs. private healthcare delivery systems, insurance structures, and administrative data infrastructures. These variations directly influence utilization rates and reporting methods; therefore, the distinction provides meaningful context for interpreting cross-regional differences in intervention rates. Where possible, utilization rates were highlighted and presented based on age categories and MECP2 mutation status. To organize and synthesize the utilization rates of diverse non-pharmacological RTT management strategies, defined as any intervention other than a pharmaceutical agent, interventions were categorized into the following four distinct groups based on their clinical purpose, service or procedure type, and delivery setting: (1) ancillary services which preserve or improve functional abilities through services, such as PT, OT, speech therapy (ST), music therapy, behavioral therapy (BT), and vision therapy (VT); (2) assistive devices which are used to compensate for impaired mobility or function, including braces, splints, wheelchairs, and eye-gaze devices; (3) surgical procedures which correct underlying deformities or impairments, such as scoliosis surgery, adenotonsillectomy; and (4) assisted interventions which aid activities of daily living, such as feeding assistance, gastrostomy, and enteral feeding.

Results

Of the 4822 unique studies identified from title and abstract screening, 554 studies were eligible for full-text screening. Of those, a total of 28 studies were selected for full-text extraction after meeting eligibility criteria (Fig. 2 and Table 1). There were no additional studies identified from the gray literature for inclusion in the full-text screening.

Fig. 2.

PRISMA flowchart. No studies have been added from gray literature in this review

Table 1.

Study characteristics assessed for non-pharmacological interventions in Rett syndrome

Study	Country	Country setting	Study design	Data source	N (Rett syndrome patients)	Age in years	Male/female, n (%)	Outcomes reported
Lavås, 2006 [13]	Sweden	OUS	Cross-sectional	Caregiver/clinician report	125	Mean 19.6	0 (0.0%)/125 (100.0%)	Speech therapy, eye-gaze devices
Schwartzman, 2008 [14]	Brazil	OUS	Cross-sectional	Caregiver survey	27	Range 2.6–21 years	0 (0.0%)/27 (100.0%)	Enteral feeding
Fortunato, 2009 [10]	USA	US	Cross-sectional	Clinician report	32	Mean 6.2	0 (0.0%)/32 (100.0%)	Fundoplication
Bartolotta, 2011 [15]	USA, Canada, Australia, and several within Western Europe	Multinational	Cross-sectional	Caregiver report	141	NR	0 (0.0%)/141 (100.0%)	Music therapy
Anderson, 2014 [16]	Multiple (24 countries including USA, Australia, Canada and UK)	Multinational	Cross-sectional	Registry	423	Median 24.9 (range 18.0 to 54.3)	0 (0.0%)/423 (100.0%)	Enteral feeding
Downs, 2014 [17]	Australia	OUS	Cross-sectional	Registry	229	Median 17 years and 11 months (range 2 years 8 months to 35 years 9 months)	0 (0.0%)/229 (100.0%)	Enteral feeding
Epstein, 2016 [18]	Australia	OUS	Cross-sectional	Registry	21	NR	0 (0.0%)/21 (100.0%)	Enteral feeding
Lambert, 2017 [19]	France	OUS	Retrospective cohort	Medical chart review	20	NR	NR	Enteral feeding
Hirano, 2018 [20]	Japan	OUS	Cross-sectional	Survey (school/facility questionnaire)	216	Mean 18.9	NR	Splints
MacKay, 2018 [21]	USA, Canada, UK, Australia, China, Ireland, Switzerland	Multinational	Retrospective cohort	Registry	399	Median 14 years 6 months (range 2–57 years)	2 (0.5%)/397 (99.5%)	Enteral feeding
Wong, 2018 [22]	Australia	OUS	Cross-sequential longitudinal survey	Registry	323	Median (range) Questionnaire years: 2000: 13 (1–24) 2002: 13 (2–27) 2004: 15 (2–29) 2006: 15 (2–30) 2009: 18 (2–34) 2011: 17 (2–35)	0 (0.0%)/323 (100.0%)	Enteral feeding
Amaddeo, 2019 [23]	France	OUS	Prospective cohort	Clinical records	17	Mean (SD) 9.5 (2.8)	0 (0.0%)/17 (100%)	Scoliosis surgery, adenotonsillectomy, fundoplication
Motil, 2019 [24]	USA	US	Retrospective cohort	Mixed method (medical records + caregiver survey)	317*	Medical records: median 21 years Questionnaire: median 11 (range 7–19) years	Medical records: 0 (0.0%)/ 46 (100.0%) Questionnaire: 5 (2.0%)/ 266 (98.0%)	Cholecystectomy
Henriksen, 2020 [25]	Norway	OUS	Cross-sectional	Registry/database	79	Mean (SD) 23 (15)	0 (0.0%)/ 79 (100.0%)	Enteral feeding
Pari, 2020 [26]	Italy	OUS	Prospective cohort	Association registry	79	NR	0 (0.0%)/ 79 (100.0%)	Wheelchair use
Sernheim, 2020 [27]	Sweden	OUS	Cross-sectional study	Clinical records	10	Mean (SD) 23.2 (4.8)	0 (0.0%)/ 10 (100.0%)	Enteral feeding
Humphrey, 2021 [28]	USA	US	Retrospective cohort	Medical records	77	NR	0 (0.0%)/ 77 (100.0%)	Enteral feeding
Humphrey, 2021 [29]	USA	US	Cross-sectional	Medical records	77	NR	0 (0.0%)/ 77 (100.0%)	Hysterectomy
Mendoza, 2021 [30]	Australia	OUS	Retrospective cohort	Database/questionnaire	210	Median 18 years 2 months (range 6–51 years)	NR	Enteral feeding
May, 2023 [4]	USA	US	Retrospective cohort	Administrative claims	5940	Mean (SD) 20.0 (14.5)	0 (0.0%)/ 5940 (100.0%)	Physical therapy, occupational therapy, speech therapy, scoliosis surgery, enteral feeding
Menachem, 2023 [31]	Israel	OUS	Retrospective cohort	Registry	100	NR	0 (0.0%)/ 100 (100.0%)	Scoliosis surgery
Neul, 2023 [32]	USA	US	Clinical trial	Clinical trial	187	Mean (SD) 10.9 (4.62)	0 (0.0%)/ 162 (100.0%)	Enteral feeding
Vilvarajan, 2023 [3]	Australia	OUS	Retrospective cohort	Clinical records	103	NR	0 (0.0%)/ 103 (100.0%)	Scoliosis surgery, enteral feeding
Berger, 2024 [33]	Israel	OUS	Retrospective cohort	Registry	141	Median 3.2 (IQR 2.3–5.7)	2 (1.4%)/ 139 (98.6%)	Enteral feeding
Peri, 2024 [34]	Italy	OUS	Retrospective cohort	Clinical records	11	Mean (SD) 13 (6)	NR	Scoliosis surgery
Weeda, 2024 [35]	Netherlands	OUS	Prospective cohort	Questionnaire + clinical records	64	Mean (SD) 2.9 (2.1)	0 (0.0%)/ 64 (100.0%)	Braces, enteral feeding
May, 2024 [11]	USA	US	Retrospective cohort	Administrative claims	455	Mean (SD) 11.8 (9.5)	0 (0.0%)/ 455 (100.0%)	Physical therapy, speech therapy, occupational therapy, scoliosis surgery, behavioral therapy, vision therapy, enteral feeding
Ferreira, 2025 [36]	Portugal	OUS	Retrospective cohort	Medical records	12	Median 11 years (range 2–19)	1 (8.3%)/ 11 (91.7%)	Physical therapy, speech therapy, occupational therapy, wheelchair use, enteral feeding

