Rehabilitation therapies in Rett syndrome across the lifespan: A scoping review of human and animal studies

Abstract

PURPOSE:

To perform a scoping review of the evidence for therapeutic interventions to manage functional impairments associated with Rett syndrome (RTT) throughout the lifespan.

METHODS:

MEDLINE, EMBASE, PsycINFO, CENTRAL, CINAHL, Scopus and Index to Chiropractic Literature were searched systematically up to December 2019. Two investigators independently reviewed all search results and extracted those that met the inclusion criteria. Human and animal model studies pertaining to therapies that increase functional ability or treat RTT-associated symptoms in all age groups were included. Relevant studies were grouped into intervention categories and rated using the Oxford Centre of Evidence Based Medicine Levels of Evidence. Demographics of participants, interventions, and outcomes were summarized.

RESULTS:

Ninety-one articles representing 88 studies met the inclusion criteria, of which 80 were human clinical studies and eight were studies using animal models. Study designs were primarily case series and only six studies involved participants above the age of 40.

CONCLUSION:

A small number of rigorously studied rehabilitation interventions have been published. Published studies aim to address a wide variety of functional impairments. Research regarding implementation of therapies for older patients with RTT is lacking and requires further exploration.

1. Introduction

Rett syndrome (RTT) is a complex neurodevelopmental condition that predominantly affects females and has an incidence of 1 in 8500 by the age of 15 [1]. Individuals with classical RTT may have typical development until six to 18 months of age, followed by onset of symptoms such as regression, seizures, bruxism, gastrointestinal dysmotility and vasomotor disturbances [2]. The diagnostic criteria for RTT has changed over the years. Currently, a clinical diagnosis of classical RTT is made when a child who experiences a period of regression followed by stabilization meets four essential criteria: partial or complete loss of acquired purposeful hand skills and spoken language, abnormal gait, and repetitive hand movements (wringing, clapping, mouthing, washing, etc.). Brain injury and psychomotor development during the first six months of life that is grossly abnormal are exclusion criteria [2]. Atypical RTT may be diagnosed if two of the four essential criteria, plus at least five of eleven supportive criteria, are present [5].

The causative gene for RTT was discovered to be MECP2 in 1999 [3]. MECP2 mutations are found in most, but not all, individuals with a clinical diagnosis of RTT [4]. Many different MECP2 mutations can cause RTT, but even individuals with the same mutation may vary with respect to clinical severity. The wide range of phenotypes displayed in RTT complicate the ability to study interventions rigorously, as the diverse spectrum of clinical severity must be considered when designing clinical trials.

Recently, systematic reviews in cerebral palsy and other neurodevelopmental disorders have been well received clinically and have allowed clinicians to understand the efficacy and quality of evidence associated with various rehabilitation interventions. Outcome measures are often derived from these major topics in rehabilitation research and allow for downstream clinical applications of research findings to lesser-known conditions with limited literature. However, unlike many other neurodevelopmental disorders, RTT symptoms are variable throughout the lifespan. This aspect often complicates the application of non-RTT research findings as specific therapies may be more effective at particular timepoints in the life of an individual with RTT. This suggests the need for increased RTT-specific research.

The assessment of functional outcomes in RTT is an emerging field. A recent systematic review into adaptive functioning in RTT concluded that this population has extremely impaired adaptive functioning skills. Additionally, current evaluation measures lack validity when assessing individuals with RTT [5]. Another recent systematic review into clinical tools for assessing gross motor, physical activity, and musculoskeletal impairments in individuals with RTT also concluded that research regarding functional evaluation tools for individuals with RTT is lacking [6]. These findings highlight some of the possible challenges faced when comparing RTT therapy intervention studies.

Research using animal genetic models has many benefits. Relevant to RTT, the use of animal models in research reduces between-subject phenotypic variation. As RTT is a relatively rare condition, animal studies are vital for identifying the potential outcomes of interventions prior to their translation towards human clinical research. Several RTT mouse models have been generated that accurately replicate RTT symptoms and have been used to demonstrate response to therapy [7, 8]. For example, one study found that increasing brain-derived neurotrophic factor improved motor impairments in RTT model mice [9]. This information ultimately led to the establishment of a clinical trial exploring a drug that increases brain-derived neurotrophic factor in humans [10].

In many ways, the gold-standard of clinical research evidence is the randomized-controlled trial. Accordingly, systematic reviews often include studies based largely, or only, on that study design. However, other study methodologies such as cohort studies, case reports, and case series are of particular value in the case of rare and heterogenous conditions [11]. Although these study types have limitations in external validity, reliability, and replicability, they provide valuable information for hypothesis generation and can often be applied towards clinical practice. The inclusion of case reports in the present scoping review is therefore appropriate given the clinical presentation of RTT.

Previous systematic reviews have been valuable in presenting available literature exploring therapies for individuals with RTT. A recent systematic review identified 22 articles providing evidence of non-pharmacological interventions for individuals with RTT [12]. Another recent systematic review studying developmental regression in RTT identified 12 articles demonstrating positive effects of behavioral interventions [13]. These previous systematic reviews have focused entirely on human clinical research and have excluded case studies and animal research, both of which provide valuable information with downstream translational potential to human clinical research. This review is more inclusive of such studies. Additionally, the current review aims to view the topic of therapies for RTT from a wider perspective and identify knowledge gaps in the field in order to inform future studies and clinical trials. As such, a scoping review methodology was adopted.

Many individuals with RTT live well into adulthood. A large cohort study found that 60% of individuals with RTT in North America were alive at age 50 [14]. The clinical features of RTT are variable as the individual ages, raising the need for dynamic therapeutic interventions that coincide with features as they come, go, and progress. A Dutch questionnaire study found that communication ability through verbalization or signs is demonstrated in one third of individuals with RTT and improves as the individual ages [15]. It has also been previously demonstrated that ambulation ability can be regained in adulthood [16, 17]. The aforementioned knowledge about lifespan and functional ability in RTT spurs the need for the implementation of intervention programs that support individuals with RTT throughout the lifespan.

The current scoping review aims to summarize and contrast all available evidence of therapeutic interventions targeted towards improving function conducted in both humans and animals. This scoping review discusses available evidence for interventions through a lifespan lens. This article aims to highlight future research areas, as well as to provide clinicians and researchers with a comprehensive summary of all available information regarding the themes and quality of the current literature.

2. Method

Items demonstrating the thorough conduct of this scoping review are specified in a Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist [18] (Appendix A). However, an a priori protocol was not registered or published for this scoping review.

2.1 Data sources

Interventions of interest were those aimed at increasing functional ability or treating a symptom associated with RTT.

All study designs were included. Study populations of females in all age groups with a primary diagnosis of RTT were included. Human studies involving males with RTT were excluded as males generally have a distinct phenotype from females with the same MECP2 mutations [23]. Studies that involved participants with a variety of conditions were included if RTT participant results could be distinguished. Studies utilizing RTT animal models of either sex were included if a therapy aimed to improve functional impairments or symptoms seen in human patients with RTT. Studies involving male mice were included as current male mice models more closely recapitulate the human female RTT phenotype [19]

Studies that included individuals diagnosed with RTT variants (“RTT-like” syndromes such as CDKL5 deficiency disorder or MECP2 duplication syndrome) were excluded. Epidemiological studies, natural history studies, basic science (cell) studies, textbooks or textbook chapters, opinion articles, and grey literature were excluded. Of note, interventions pertaining to pharmacology interventions, gene therapy, scoliosis, bone health, epilepsy, and perioperative management strategies were excluded, as these areas are extensive fields that warrant their own exhaustive review. Additionally, many of these excluded interventions already have been reviewed or have guidelines in the context of RTT. Cohort survey studies such as those focusing on natural history were excluded if treatment outcomes were not evaluated. Publications with non-English full-texts were excluded.

A search strategy was created by a medical librarian and one investigator (HLR, VG). Citations were obtained by systematically searching from the earliest date found to June 15, 2019 and then re-run on December 19, 2019. The search included the following databases: MEDLINE, EMBASE, PsycINFO, CENTRAL, CINAHL, Scopus and Index to Chiropractic Literature. Search terms used included the following subject headings plus keywords and synonyms derived from them: Rett Syndrome, Methyl-CpG-Binding Protein 2, Therapeutics, Physical Therapy Modalities, Exercise, Animal Assisted Therapy, Transcutaneous Electric Nerve Stimulation, Language Therapy, Deglutition, Respiratory Therapy, Hyperbaric Oxygenation, Complementary Therapies, Counseling, Self-Help Devices, Communication Aids for Disabled, Patient Positioning. The full search strategy is lengthy, please see Appendix B for the detailed OVID MEDLINE strategy. A manual search of reference lists from manuscripts was performed to identify additional literature not found by the original search strategy.

2.2 Study selection

Duplicates were removed. Two investigators (DY, VG) independently reviewed all titles and abstracts using Rayyan QRCI [20] to select articles for full-text review. Full-texts were reviewed using Covidence [21]. Conflicts were resolved upon discussion (DY, VG).

