DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY SCOPING REVIEW

Rehabilitation interventions in Rett syndrome: a scoping review

JAN LIM 1 | DAYNA GREENSPOON 1 | ANNE HUNT 1,2 | LAURA MCADAM 1,3,4
1 Bloorview Research Institute,Holland Bloorview Kids Rehabilitation Hospital, Toronto; 2 Department of Occupational Science and Occupational Therapy, University of
Toronto, Toronto; 3 Department of Pediatrics, University of Toronto, Toronto; 4 Holland Bloorview Kids Rehabilitation Hospital, Toronto, Canada.
Correspondence to Laura McAdam, Holland Bloorview Kids Rehabilitation Hospital, 150 Kilgour Rd, Toronto, Ontario M4G1R8, Canada. E-mail: lmcadam@hollandbloorview.ca

PUBLICATION DATA AIM To summarize existing interventions and their outcomes in Rett syndrome (RTT)
Accepted for publication 2nd March 2020. rehabilitation and identify gaps in the literature.
Published online 30th May 2020. METHOD Five databases (Ovid MEDLINE, Ovid Embase Classic, Ovid PsycINFO, EBSCO
CINAHL Plus, and ProQuest ERIC) were systematically searched up to 23rd July 2018 for
ABBREVIATIONS studies describing rehabilitation interventions. Data on study participants, design, and
ETT Eye-tracking technology outcomes were extracted.
RTT Rett syndrome RESULTS Sixty-two articles were included in the final review. Evidence consistently
demonstrated that females with RTT can improve their gross motor, fine motor, and
communicative skills with rehabilitation. All 11 interventions targeting gross motor function,
namely ambulation, achieved functional improvements. Twenty of 24 articles describing fine
motor rehabilitation studies succeeded in decreasing stereotypies, improving functional hand
use, and/or reducing self-injurious behaviors. Twenty-one of 22 studies describing
communication interventions succeeded in training choice-making, communicative language,
or socialization behavior. Other key findings include the positive interplay between physical
and communicative rehabilitation outcomes, and the ability of females with RTT to improve
their cognitive abilities during intervention.
INTERPRETATION Rehabilitation can impact the daily lives of females with RTT and their
caregivers in clinically meaningful ways.

An absence of validated rehabilitation interventions is a
barrier to optimizing functional potential for females with
Rett syndrome (RTT) who may be capable of developing
gross motor, fine motor, and communication skills. Cur-
rent interventions are promising, with multiple studies
reporting participants with RTT improving physically and
cognitively after rehabilitation.1,2 Despite this, the evidence
base of RTT rehabilitation interventions has not yet been
summarized. The consequence is a lack of awareness
among families, allied health practitioners, clinicians, and
educators regarding the ability of targeted interventions to
improve the daily lives of individuals with RTT. As the
medical prognosis of individuals with RTT continues to
improve, systematic knowledge of rehabilitation interven-
tions is imperative to optimize development and have an
impact on quality of life for individuals with RTT and
their caregivers, and to advance rehabilitation research for
this population.
RTT is the second most common genetic disorder in
females, predicating the urgent need to examine rehabilita-
tion interventions.3 RTT affects approximately 1:10 000
females by the age of 12 years,4 with most individuals
experiencing permanent disability due to a mutation in the
gene encoding methyl-CpG-binding protein 2 (MECP2).5
The extent to which rehabilitation ameliorates disability in
RTT is not well known. Guidelines have been established
for medical monitoring in RTT;6–8 however, there are no
evidence-informed rehabilitation guidelines. RTT rehabili-
tation research has largely focused on communication abil-
ities, with communicative acts, including gestures, and
language-generating assistive technologies such as eye-
tracking technology (ETT) being evaluated to a greater
extent than physical or behavioral interventions.9 Conse-
quently, with the exception of select clinical reports,10–13
there are no holistic analyses of published rehabilitation
strategies, thereby justifying the need for this scoping
review.
Mutations in MECP2 and its regulatory regions result in
neurological, physical, and intellectual disabilities with high
interindividual variability. As a result, RTT is a clinical
diagnosis characterized by phenotype.14 One unifying cri-
teria for RTT diagnosis is a period of dramatic psychomo-
tor regression between 6 and 18 months of age, whereby
loss of language, hand skills, and gross motor function, as
well as stereotypical hand movements begin to manifest.14
Four clinical stages of RTT have been identified and are
used to track progression. The regression period is known
as stage 2 and follows stage 1 of typical or near-typical
development. Individuals with RTT will then progress
from stage 2 to stage 3 between 2 and 10 years of age,

