Research in Developmental Disabilities 34 (2013) 1897–1905

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Research in Developmental Disabilities

Normal reactions to orthostatic stress in Rett syndrome

Gunilla Larsson a,b,*, Peter O.O. Julu b,c, Ingegerd Witt Engerstrom b,Marlene Sandlund a, Britta Lindstrom a

a Department of Community Medicine and Rehabilitation, Physiotherapy, Umea University, Swedenb Swedish Rett Center, Jamtland County Council, Ostersund, Swedenc Breakspear Medical Group, Hertfordshire, United Kingdom

A R T I C L E I N F O

Article history:

Received 11 December 2012

Received in revised form 23 February 2013

Accepted 24 February 2013

Available online 11 April 2013

Keywords:

Rett syndrome

Autonomic function

Healthy controls

Orthostatic reaction

Orthostatic hypotension

A B S T R A C T

The aim of this study was to investigate orthostatic reactions in females with Rett

syndrome (RTT), and also whether the severity of the syndrome had an impact on

autonomic reactions. Based on signs of impaired function of the central autonomic system

found in RTT, it could be suspected that orthostatic reactions were affected. The orthostatic

reactions in 21 females with RTT and 14 normally developed females matched by age were

investigated when they rose from a sitting position, and during standing for 3 min.

Reactions of the heart, the blood pressure and the time for recovery of systolic blood

pressure, were studied in real time, heartbeat by heartbeat, simultaneously. There was no

difference between participants with RTT and the normally developed controls regarding

general orthostatic reactions (heart rate, systolic and diastolic blood pressure, and mean

arterial pressure) when getting up from a sitting position, and when standing erect for

3 min. In the specific immediate response by the heart to standing up, the 30:15 ratio,

significantly lower values were found for females with RTT. In the RTT group, the

maximum fall of systolic blood pressure showed a tendency to a larger decrease, and the

initial decrease in systolic blood pressure was significantly faster. The time for recovery of

systolic blood pressure from standing erect did not differ between groups. At baseline the

females with RTT had significantly lower systolic blood pressure and a tendency to a

higher heart rate. The results do not indicate any autonomic limitations for people with

RTT in getting up from a sitting position and standing. The participants with RTT had

normal orthostatic reactions indicated by the heart and blood pressure responses when

standing erect for 3 min. A faster initial drop in systolic blood pressure in people with RTT

1. Introduction

Rett syndrome (RTT) is a complex, X-linked dominant neurodevelopmental disorder with great individual variation thatalmost exclusively affects girls: 1 in 10,000 (Kerr & Witt-Engerstrom, 2001; Leonard et al., 2001). For diagnosis, clinicalcriteria have been confirmed internationally, both for classic RTT and variants of RTT (Hagberg, Hanefeld, Percy, & Skjeldal,

was notable.

� 2013 Elsevier Ltd. All rights reserved.

Abbreviations: RTT, Rett syndrome; HR, heart rate; POTS, postural orthostatic tachycardia syndrome; SBP, systolic blood pressure; DBP, diastolic blood

pressure; MAP, mean arterial pressure; BP, blood pressure; OH, orthostatic hypotension; ECG, electrocardiogram; EEG, electroencephalogram; pO2, partial

pressures of oxygen; pCO2, partial pressure of carbon dioxide; VT, vibroacoustic stimulation; ISS, International Severity Score; CP, cerebral palsy; WHO,

World Health Organization.

* Corresponding author at: Department of Community Medicine and Rehabilitation, Physiotherapy, Building 15, Umea University, S-901 87 Umea,

Sweden. Tel.: +46 63 15 48 10/910 392 41; fax: +46 63 15 45 00; mobile: +46 70 658 70 42.

E-mail addresses: gunilla.e.larsson@jll.se, gl@reago.se (G. Larsson).