Figure 1.

PRISMA flow diagram.

2.3 Data extraction

Relevant information from included studies was extracted. This included: study design, participant demographics and diagnosis details, intervention, and outcome. Age of animals can be extrapolated into approximately equivalent human phases of development based on growth and physiologic processes. However, the RTT animal models do not develop symptoms on the same time course as humans. Thus, the age of RTT animal models cannot be generalized to humans with RTT. As such, animal model ages were not extracted.

The Oxford Centre of Evidence Based Medicine Levels of Evidence 2 were utilized to assess the quality of study results [22].

3. Results

There were 4657 articles originally identified along with an additional 24 articles found by manually searching reference lists. There remained 2996 articles after removal of duplicates. Title and abstract screening identified 535 articles that met selection criteria. Of these, 444 articles were excluded during full-text screening as a result of six broad exclusion categories. Many did not study a therapeutic intervention ( $N=$ 352). Other studies pertained to the pre-determined excluded intervention categories ( $N=$ 35), non-RTT patient populations ( $N=$ 31), or basic science topics ( $N=$ 23). A small number were excluded due to non-English language of manuscript or having no functional outcome. A remaining 91 articles after full-text screening were included in the final data extraction stage.

In two instances, one study was published more than once [23, 24, 25, 26]. All articles are presented in the results (Tables 1–8), but papers describing the same study were counted once in summary tables (Table 9). As such, 88 studies were included.

The 80 human studies are categorized into the following broad study design categories: randomized controlled trials ( $N=$ 3), cohort studies ( $N=$ 6), cross-sectional studies ( $N=$ 9), observational case series ( $N=$ 9), experimental case series ( $N=$ 29), observational case reports ( $N=$ 18), and experimental case reports ( $N=$ 6). A total of 546 study participants are included. Most animal studies were randomized or non-randomized controlled trials with RTT model animals and wild-type control animals either receiving or not receiving an intervention. One animal study was a cohort study and one was a case-control study.

To optimize clarity in presentation of the findings, studies were grouped broadly by intervention type because some interventions targeted a variety of functional outcomes.

Of 80 human studies, 25 included participants over 18-years-old and only six included participants over 40-years-old. The remaining human studies focused entirely on children and adolescents. As many studies only reported a range of participant ages, it was impossible

Table 1

Communication, cognition, and behavior interventions

Lead author and year Study location	Title	Study design (CEBM level of evidence)	Number of study participants with RTT Age Method of diagnosis	Intervention	Outcome
Communication therapies
Ahonniska-Assa 2018 [29] Israel	Assessing cognitive functioning in females with Rett syndrome by eye-tracking methodology	Cohort study (2b)	$N=$ 22 enrolled in study, 17 completed Age: 3.3–12 years (mean: 6.6 years) Genetic diagnoses	Practiced eye tracking technology (ETT) by playing video games over months, then used ETT to assess receptive language.	Some patients (number not specified) gained proficiency in ETT. Subjects performed variably on the receptive language assessment, which is outside the scope of this review.
Bartolotta 2013 [27] USA	Coaching communication partners: A preliminary investigation of communication intervention during mealtime in Rett syndrome	Experimental case series (4)	$N=$ 4 females Age: 5, 10, 11, 14 years Clinical diagnoses	Individualized mealtime communication coaching provided to teacher, aide, and speech and language pathologist (SLP).	Compared with baseline, post coaching mealtime sessions demonstrated increased feeder “bids for communication” and student responses.
Byiers 2014 [30] USA	Functional communication training in Rett syndrome: A preliminary study	Experimental case series (4)	$N=$ 3 females Age: 15, 27, 46 years Clinical diagnoses	Functional communication training (FCT) sessions following switch practice.	All subjects became able to alter their communicative behaviors based on reinforcement contingencies to either communicate using vocalizations or switches.
Koppenhaver 2001 [24] Koppenhaver 2001 [25] Skotko 2004 [28] USA	Storybook-based communication intervention for girls with Rett syndrome and their mothers Supporting communication of girls with Rett syndrome and their mothers in storybook reading Parent reading behaviors and communication outcomes in girls with Rett syndrome	Experimental case series (4)	$N=$ 6 females Age: 3.6–7 years Diagnosis method not reported	Basic parent training on symbolic communication and labeling behaviors. Use of augmentative communication systems during reading with mother and daughter dyads. Use of resting hand splints. Analysis of parent actions on child responses.	Increased in symbolic communication (use of augmentative and alternative communication symbols, voice output devices). Hand splints allowed some girls to point more, when picture symbols were available. Changes in mother reading behaviors over the intervention (ex. increased questions asking, modeling use of communication devices, etc.).
Lariviere 2007 [32] USA	Exploring options for access: enhancing communication and learning for girls with Rett syndrome	Observational case series (4)	$N=$ 2 females Age: 11, 17 years Diagnosis method not reported	Use of various pieces of assistive technology (single switch row column scanning, choosing from 4 photos with eye gaze, yes/no buttons, and others) for eye gaze or hand control.	Description of improved communication and use of various forms of augmentative and alternative communication.
Sigafoos 1996 [33] Australia	Teaching children with Rett syndrome to request preferred objects using aided communication: Two preliminary studies	Experimental case series (4)	$N=$ 4 females (2 per study) Age: study 1 (12, 17 years) study 2 (7, 15 years) Diagnosis method not reported	Study 1: Learning to use “want” symbol communication board to request preferred object. Study 2: Using subject specific items (Custom symbol board, or plate switch) to teach requesting of potato chips or music, respectively.	Increased independent use of communication modality.
Simacek 2016 [34] USA	Communication intervention to teach requesting through aided AAC for two learners with Rett syndrome	Experimental case series (4)	$N=$ 2 females Age: 7, 27 years 1 genetic diagnosis, 1 clinical diagnosis	Multiple interventions, including various forms of prompting, to increase aided AAC communication requests.	Increased responses using touch screen and fixed eye-gaze technology.

Table 1, continued
Lead author and year Study location	Title	Study design (CEBM level of evidence)	Number of study participants with RTT Age Method of diagnosis	Intervention	Outcome
Stasolla 2014 [36] Italy	Comparing PECS and VOCA to promote communication opportunities and to reduce stereotyped behaviors by three girls with Rett syndrome	Experimental case series (4)	$N=$ 3 females Age: 9.2, 8.4, 10.5 years Diagnosis method not reported	Learned to use a picture exchange communications system (PCES) or vocal output communication aid (VOCA) speech device to obtain desired items.	Potential means of making requests. Improved indices of happiness and reduced stereotypic hand movements.
Stasolla 2015 [37] Italy	Technological aids to support choice strategies by three girls with Rett syndrome	Experimental case series (4)	$N=$ 3 females Age: 9.6, 10.5, 12.4 years Diagnosis method not reported	Used assistive technology to insert object into one of three containers. Subject exposed to a preferred song, video, or light.	Potential means of making choices. Improved indices of happiness and reduced stereotypic hand movements.
Stasolla 2019 [35] Italy	Experimental examination and social validation of a microswitch intervention to improve choice-making and activity engagement for six girls with Rett syndrome	Experimental case series (4)	$N=$ 6 females Age: 8.64, 8.16, 8.28, 9.36, 10.2,11.52 years Diagnosis method not reported	Participants taught to sort and insert a familiar object into one of three rectangular containers, resulting in subject-specific preferred stimuli.	Most subjects sorted and inserted more for relatively more preferred stimuli. Improved indices of happiness. Reduced stereotypic hand movements.
VanAcker 1995 [38] USA	An effective computer-based requesting system for persons with Rett syndrome	Experimental case series (4)	$N=$ 3 females Age: 11.5, 6.5, 5 years Diagnosis method not reported	Specially-designed software and touch screen computer-based request systems.	Increased differential requesting of “liked” over “disliked” foods.
Lancioni 2014 [31] Italy	Microswitch-aided programs for a woman with Rett syndrome and a boy with extensive neuro-motor and intellectual disabilities	Observational case series (4)	$N=$ 1 female (non-RTT male participant) Age: 21 years Diagnosis method not reported	Head-activated microswitch intervention. Animation films with music.	Increase in microswitch response and level/indices of happiness.
Communication therapies – animal studies
Engineer 2015 [40] USA	Degraded neural and behavioral processing of speech sounds in a rat model of Rett syndrome	Cohort animal study (5)	$N=$ 6 female RTT model rats (5 age-matched controls) Heterozygous MECP2 ${}^{\mathrm{\text{tm1sage}}}$ rats	Rats trained to discriminate speech sounds (consonant discrimination, vowel discrimination) in varying levels of background noise.	RTT model rats able to discriminate speech sounds in quiet environments but unable to discriminate speech sounds with background noise. Ability improved with training to a level comparable to control animals.
Cognition therapies
Ainsworth 2016 [41] USA	Teaching phonics to groups of middle school students with autism, intellectual disabilities and complex communication needs	Experimental case series (4)	$N=$ 1 female (among 8 patients with other conditions) Age: 14 years Diagnosis method not reported	Teaching letter-sound correspondence over 22 sessions using Accessible Literacy Learning (ALL) curriculum.	Indicated, using eye gaze or reach approximation, learning of letter-sound correspondence of 5 letters.
Fabio 2011 [43] Italy	The increase of attention in Rett syndrome: A pre-test/post-test research design	Experimental case series (4)	$N=$ 12 females Age: 5.5, 6, 6, 12, 12.5, 13, 14, 14, 15, 17, 20, 26 years Met 1988 Rett Syndrome Diagnostic Criteria Work Group criteria and genetic diagnosis	Subject-specific reinforcements, containment of stereotypies, and other strategies, to maintain attention.	Increased span of selective attention to a specific discrimination task.
Fabio 2013 [42] Italy	Training communication abilities in Rett syndrome through reading and writing	Experimental case report (5)	$N=$ 1 female Age: 21 years (intervention started at 8 years) Genetic diagnosis	Pre-training prior to reading and writing and cognitive rehabilitation training.	Separation of words into syllables, constructing sentences since age 15.