906 DOI: 10.1111/dmcn.14565 © 2020 Mac Keith Press


where they reach a plateau of communicative and ambula-
tory function.15 Further motor regression may occur in
stage 4 during adulthood.15,16 Rehabilitation has the
potential to partially restore function and mitigate disabil-
ity,2 with the goal of improving the quality of life of indi-
viduals with RTT.
Since the discovery of RTT in 1965, life expectancy has
risen fourfold and females with RTT are now expected to
survive into their fifth decade,17,18 underscoring the need
for evidence-informed rehabilitation strategies to optimize
function over the life span. As females with RTT age, the
demand for effective rehabilitation strategies will increase,
and intervention is increasingly needed to mitigate the
high levels of caregiver burden reported in this popula-
tion.19 Moreover, as disease-modifying treatments and
gene therapies for RTT become available, rehabilitation
studies are needed to strengthen our understanding of the
developmental potential in RTT and optimize the func-
tional abilities of individuals after pharmacological or
genetic treatment.20 The purpose of this review is to dis-
seminate knowledge of RTT rehabilitation interventions
by summarizing existing rehabilitation studies and their
outcomes, as well as identifying gaps in the existing litera-
ture.
METHOD
Study design
Our scoping review protocol adheres to the framework
developed by Levac et al.21 and Arksey and O’Malley,22
which consists of: (1) identifying the research question; (2)
identifying the relevant studies; (3) selecting studies; (4)
charting the data; (5) collating, summarizing, and reporting
the results.
Research question
The following research question guided our scoping
review: What is known about rehabilitation interventions
and their outcomes for females diagnosed with typical and
atypical RTT?
We used the Population, Intervention, Comparison,
Outcome framework to outline the scope of our research
question.23 Our population of concern consisted of females
with a clinical diagnosis of RTT. The intervention was
defined as a rehabilitation technique. The comparison cate-
gory did not apply to a scoping review article. Our out-
come of interest was the altered functional skill set of
females with RTT.
Inclusion criteria
Our study included original research, peer-reviewed, full-
length articles written in the English language; studies
reported in the articles tested a rehabilitation intervention
and described its outcome for one or more females with
RTT.
Rehabilitation intervention was defined as a physical,
cognitive, or social activity focused on improving the
functional skill set of females with RTT. We included
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What this paper adds
• Females with Rett syndrome (RTT) can make developmental gains across
their life span.
• Long-term intervention can improve the physical abilities of individuals with
RTT.
• Low-, medium-, and high-technology interventions can improve the commu-
nicative abilities of individuals with RTT.
interventions administered by therapists, including occu-
pational therapists, physiotherapists, speech-language
pathologists, recreation therapists, and music therapists, as
well as family members, community workers, and educa-
tional staff. No limitations were placed on the type of
study included in the review. Gray literature was
excluded.
Search strategy
The final search was conducted within the following five
databases for all available years until 23rd July 2018: Ovid
MEDLINE; Ovid Embase Classic; Ovid PsycINFO;
EBSCO CINAHL Plus; and ProQuest ERIC. Articles
from the reference lists of existing RTT rehabilitation
reviews and clinical reports were also extracted.
Search terms
The full search strategy for each database is reported in
Appendix S1 (online supporting information). Developing
the search strategy was an iterative process that relied on
compiling rehabilitation-related key terms (e.g. physiother-
apy, occupational therapy, speech-language pathology) and
RTT clinical terms (e.g. Rett syndrome, stereotypies, dys-
phagia).
Subject headings and keywords were directly translated
between Ovid MEDLINE, Ovid Embase Classic, Ovid
PsycINFO, and EBSCO CINAHL Plus. The search strat-
egy was modified for ERIC since ProQuest could not
accommodate the same number of search terms used in the
Ovid and EBSCO databases.
Data collection and analysis
Titles and abstracts were first reviewed to screen out arti-
cles that did not meet the inclusion criteria. Then, all full
texts of the remaining relevant articles were obtained and
reviewed by two authors (JL, LM) using an iterative pro-
cess. A third reviewer (DG) resolved any discrepancies
where disagreement between the first two reviewers
occurred. Data extracted from each study included dura-
tion, location, participant population, intervention descrip-
tion, and outcome.
Data were analysed to identify common themes and gaps
in the literature. The studies included were grouped and
analysed according to the authors’ primary intervention
objective.
Evidence grading and quality appraisal
All papers were graded using the Oxford Centre for Evi-
dence-based Medicine Levels of Evidence rubric.24 The
quality of papers was assessed using the Joanna Briggs
Review 907