0891-4222/$ – see front matter � 2013 Elsevier Ltd. All rights reserved.

http://dx.doi.org/10.1016/j.ridd.2013.02.027

G. Larsson et al. / Research in Developmental Disabilities 34 (2013) 1897–19051898

2002; Kerr & Witt-Engerstrom, 2001). The children are born after a normal pregnancy and seem to develop normally untilapproximately 6–18 months of age. After a period of developmental stagnation they lose abilities such as communication,and fine and gross motor skills. The point in time when different symptoms first appear varies, as does the severity of thesymptoms, but after the regression, all of the children suffer from severe motor and communicative disabilities, with adegree of intellectual disability that is difficult to define. Diagnosis is based on clinical criteria, but since 1999, an associationwith mutations in the methyl-CpG-binding protein2-gene (MECP2) has been confirmed in 95% of those with classic RTT,mainly as de novo mutations (Amir et al., 1999; Hagberg et al., 2002; Percy, 2008). Correlation between mutation anddisability, that is genotype-phenotype, is being studied and has been discussed as a prognostic predictor of severity ofdisability. So far this has been of limited value, since there is extensive variability (Ager et al., 2006; Bebbington et al., 2008;Charman et al., 2005; Halbach et al., 2012; Kerr & Prescott, 2005; Leonard et al., 2003). Deficient growth as well asimmaturity of the central nervous system is apparent in RTT (Armstrong & Kinney, 2001; Julu, 2001; Tarquinio et al., 2012).The immaturity of the central autonomic control is particularly disabling, manifested as breathing dysrhythmia, abnormalvariation in heart rate and blood pressures, peripheral vasomotor disturbance and gastrointestinal problems. Theimmaturity causes imbalance, where the parasympathetic function appears more affected than the sympathetic. A steadyand well-adapted autonomic system is essential to adjust to physiological needs and activities. In people with RTT, thedeficient adaptation of the autonomic nervous system frequently causes a state of stress (Bieber Nielsen, Friberg, Lou, Lassen,& Sam, 1990; Julu, 2001; Julu et al., 2001; Kerr & Witt-Engerstrom, 2001; Low & Benarroch, 2008; Nomura, Kimura, Arai, &Segawa, 1997; Weese-Mayer et al., 2006; Weese-Mayer et al., 2008; Witt-Engerstrom, 1990). Opinions have been presentedthat people with RTT may improve with physical activity (i.e. the effects of stress may be reduced), but knowledge is limited.The effect on heart rhythm and blood pressures when people with RTT perform activities such as standing up and standingfor 3 min has not been studied (Guideri, Acampa, Hayek, Zappella, & Di Perri, 1999; Julu, Kerr, Hansen, Apartopoulos, & Jamal,1997b; Madan, Levine, Pourmoghadam, & Sokoloski, 2004; Rohdin et al., 2007; Sekul et al., 1994).

Since 1998, studies have been in progress at the Rett Center in Froson, Sweden, to examine how the central control of theautonomic nervous system functions in people with RTT. Respiratory dysrythmia has been investigated during sitting, aswell as abnormal variations in blood pressures, blood gases and heart rhythm (Julu et al., 2001; Julu & Witt-Engerstrom,2005). Autonomic responses to music and to vibroacoustic stimulation have also been studied, but so far not orthostaticreactions (Bergstrom-Isacsson, 2011; Bergstrom-Isacsson, Julu, & Witt-Engerstrom, 2007; Julu, 2001; Julu et al., 2001; Julu,Kerr, Hansen, Apartopoulos, & Jamal, 1997a; Julu et al., 1997b; Julu & Witt-Engerstrom, 2005).