Table 1, continued
Lead author and year Study location	Title	Study design (CEBM level of evidence)	Number of study participants with RTT Age Method of diagnosis	Intervention	Outcome
Fabio 2016 [44] Italy	Cognitive training modifies frequency EEG bands and neuropsychological measures in Rett syndrome	Randomized controlled trial (1b)	$N=$ 34 females (21 trainingpatients, 13 control) Age: 18 (5–11 years), 7 (12–18 years), 8 (18–40 years),1 unknown Genetic diagnoses	Long-term cognitive training versus usual care.	Improvement in eye tracking behavior.
Hetzroni 2002 [45] Israel	The use of assistive technology for symbol identification by children with Rett syndrome	Experimental case series (4)	$N=$ 3 females Age: 8, 9, 10 years Diagnosis method not reported	Learning symbols, using individualized computer-based interactive symbol identification system.	Demonstrated learning of symbols over time.
Velloso 2009 [39] Brazil	Using eye-tracking technology for communication in Rett syndrome: perceptions of impact	Cross-sectional study (4)	$N=$ 10 females Age: 4.5–13 years 8 genetic diagnoses, 2 clinical diagnoses	Single eye-tracking assessment of color, shape, size, and spatial position knowledge.	Patients unable to indicate knowledge of color, shape or size. Due to small study size, authors discuss but are unable to make conclusions about effect of aging on performance.
Watson 1996 [48] USA	Intention and preference in a 3-year-old girl with Rett syndrome	Experimental case report (5)	$N=$ 1 female Age: 3 years Diagnosis method not reported	Computer game. Required bilateral upper extremity use to control outcome.	Subject appeared to learn to press buttons to achieve desired stimulus.
Watson 1996 [47] USA	Behavioral competition in a case of Rett syndrome	Experimental case report (5)	$N=$ 1 female Age: 3 years Diagnosis method not reported	Parent-led contingency game intervention.	Certain games more effective in eliciting functional behaviors and influencing learning.
Hirano 2015 [46] Japan	Fixation duration changes in Rett syndrome after habilitation intervention	Experimental case report (5)	$N=$ 1 female Age: 22 years Diagnosis method not reported	Eye-tracking technology intervention. Care staff and family assisted in familiarizing patient with technology and task.	Increased fixation duration on experimental targets.
Behavioral therapies
Evans 1999 [49] New Zealand	Modifying adult interactional style as positive behavioural intervention for a child with Rett syndrome	Observational case report (5)	$N=$ 1 female Age: 6 years Met RTT DSM IV criteria (American Psychiatric Association 1994)	Various multidisciplinary school-based services.	Reducing demands on student associated with reduced excess behaviors (hand movements).
Smith 1995 [106] USA	Behavioral treatment of Rett’s disorder: Ineffectiveness in three cases	Observational case series (4)	$N=$ 3 females Age: 2.6, 2.75, 3.1 years Clinical diagnoses	Gradual progression through behavioral treatment program based on operant conditioning principles.	Primarily negative outcomes (fluctuating sensory deficits, increase in hand stereotypies, non-responsiveness). Positive outcomes included decrease in tantrums.
Titlestad 2019 [112] Norway	Brief report: Modest but clinically meaningful effects of early behavioral intervention in twins with Rett syndrome-a case study	Observational case series (4)	$N=$ 2 females Age: 3.5 years (twins) Genetic diagnoses	Early Intensive Behavioral Intervention (EIBI).	Gains in multiple functional domains.
Iwata 1986 [113] USA	Operant studies of self-injurious hand biting in the Rett syndrome	Experimental case series (4)	$N=$ 2 females Age: 3, 11 years Diagnosis method not reported	Various behavior modification techniques such as differential reinforcement, combined with response interruption.	Decreased hand biting in both girls. Increased motor performance (instruction following, toy play) in one girl.

Table 1, continued
Lead author and year Study location	Title	Study design (CEBM level of evidence)	Number of study participants with RTT Age Method of diagnosis	Intervention	Outcome
Paisey 1993 [114] USA	Case study: Noninvasive behavioral treatment of self-injurious hand stereotypy in a child with Rett syndrome	Observational case report (5)	$N=$ 1 female Age: 3.5 years Diagnosis method not reported	Competing functional responses plus response interruption.	Various treatments associated with differing reductions in hand mouthing, hand stereotypies, tongue thrusts.
Roane 2001 [50] USA	Analysis of aberrant behaviour associated with Rett syndrome	Experimental case series (4)	$N=$ 2 females Age: 14, 23 years Diagnosis method not reported	Used functional analysis to develop subject-specific techniques to influence occurrence of subject-specific behavior (ex. verbally then physically interrupting hand wringing).	Reductions in levels of targeted behaviors.

Table 2

Gross motor interventions

Lead author and year Study location	Title	Study design (CEBM level of evidence)	Number of study participants with RTT Age Method of diagnosis	Intervention	Outcome
Ambulation therapies
Borst 2018 [61] The Netherlands	Abnormal foot position and standing and walking ability in Rett syndrome: An exploratory study	Cross-sectional study (4)	$N=$ 45 physiotherapist surveys on 67 patients Age: 2 (2–4 years), 19 (4–12 years), 22 (12–19 years), 18 (19–40 years), 3 (40–50 years), 3 ( $>$ 50 years) Clinical diagnoses	In an online survey of physiotherapists, therapists commented on effect of bracing in their patients.	Physiotherapists commented that abnormal distribution of pressure on foot and asymmetry in weight bearing through legs negatively correlated with standing and walking ability.
Jacobsen 2001 [16] Norway	Rett syndrome and ageing: A case study	Observational case report (5)	$N=$ 1 female Age: Intervention at approximately 40 years Diagnosis method not reported	Intensive motor training three years.	Regained walking ability at age 40 after not walking for 20 years. Walking subsequently declined, but never ceased totally after motor training ceased.
Larsson 2001 [55] Sweden	Gross motor ability in Rett syndrome-the power of expectation, motivation and planning	Observational case series (4)	$N=$ 3 families Age: 10, 15, 40 years Diagnosis method not reported	Various physiotherapy and equipment interventions such as walker and lower extremity orthoses.	Increased standing and walking ability. Improved lower extremity contracture management.
Larsson 2018 [54] Sweden	Walking on treadmill with Rett syndrome-Effects on the autonomic nervous system	Cohort study (2b)	$N=$ 12 with RTT, 14 typically developing (26 females total) Age: 5–46 years Genetic diagnosis in 9 of the 10 classic RTT patients	Treadmill walking assessment. Ability to walk up to 6 minutes at their own maximum sustainable speed on treadmill.	Valsalva maneuvers at rest normalized during treadmill walking. Participants with RTT able to walk the full six minutes at self-selected speed.
Layne 2018 [52] USA	Temporal gait measures associated with overground and treadmill walking in Rett syndrome	Cross-sectional study (4)	$N=$ 14 females Age: 5–20 years (mean: 10.4 years) Genetic diagnoses	Assessing temporal gait parameter variability, during overground walking on instrumented mat vs. motorized treadmill while in safety harness.	Decreased variability in several gait parameters during treadmill walking.
Layne 2019 [53] USA	Kinematics associated with treadmill walking in Rett syndrome	Cross-sectional study (4)	$N=$ 17 females Age: 4–20 years (mean: 10.8 years) Genetic diagnoses	Kinematics assessment of independently ambulatory patients, at increasing treadmill speeds. Assessment of gait adjustment as treadmill speed increases.	Reduced gait parameter variance as walking speeds increased. Three participants able to walk up to 0.6 m/s, others had slower maximum gait speeds.
Lotan 2004 [51] Israel	Improving functional skills and physical fitness in children with Rett syndrome	Cohort study (2b)	$N=$ 4 females Age: 8.5–11 years Diagnosis method not reported	Independently ambulatory patients underwent daily treadmill training program.	Improvement in walking speed, knee walking, ability to ascend/descend stairs, reduced pulse at rest.
Lotan 2012 [17] Israel	Regaining walking ability in individuals with Rett syndrome: A case stud	Observational case report (5)	$N=$ 1 female Age: Approximately 23 years (exact age not reported) Diagnosis method not reported	Multidisciplinary program (baclofen, physiotherapy and handling, prone positioning, special walker).	Regained walking ability at age 28 after not walking for more than 5 years.
Lotan 2015 [56] Israel	Enhancing walking ability in individuals with Rett syndrome through the use of applied behavioral analysis (ABA): review and a case study	Observational case report (5)	$N=$ 1 female Age: not reported (adult patient) Diagnosis method not reported	Applied behavioral analysis techniques to extend daily walking ability. Eliminated negative reinforcers such as preventing chair availability. Enhanced positive reinforcers (ex. verbal praise).	Increased daily steps 10-fold.