IQR interquartile range, NR not reported, OUS Outside of the US, SD standard deviation, USA United States of America

*Data derived from a mixed-method approach consisting of medical record reviews (n = 46) and parent/caregiver questionnaires (n = 271)

Of the 28 studies, 25.0% (n = 7) were conducted in the US, 64.3% (n = 18) were conducted OUS including Australia (17.9%, n = 5); France, Sweden, Italy, and Israel (each 7.1%, n = 2); and Norway, Japan, Brazil, Portugal, and the Netherlands (each 3.6%, n = 1), and 10.7% (n = 3) were multinational. Overall, 42.9% (n = 12) were cross-sectional studies (including one cross-sequential longitudinal survey), 42.9% (n = 12) were retrospective cohort studies, 10.7% (n = 3) were prospective cohort studies, and one study (3.6%) was a clinical trial (Fig. 3). In total, 20 studies reported participant age at study initiation using mean, median, or range. Of these studies, 11 reported mean age, ranging from 6.1 to 23.2 years [4, 10, 11, 13, 20, 23, 25, 27, 32, 34, 35]; eight reported median age, ranging from 3.2 to 24.9 years [16, 17, 21, 22, 24, 30, 33, 36]; and one reported an age range of 2.6 to 21.0 years [14]. Overall, the reported ages of RTT ranged from 1 to 66 years, reflecting the potentially wide age distribution of RTT patients. While most studies focused on women (71.4%, n = 20), 14.3% (n = 4) studies examined both male and female patients, while the remaining 14.3% (n = 4) studies did not report the gender of the RTT population. Of the four studies that examined male patients with RTT, prevalence estimates ranged from 0.5% [21] to 8.3% [36].