Normal values for orthostatic reaction may vary somewhat (O’Brien, O’Hare, & Corrall, 1986; Wieling & van Lieshout,2008). Wieling and van Lieshout (1993) stated that using standing up to assess cardiovascular autonomic function is easy,useful and clinically relevant, and the standing-up test can be used from 5 years of age (Hynninen, 2006; Wieling & vanLieshout, 1993). When standing up, the autonomic nervous system accommodates to supply the brain with blood/oxygenwhen the force of gravity transfers the blood to lower parts of the body, such as the abdomen and legs. The body compensatesthe change in blood pressure in a very finely tuned and complex way. In RTT, deviant orthostatic reactions could be suspecteddue to deficient autonomic function (Agelink et al., 2001; Borst, Van Brederode, Wieling, Van Montfrans, & Dunning, 1984;Borst et al., 1982; Hynninen, 2006; O’Brien et al., 1986; Schatz et al., 1996; Smith, Porth, & Erickson, 1994; Sprangers,Wesseling, Imholz, Imholz, & Wieling, 1991; Wieling & van Lieshout, 2008). With our equipment, it is possible to study thereactions of the heart, blood pressures and time for recovery in real time, heartbeat by heartbeat, and thus investigate howcentral autonomic reactions in people with RTT are affected by a physical task such as standing up from a sitting position.This may provide indications of whether exercise and activity are advisable and not dangerous for people with RTT, who havea weak parasympathetic nervous system.

Therefore, the main aim of this study was to investigate orthostatic reactions in females with RTT, compared with those ofnormally developed females, when getting up from a sitting position and during standing. Due to the heterogeneity withinthe group with RTT, the International Severity Score (ISS) for RTT was used to study whether the severity of the syndrome hadan impact on the autonomic reaction (Kerr et al., 2001).

2. Methods

2.1. Participants

The participants were a consecutive selection of females with RTT, referred to the Rett Center for assessment of the centralcontrol of the autonomic nervous system. They had been diagnosed earlier by co-author IWE or by their local physician orpaediatrician, and the diagnosis was confirmed at a medical examination before autonomic assessment at the Swedish RettCenter by IWE. They were diagnosed according to clinical criteria for RTT (Hagberg et al., 2002; Kerr & Witt-Engerstrom,2001). To be included in this study the females had to be able to get up from sitting to standing, by themselves or with somesupport, and be able to sustain standing for 3 min. In Table 1 individual characteristics are given. Age-matched females ascontrols were recruited through friends and colleagues in the Ostersund area. The control participants were recruited on thebasis that they did not suffer from any medical complaints, and they were not on any medication.

Informed consent was received from all participants and all could opt out at any time. Ethical approval was granted by theRegional Ethical Review Board in Umea 2010-03-02, Dry 09-192M.

Table 1

Description of the participants with Rett syndrome.

Subject Age Mutation Clinic

type

Stage CRPh Valsalvas EP ASBA BMI ISS Scoliosis Operation

scoliosis

Standing ability Walking ability

2 10 p.G269fs Classic III FoB Yes Yes Few 16.3 18 No NA Med. support No

4 38 neg Classic III FeB No Yes Few 15.2 26 Yes No Max. support Max. support

6 9 R9fs Classic III–IV FeB No No Frequent 17.4 23 Yes No Min. support Max. support

7 15 R168X Classic IV ApnB Yes No Frequent 22.8 26 Yes No Med. support No

8 15 R255X Classic III ApnB No No Few 26.7 11 Yes Yes Independent Independent

9 23 c.916C>T Classic III FoB No No Very frequent 18.9 16 No NA Min. support Med. support

10 10 R133C Classic III ApnB Yes Yes Very frequent 18.4 15 Slight No Independent Independent

11 46 neg Variant III FeB No No No 21.2 15 Yes No Independent Independent

12 35 R133C Classic III FeB Yes Yes Few 17.4 34 Yes Yes Med. support Max. support

13 34 p.R294X Classic III FeB Yes Yes Frequent 17.4 23 Yes No Med. support Med. support

14 30 neg Variant III FeB No No Few 17.8 18 Slight No Independent Independent

15 20 R168X Classic III ApnB yes Yes Few 15.1 22 Yes Yes Med. support Med. support