Table 2, continued
Lead author and year Study location	Title	Study design (CEBM level of evidence)	Number of study participants with RTT Age Method of diagnosis	Intervention	Outcome
Schaefer-Campion 2015 [57] USA	Fostering ambulation for a preschool child with Rett syndrome: A case report	Observational case report (5)	$N=$ 1 female Age: 4.5 years Diagnosis method not reported	Use of metal toy shopping cart to establish and practice ambulation.	Progression from use of toy cart to use of anterior opening walker.
Stahlhut 2019 [60] Denmark	Feasibility and effectiveness of an individualized 12-week “uptime” participation (U-PART) intervention in girls and women With Rett syndrome	Cohort study (2b)	$N=$ 16 Age: 5–48 years Genetic and clinical diagnoses	Individualized intervention, in patients’ naturalistic settings to increase daily physical activity.	Improvements in sedentary time, daily step count, walking capacity, quality of life, and gross motor capacity.
Stasolla 2013 [58] Italy	Promoting adaptive behaviors by two girls with Rett syndrome through a microswitch-based program	Experimental case series (4)	$N=$ 2 females Age: 2, 17 years Diagnosis method not reported	Use of wobble microswitch, then photocells on walker, to obtain a preferred stimulus (music, vibrations, lights). Physical manipulation of microswitch or walking 4 steps in 3 seconds required to obtain preferred stimuli.	Improved self-determination to access preferred stimuli, ambulation, indices of happiness, and reduced stereotypic hand movements.
Stasolla 2018 [59] Italy	Fostering locomotion fluency of five adolescents with Rett syndrome through a microswitch-based program: Contingency awareness and social rating	Experimental case series (4)	$N=$ 5 females Age: 14, 13, 16, 15, 17 years Diagnosis method not reported	Taught to walk four steps forward in three seconds to obtain a preferred stimulus (amusing songs, familiar voices, colored lights, and tactile vibrations). Comparison of two conditions: no stimuli present, stimuli present all the time.	Increased auto initiation and ambulation. Improved indices of happiness and reduced stereotypic movement.
Multimodal therapies
Pizzamiglio 2008 [66] Italy	Sensory-motor rehabilitation in Rett syndrome: A case report	Observational case report (5)	$N=$ 1 female Age: 5 years Genetic diagnosis	Physical, language, and cognitive rehabilitation.	Benefits relating to postural control, contracture management, sialorrhea, use of gestures, interest in environment, and others.
Bhalla 2015 [62] India	Cognitive and Motor Rehabilitation in Rett’s Syndrome	Observational case report (5)	$N=$ 1 female Age: 7 years Genetic diagnosis	Multifaceted, multidisciplinary therapy program. Physical level of therapy increased and became more complex, treatment time shortened.	Improvement in Brief Ataxia Rating Scale and reduced high guard hand position. No improvement in breathing pattern or bruxism.
Hanks 1990 [63] USA	Motor disabilities in the Rett syndrome and physical therapy strategies	Observational case series (4)	$N=$ 23 females Age: 2–21 years Met Hagberg 1986 criteria	Various gross motor therapies described in single site retrospective chart review.	One case of gross motor intervention re-established independent walking. Specific outcomes not clearly outlined.
Lotan 2012 [64] Israel	The conductive environment enhances gross motor function of girls with Rett syndrome. A pilot study	Experimental case series (4)	$N=$ 3 females Age: 3, 4, 5 years Genetic diagnoses	Conductive education program (as an educational approach).	Various objective and subjective improvements in self-care skills, social skills, hand function.
Pereira 2017 [65] Brazil	General and oral characteristics of Rett syndrome: Case report	Observational case report (5)	$N=$ 1 female Age: 7.5 years Genetic diagnosis	Implementations of various therapies (ex. physio-, speech, hearing, occupational, hydro-, equine therapy and kinesiotape).	Qualitative description of functional improvements.

Table 3

Fine motor interventions

Lead author and year Study location	Title	Study design (CEBM level of evidence)	Number of study participants with RTT Age Method of diagnosis	Intervention	Outcome
Orthoses
Aron 1990 [115] USA	The use and effectiveness of elbow splints in the Rett syndrome	Observational case series (4)	$N=$ 8 females Age: 2–14 years Diagnosis method not reported	Elbow splints implemented due to self-injurious behaviors.	Increased socialization, increased interaction with the environment, decreased hand to mouth movements, decreased hand wringing.
Bumin 2002 [107] Turkey	The effect of hand splints on stereotypic hand behavior in Rett’s syndrome	Experimental case series (4)	$N=$ 4 females Age: 8, 9, 10, 11 years Clinical diagnoses	Hand splints and elbow restraints.	Minor decrease in stereotypic movements. Increased feeding activity and functional use of the hand.
Kubas 1992 [109] USA	Use of splints to develop hand skills in a woman with Rett syndrome	Observational case report (5)	$N=$ 1 female Age: 15 years Diagnosis method not reported	Various upper extremity orthoses.	Deltoid suspension sling, scoop dish, and built-up handled spoon improved feeding and other tasks. Dorsal wrist splint maintained hand contact with switch, rather than under chin.
Naganuma 1988 [108] USA	Effect of hand splints on stereotypic hand behavior of three girls with Rett syndrome	Experimental case series (4)	$N=$ 3 females Age: 13, 16, 16 years Diagnosis method not reported	Wrist cuffs, abducted thumb.	Duration percentage of stereotypic hand behavior and functional hand use assessed. All 3 showed reduction in time, and one showed increase in finger-feeding skills.
Sharpe 1990 [116] USA	Use of an elbow restraint to improve finger-feeding skills in a child with Rett syndrome	Experimental case report (5)	$N=$ 1 female Age: 5 years Diagnosis method not reported	Elbow restraint splint.	Improved amount of dry cereal self-feeding.
Sharpe 1992 [67] USA	Comparative effects of bilateral hand splints and an elbow orthosis on stereotypic hand movements and toy play in two children with Rett syndrome	Experimental case series (4)	$N=$ 2 females Age: 6, 6 years Both had RTT (one with atypical RTT due to cerebral palsy comorbidity	Comparison of bilateral hand splints and elbow orthoses.	Increased toy contact and reduced stereotypic movements with elbow splints. No change with hand splints.
Tuten 1989 [68] USA	Effect of hand splints on stereotypic hand behavior of girls with Rett syndrome: A replication study	Experimental case series (4)	$N=$ 2 females Age: 5, 5 years Diagnosis method not reported	Hand splints.	No difference in hand-wringing, stereotypic hand behavior or independent feeding skills.
Independence therapies
Mraz 2016 [71] USA	The effects of virtual reality on the upper extremity skills of girls with Rett syndrome: A single case study	Observational case report (5)	$N=$ 1 female Age: 9 years Diagnosis method not reported	Virtual reality intervention. Arms used to bend forward and reach in various directions to play various YouTube videos.	Improvements in upper extremity use to complete multiple self-care activities. Functional Reach test improvements of uncertain clinical significance. Decreased stereotypical hand movements.
Piazza 1993 [70] USA	Teaching self-feeding skills to patients with Rett syndrome	Experimental case series (4)	$N=$ 5 females Age: 3, 8, 10, 18, 23 years Clinical diagnoses	Teaching of spoon-feeding using instructions, hands-on assistance, and verbal praise.	Improvements in feeding (scooping food, spoon-to-mouth).
Qvarfordt 2009 [69] Sweden	Guided eating or feeding: Three girls with Rett syndrome	Experimental case series (4)	$N=$ 3 females Age: 9, 14, 18 years Diagnosis method not reported	Guided eating (hand-on-hand, verbal prompts, and other techniques) vs. being fed.	Guided eating improved involvement and participation in the eating process.