Fig. 3.

Classification and reporting frequency of non-pharmacological intervention categories in Rett syndrome. *Other surgical procedures included fundoplication, cholecystectomy, and hysterectomy. N represents number of studies. The studies are not mutually exclusive; for example, among ancillary services, one study reported all three types of ancillary services, hence it will be counted in all three categories

Utilization Patterns of Non-pharmacological Interventions

Of the non-pharmacological interventions examined, ancillary services and assistive devices were reported in 21.4% (n = 6) studies each. Surgical procedures were reported in 32.1% (n = 9) studies whereas assisted interventions were reported in 64.3% (n = 18) studies.

Ancillary Services

Six studies examined ancillary services; the sample size of patients with RTT ranged from 12 to 5940 [4, 11, 13, 15, 35, 36]. In total, four studies reported the use of PT, with three being retrospective claims studies and the other being a prospective study [4, 11, 35, 36]. Of the four, a retrospective study of 12 patients was conducted OUS which found 100% of these patients with RTT received PT [36], whereas a longitudinal, prospective multicenter study of 64 RTT patients with scoliosis conducted OUS found that 92.2% received PT [35]. In contrast, the two US retrospective claims analysis, involving cohorts of 455 and 5940 patients with RTT, reported varying rates of PT utilization at 77.8% and 24.4%, respectively. In both studies, younger patients showed higher utilization of PT (< 18 years, 87.3% and 33.3%) compared to adults (≥ 18 years, 40.2% and 14.9%), respectively [4, 11].

In total, three retrospective studies reported the use of OT [4, 11, 36]. The single OUS study reported the highest OT utilization rate of 91.7% [36]. In comparison, two US-based retrospective claims analyses reported overall OT utilization rates of 70.5% and 11.5%, respectively [4, 11]. Both US studies demonstrated a consistent age-based trend, where pediatric patients utilized higher OT (82.1% and 16.5%) compared to adult patients (25.0% and 6.0%) [4, 11].

In total, four studies examined the use of ST [4, 11, 13, 36]. The two US-based retrospective claims analyses reported ST utilization rates of 74.1% and 13.3%, respectively [4, 11]. In both studies, utilization was higher in pediatric patients (86.8% and 21.7%) than in adults (23.9% and 4.3%) [4, 11]. Conversely, an OUS retrospective study of 12 patients with RTT reported 91.7% ST utilization [36], while another OUS cross-sectional survey of 125 patients with RTT reported that 16.8% received ST [13]. On the other hand, a single multinational cross-sectional survey of 141 patients with RTT reported that 38.2% received music therapy [15]. Additionally, one US retrospective study reported utilization rates of 10.5% for BT and 4.4% for VT [11].

Assistive Devices

Of the six studies that reported the use of assistive devices, sample size ranged from 10 to 125 [13, 20, 26, 27, 35, 36]. Of these, three OUS studies [26, 27, 36] reported the use of assistive devices such as wheelchairs. The first, a prospective observational study of 79 patients with RTT in a neurology and psychiatric unit found that 83.5% used wheelchairs [26]. Second, a cross-sectional survey of 10 patients with RTT reported that three out of four teenagers, and all six (100%) young adults reported wheelchair use [27]. Third, a retrospective study of 12 patients with RTT reported that 41.7% used wheelchairs [36]. In an OUS cross-sectional survey of 215 patients with RTT, 5.6% used upper extremity splints, including elbow (4.7%), forearm/hand (0.5%), and finger splints (0.9%) [20]. Additionally, a longitudinal prospective multicenter OUS study of 64 patients with RTT reported 6.3% utilized braces for scoliosis [35]. Finally, a multinational survey of 141 patients with RTT reported approximately three-fifths (57.4%) of the girls used eye-gaze devices as their primary or supplemental communication method [13].