Institute Prevalence Critical Appraisal tools for case
reports (Table S1, online supporting information),25,26 case
series (Table S2, online supporting information),25,26 and
quasi-experimental studies25,26 (Table S3, online support-
ing information) are provided. Discrepancies were resolved
between the first and last authors.
Studies scoring a ‘yes’ received 1 point; studies scoring
an ‘unclear’ received half a point. A ‘strong’ quality rating
was assigned to case reports scoring 6 to 8, case series
scoring 7 to 10, and quasi-experimental studies scoring 7
to 9. A ‘moderate’ quality rating was assigned to case
reports scoring 4 and 5, case series scoring 5 and 6, and
quasi-experimental studies scoring 5 and 6. Studies scoring
below these numbers were designated as ‘low’ quality. To
provide a full summary of all published research interven-
tions, no articles were excluded by the authors based on
low quality.
Gross motor function
Interventions targeting ambulation and transitional move-
ments were categorized as gross motor function studies.
The primary outcome for all gross motor function studies
was improved ambulation and/or transitional movements.
Therefore, the studies included in the review were orga-
nized based on their intervention method, that is, cognitive
or environmental enrichment, hydrotherapy, or traditional
physiotherapy.
Fine motor function
Interventions aimed at improving voluntary hand function,
functional hand skills, or reducing hand stereotypies were
categorized as fine motor function studies. Fine motor
rehabilitation studies had different primary outcomes;
hence, articles were subgrouped based on their objectives.
The subcategories were decreasing stereotypies, improving
functional hand use, or reducing self-injurious behavior.
Communication
Interventions aimed at improving choice-making abilities
between symbols or items, developing expressive language
with communicative acts, or increasing social communi-
cation were categorized as communication rehabilitation
studies. The subcategories, based on the intervention
outcome, were facilitating choice-making, improving
communicative language, and improving social participa-
tion.
Table 1: Search results obtained from each database
Database Search date Database date range
EBSCO CINAHL Plus 23rd July 2018 1937–23rd July 2018
Ovid Embase Classic 23rd July 2018 1974–23rd July 2018
ProQuest ERIC 23rd July 2018 1966–July 2018
Ovid MEDLINE 23rd July 2018 1946–July week 3, 2018
Ovid PsycINFO 23rd July 2018 1806–July week 3, 2018
908 Developmental Medicine & Child Neurology 2020, 62: 906–916
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RESULTS
There were 4044 records identified in the initial search
and one article was identified from an existing reference
list. After deduplication of database search results using the
Bramer method, 2496 articles were identified (Table 1).27
A total of 2283 articles were excluded after title and
abstract screening. Therefore, 213 full-text articles were
assessed for eligibility. Of the 151 articles excluded from
the full-text review, 130 did not contain an RTT rehabili-
tation intervention, nine were conference abstracts,28–36
two were commentaries,37,38 four had no measurable out-
come attached to an intervention,39–42 five did not have a
population of females with RTT,43–47 and one was an erra-
tum.48 The remaining articles did not describe a rehabilita-
tion intervention or its associated outcome. The PRISMA
(Preferred Reporting Items for Systematic Reviews and
Meta-Analyses) flow diagram in Figure S1 (online support-
ing information) outlines the study selection process.49
Overall, 62 articles were included in the final review. Full
data extraction details of the articles included in the review
are available in Table S4 (online supporting information).
In Tables S5 to S8 (online supporting information), the
studies included in the review are categorized according to
interventions targeting gross motor function, fine motor
function, communication, and other interventions respec-
tively. Table 2 outlines the frequency and duration of the
intervention studies across all categories. Table S9 (online
supporting information) includes the data which were used
to calculate the values found in Table 2.
The following sections identify overall study quality, fol-
lowed by key target outcomes and interventions for each
rehabilitation intervention category, as well as avenues for
future research.
Study quality
Low levels of evidence were found across all RTT rehabili-
tation areas. Out of 62 articles, we identified 24 case
reports, 35 case series, and three quasi-experimental trials
(Tables S5–S8). Case reports were assigned level 5, case
series level 4, and quasi-experimental trials level 3 on the
Oxford Centre for Evidence-Based Medicine Levels of Evi-
dence rubric.24
Out of 24 case reports, 18 were strong-quality reports,
five were of moderate quality, and one was a low-quality
report (Tables S5–S8). Outcome assessment measures were
inconsistent across all case reports. Additionally, seven
Number of records
Number of records after removal of duplicates
265 52
2125 1204
70 16
1061 1055
523 169
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Table 2: Frequency and duration of rehabilitation interventions
and 4 days per week for 61.6 weeks (Table 2), suggesting
that clinically meaningful change may necessitate high-in-
Days tensity interventions.
Minutes Sessions per Length of inter-
per session per day weeka vention (wks) Within the level 3 evidence category, one physiother-
apy-based, quasi-experimental study succeeded in facilitat-
Gross motor function (n=11)
ing an average 8-point gain on the Rett Syndrome Gross
Available 5 2 6 10
records Motor Scale in 12 participants with RTT.54 In the same
Mean 50 3 4 61.6 trial, there was also a significant increase in a gross motor
Median 20 3 4 24
function serum biomarker (brain-derived neurotrophic fac-
Fine motor function (n=24)
Available 18 6 11 14 tor).54 The intervention was frequent and long-term
records (Table S5), with the high quality of reported results sug-
Meanb – – – –
gesting that individualized physiotherapy could be an effec-
Medianb – – – –
Communication (n=22) tive intervention for females with RTT.54
Available 10 3 11 13 In the levels 4 and 5 evidence category, seven partici-
records
pants partially regained their ambulatory abilities during
Mean 24 4 4 76.2
Median 30 3 3 24 physiotherapy or hydrotherapy.2,57,59–61 Participant ages
Other (n=5) ranged from 9 to 60 years, indicating that females with
Available 2 0 0 3
RTT can improve gross motor function across their life
records
Mean 13 – – 30.4 span. In the same evidence category, four females with
Median 13 – – 20 RTT increased their cardiovascular fitness through tread-
a
Daily interventions were scored as 7 days per week. Interventions
mill training1 and one participant regained the ability to
which took place once every two weeks were scored as 0.5 days walk independently using a toy shopping cart.58
per week. The uppermost limits of reported session frequency and Other interventions, including Snoezelen room therapy,
duration were used. bMean and median intervention durations
were not calculated in the fine motor function category due to
improved gross motor function. Participants demonstrated
splint wearing consistently occurring for 6 hours or more, e.g. improved behavior (n=1), improved balance (n=1), and
9:00am to 5:00pm. For the raw data, please see Table S9 (online facilitated stretching (n=1).15 The novel use of micro-
supporting information).
switches to provide positive encouragement improved
walking fluency (n=5).62 Six gross motor rehabilitation
articles did not provide a reproducible intervention studies had strong methodological quality, thereby signal-
methodology and eight did not clearly describe the out- ing a promising area for future studies.
come measurement (Table S1). Improvements in gross motor function also benefitted
Out of 35 case series, 10 were high-quality case series, 22 other developmental areas. Three studies reported gains in
were of moderate quality, and three were low-quality case fine motor function alongside gross motor improvements,
series (Tables S5–S8). Only 3 out of 36 case series articu- namely increased grasp duration, stereotypy reduction, and
lated their inclusion criteria within the text (Table S2).50–52 enhanced finger feeding abilities.59,61,63 Five studies
Site or clinic demographic information was reported in 1 reported increased happiness, increased sociability, and
out of 36 studies.53 Hence, the findings of the case series reduced anxiety.15,60,61,63,64 One case of long-term
have limited generalizability, with a risk of selection bias hydrotherapy targeting movement and breath control also
for high-performing or well-supported participants. improved choice-making with eye-pointing outside of the
All quasi-experimental studies received a ‘strong’ quality pool.60
rating (Table S3); however, only three were identified in Gaps in the literature include the absence of replication
the literature.54–56 As a corollary, 59 out of 62 research studies and only one controlled clinical trial. There is also
studies were conducted with 12 or fewer participants. Fur- a lack of research surrounding assistive mobility devices.
thermore, across all studies, no adverse or unanticipated Treadmill training may be a promising intervention that is
events from the intervention trials were discussed. both accessible and effective; thus, it merits further investi-
gation.
Gross motor function interventions
Eleven studies targeted gross motor function (Table S5), Fine motor function interventions
affecting 35 distinct individuals with RTT. All studies Twenty-four fine motor intervention studies targeted
achieved partial gains in function, namely improved ambu- decreased stereotypies, improved functional hand use, or
lation and/or transitional movements. Functional skills that reduced self-injurious behaviors (Table S6), affecting a
improved included walking, stair climbing, and ambulatory total of 61 participants. Although all studies identified were
gait. Oxford Centre for Evidence-Based Medicine levels 4 or 5,
All studies were conducted at rehabilitation facilities, most case series and reports had strong methodological
with the exception of two interventions that occurred at quality (n=15) (Tables S1 and S2). Therefore, it is mean-
educational facilities.57,58 The mean duration of interven- ingful that participants in 20 out of 24 studies achieved
tion was 50 minutes per session, three sessions per day, fine motor function improvements (Table S6).