Table 4

Music therapy

Lead author and year Study location	Title	Study design (CEBM level of evidence)	Number of study participants with RTT Age Method of diagnosis	Intervention	Outcome
Chou 2019 [72] Taiwan	The effectiveness of music therapy for individuals with Rett syndrome and their families	Cohort study (2b)	$N=$ 23 patients (12 musicprogram, 11 control patients) Age: 3–25 (mean: 14.45 studygroup, 12.8 control group) Genetic diagnoses	Music therapy program.	Improved social interaction, communication skills, eye contact, hand function, reduced seizure frequency. Reduced parent stress.
Elefant 2005 [73] Norway	Learning ability in children with Rett syndrome	Cohort study (2b)	$N=$ 7 females Age: 4–10 years Met 1988 Rett Syndrome Diagnostic Criteria Work Group criteria	Physiotherapist-led music choice-making intervention.	Participants showed ability to learn to choose songs and remembered how to and song choice over time.
Elefant 2004 [23] Lotan 2006 [117] Norway	Rett syndrome: Dual intervention –music and physical therapy Physiotherapy and music therapy for a girl with Rett syndrome – a dual treatment approach	Observational case report (5)	$N=$ 1 female Age: 9 years Diagnosis method not reported	Dual music therapy and physiotherapy intervention.	Allowed shorter treatment time, and additional therapy possibilities, compared with single discipline physiotherapy. Choice making improved.
Francis 2011 [74] Israel	Effects of ‘The Listening Program’ on children with profound and multiple learning difficulties …including commentary by Banai K	Experimental case series (4)	$N=$ 5 females Age: 11.5, 14.6, 17, 16, 15.8 years Diagnosis method not reported	“The Listening Program” – a commercially available music-based auditory stimulation technique. Each participant also received a placebo: regular classical music cycle.	The Listening Program resulted in relative improvements in mood and engagement. Other outcomes reported, but unable to distinguish RTT participant data.
Hackett 2013 [75] UK	A retrospective practice based evaluation of music therapy: A single-case study of a four-year-old girl with Rett syndrome-Rebecca’s story	Observational case report (5)	$N=$ 1 female Age: 4 years Genetic diagnosis	Retrospective video analysis of music therapy intervention.	Improvement in hand function and turn-taking during first 6 months.
Hill 1997 [76] UK	Focus on practice: The relevance and value of music therapy for children with Rett syndrome	Observational case series (4)	$N=$ 2 females Age: 7, 12 years Diagnosis method not reported	Music therapy program.	Improvements in vocalization and visual attentiveness in one participant, increased spontaneous physical contact, eye contact, and vocalization in other participant.
Merker 2001 [80] Sweden	Music and the Rett disorder: The Swedish Rett center survey	Cross-sectional study (4)	70 of 144 forms returned. Age: 4–53 years Diagnosis method not reported	Survey mailed to parents/caregivers of the Swedish Rett Centre 1999.	Music resulted in a range of “behavioral reactions” in 42% of patients (“lighting up, smiling” and “cessation of stereotypic behavior”).
Wigram 2005 [77] Denmark	Music therapy as a tool for assessing hand use and communicativeness in children with Rett syndrome	Observational case report (5)	$N=$ 1 female Age: 6 years Clinical diagnosis	Single music therapy assessment. Assessed eye contact, smiling, laughing, and vocalizations evoked.	Indications of latent communicative responsiveness and intentionality, sense of humor, turn-taking, and sharing.
Wylie 1996 [78] USA	A case study to promote hand use in children with Rett syndrome	Experimental case series (4)	$N=$ 2 females Age: 4.5, 5 years Diagnosis method not reported	Rhythm instrument intervention.	Improvements in purposeful hand use.

Table 4, continued
Lead author and year Study location	Title	Study design (CEBM level of evidence)	Number of study participants with RTT Age Method of diagnosis	Intervention	Outcome
Yasuhara 2001 [79] Japan	Music therapy for children with Rett syndrome	Experimental case series (4)	$N=$ 3 females Age: 4, 5, 6 years Diagnosis method not reported	Individualized music therapy program.	4-year-old patient displayed responsiveness and requested things through verbalization. 5-year-old patient displayed preference, turn-taking, and verbalization. 6-year-old patient learned to play drums to a tempo.

Table 5

Environmental enrichment

Lead author and year Study location	Title	Study design (CEBM level of evidence)	Number of study participants with RTT Age Method of diagnosis	Intervention	Outcome
Downs 2018 [82] Australia	Environmental enrichment intervention for Rett syndrome: an individually randomised stepped wedge trial	Randomized controlled trial (1b)	$N=$ 12 females Age: 1.5–5 years Genetic diagnoses	Rich sensori-motor environment and multiple supported activities selected to target individual goals in the development of motor skills and endurance.	Participants gained on average 8 points on the 45 point scale after 6 months (On Rett Syndrome Gross Motor Scale).
Lotan 2006 [81] Israel	Management of Rett syndrome in the controlled multisensory (Snoezelen) environment. A review with three case stories	Observational case series (4)	$N=$ 3 females Age: 24, 58, 63 years Diagnosis method not reported	Various multisensory room implementations discussed.	Reduced agitation and tantrums after 3 months (63 yr). Falls ceased (58 yr). Improved range of motion and contractures (24 yr).
Environmental enrichment – animal studies
Kondo 2008 [83] Australia	Environmental enrichment ameliorates a motor coordination deficit in a mouse model of Rett syndrome – MECP2 gene dosage effects and BDNF expression	Randomized controlled animal study (5)	$N=$ 24 female RTT model mice (20 age-matched controls), 10 male RTT model mice (19 age-matched controls) MECP22 ${}^{\mathrm{\text{tm1Tam}}}$ mice (females: MECP2 ${}^{\mathrm{+}\mathit{}\mathrm{/}\mathrm{-}}$ males: MECP2 ${}^{\mathrm{\text{y}}\mathit{}\mathrm{/}\mathrm{-}}$ )	Standard housing versus environmental enrichment (larger cages with regularly changed toys and a running wheel).	Impaired motor coordination in females not present in those exposed to environmental enrichment. Did not have the same impact on male RTT mice.
Kondo 2016 [84] Australia	Affective dysfunction in a mouse model of Rett syndrome: Therapeutic effects of environmental stimulation and physical activity	Non-randomized controlled animal study (5)	$N=$ 22 female RTT model mice (30 age-matched controls) MECP2 ${}^{\mathrm{\text{tm1Tam}}}$ mice (females: MECP2 ${}^{\mathrm{+}\mathit{}\mathrm{/}\mathrm{-}}$ males: MECP2 ${}^{\mathrm{-}\mathit{}\mathrm{/}\mathrm{\text{y}}}$ )	Standard housing versus environmental enrichment (larger cages with regularly changed toys and a running wheel) or physical exercise alone (larger cages with two running wheels).	Aberrant anxiety-related anddepression-related behaviors notpresent in those exposed to environmental enrichment. Physical exercise alone had benefits only in some assessments.
Lonetti 2010 [85] Italy	Early environmental enrichment moderates the behavioral and synaptic phenotype of MECP2 null mice	Non-randomized controlled animal study (5)	$N=$ 24 female RTT model mice (25 age-matched controls), $>$ 90 male RTT model mice ( $>$ 120 age-matched controls) Heterozygous MECP2 ${}^{\mathrm{\text{tm1Jae}}}$ mice (females: MECP2 ${}^{\mathrm{+}\mathit{}\mathrm{/}\mathrm{-}}$ males: MECP2 ${}^{\mathrm{\text{y}}\mathit{}\mathrm{/}\mathrm{-}}$ )	Standard housing (one mother and pups) versus early environmental enrichment (larger cage, several nesting materials, toys and running wheel repositioned and changed regularly with at least 2 mothers and 10 pups).	Impaired spatial memory and anxiety-related behavior in female RTT mice as well as motor coordination and motor learning in male RTT mice improved in those exposed to the enriched environment.
Nag 2009 [86] USA	Environmental enrichment alters locomotor behaviour and ventricular volume in MECP2 ${}^{\mathrm{\text{1lox}}}$ mice	Non-randomized controlled animal study (5)	$N=$ 35 male RTT model mice (40 age-matched controls) MECP2 ${}^{\mathrm{\text{1lox}}}$ mice (MECP2 ${}^{\mathrm{\text{y}}\mathit{}\mathrm{/}\mathrm{-}}$ )	Standard housing versus environmental enrichment (larger cage, climbing, and running structures changed weekly).	Impaired locomotor activity in male RTT mice improved in those exposed to environmental enrichment. Impaired coordination and associative learning in male RTT mice not impacted by environmental exposure.