Surgical Procedures

Of the nine studies that examined surgical procedures, six studies reported the use of scoliosis surgery, sample size ranged from 11 to 5940 patients [3, 4, 11, 23, 31, 34]. Scoliosis surgery rates appear to vary widely, from 1.2% to 50.0%. A retrospective OUS study of 36 hospitalized patients with RTT reported that half (50.0%) of the patients had scoliosis surgery [31], whereas a single center OUS study of 11 patients with RTT conducted at a children’s research hospital reported that 9.1% required scoliosis surgery [34]. Two other OUS studies reported similar scoliosis surgery rates of 11.7% and 12.0% [3, 23]. In a large-scale US retrospective study of 5940 patients with RTT, only about 1.2% underwent scoliosis surgery, with a slightly higher utilization rates in pediatric patients (2.1%) compared to adult patients (0.2%) [4], while another US retrospective study of 455 patients with RTT reported 32.5% underwent scoliosis surgery with a higher utilization rates in pediatric patients (34.4%) compared to adult patients (25.0%). Of the two studies [23, 34] reporting adenotonsillectomy, a single-center OUS study of 11 patients with RTT conducted at a children’s research hospital reported that 9.1% underwent adenotonsillectomy [34]. On the other hand, a prospective OUS study of 17 patients with RTT reported 11.8% underwent adenoidectomy along with Nissen fundoplication, which is a surgical procedure to treat gastroesophageal reflux disease, while 23.5% underwent adenotonsillectomy [23].

Other procedures such as cholecystectomy (laparoscopy or otherwise), surgical ablation, or hysterectomy were infrequently reported. A US cross-sectional survey of 46 patients with RTT reported that 84.8% underwent cholecystectomy, with 80.4% undergoing the procedure via a laparoscopic approach [24]. Another US survey of 50 patients with RTT reported that 2.0% had surgical ablation or hysterectomy [29].

Assisted Interventions

Eighteen studies in total reported the use of assisted interventions requiring feeding assistance of some kind or feeding assistance through enteral feeding (a tube inserted through digestive system). Of these, a US retrospective study of 5940 patients with RTT found that 37.9% required some form of feeding assistance, with 43.3% utilization among pediatric patients compared to 32.2% among adults [4].

Seventeen of these 18 studies, with a sample size ranging from 10 to 455 [3, 11, 14, 16–19, 21, 22, 25, 27, 28, 30, 32, 33, 35, 36], reported enteral feeding as a form of feeding assistance. Of these, three studies [21, 28, 30] examined enteral feeding without specifying the route of enteral feeding. One OUS survey of 399 patients with RTT reported that 37.1% received enteral feeding. Interestingly, the study further explored the findings among patients in the different age categories and MECP2 mutation types, with the highest rates of enteral feeding among patients aged 13 to 19 years (34.5%) and the lowest among those below 7 years (9.5%). By mutations, p.Arg255 was associated with the highest rate of enteral feeding use (15.5%), while patients with p.Arg133Cys mutation reported the lowest rate of enteral feeding use (1.4%) [21]. The three retrospective cohort studies, two conducted in the US (455 patients and 77 patients) and one in OUS (210 patients), reported rates of enteral feeding in 1.8%, 19.5%, and 52.0% patients with RTT, respectively [11, 28, 30].

Among the 17 studies reporting the use of enteral feeding, 14 studies (sample size ranging from 10 to 455) reported gastrostomy a tube inserted through the stomach tube as the specific method of enteral feeding [3, 11, 14, 16–19, 22, 25, 27, 32, 33, 35, 36]. Of these 14 studies, a total of 11 were conducted OUS, two in the US, and one being a multinational study. Gastrostomy use in the OUS studies ranged from 3.7% to 37.5% [3, 14, 17–19, 22, 25, 27, 33, 35, 36], while a multicenter cross-sectional study found gastrostomy use in 27.3% of patients with RTT [16], and a US clinical trial reported 38.0% of patients utilized gastrostomy [32]. The US-based retrospective study reported 13.7% patients utilized gastrostomy, with a higher utilization rate in pediatric patients (16.7%) compared to adults (2.7%) [11].

Of these studies, a longitudinal OUS survey of 323 patients with RTT reported that the gastrostomy use rate increased from 11.9% to 27.0% between 2000 and 2011 [22]. Another OUS survey of 79 patients with RTT found that gastrostomy utilization rate was 35.4%, with the highest use among patients aged 21 to 35 years (50.0%), followed by those aged 1 to 20 years (37.5%), and the lowest use among those > 35 years (11.7%) [25]. Additionally, the cross-sectional OUS survey of 27 patients with RTT reported that nearly 92.6% of patients required feeding assistance; 3.7% of patients used gastrostomy tubes, while the form of feeding assistance was unknown for the rest of the study population [14]. Finally, a cross-sectional survey of 229 patients with RTT conducted OUS also reported gastrostomy/jejunostomy button or nasogastric tube use in 25.3% of patients. Among these, patients aged > 18 years (46.5%) used it the highest and those aged 0–7 years (12.1%) used it the lowest. By MECP2 mutation type, patients with the p.Arg168 mutation had the highest use of gastrostomy tubes (16.7%) while those with p.Arg306Cys mutation reported none [17].