16 25 p.R306C Classic III ApnB No No No 20.2 26 Yes Yes Max. support Max. support

17 20 R168X Classic IV ApnB No No No 26.7 22 Yes Yes Max. support No

18 15 1084-1197,del113 Classic III FeB Yes No Few 19.5 28 Yes Yes Min. support Min. support

19 18 p.R270fs Classic IV ApnB No Yes Few 16.1 30 Yes No Max. support No

20 32 neg Variant III FoB No No No 25.6 13 No NA Independent Independent

21 5 neg Classic III FoB No No Frequent 14.0 23 No NA Independent Min. support

22 32 p.R1294X Classic III ApnB No Yes Very frequent 22.4 20 Yes Yes Independent Independent

23 5 p.R294X Classic III FoB Yes Yes Frequent 12.6 22 No NA Independent Independent

24 29 c.907_C>T Classic III FoB Yes No Few 18.7 31 Yes Yes Min. support Min. support

CRPh: cardiorespiratory phenotype; EP: epilepsy; BMI: body mass index; ASBA: abnormal spontaneous brainstem activation; FeB: feeble breather; FoB: forceful breather; ApnB: apneustic breather; ISS:

International Severity Score (most severe: 40); NA: not applicable.

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2.2. Assessments and devices

The device used for measuring autonomic function, the NeuroScopeTM (MediFit Diagnostics Ltd, London, UK), uses arelatively new technique (US patent no. 6442420, 2002) developed by the specialist in autonomic neurophysiology Dr. PeterJulu (Al-Rawi, Sigaudo-Roussel, & Gaunt, 2004; Julu, 1992; Julu, 2001; Julu, Cooper, Hansen, & Hainsworth, 2003; Julu &Hondo, 1992; Julu et al., 1997a; Julu & Little, 2002; Little, Julu, Hansen, & Reid, 1999; Sigaudo-Roussel, Julu, & Gaunt, 2001). Itmeasures all parameters and displays them in real time, heartbeat by heartbeat. The technique has been fully describedelsewhere (Julu et al., 2001).

The NeuroScope uses VaguSoft software (MediFit Diagnostics Ltd, London, UK) to simultaneously record theelectrocardiogram (ECG), blood pressure (BP) waveforms, and transcutaneous partial pressures of oxygen (pO2) andcarbon dioxide (pCO2), and breathing movements. From this, further parameters are derived: heart rate (HR), cardiac vagaltone (CVT), systolic, mean and diastolic BPs and cardiac sensitivity to baroreflex (CSB). This equipment, along with asynchronised, simultaneously working electroencephalogram (EEG) machine, was used for a 1-h investigation of the RTTpatients who were referred for autonomic assessment. This preceded the orthostatic assessment for participants with RTT,for which the EEG was not used. Thus, prior to the current study, the EEG cap was removed from RTT participants. Theremaining equipment and measurements were used both for participants with RTT and controls. Further details andadditional equipment used for the measurement of orthostatic reaction were:

� A

non-invasive method for measuring BP waveform was deployed, using a finger photoplethysmograph (Portapres,Finapres Medical Systems B.V., The Netherlands). The beat-by-beat systolic (SBP), diastolic (DBP) and mean (MAP) bloodpressures were derived from the BP waveform by the NeuroScope. The MAP was calculated as the true arithmetic mean ofpressures throughout the whole cardiac cycle. � A height compensation unit, going from heart level to hand (blood pressure cuff), was used to compensate for change in

level when a person is not able to keep the hand at heart level.

� A s people with RTT have difficulty in standing up quickly from lying down, standing up from a sitting position was used. � C ontinuous video recordings, time-locked with the physiological measurements, were kept for further analysis.

The assessment is non-invasive and the setup was developed for patients sitting with family members or some other familiarperson close to and well known by the patient.