Table 6

Brain stimulation

Lead author and year Study location	Title	Study design (CEBM level of evidence)	Number of study participants with RTT Age Method of diagnosis	Intervention	Outcome
Fabio 2018 [87] Italy	Neurophysiological and cognitive effects of Transcranial Direct Current Stimulation in three girls with Rett syndrome with chronic language impairments	Experimental case series (4)	$N=$ 3 females Age: 29, 30, 31 years Genetic diagnoses	Transcranial direct current stimulation (tDCS) together with linguistic training.	Improvements in language abilities and motor coordination.
Gangemi 2018 [88] Italy	Transcranial direct current stimulation (TDCS) and cognitive empowerment for the functional recovery of diseases with chronic impairment and genetic etiopathogenesis	Randomized controlled trial (1b)	$N=$ 14 females (7 treatment, 7placebo tDCS) Age: 10–40 years (mean:18.34 years) Diagnosis method not reported	Transcranial direct current stimulation (tDCS) to Broca’s area coupled with linguistic training.	Improvements in language abilities, and motor coordination.
Brain stimulation – animal studies
Hao 2015 [89] USA	Forniceal deep brain stimulation rescues hippocampal memory in Rett syndrome mice	Randomized controlled animal study (5)	$N=$ 67 female RTT model mice (78 wild-type controls) MECP2 ${}^{\mathrm{+}\mathit{}\mathrm{/}\mathrm{-}}$ mice (unknown mutation specifics)	Forniceal deep brain stimulation (DBS).	Impaired contextual fear memory and deficits in spatial learning and memory improved. Effects were specific to DBS target with no improvements noted in motor, affective or sensory impairments.
Zhang 2014 [90] China	Deep-brain magnetic stimulation promotes adult hippocampal neurogenesis and alleviates stress-related behaviors in mouse models for neuropsychiatric disorders	Non-randomized controlled animal study (5)	$N=$ 26 RTT model mice (8 controls) MECP2 ${}^{\mathrm{\text{308/y}}}$ mice used in anxiety experiment and MECP2 ${}^{\mathrm{\text{flox/y }}}$ mice used in survival experiment	Daily deep-brain magnetic stimulation (DMS).	Increased anxiety-related behaviors in MECP2 ${}^{\mathrm{\text{308/y}}}$ mice improved with DMS. DMS dramatically prolonged lifespan in MECP2 ${}^{\mathrm{\text{flox/y}}}$ mice.

Table 7

Hydrotherapy

Lead author and year Study location	Title	Study design (CEBM level of evidence)	Number of study participants with RTT Age Method of diagnosis	Intervention	Outcome
Bumin 2003 [91] Turkey	Hydrotherapy for Rett syndrome	Experimental case report (5)	$N=$ 1 female Age: 11 years Diagnosis method not reported	Halliwick method hydrotherapy.	Decreased stereotypical movements, hyperactive behavior, and anxiety. Increased feeding activities, hand skills, balance, and interaction with environment.
Escobar-Torres 2019 [93] Spain	Efficacy of an aquatic exercise program for 3 cases of Rett syndrome	Experimental case series (4)	$N=$ 3 females Age: 4, 6, 7 years Diagnosis method not reported	Individualized aquatic exercise.	Improved exercise heart rates, endurance during functional activities, mood, and others.
Lotan 2009 [92] Israel	Hydrotherapy for a young child with Rett syndrome. Review of the literature and a case study	Observational case report (5)	$N=$ 1 female Age: Received water therapy age5–8 years Diagnosis method not reported	Structured hydrotherapy, as part of therapy program.	Improved communication with eye pointing, movement in water, land locomotion, and assisted stair walking.

Table 8

Other interventions

Lead author and year Study location	Title	Study design (CEBM level of evidence)	Number of study participants with RTT Age Method of diagnosis	Intervention	Outcome
Breathing therapies
Amaddeo 2019 [94] France	Polysomnographic findings in Rett syndrome	Cross-sectional study (4)	$N=$ 17 females Age: Average 9.5 Genetic diagnoses available in 15 (2 clinical diagnoses results not available)	Polysomnography to assess sleep disordered breathing or pre-spine surgery evaluation. 2/17 participants experienced severe central apneas – implemented noninvasive ventilation or nocturnal oxygen therapy.	Severe central sleep apneas resolved in those 2 subjects.
Julu 2013 [95] UK	Treating hypoxia in a feeble breather with Rett syndrome	Observational case report (5)	$N=$ 1 female Age: 25 years Genetic diagnosis	Use of CPAP for long apneas and prominent Valsalva maneuvers, during which face turns grey or bluish.	Tissue P02 prevented from falling below 49 mmHg.
Aerophagia therapies
Anzai 2001 [118] Japan	A case of effective gastrostomy for severe abdominal distention due to breathing dysfunction of Rett’s syndrome: A treatment of autonomic disorder	Observational case report (5)	$N=$ 1 female Age: 13 years Diagnosis method not reported	Placement of gastrostomy tube.	Helpful for abdominal distension, clinical seizures, sleep disturbance, hypocapnaemic alkalemia, and feeding.

Table 8, continued
Lead author and year Study location	Title	Study design (CEBM level of evidence)	Number of study participants with RTT Age Method of diagnosis	Intervention	Outcome
Morton 2000 [97] UK	Air swallowing in Rett syndrome	Cross-sectional study (4)	$N=$ 33 patients Age: 3-44 years Diagnosis method not reported	Gum shield to prevent full mouth closure and trapping of air implemented in 4 participants. Palatal training devices implemented in 3 participants. Mothers put fingers between child’s teeth when child upset to prevent air bloat.	All treatments mentioned to have benefit for air bloat.
Vision therapies
Saunders 1995 [98] UK	Visual function in Rett syndrome	Cross-sectional study (4)	$N=$ 11 patients (18 “developmentally normal” control participants Age: 4.8–24.3 years (treatmentgroup) Clinical diagnosis	Following ocular and vision assessment, glasses prescribed to certain subjects.	Participants observed to enjoy wearing glasses. Parents enthusiastic about glasses and reported increases in sociability, alertness and enjoyment of surroundings.
Vision therapies – animal studies
Durand 2012 [99] USA	NMDA receptor regulation prevents regression of visual cortical function in the absence of MECP2	Case-control animal study (5)	$N=$ 8 males (wild-type littermate controls) MECP2 knockout mice	Early sensory deprivation.	Reduced visual acuity in RTT model improved with dark exposure.
Sleep therapies
Piazza 1991 [100] USA	Behavioral treatment of sleep dysfunction in patients with the Rett syndrome	Experimental case series (4)	$N=$ 3 females Age: 4, 8, 8 years Clinical diagnoses	“Fading procedure” used to advance bedtimes nightly, based on sleep latency the night prior.	Improved nighttime sleep, reduced daytime sleep, and reduced nighttime behaviors like night awakenings.
Dental therapies
Magalhaes 2002 [101] Brazil	General and oral characteristics in Rett syndrome	Cross-sectional study (4)	$N=$ 13 females Age: 3–16 years Diagnosis method not reported	Modified biteplates for daytime use and acupuncture to treat bruxism.	Mothers described temporary resolution, or reduction in bruxism.
Chiropractic therapies
Gossett 1999 [102] USA	The effect of chiropractic care on Rett syndrome: A case report	Observational case report (5)	$N=$ 1 female Age: 13 years Diagnosis method not reported	Chiropractic care following auto accident (focus on traction, heel lift, full spine adjustments, massage therapy, etc.).	Various positive outcomes. Reduced menstrual pain, normalized bowel movement frequency, improved mood and increased laughing.

to determine the exact number of participants in each age group included in the cumulative total of 546 participants across all studies.

3.1 Communication, cognition, and behavior therapies (Table 1)

The studies fell under four subcategories: communication ( $N=$ 13), animal communication ( $N=$ 1), cognition ( $N=$ 9), and behavioural therapies ( $N=$ 6). Study designs included a randomized controlled trial ( $N=$ 1), a cross sectional study ( $N=$ 1), a cohort study ( $N=$ 1), experimental case series ( $N=$ 14), experimental case reports ( $N=$ 5), observational case series ( $N=$ 4), and an observational case report ( $N=$ 1). One cohort animal study was included.

Of the 13 studies pertaining to communication therapies, one study coached or trained teachers or therapists, resulting in increased “bids” of communication by RTT participants [27]. Similarly, three articles from one single study investigated trained mother-daughter dyads to improve communication interactions during storybook reading [24, 25, 28]. Eleven studies trained participants to use various technologies to communicate needs or answer questions [29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39]. These interventions used various modes of communication such as touch screens, eye tracking, head- or hand-activated switches, or picture exchange systems.

The studies are also diverse with respect to intervention duration. For example, one study of 17 participants utilizing eye tracking allowed users to practice using the technology prior to assessment while other studies did not allow time for practice. The authors suggest this was the reason why subjects performed better than in previous studies [29].

An animal study found that RTT model rats benefited from intensive speech discrimination training in noisy environments and revealed improved ability to discriminate sounds to levels comparable to control rats with similar training [40].

Eight studies investigated cognitive therapies. Two case reports aimed to teach language skills. In one, the sounds and written appearances of five letters were successfully taught to a 14-year-old participant using a literacy curriculum [41]. In another case report, a participant was enrolled in a reading and writing program, as well as a cognitive rehabilitation program between age eight and 21. The individual learned to write sentences by 15 years of age [42]. The other studies implemented cognitive training programs, educational programs, computer games, contingency games, and other techniques to improve outcomes such as cognitive performance, attention span, symbol learning, writing sentences, and eye gaze [43, 44, 45, 46, 47, 48]. The studies in this subcategory generally showed some benefit over time. In one study, participants were unable to use eye gaze to answer questions about color, shape and position, but it is unknown if those subjects had the ability to answer those questions correctly in another way [39]. As such, this study may be better characterized as a knowledge assessment study, rather than an eye gaze intervention study.