Discussion

To our knowledge, this review is the first to systematically examine global utilization patterns of non-pharmacological interventions as part of best supportive care in managing symptoms associated with RTT. Our review suggests that the literature on the use of non-pharmacological management in RTT is sparse, with only a small number (n = 28) of studies examining the use of best supportive care management. The predominance of cross-sectional surveys and retrospective designs among the eligible studies that were included in this review underscores the need for more rigorous longitudinal, observational research to better characterize the natural history of intervention use in RTT. The geographic distribution of studies with approximately one-fourth being conducted in the US and the remainder in OUS or multinational settings reflects both the global nature of RTT research and the differential infrastructure for patient registries and administrative data across healthcare systems. Notably, assisted interventions such as enteral feeding were the most studied category, whereas ancillary services such as PT were studied the least, despite being among the most universally recommended components of RTT care.

Ancillary services, specifically PT, ranged from 24.4% in a large US claims analysis [4] to 100% in smaller OUS retrospective cohort [36]. The discrepancy in reported utilization of PT between US and OUS clinic-based estimates may suggest that US-based administrative databases may substantially underestimate the true intensity of supportive care needs in RTT. PT use was also reported to be over two times higher among pediatric patients with RTT compared to adults the US [4, 11]. This pattern of higher utilization in pediatric patients was mirrored in OT and ST use, with a threefold increase in OT, and four- to fivefold increase in ST utilization compared to adults [4, 11]. A systematic review by Fonzo et al. described “traditional” PT (with or without assistive devices) and reported functional gains (e.g., prevention of contractures), but noted the evidence was limited by low methodological evidence and inconsistent reporting of exposure and outcomes [37]. However, the high utilization observed in children, while the converse is true among adults, should be interpreted with caution given the sparseness of literature on this topic. Our review of the literature and descriptive findings should not be assumed to represent either appropriate service utilization or a gap in care. These patterns may reflect several factors, including age-specific therapeutic priorities, transition to consultative or maintenance-focused models, differences in access or insurance coverage, variation in caregiver goals, or limited evidence base to service delivery in RTT [12, 37]. An important methodological consideration when interpreting the utilization rates across studies is the heterogeneity of data sources used to ascertain service use. Studies in this review drew on diverse data sources including caregiver surveys, medical chart reviews, administrative claims databases, and registries, each of which may capture utilization differently. For example, administrative claims databases in the US may result in the under-capture of services delivered through the educational system or private pay arrangements, which may be the common pathways for PT, OT, and ST in pediatric populations. Conversely, caregiver-reported surveys may overestimate utilization if respondents report the history of receiving services rather than current use due to potential recall biases. On the other hand, registry-based studies may reflect referral center populations with more severe disease burden, while population-level surveys may better approximate real-world community patterns. These data source effects likely contribute substantially to the wide variability in reported utilization rates, for instance, the 24.4% PT utilization from a large US administrative claims analysis versus 100% from a smaller OUS clinic-based cohort and should be considered when comparing findings across studies. Future research would benefit from standardized definitions of utilization, prospective data collection, and differentiation of ongoing versus episodic care. It should also be noted that BT, including applied behavioral analysis and related approaches, was captured in the search strategy and reported in one US study with a 10.5% utilization rate [11]; however, the broader BT literature in RTT largely originates from studies on neurodevelopmental disorders with mixed etiologies, and a dedicated systematic review of BT approaches specific to RTT is warranted.

This review also shows that utilization of assistive devices, particularly wheelchairs, was frequent, ranging from 41.7% to 90.0% in the three OUS studies [27, 36]. Although no US-based studies reported the use of wheelchairs, it is unclear if the OUS studies represented more severe patients with RTT or if patients in the OUS are more severe, potentially driven by delayed diagnosis. Nonetheless, it is interesting that wheelchair use was considerably high among patients with RTT in OUS settings. Beyond utilization rates, mobility scale assessments reveal that wheelchair use in RTT is distance dependent. For example, some patients may utilize walkers for short distances (5 m), but median scores indicate a transition to total wheelchair dependence for community distances of 50–500 m [38, 39]. This suggests that the lower utilization rates (42%) seen in retrospective cohorts [36] may reflect patients who maintain limited indoor mobility, whereas higher rates (~ 90%) likely capture the pervasive need for wheeled mobility in school and community settings. Importantly, such distance‑dependent mobility limitations impose substantial burden on patients and caregivers, as wheelchair reliance often requires assistance for transfers, specialized seating, and caregiver involvement in managing mobility across home, school, and community settings. As with therapy utilization, the available literature does not provide normative benchmarks for wheelchair prescription or use in RTT, and variation across studies may reflect differences in ambulatory status, environmental demands, caregiver preferences, and access to equipment rather than over- or underutilization alone [12, 40]. On the other hand, communication devices such as eye-gaze systems were used by over half of patients in a multinational survey [13], while upper extremity splints were uncommon (< 6%) [20, 26, 27]. The costs of assistive devices in RTT can impose a substantial and recurring economic burden, ranging from as low as $1,500 to $20,000 for complex rehab/custom specialized electric models [41, 42]. Similarly, eye-gaze devices typically priced around $1000 to $10,000 may be financially inaccessible for caregivers and school systems [43].