Review 909

Notably, selection and/or observation bias is inherent to
studies with low levels of evidence. In studies that target
functional hand use, selection bias for well-performing par-
ticipants is likely given that partial or complete loss of
hand function is a clinical hallmark of RTT diagnosis.
Adding to the risk of participant selection bias is the lack
of reporting participants’ past rehabilitation or medical
treatments, which affected most case reports (n=8)
(Table S1).65–72 Thus, the following trends in fine motor
rehabilitation should be interpreted with caution.
Fine motor rehabilitation interventions were conducted
at rehabilitation facilities,71–79 educational facilities,65–68,80–
84
and residential homes.64,70,85,86 Two case series did not
specify the location of the interventions.69,87 Specific
details regarding intervention intensity are available for 18
of 24 studies (Tables 2, S4, and S6). Apart from the vari-
ous types of interventions, such as splinting for whole days,
the mean or median values were not reported.
Eleven studies targeted reduced stereotypies (Table S6).
There was consistent evidence that hand and/or elbow
splinting is an effective intervention, with 18 out of 20 par-
ticipants across six splinting studies experiencing a decrease
in their stereotypic hand movements.61,65,68,80,81,83 Addi-
tional strategies that partly decreased stereotypies included
physical interruption of hand mouthing during playing
with toys (n=1),85 three parent-administered games involv-
ing mirrors, hanging mobiles, puppets (n=1),70 and operant
conditioning (n=2).75 Interventions that did not reduce
stereotypies involved social facilitation of fine motor tasks
(n=1)67 and independent playing with toys (n=1).66 Thus,
splinting, gentle physical interruption, interactive game
play, and operant conditioning reduced hand stereotypies.
Twelve studies targeted functional hand use through
facilitating specific tasks, such as playing a musical instru-
ment, self-feeding, and pressing a microswitch (Table S6).
Task-based interventions were trialed with 33 participants;
in 11 out of 12 studies, females with RTT partly achieved
targeted hand skills (Table S6). These preliminary findings
suggest that some individuals with RTT can learn fine
motor skills, potentiating a reduction in caregiver burden
or increased social interaction.
All participants across five music therapy studies experi-
enced partial improvements in voluntary hand function
(n=20).71,72,74,77,79 In a case series, Go et al.79 facilitated
rhythmic tambourine beating in 4 out of 10 participants
with back and forth body-rocking movements. An operant
conditioning paradigm successfully improved self-feeding
skills in five females, two of whom did not have self-feed-
ing skills before the intervention.86 No functional change
was observed in a different self-feeding study, which used
an orthosis-based rather than psychological intervention.82
Three studies resulted in five participants adopting micro-
switch use, manifesting in voluntary and independent
switch pressing and swatting.64,84,87 Other fine motor func-
tion interventions included toy playing with a parent68 and
sensorially stimulating computer-based tasks.78 Umansky
et al. found that toy playing with a participant’s mother
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increased purposeful hand use with toys fivefold; hence,
social facilitation of functional hand use may warrant fur-
ther exploration.69
One intervention (n=2) sought to mitigate hand biting
using positive reinforcement strategies and hand-on-hand
interruption (Table S6).73 Self-injurious behaviors
decreased during the intervention; however, long-term
maintenance was not tested.
Improvements in fine motor ability often coincided with
gains in gross motor and communication skills. Fine motor
rehabilitation led to increases in spontaneous and symbolic
toy playing,69,82 choice-making from symbols,55,72 transi-
tional movement from sitting to standing,85 phoneme pro-
nunciation,85 language comprehension,72,78 self-feeding
skills,86 and learning speed.55 Improved happiness, sociabil-
ity, and expressivity64,65,71,83 after fine motor rehabilitation
were also reported.
Multiple gaps exist for further research in RTT fine
motor rehabilitation. Of 24 fine motor function rehabilita-
tion studies, only one was a replication,81 signaling the
need to validate existing studies. Most case reports and
case series clearly reported their intervention methods
(Tables S1 and S2), offering reproducible methodology for
future research.
Communication interventions
Twenty-two studies targeting communication rehabilita-
tion were identified, affecting a total of 107 partici-
pants (Table S7). All studies in communication
rehabilitation reported gains in participants’ primary goals,
which consisted of improvements in choice-making, com-
municative language, and social communication abilities.
Forty-one percent of all participants (n=44) were included
in two strong-quality, quasi-experimental trials (Table S3
and S7). The remaining participants were followed in 20
case reports and case series. Out of four case reports, three
were strong-quality reports and one was a moderate-qual-
ity report (Table S1). Out of 16 case series, 11 were mod-
erate-quality case series and five were strong-quality case
series (Table S2). No low-quality studies were identified
across the communication rehabilitation literature.
Most communication interventions took place at educa-
tional facilities49,52,87–91 and in the home environ-
ment.51,55,93–100 Only four studies101–105 were conducted at
rehabilitation facilities and one study did not specify the
location of the intervention.56 Specific details regarding the
intensity of the intervention are available for 13 of 22 stud-
ies (Table 2), reporting a mean duration of 24 minutes per
session and four sessions per day for 4 days per week. The
median intervention lasted 24 weeks on average (Table 2).
Multiple interventions lasted for over 6
months,53,88,90,94,97,102,104 signaling that long-term inter-
ventions may be necessary to obtain clinically meaningful
communication outcomes.
Eight studies focused on building choice-making skills,
engaging a total of 41 participants. Long-term intervention
strategies were used to improve choice-making skills in