Four observational and two experimental case series studied behavioral therapies. The interventions and outcomes were varied, and generalizability would be challenging. For example, one case reported that a reduction in demands on a six-year-old student improved pleasure and resulted in reduced stereotypic hand movements [49]. Alternatively, in a study of two subjects aged 14 and 23, physically interrupting hand wringing and hand mouthing resulted in reductions in the levels of these behaviors [50].

3.2 Gross motor therapies (Table 2)

The studies fell under two subcategories: ambulation ( $N=$ 12) and multimodal therapies ( $N=$ 6). Study designs included cross-sectional studies ( $N=$ 3), cohort studies ( $N=$ 3), experimental case series ( $N=$ 3), observational case series ( $N=$ 2), and observational case reports ( $N=$ 7).

Thirteen studies pertained to improving ambulation. Four investigated treadmill walking. A cohort study in 2004 demonstrated functional benefits of a two-month daily treadmill intervention [51]. Two subsequent cross-sectional studies showed that participants with RTT have benefits such as improved gait variability on a treadmill compared to over ground walking [52], and that within a certain range, increased treadmill speeds are able to increase participant gait speed [53]. A cohort study showed that treadmill walking normalized abnormal breathing in participants [54]. A relatively small number of participants with RTT were included in these treadmill studies, three of which were single event assessments. The 2004 cohort study of four participants remains the only long-term treadmill intervention study [51].

A group of case series and a cohort study described gross motor interventions, and how they improved or restored ambulation. Interventions include using a toy shopping cart prior to introducing a walker to a preschooler, using a microswitch-equipped walker to play a preferred stimuli (ex. a song or familiar voice), behavioral interventions, walkers, orthoses, and other individualized therapies [16, 17, 51, 55, 56, 57, 58, 59, 60].

The final study in the ambulation therapies category is a survey of physiotherapists, reporting on their patients with RTT. They described a negative correlation between foot position weight bearing and walking ability. This was assessed in conjunction with the role of orthopedic footwear, orthoses, and gross motor function [61].

The five studies in the multimodal therapies are diverse. This category is entirely comprised of case reports and series. They described multidisciplinary physical therapy, cognitive, and conductive education programs, among many others. They observed functional improvements in contractures, posture, sialorrhea, self-care skills, social skills, stereotypic hand movements, ataxia, and other positive outcomes [62, 63, 64, 65, 66].

3.3 Fine motor therapies (Table 3)

The studies fell under two subcategories: orthoses ( $N=$ 7), and independence therapies ( $N=$ 3). Study designs included experimental case series ( $N=$ 6), an experimental case report ( $N=$ 1), an observational case series ( $N=$ 1), and observational case reports ( $N=$ 2).

The seven orthotics studies examined heterogenous interventions resulting in diverse outcomes. Various orthoses were used such as: elbow splints, hand and thumb splints, and wrist cuffs of various designs. Outcomes studied included feeding ability with hands or utensils, switch use, environmental interaction, hand wringing, hand mouthing, and other stereotypic behavior. These studies reported positive outcomes, with the exception of two case series which found no improvement in stereotypic movements or independent feeding with the use of hand splints [67, 68].

Three studies, aimed to increase upper extremity-related independence or function without the use of orthoses, were grouped together. Two studies assessed therapy directed at increasing independent feeding. A study on independent eating using physical and verbal guidance in three individuals suggested that guided eating increased participation in the eating process and improved arm and mouth movements compared with caregiver feeding [69]. Similarly, a case series of five suggested that using hands-on instructions and verbal praise resulted in improved self-feeding skills and communication [70]. More recently, a 12-week virtual reality intervention was associated with improved reaching and reduced stereotypic movements in one participant [71].

3.4 Music therapy (Table 4)

Of the 10 studies, study designs included a cross-sectional study ( $N=$ 1), cohort studies ( $N=$ 2), experimental case series ( $N=$ 3), an observational case series ( $N=$ 1), and observational case reports ( $N=$ 3).

Music therapy was studied in groups of one to 23 patients. All studies described benefits to varying degrees. These included improvements in social interaction, communication, eye contact, hand function, mood, choice-making, vocalization, social play, turn-taking, and parent stress [72, 73, 74, 75, 76, 77, 78, 79].

Two studies used music therapy to increase patient engagement, enrich a physiotherapy session, or complete a gross motor assessment [23, 73].

As part of a survey done through the Swedish Rett Centre, 70 parents and caregivers outlined the functional benefits they believed were gained from music therapy. Almost all respondents described that participants responded positively to music by eliciting physical responses such as rocking, clapping, vocalizations, smiling [80].

3.5 Environmental enrichment (Table 5)

Of the five studies, the one human study was an observational case series. Other studies consisted of one randomized controlled and three non-randomized animal studies.

In a case series of three participants, a Snoezelen multisensory environment facilitated the successful implementation of a behavioral modification program. These environments provide immersive atmospheres through specialized equipment that target all senses through lights, textures, sounds, and other forms of sensory stimulation. Authors suggested that this was facilitated through relaxation and reduced agitation in a 63-year-old. A functional therapy and reaching program to reduce falls in a 58-year-old and a range of motion program to reduce contractures in a 24-year-old [81] were also facilitated with multisensory environments.

A randomized controlled trial had 12 preschool-aged participants participate in a sensory stimulation intervention for two to three hours, six days per week, for six months. During the intervention period, children participated in balance and walking activities, visual stimulation with toys and electronic devices, auditory stimulation, and taste stimulation. Improvements in gross motor skills were quantified using the Rett Syndrome Gross Motor Scale. Additionally, sleep and mood changes were studied using questionnaires, but were unaffected [82].

Four animal studies were included. These studies found that stimulating RTT model mice through environmental enrichment and physical activity had a range of benefits including anxiety reduction, improved motor coordination, spatial learning, and cognitive performance. These four studies used various RTT genetic models of both male and female sexes and compared standard housing to enriched housing. Enriched environments included a variety of toys or running wheels to encourage physical activity [83, 84]. Behavioral testing for anxiety, depression, and memory was done using previously established assessments such as elevated mazes, the Morris water maze, observations of mouse behavior in open areas, and food-seeking tasks. Locomotor activity was measured using sensors and motor learning was assessed with a rotarod performance test [83, 84, 85]. One study reported that the reduced response to fear conditioning by freezing seen in RTT model mice was improved by environmental enrichment [86]. However, these findings did not reach statistical significance. No negative effects of environmental enrichment were reported in these four animal studies.

3.6 Brain stimulation (Table 6)

Of the four studies, study designs included a randomized controlled trial and an experimental case series, in addition to one non-randomized and one randomized controlled animal study.

Transcranial direct current stimulation (tDCS) together with linguistic training improved language abilities and motor coordination in three participants with RTT [87]. tDCS in another study of seven subjects (seven treatment, seven placebo) showed similar results [88].

Female MECP2 ${}^{\mathrm{+}\mathit{}\mathrm{/}\mathrm{-}}$ mouse models demonstrated improvements in fear memory, spatial learning, and spatial memory after forniceal deep brain stimulation (DBS) [89]. Deep-brain magnetic stimulation (DMS) reduced stress behaviors and increased the lifespan of two RTT mouse models [90]. The apparent magnitude of the effect of these animal study interventions is large. However, the clinical relevance of these findings to RTT is uncertain as these forms of brain stimulation are invasive with potential risks.

3.7 Hydrotherapy (Table 8)

Of the three studies, study designs included an experimental case series, an experimental case report, and an observational case report.

Two case studies examined the effectiveness of hydrotherapy programs of different lengths in two participants aged five and 11 years, on a wide range of symptoms. The authors describe improved anxiety, hand skills, communication with pointing, and stair walking in both participants, among others [91, 92]. A case series of three participants aged four, six, and seven years who received a 20-month individualized aquatic exercise intervention underwent baseline and follow up assessments in physiological, functional and psychosocial domains. Improvements were assessed quantitatively or qualitatively, and included reduced resting heart rate, increased joint mobility, improved peer relationships, and improvements in the Functional Independence measure (FIM) [93].

3.8 Other therapies (Table 8)

Included studies not pertaining to the aforementioned categories are as follows: breathing therapies, vision therapy, therapy for aerophagia, sleep, dental and chiropractic intervention.

A cross sectional study and an observational case report studied breathing therapies. Two participants who underwent polysomnography to assess sleep disordered breathing demonstrated that severe central apneas resolved from the implementation of noninvasive ventilation or nocturnal oxygen therapy [94]. Long apneas and prominent Valsalva maneuvers were reduced in a 25-year-old patient with the introduction of continuous positive airway pressure (CPAP) [95].

A cross sectional study and an observational case report studied aerophagia therapies. The placement of a gastrostomy tube in a 13-year-old helped with severe abdominal distension [96]. A study on air-swallowing reported various beneficial therapies including: gum shields, specialized pacifiers, palatal training devices, and manual placement of fingers between the child’s teeth. The exact number of patients receiving these interventions was not reported [97].