2.3. Procedure of orthostatic test

To investigate the orthostatic reaction the participants sat in an ordinary chair, where they could support their feet on thefloor. They would sit in this chair for at least 3 min, then stand up and remain standing upright for 3 min, and after that sitdown again. This procedure was repeated.

Postural orthostatic changes in blood pressure can be measured in SBP or DBP. For this study, postural orthostatichypotension (OH) is defined as a 10 mmHg drop in DBP after standing for 3 min (Low & Singer, 2008; Schatz et al., 1996).

The participants were not allowed to drink coffee or tea for 4 h before being tested. During the test, the participants weresupported and encouraged by the test leader or family member in a neutral vocal pitch.

2.4. Processing and data collecting

The reactions of the heart and blood pressures (SBP, DBP and MAP) were measured in three positions: sitting, directlyafter rising to a standing position, and after standing for 3 min. The sitting lasted 3 min or more, in order to obtainbaseline values that were as stable as possible. To be interpreted as stable, the values were to be collected from a periodof normal breathing without agitation, with normal levels of blood gases and blood pressures. The chosen period foranalysis had to be longer than 20 heartbeats. The measurements for rising to a standing position were collectedimmediately after the person had assumed an upright position. Measurements for the standing period were taken asclose as possible to the end of the 3 min of standing, taking into account that some participants would react as thoughthey understood it was time to sit down just before they were told to do so. The 30:15 ratio, that is the immediateresponse by the heart to standing up, was measured immediately after getting up from a sitting position. With ourequipment, it was possible to record the max and min R-R interval and thus obtain exact values (Ewing & Clarke, 1982;Julu & Hondo, 1992; Wieling, van Brederode, De Rijk, Borst, & Dunning, 1982). The postural orthostatic tachycardiasyndrome (POTS) was assessed by calculating the difference between the HR after standing for 3 min and the HR in asitting position (Low, Sandroni, Joyner, & Shen, 2008). The maximum fall in SBP was also measured after rising to astanding position.

The time of the initial fall in SBP was measured, as well as the time of recovery of BP, from the lowest level back to normalor the overshoot of SBP. Two phases of recovery were noted. There was an initial drop followed by a rise from the drop to fullrecovery or overshoot ‘‘short time’’. The period of overall recovery, ‘‘long time’’, starting from the beginning of the rise up tothe full recovery or overshoot of SBP, was also measured (Wieling & van Lieshout, 2008). To examine OH, the difference

G. Larsson et al. / Research in Developmental Disabilities 34 (2013) 1897–1905 1901

between the DBP in sitting position and after standing up for 3 min was used. All heart rate and blood pressure values werecollected simultaneously and synchronously.

2.5. Statistics

The IBM SPSS statistics version 20 was used. All analysed variables were normally distributed, with the exception of DBPwhen rising to a standing position for controls, and HR in standing for 3 min and the 30:15 ratio for participants with RTT.Multilevel linear mixed models (LMM) were constructed to analyse general differences in orthostatic reactions betweenpositions and groups. A two-level mixed model was applied for each variable with ‘‘group’’ (RTT/controls) and ‘‘position’’ (sit,get up, and stand) as fixed factors. The interaction between group and position was also included in the analyses. As repeatedtrials from the same individual were assessed, the intercept for each individual was set as random to create a hierarchicalstructure (i.e. the individual was treated as a two-level variable). In addition, to analyse if individual severity of RTT couldpredict the outcome in the blood pressure variables and heart rate, separate models were created for the patient group. Inthese two-level models, the ‘‘position’’ was also treated as a fixed factor, but the ISS (Kerr et al., 2001) was added as acovariate, together with the interaction between position and ISS. Finally, to verify the robustness of the models, theresiduals were checked for normality. In all the above-mentioned LMM, there was significant variance in intercepts acrossparticipants, which indicates that modelling a hierarchical structure of the data improved the predictions of the models. Theresiduals of all models were normally distributed, confirming the robustness of the models. For the specific reactions in:30:15 ratio; POTS; decrease in SBP when rising to a standing position; time of initial fall of SBP, ‘‘long’’ and ‘‘short’’ recovery ofSBP; and postural orthostatic changes in DBP (OH), there was only one value for each individual. In these analyses, the Mann–Whitney U-test was used for comparisons between groups. For all analyses a significance level was set to p � 0.05.