females with RTT, with all included studies lasting
between 5 and 9 months (Table S7). The study with the
highest level of evidence in this category (level 3) found
that containing participants’ hand stereotypies helped them
select a correct stimulus more quickly using touch and/or
eye gaze (n=10).55 Another level 4 study reported a physi-
cal reduction in stereotypic hand movements, which facili-
tated an increase in the correct choice of symbol and
attention to the choice-making task (n=12).53 Thus, stereo-
typy reduction may positively impact choice-making.
Interventions using low-technology communication
boards89,101,102 or computer touchscreens88,90 also
improved the choice-making outcomes of 16 participants.
Choice-making between snacks or songs occurred in two
interventions each; assigning words to symbols occurred in
one intervention (see Table S4 for the full intervention
details). One case series used photocells to facilitate
choice-making (n=3),93 with the photocells playing encour-
aging stimuli each time an object was inserted into its cor-
rect container.93 Overall, low-, medium-, and high-
technology interventions were uniquely effective with facil-
itating choice-making in females with RTT.
A total of 50 participants across eight studies underwent
rehabilitation to improve their communicative language
skills. In this category (Table S7), the quasi-experimental
study by Fabio et al.56 (n=34) received a level 3 evidence
grade and a strong-quality score (Table S3). They found
that a 5-day (n=21) rather than 1-day (n=12) training para-
digm significantly improved participants’ use of an eye-
tracking communication device.56 Participants with 1 day
of training did not increase their duration of eye tracking
on a communication target, nor did they decrease the time
spent before first fixating on a target; however, those with
5 days of training improved in both areas.56 Another level
4 study similarly employed ETT to achieve the communi-
cation goals of 3 out of 4 participants after a 6-month
intervention.97
Three level 4 studies increased the number of commu-
nicative acts performed by their participants with RTT
(n=7). These studies used either home-based microswitch
training or a picture exchange system intervention,51,95,96
lasting from two to three sessions95 to over 4 months.96
One case series found that repeated transcranial direct cur-
rent stimulation over Broca’s area increased participants’
vocal utterances (n=3).103 Other key studies in the commu-
nicative language category include a 7-year-long case
study, whose participants learned to communicate in full
sentences with an alphabet table (n=1);94 another case
study reported 22 sessions that increased participants’ abil-
ity to identify phonic sounds correctly (n=1).50
The evidence from seven level 4 or 5 studies targeted
social communication. All interventions in this category
trained an intervenor to recognize or promote communica-
tive acts, affecting a total of 16 participants (four partici-
pants were excluded due to study duplication; see
Table S7). Three studies used storybook reading as an
intervention.98–100 Koppenhaver et al.98 demonstrated that
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weekly storybook reading, combined with augmentative
and alternative communication training for parents and
assistive device use, resulted in a positive trend toward
increased symbolic communication (n=6).98 Similarly,
Skotko et al.100 trained mothers to incorporate microswitch
use when reading, thus increasing symbolic communication
from their daughters. Additional strategies include coach-
ing caregivers who feed females with RTT at school to
recognize and encourage participants’ bids and responses
for communication.92 Music therapy interventions in two
level 5 case reports increased turn-taking and emotional
responses in females with RTT (n=2).104,105
The benefits of communication interventions extended
into other areas of child development, including a positive
impact on mood37,87,93,94,96,105 and attention span.53,56
Communication interventions also decreased anxiety,56
stereotypies, and idiosyncratic behaviors.37,51,93,96 Another
important corollary was an observed increase in caregiver
quality of life, given that parents often reported psychoso-
cial improvements on learning how to communicate with
their children.94,97
Existing RTT communication rehabilitation studies
delineate many areas for future research. Despite the
increasing use of ETT in personal and educational envi-
ronments, there is a dearth of peer-reviewed studies vali-
dating the efficacy and implementation of ETT.56,96,97
More evidence to support the use of ETT is needed to
increase access to ETT for individuals with RTT. Never-
theless, the inconsistent evidence surrounding the efficacy
of training communication partners in RTT rehabilita-
tion91,92 signals that further studies in communication
partner training could succeed in developing much-needed
guidelines for parents, educators, and clinicians for com-
municating with females with RTT. Low-cost intervention
strategies, such as alphabet board training and storybook
reading, should be replicated given the promise of existing
studies.94,98 Lastly, only 3 of 22 communication interven-
tion studies had a sample size of 10 or more participants,
indicating the need for more robust studies with larger
numbers of participants.53,55,56
Other interventions
Five additional studies had varied primary outcomes. Study
quality in this category was heterogenous (Table S8). Many
case series did not include participants’ demographic infor-
mation, nor their ongoing or previous rehabilitation treat-
ments, indicating that the recruited individuals may be
unrepresentative of the general RTT population.106–108
One moderate-quality case series used a behavioral train-
ing procedure, which interrupted daytime napping to elim-
inate aberrant sleep patterns in three participants with
RTT.107 Another behavioral intervention based on autism
research, which targeted overall behavioral improvements,
did not result in meaningful gains for participants with
RTT (n=3).109 In another attempt to optimize behavioral
training methods, Bowman et al.106 sought to compare
preferences for a single high-quality reward versus multiple
Review 911