Table 9

Included study summary

Table number	Category subcategories	Total number of studies	Number of human participants with RTT	CEBM levels of evidence
1	Communication, cognition, and behavior therapies Communication therapies (13 studies) Communication therapies – animal studies (1 study) Cognition therapies (9 studies) Behavioral therapies (6 studies)	28	128	1b (1 study) 2b (1 study) 4 (19 studies) 5 (7 studies)
2	Gross motor therapies Ambulation therapies (13 studies) Multimodal therapies (5 studies)	18	174	2b (3 studies) 4 (8 studies) 5 (7 studies)
3	Fine motor therapies Orthoses (7 studies) Independence therapies (3 studies)	10	30	4 (7 studies) 5 (3 studies)
4	Music therapy	10	104	2b (2 studies) 4 (5 studies) 5 (3 studies)
5	Environmental enrichment Environmental enrichment – animal studies (4 studies)	6	15	1b (1 study) 4 (1 study) 5 (4 studies)
6	Brain stimulation Brain stimulation – animal studies (2 studies)	4	10	1b (1 study) 4 (1 study)
7	Hydrotherapy	3	5	4 (1 study) 5 (4 studies)
8	Other therapies Breathing therapies (2 studies) Aerophagia therapies (2 studies) Vision therapies (1 study) Vision therapies – animal studies (1 study) Sleep therapies (1 study) Dental therapies (1 study) Chiropractic (1 study)	9	80	4 (5 studies) 5 (4 studies)
Total		88	546	1b (3 studies) 2b (6 studies) 3b (8 studies) 4 (47 studies) 5 (24 studies)

A cross sectional study and a case-control animal study explored vision therapy. One study pertained to vision function. In the cross-sectional study, 11 participants underwent an ocular and vision assessment, and an unspecified number received glasses [98]. Authors describe participants and caregivers as enthusiastic about the benefits of the glasses. An animal study on MECP2 knockout mice used an optomotor functional task to assess vision and used visual evoked potentials along with other tests localizing the functional deficit to a visual pathway rather than motor pathway. The RTT model mice showed decline in vision after about four weeks of age. However, mice who were raised in the dark from birth or eye-opening showed visual acuity comparable to wild-type animals [99].

An experimental case series aiming to improve sleep in three patients with RTT was included. Baseline data was collected, which helped establish initial sleep and wake times. Various behavioral techniques were used such as a “fading procedure” to gradually advance bedtimes based on sleep latency the night before, reducing non-scheduled daytime sleep, and removing individuals from bed if they were not sleeping. This resulted in more regular sleep patterns and increased nighttime sleep [100].

One cross-sectional study regarding dental therapies was included. Observations of a group of 13 patients with RTT suggested the effectiveness of bruxism treatments including modified biteplates for daytime use and acupuncture [101].

One observational case report on chiropractic treatment was included. It described a 13-year-old patient who received several treatment modalities from a chiropractor over one year [102]. Numerous benefits were reported. Causality cannot be attributed.

4. Discussion

This is the most comprehensive published review of therapeutic interventions for individuals with RTT to date. It is also the first review of RTT therapies to include clinical studies, animal model studies, and case studies, recognizing the value that these study designs play in this rare and heterogenous disorder. Previous reviews have omitted such publications despite the potentially meaningful information that they provide.

There is a clear lack of high-quality literature regarding outcomes of therapeutic interventions for individuals with RTT. The majority of identified studies were lower-quality study designs according to the Oxford Centre of Evidence-based Medicine Levels of Evidence with all but 17 studies belonging to the two lowest-quality levels [22]. The number of participants were usually small, control groups were lacking, and investigators were not blinded.

Communication, behavior, and cognition interventions were most often studied in humans while environmental enrichment was most often studied in animal RTT models. Several interventions indicated positive outcomes. Cognitive and behavioral therapies improved cognitive performance, increased attention skills, and reduced stereotypic movements. The majority of studies examining arm and hand orthoses and upper-extremity independence programs found numerous improvements in stereotypic movements, feeding, and communication, among other positive outcomes. Improvements in social skills, communication, and mood were observed in all studies pertaining to music therapy. Despite the low-quality study designs of the mentioned studies, this information provides vital information for the development of future studies and clinical implementation.

Older individuals with RTT were seldom included in the identified studies, indicating a clear lack of data pertaining to this age group. As individuals with RTT often live to an advanced age and are able to regain functional ability such as ambulation following therapy or use of assistive devices, this deficiency of research in adults is concerning. The natural history of RTT is becoming better understood, but given lack of knowledge, it is unclear whether the interventions under study are similarly effective across the lifespan. Additionally, it has been demonstrated that health service use decreases as the individual with RTT ages [103]. This suggests that older individuals with RTT are relatively medically stable and are in a position to benefit from gait, communication, or other therapy interventions. As such, increased research efforts must be directed towards therapies for older individuals with RTT. The current review found preliminary evidence of positive outcomes using Snoezelen environments in older individuals with RTT, suggesting the potential for future use of this intervention in this age range.

Over one-quarter of the 88 identified studies involved communication, cognition, or behaviour therapies. Functional outcomes such as attention, verbalization, and learning, among others, were reported. This highlighted an emphasis on enhancing functional communication in these patients. However, these studies possessed very low to low quality of evidence. In 2009, communication interventions in individuals with RTT were systematically reviewed. The authors found that “the evidence base supporting current approaches to communication interventions for individuals with Rett syndrome remains inconclusive” [104]. Only four additional studies addressing communication interventions for RTT have been published in the intervening decade.

Half of the animal studies explored the impact of environmental enrichment in mouse RTT models. Stimulating RTT mice by means of their physical and social surroundings has a range of benefits including anxiety reduction, improved motor coordination, spatial learning and cognitive performance effects [83, 84, 85, 86]. These findings potentially have downstream influences on the design of human clinical trials but should however be approached with caution as environmental enrichment studies in animals have often been criticized to be misrepresentative of human conditions [105]. Preclinical characteristics of animal studies such as dose and age at treatment onset cannot be generalized to the human population. However, concepts of functional benefit following therapy is important to note.

As with all systematic and scoping reviews, the present study was vulnerable to publication bias. Most included articles report some degree of functional improvement in response to the intervention under study; only two studies showed an entirely neutral or negative response to intervention [49, 106] and a small number of studies discussed neutral or negative secondary outcomes. As authors and journals are more inclined to publish positive results, this may have led to the over-representation of beneficial therapies.

Because the diagnostic criteria for RTT has changed over time, articles published prior to 2010 may include patients who would not meet current criteria for RTT diagnosis [2]. All studies with patients diagnosed with RTT at the time of the study were included, as the criteria by which the diagnosis was made (clinical and/or genetic) was often not specified. This is a study limitation as the findings potentially included results from individuals who were incorrectly diagnosed.

Significant heterogeneity in therapeutic interventions is apparent in this scoping review. For example, hand splint design and implementation differ widely from one study to the next. While three studies demonstrated reductions in stereotypic hand movements using similar hand splint designs [68, 107, 108], another study demonstrated similar outcomes with a different form of hand splint [109]. Furthermore, although stereotypic hand movements become more frequent during times of stress [110], it is still unclear if these behaviors are maladaptive or beneficial. This heterogeneity and lack of knowledge about natural history complicates clinical decision making and future study design. Caution should be taken, and the original manuscript should be consulted prior to making clinical treatment decisions.

Future studies will benefit from more consistent use of outcome measures, specifically those validated for RTT. Currently, there is a small number of measures that consider RTT-specific medical, behavioural, genetic, or psychosocial outcomes. These measures lack consistency and often do not consider behavioural or physiological characteristics of RTT. With some measures considering clinical severity and others only considering genetic diagnoses, these measures are inconsistent in their conclusions [111]. The inconsistency of these non-inclusive measures influences the need for comprehensive, RTT-specific outcome measures. This would ultimately help facilitate the comparison of study results and creation of cohesive conclusions to intervention outcomes.

In conclusion, this scoping review of therapeutic interventions for RTT is the first to include valuable findings from animal studies and case reports. The included studies demonstrate that there is a paucity of high-quality evidence, particularly pertaining to therapies for older individuals with RTT. Current human RTT research emphasizes the support of communication, cognition, and behaviour, while animal studies primarily examine environmental enrichment interventions. Future studies inclusive of the older age groups of individuals with RTT will provide age-specific information regarding the effectiveness of therapies at advanced points along an individual’s lifespan. Natural history knowledge of RTT and standardized, comprehensive outcome measures will inform future therapy studies if further elucidated. This review allows for an understanding of the current available approaches to improving function in individuals with RTT, which informs future research design and clinical practice.

Footnotes

Conflict of interest

The authors have no conflicts of interest to disclose.

Supplementary data

The Appendix files are available to download from http://dx.doi.org/10.3233/PRM-200683.