Overall, surgery procedure utilization showed the greatest variability. While scoliosis surgery appeared to be rare in a broad US claims cohort (~ 1%) analysis, it was more common in OUS cohorts (~ 9–12%) and reached 50.0% in a hospitalized sample [4, 23, 31, 34]. In contrast to the low rates observed in broad claims analysis, a separate US cohort showed substantially higher (one-third) scoliosis surgery utilization; that study also indicated the greater use of scoliosis surgery among pediatric patients (34.4%) compared with adults (25.0%) [11]. Other procedures such as adenotonsillectomy or cholecystectomy were less frequently reported and limited to smaller samples [23, 34]. Although the need for scoliosis surgery may be variable among the RTT population, published analysis suggests that patients with RTT undergoing surgery for scoliosis incur significantly higher rates of immediate postoperative complications such as pneumothorax, respiratory failure, and pneumonia [44]. Compounding this, the cost of scoliosis surgery and associated postoperative care may be quite costly [45, 46]. The variability in scoliosis surgery rates may not be unique to RTT; such rates may vary broadly across pediatric populations, influenced by differences in surgical philosophy, institutional volume, and risk tolerance at specialized centers. The wide range observed in this review potentially reflects both the systemic determinants and RTT-specific clinical factors.

Studies reporting assisted interventions indicate that feeding assistance, specifically enteral feeding was commonly used, with 52.0% needing it, and often (i.e., 38.0%) delivered through gastrostomy tubes [30, 32]. Mutation-specific differences with enteral feeding of some forms are most common in patients with the p.Arg255 variant and least in those with p.Arg133Cys, while specifically gastrostomy use was highest in p.Arg168 and absent in p.Arg306Cys variants [17, 21]. These mutation-specific differences are broadly consistent with established genotype–phenotype relationships in RTT, whereby mutations affecting the methyl-binding domain or transcription repression domain of MECP2 such as p.Arg255 are generally associated with more severe clinical phenotypes, including greater impairments in swallowing and oro-motor function, which may partly explain the higher enteral feeding utilization rates observed in patients with these mutation types [47]. A longitudinal series also showed rising gastrostomy prevalence over time (from 11.9% to 27.0% between 2000 and 2011), reflecting evolving clinical management practices [22]. According to international consensus guidelines, the transition to intensive enteral support is typically driven by failed growth, dysphagia, or excessive mealtime stress [48], and our findings suggest these requirements vary by mutation subtype.

More broadly, the utilization findings in this review should be interpreted in the context of available RTT supportive care guidance, which generally recommends individualized multidisciplinary management but does not provide quantitative standards for how often most non-pharmacological services should be used. For example, rehabilitation therapies such as PT, OT, and ST are commonly recommended as part of supportive management based on functional needs, but there is little RTT-specific evidence to define whether ongoing, episodic, intensive, or consultative therapy models are optimal at different ages [12, 37]. Likewise, augmentative and alternative communication supports, including eye-gaze technologies, are encouraged when appropriate, yet the literature does not define expected uptake rates in routine practice [49]. In contrast, nutritional support and enteral feeding are more clearly linked to clinical indications such as dysphagia, poor growth, prolonged mealtimes, and feeding burden, suggesting that variability in gastrostomy or enteral feeding use may be driven more by patient need than by differences in care quality [48]. Orthopedic and mobility-related interventions, including wheelchairs, bracing, and scoliosis-related procedures, are similarly individualized and likely depend on motor ability, deformity progression, positioning needs, surgical candidacy, and care setting [40].