low-quality rewards in females with RTT; however, no
preference was noted.106
One guided eating intervention improved females’ atten-
tion to food, the frequency of mouth opening, and mood
during mealtimes (n=3).108 Finally, an intervention known
as ‘The Listening Program’ was used to stimulate the
vestibulocochlear system of five participants, increasing
positive mood and engagement.52
Each rehabilitation study in the ‘Other’ category has yet
to be replicated. In particular, the bedtime fading proce-
dure implemented by Piazza et al.107 was successful in all
participants, suggesting a promising study for replication.
Gaps in the literature
Most studies identified in this review, specifically case ser-
ies or individual case reports (59 out of 62), reported lower
levels of evidence. Few studies contained 10 or more par-
ticipants53–56,79,110 and very few were clinical trials.54–56
Moreover, only six case reports extended beyond 1 year in
length,15,57,63,67,78,94 resulting in a dearth of literature con-
taining information on skill maintenance after rehabilita-
tion. RTT is not a neurodegenerative disorder; therefore,
long-term follow-up is important to test skill retention and
quality of life over the life span.111 Only two case series
were replication studies, signifying that the wealth of inter-
vention techniques investigated in this review have yet to
be verified.81,100 Lastly, larger studies designed to compare
the impact of rehabilitation interventions are needed.
There is a paucity of rehabilitation literature for adult
females with RTT that impacts our understanding of the
rehabilitation potential in adulthood. Adult females with
RTT have demonstrated the ability to acquire new skills
and restore function.2,15,53,55,56,59,66,83,87,94,95,103,108 Evi-
dence of effective rehabilitation interventions for adults is
essential since therapy resources are frequently reduced in
adulthood compared to young people,112 an obstacle that
may be ameliorated if rehabilitation research in adults with
RTT demonstrates benefits.
Finally, when evaluating the potential effectiveness of
rehabilitation interventions, it is important to understand
the participants’ clinical and genetic diagnoses pertinent to
RTT since there are general phenotype–genotype correla-
tions regarding different developmental domains. Only 13
of 62 studies specified the clinical stage of their partici-
pants,1,56,61,77,81,89,90,92,94,97,101–103 which is problematic
given the functional differences during each stage of RTT.
Only 12 studies confirmed MECP2 mutations (Table S4)
and 10 provided specific mutation information.53-
57,69,78,94,103,104
Only two preserved speech variants were
tested in all studies identified in this review.15,69 Thus,
stage- and variant-specific effects on rehabilitation out-
comes represent a gap in knowledge.
DISCUSSION
Before this scoping review, all published interventions in
RTT rehabilitation had not been inclusively and compre-
hensively summarized. It is significant that this review
912 Developmental Medicine & Child Neurology 2020, 62: 906–916
14698749, 2020, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/dmcn.14565 by Cochrane Saudi Arabia, Wiley Online Library on [02/04/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
identified overwhelmingly positive outcomes, with only 7
out of 62 included interventions reporting no functional
improvements in their participants with RTT.66–
68,81,89,106,109
Thus, there is consistent evidence across the
literature, albeit largely from levels 4 and 5 evidence, that
is, case series and case reports, that regular intervention
enables individuals with RTT to acquire new gross motor,
fine motor, and communication skills.
Case reports and case series have high utility in rare dis-
ease rehabilitation studies, given that they can be used to
inform personalized treatment plans and the development
of definitive studies. However, by definition, these studies
lack a comparison or control group, as well as assessor
blinding. These attributes increase the risk of selection and
observational bias within a study, thus limiting the general-
izability of study outcomes. In our review, varied outcome
measures, significant differences in study design, and low
participant numbers prevented effect sizes from being cal-
culated across the quasi-experimental studies included in
the review. As the RTT rehabilitation literature evolves
and more authors begin to evaluate similar interventions
and outcomes, calculating effect sizes will become essential
for evidence synthesis.
Despite these limitations, the available literature strongly
supports the ability of rehabilitation to improve the com-
municative abilities of females with RTT. Participants with
RTT demonstrated the capacity to make choices using
eye-tracking devices, physical switches, and physical touch
(Table S7). Although numerous interventions had high
resource demands for extended periods of time, all 22
studies ultimately demonstrated the ability of females with
RTT to increase their communicative abilities in clinically
meaningful ways, such as expressing their needs and wants.
Additionally, participants’ caregivers often reported satis-
faction after each communication-focused intervention.
These findings, in conjunction with the rising number of
females with RTT living late into adulthood, necessitate
further research into how high-, medium-, and low-tech-
nology communication interventions can optimize the
developmental potential of females with RTT.
Interventions focused on gross motor function revealed
that severe physical disability does not negate the capacity
of females with RTT to rehabilitate. All 11 rehabilitation
studies targeting gross motor skills achieved functional
improvements. Through individualized physiotherapy, 10
females with RTT improved their ambulation.1,2,57–59 In
several case reports featuring individuals with reportedly
limited physical abilities, each participant improved their
gross motor skills and even partly relearned how to
walk.2,59 These positive trends challenge clinicians to
rethink the ability of females with RTT to improve and
learn motor functions, especially during the late motor
deterioration stage. Only one study described the use of
pharmacology to decrease tone and rigidity; thus, the syn-
ergistic effects of physiotherapy and pharmacology should
be further investigated since tone and rigidity increase with
age in individuals with RTT.63