A core implication of this review is that valid cross-study comparisons and pooled analysis of non-pharmacological utilization rates are not possible, largely because of the absence of a shared framework for characterizing disease severity and functional status across RTT cohorts in a homogeneous fashion. Symptom heterogeneity and variation in age, sex, care setting, geography, and genetic subtype may contribute to differences in disease severity and, consequently, utilization patterns. Therefore, it is important for clinicians and researchers to examine disease severity and its association with the type of non-pharmacological service utilization. We believe that well-validated severity and functional assessment tools could be routinely incorporated into future research. These include clinician-reported measures such as the Rett Syndrome Clinical Severity Scale (CSS) and the Revised Motor-Behavior Assessment Scale (R-MBA), caregiver-reported measures such as the Rett Syndrome Behaviour Questionnaire (RSBQ) and the Rett Caregiver Assessment of Symptom Severity (RCASS), domain-specific tools such as the Rett Syndrome Gross Motor Scale (RSGMS) for motor function, and the Rett Syndrome Assessment Rating Scale (RARS). International stakeholders, including the International Rett Syndrome Foundation (IRSF) and recent expert consensus workshops [50], have begun to converge on a fit-for-purpose core set of clinical outcome assessments for clinical trial readiness, and the same principles should be extended to observational, registry, and claims-based utilization research.

Given the recent introduction of trofinetide, the first US Food and Drug Administration-approved treatment for RTT, studies examining shifts in RTT management paradigm are warranted. Such research should explore the drug’s potential to alleviate the burden of expensive non-pharmacological care [51]. Studies that focus on capturing the non-pharmacological utilization would address the core gaps: standardized definitions, routine capture of frequency, duration, indications, and complications, linkage to payer claims and family-reported non-medical costs, pre-specified stratification by age bands, MECP2 mutation type, baseline severity, and geography. Such analysis would help identify components with diminishing returns, quantify opportunities for cost-effective avoidance, and test whether modern care can reduce or delay the most burdensome supportive interventions.

This review of the literature should also be contextualized relative to the prior systematic review by Amoako and Hare, 2019, which synthesized evidence on the effectiveness of non-medical interventions in RTT [52]. Whereas Amoako and Hare, 2019 examined whether specific non-medical interventions such as sensory-based, behavioral, and communication-focused approaches produced measurable improvements in clinical, functional, or behavioral outcomes [52], the present review was designed to be complementary in scope and purpose. Our review, therefore, aimed to characterize the real-world frequency, geographic distribution, and age-based patterns of utilization of non-pharmacological services across the broader RTT population worldwide. Since our review applied a minimum sample size threshold of N ≥ 10 patients to ensure that utilization estimates were drawn from cohorts of sufficient size, several single-case experimental designs and small intervention-specific studies that were included in the Amoako and Hare, 2019 review were not eligible for the present review. Taken together, the two reviews may provide a more holistic representation of the non-pharmacological, best supportive care management of RTT by addressing complementary questions of efficacy and utilization.

Our search strategy was anchored to a broad discipline and service-based terminology to capture studies reporting utilization of distinct non-pharmacological ancillary services such as PT or OT use in RTT rather than focus on the type and effectiveness of interventions or methods used by ancillary service providers. Therefore, intervention-specific descriptors (e.g., “environmental enrichment,” “sensory integration”) were not used as primary search terms. Given this, studies or articles focusing on interventions such as the one cited in Downs et al., 2018 or Koppenhaver et al., 2001 fell outside the scope of this review [53, 54]. Future studies focusing on reviewing the effectiveness (i.e., functional change scores) of various non-pharmacological intervention methods in RTT management may help complement our review. Given the specific aims of the study to focus only on the utilization patterns within the RTT population, a broader search strategy of neurodevelopmental disorders (NDD) was not included to avoid the inclusion of other conditions such as autism spectrum disorder (ASD), intellectual disability (ID), cerebral palsy, Down syndrome, and fragile X syndrome in our review. It is possible, therefore, articles that examined utilization patterns of patients with mixed etiologies such as ASD, ID, or others may be excluded. Relatedly, we acknowledge that the more standard descriptors such as augmentative and alternative communication (AAC) were not used as discrete search terms; this, in combination with our deliberate decision to anchor the search to RTT-specific rather than broader neurodevelopmental disorder terminology, means that AAC utilization studies conducted in mixed-etiology populations fell outside the scope of the present review. Future utilization research in RTT would benefit from harmonized AAC terminology and from RTT-specific subgroup reporting in mixed-cohort studies. Terminology for upper-extremity supports is also heterogeneous in the rehabilitation literature, with terms such as “splint,” “orthosis,” “orthotic,” and “brace” often used interchangeably (per American Society of Hand Therapy guidance [55]). Future utilization research in RTT would benefit from standardized terminology to facilitate cross-study comparisons.

Limitations

Overall, reviews often encounter the same limitations inherent to the underlying literature such as the availability and quality of existing studies that may provide biased or inconsistent findings. Variability in study designs, populations, and outcome measures often introduces heterogeneity, limiting the ability to synthesize findings directly. First, the time period (2001–2025) of the search was limited to 25 years, resulting in exclusion of published studies outside of the search time period. The search was anchored to January 2000 to align with the post-MECP2 discovery era. The identification of MECP2 as the causative gene for RTT by Amir et al. [56] in 1999 fundamentally transformed the diagnostic and scientific understanding of RTT, making post-2000 literature more genetically characterized and clinically comparable. However, given the 25-year time frame used for our research, the included articles are likely to provide a robust review about the evolving patterns of non-pharmacological services. Second, it is possible the review may have a language bias as it excluded non-English publications. This limitation may be offset by the fact that English language remains the predominant language of peer-reviewed biomedical literature globally, and the majority of indexed RTT research has been conducted and published in English, including studies from non-English-speaking countries such as those in Europe and Asia. Third, a key limitation of this review is the substantial heterogeneity in how utilization was ascertained across studies resulting in wide variation in the reported utilization of ancillary services. This heterogeneity in data sources and ascertainment methods may be the primary driver of the wide variability in utilization estimates observed across studies. While this may limit the ability to draw definitive cross-study comparisons, it provides a glimpse into the sparseness of literature on this important topic. Fourth, only 11% of the studies included were prospective and longitudinal in design. It is important to recognize that cross-sectional assessments capture utilization at a single point in time and may not accurately reflect patient’s natural history of disease progression and treatment journey over their lifetime, particularly given the dynamic care needs of patients with RTT across developmental stages. Fifth, the severity of RTT was not uniformly reported or standardized across studies, making it difficult to determine whether differences in utilization reflect true regional or systemic variation or simply differences in disease severity between study populations. Notwithstanding these limitations, this review provides a valuable global synthesis of real-world utilization patterns and highlights critical areas where further standardized, longitudinal research is needed.

Conclusion

This review demonstrates that the management of RTT is highly reliant on a wide array of non-pharmacological interventions, yet these services remain inadequately studied in existing literature. Current evidence is derived predominantly from cross‑sectional surveys and retrospective cohorts, underscoring a critical lack of longitudinal research to characterize how supportive care utilization evolves across the full lifespan.

Across studies, ancillary services such as PT (~ 24–100%) and assistive devices including wheelchairs (~ 90%) were frequently utilized, while assisted interventions including enteral feeding (~ 2–52%) and scoliosis surgery showed more variable rates across settings. Conversely, specialized communication aids and orthopedic bracing appear less commonly utilized or reported. Utilization patterns reveal distinct age-based trajectories where ancillary services, such as physical and occupational therapy, are most heavily utilized during childhood. This trend is particularly evident in the twofold, threefold, and fourfold increase in PT, OT, and ST utilization, respectively, among pediatric patients compared to adults.

Notably, while RTT primarily affects women, this review underscores that male patients with RTT have not been sufficiently studied, leaving a gap in our understanding of the specific supportive care needs among male patients. This review also suggests that RTT management approaches vary between US and OUS settings: scoliosis surgery appears more frequently in OUS cohorts, while ancillary services do so in the US. Ultimately, these results highlight the unknown, yet significant role of non-pharmacological supportive interventions in RTT management. The higher utilization of these interventions reflects functional challenges of the RTT population and suggests substantial economic and caregiver burden. Future research prioritizing standardized, large-scale longitudinal studies that quantify the impact of non-pharmacological and novel pharmacological treatments for RTT population are needed.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Authors Nazia Rashid, Safiuddin Shoeb Syed, Krithika Rajagopalan, Vinod Kumar Yakkala, Mirko Sikirica, and Ismaeel Yunusa contributed to the study conception and design. Material preparation, literature search and data extraction were performed by Safiuddin Shoeb Syed and Vinod Kumar Yakkala. The first draft of the manuscript was written and reviewed by Nazia Rashid, Safiuddin Shoeb Syed, Krithika Rajagopalan, Vinod Kumar Yakkala, Mirko Sikirica, and Ismaeel Yunusa. All authors commented on previous versions of the manuscript and have read and approved of the final version of the manuscript.

Funding

This study was funded by Acadia Pharmaceuticals Inc, San Diego, CA, USA. The journal’s Rapid Service Fee was also funded by Acadia Pharmaceuticals Inc, San Diego, CA, USA.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of Interest

Nazia Rashid and Mirko Sikirica are employees of Acadia Pharmaceuticals. Safiuddin Shoeb Syed, Krithika Rajagopalan, and Vinod Kumar Yakkala are current employees of Anlitiks Inc., a company that received funding from Acadia Pharmaceuticals to conduct this study. Ismaeel Yunusa is an Assistant Professor at the College of Pharmacy, University of South Carolina, Columbia, SC, USA.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. As a literature review of secondary, published data, ethics committee approval was not required.