Despite the low levels of available evidence across the
RTT fine motor rehabilitation literature, there is a clear
pattern demonstrating that hand bracing, thumb splinting,
and/or elbow orthoses can help reduce stereotypies
(Table S6). Five out of six splinting studies achieved func-
tional improvements.65,68,76,80,83 Another interesting trend
throughout the literature was the ability of social interac-
tion, whether through playing with toys, game play, or
operant conditioning reinforcements, to improve fine
motor function.69,70,75,86 Therefore, an intervention’s social
environment has clinical relevance. Additional findings in
fine motor rehabilitation included that multiple partici-
pants could learn or relearn voluntary hand functions
(Table S6), many through music therapy.71,72,74 Thus,
music therapy may provide a promising avenue for future
interventions that address apraxia.
A key finding in our review was the interplay between
positive outcomes in targeted areas and other areas of
rehabilitation. Gains in gross motor function often initi-
ated learning of fine motor skills; for example, when train-
ing transitional movement from sitting to standing, hand
grabbing of furniture was also facilitated.2 Operant condi-
tioning and splinting in one case study improved fine
motor function alongside standing abilities.85 Furthermore,
newly learned motor skills, such as eye-pointing, often
enhanced communication abilities.60 In select music ther-
apy studies, instrument playing increased choice-making
and vocal utterances,72 and improvements in fine motor
abilities facilitated the recognition of new words.78 The
interaction between physical and cognitive interventions
for females with RTT reveals the breadth of impact of
rehabilitation on daily life. Researchers should consider
using validated scales that evaluate the broader phenotype
in RTT as a uniform outcome measure in future rehabili-
tation studies.
Results from this scoping review support recent advance-
ments in understanding the cognitive and social profile of
females with RTT. Females with RTT can recognize and
fixate on novel stimuli113,114 like typically developing chil-
dren. When ETT was used to assess verbal comprehension
in females with RTT, 32% of participants tested in the
mild-to-no cognitive impairment range.115 Correspond-
ingly, RTT rehabilitation studies targeting choice-making
reported that participants decreased the number of
attempts94,102 and response time,78,102 and increased the
number of correct responses78,90 during intervention,
thereby signaling learning. Regarding socialization, fixation
on social stimuli is significantly higher in females with
RTT compared to females with autism and even compared
to some typically developing participants.114 Studies in this
review also reported that a social environment enhances
learning and rehabilitation outcomes.67,69 Furthermore,
current literature suggests that females with RTT can
access previous memories. When physiotherapists brought
an adult with RTT to the last place where she could get
up from the floor on her own, she succeeded in relearning
to stand independently.2 More research is needed to design
14698749, 2020, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/dmcn.14565 by Cochrane Saudi Arabia, Wiley Online Library on [02/04/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
and test interventions that address the complex cognitive
and social profile of RTT to optimize rehabilitation out-
comes.
Given the rare occurrence of RTT and its interindivid-
ual phenotypic variability, it is inherently difficult to con-
duct controlled interventional studies. Alternative study
designs, such as crossover studies or historical case control
studies, and the use of standardized, broad-based outcome
measures will facilitate comparison between studies and
refine future rehabilitation research. Additionally, more
consistent reporting of intervention methodology, such as
session duration and frequency, is needed to improve the
reproducibility of RTT rehabilitation studies.
Limitations
Because of the prevalence of case reports and case series
identified in this review, we cannot make clinical recom-
mendations regarding specific rehabilitation interventions.
Additionally, our inclusion criteria are limited to peer-re-
viewed journals written in the English language, thereby
excluding meaningful work that may have been published
in magazines, books, or other languages. Lastly, stage- and
mutation-specific rehabilitation effects could not be identi-
fied in this review due to the lack of disclosure of clinical
stages and genetic mutations.
CONCLUSION
This scoping review has identified numerous promising inter-
vention studies, each demonstrating the capacity of females
with RTT to regain or learn anew gross motor, fine motor, or
communication skills, as well as developing personal interests
and increasing socialization. To date, limited research has been
conducted in the field of RTT rehabilitation. This review
highlights the necessity of further research to understand and
optimize the functional abilities of individuals with RTT and
elicit concomitant impacts on quality of life.
Implications for research
The authors recommend immediate future research in using
alternative study designs to replicate existing intervention
studies, specifically: investigating splinting and low-technol-
ogy communication interventions; increasing physiotherapy
research due to the low number of existing, although promis-
ing, studies; researching validating ETT use for communica-
tion; developing physical and cognitive rehabilitation
strategies for adults with RTT; and investigating the synergis-
tic effects of improved cognition, socialization, and pharmaco-
logical treatment alongside rehabilitation.
A CK N O W L E D G E M E N T S
We thank librarian scientist Pui-Ying Wong for her invaluable
assistance with developing the search strategy. We also thank reg-
istered practical nurse Erin Brandon for her edits to our final
manuscript. This project was funded through a grant from the
Holland Bloorview Kids Rehabilitation Hospital Foundation. The
authors have stated that they had no interests that might be per-
ceived as posing a conflict or bias.
Review 913

SUPPORTING INFORMATION
The following additional material may be found online:
Appendix S1: Full search strategy.
Table S1: Summary of criteria as rated by the critical appraisal
tool for the included quasi-experimental studies (non-randomized
experimental studies)
Table S2: Summary of criteria as rated by the Critical Apprai-
sal Tool for the included Case Series (CEBM Level 4)
Table S3: Summary of criteria as rated by the Critical Apprai-
sal Tool for the included Quasi-Experimental Studies (non-ran-
domized experimental studies) (CEMB level 3)
14698749, 2020, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/dmcn.14565 by Cochrane Saudi Arabia, Wiley Online Library on [02/04/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Table S4: Full data extraction tables
Table S5: Summary of gross motor function rehabilitation
interventions
Table S6: Summary of fine motor function rehabilitation inter-
ventions
Table S7: Summary of communication rehabilitation interven-
tions
Table S8: Summary of other rehabilitation interventions
Table S9: Frequency and duration of rehabilitation interven-
tions
Figure S1: PRISMA study selection flow diagram.

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DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY ORIGINAL ARTICLE

DE INTERVENCIONES DE REHABILITACION
REVISION
EN EL S
INDROME DE RETT

OBJETIVO

n del s
ındrome de Rett (RTT) e identificar brechas en la lite-
Resumir las intervenciones actuales y sus resultados en la rehabilitacio
ratura.
M

ETODOS

una bu
Se realizo
squeda sistema
tica de estudios que describieran intervenciones de rehabilitacio

n en cinco bases de datos (Ovid
MEDLINE, Ovid Embase Classic, Ovid PsycINFO, EBSCO CINAHL Plus y ProQuest ERIC) hasta el 23 de julio de 2018. Se extrajeron
~ o y los resultados.
los datos sobre los participantes del estudio, el disen
RESULTADOS
Sesenta y dos art
ıculos fueron incluidos en la revisio
n final. La evidencia demostro
que, con rehabilitacio

n, las mujeres con RTT
pueden mejorar sus habilidades motoras gruesas, motoras finas y comunicativas. Las 11 intervenciones dirigidas a mejorar la

n motora gruesa, particularmente la deambulacio
funcio
n, lograron mejoras funcionales. Veinte de 24 art
ıculos que describen estu-

n de la funcio
dios de rehabilitacio
n motora fina lograron disminuir las estereotipias, mejorar el uso funcional de las manos y / o
reducir las conductas autoagresivas. Veintiuno de 22 estudios que describen intervenciones de comunicacio
n lograron una mejor
ıa
en la toma de decisiones, la comunicacio
n o conductas de socializacio
n. Otros hallazgos claves incluyen la interaccio

n positiva
entre los resultados de rehabilitacio
n f
ısica y la comunicacio
n, y que las mujeres con RTT pueden mejorar sus habilidades cogniti-
vas durante la intervencio
n.


INTERPRETACION

n puede mejorar la vida cotidiana de las mujeres con RTT y sus cuidadores de manera cl
ınicamente significativa.
La rehabilitacio

~ DE REABILITAC
ß OES
INTERVENC ~ EM S
INDROME DE RETT: UMA REVISAO
ß AO ~ DE ESCOPO

OBJETIVO
~ es existentes e seus resultados na reabilitacßa
Sintetizar intervencßo ~o da s
ındrome de Rett, e identificar lacunas na literatura.
M

ETODO
Cinco bases de dados (Ovid MEDLINE, Ovid Embase Classic, Ovid PsycINFO, EBSCO CINAHL Plus, e ProQuest ERIC) foram revisa-
das sistematicamente ate ~o. Dados sobre participan-
~ es de reabilitacßa

23 de julho de 2018 quanto a estudos descrevendo intervencßo
tes dos estudos, desenho e resultados foram extra
ıdos.
RESULTADOS
Sessenta e dois artigos foram inclu
ıdos na revisa ~o final. A evide
^ncia mostrou consistentemente que mulheres com RTT podem
melhorar suas habilidades motoras grossas, finas e de comunicacßa ~o. Todas as 11 intervencßo
~ o com a reabilitacßa ~ es com foco na
~o motora grossa, ou seja, deambulacßa
funcßa ~o, mostraram melhoras funcionais. Vinte dos 24 artigos descrevendo reabilitacßa ~o da
~o motora fina foram bem sucedidos em diminuir estereotipias, melhorando o uso funcional da ma
funcßa ~o, e/ou reduzindo compor-
tamentos de auto-lesa ~o. Vinte e um dos 22 estudos descrevendo intervencßo~ es para comunicacßa~ o foram bem sucedidos em treinar
tomadas de deciso ~ es, linguagem comunicativa, ou comportamento de socializacßa ~o. Outros achados chave incluem a relacßa ~ o posi-
~o, e a capacidade das mulheres com RTT em melhorar suas capacidades cognitivas
tiva entre resultados f
ısicos e de comunicacßa
durante a intervencßa~ o.
~
ß AO
INTERPRETAC
~o pode impactar a vida dia
A reabilitacßa
ria de mulheres com RTT e seus cuidadores, de formas clinicamente significativas.