3. Results

3.1. Background data for participants

Of the 24 recruited girls and women with RTT, 21 completed the study. Three were excluded because of missing data. Ofthe 21 included, 18 were diagnosed as classic RTT and 3 as variants of RTT, according to clinical criteria for diagnosis of RTT(Hagberg et al., 2002; Kerr & Witt-Engerstrom, 2001). Mutations were tested in all 21, and confirmed in 16 of the 18 classicparticipants with RTT. Median age at assessment was 20 years (min–max 5–46 years). For participants with RTT, ISSs weremedian 22 (min–max 11–34). For further details, see Table 1. These data were collected both from medical records and bypersonal professional assessment (GL).

Of the 15 age-matched normally developed girls and women volunteering as controls, one was excluded because of adeviant heart reaction. The remaining controls had a median age of 24 years (min–max 5–43 years). There was a significantdifference between groups for weight and height, p = 0.002 and p = 0.001, respectively. For further details and comparisonsbetween groups, see Table 2.

3.2. General orthostatic reactions during the three positions

The LMM of the three positions (sitting, rising to a standing position, and standing for 3 min) showed that changes in positionhad a significant effect on HR, SBP, DBP and MAP (Fig. 1). The interactions between group and positions were not significant forany of these variables. Thus, there were no significant differences in the reactions of those with RTT when getting up andstanding, compared with the controls. However, regarding levels of the outcome variables, differences between RTT andcontrols were seen in SBP: F(1, 34) = 9.640, p = 0.004, and those with RTT had lower values than the controls. For both the DBPand the MAP, the lower values for those with RTT were not significantly different: F(1, 34) = 0.001, p = 0.975 and F(1, 34) = 1.804,p = 0.188, respectively. The HR showed a tendency to higher values in the group with RTT: F(1, 34) = 3.68, p = 0.063 (Fig. 1a–d).

For the group with RTT, the ISS was a significant predictor of SBP: F(1, 20) = 6.298, p = 0.021, DBP: F(1, 20) = 5.648,p = 0.027, and MAP: F(1, 20) = 6.515, p = 0.019, and a higher ISS was associated with lower blood pressure values when

Table 2

Background data and baseline (in sitting) values for the individuals with Rett syndrome and controls. The median and minimum–maximum (min–max

values and the differences between groups are shown.a

Rett syndrome (n = 21) Controls (n = 14) p-Value

Age (years) 20 (5–46) 24 (5–43) 0.52

Height (cm) 148 (98–170) 169 (118–178) 0.001

Weight (kg) 42 (12–74) 59 (22–81) 0.002

Body mass index 19 (13–27) 21 (16–29) 0.103

Heart rate (bpm) 88 (67–126) 83 (55–96) 0.56

Systolic blood pressure (mmHg) 94 (70–131) 110 (90–139) 0.06

Diastolic blood pressure (mmHg) 56 (40–88) 57 (49–80) 0.31

Mean arterial blood pressure (mmHg) 68 (53–97) 77 (63–100) 0.08a For comparisons between groups Mann–Whitney U-test is used.

)

Fig. 1. The group mean values and 95% CI of the individuals with RTT and the controls are presented for (a) heart rate, (b) systolic blood pressure, (c) diastolic

blood pressure and (d) mean arterial pressure (MAP) at the 3 positions, sitting �3 min, changes upon standing up and changes after standing upright for 3 min.

G. Larsson et al. / Research in Developmental Disabilities 34 (2013) 1897–19051902

position was taken into account. However, the ISS was not a significant predictor of HR: F(1, 20) = 0.975, p = 0.335. Theinteraction between the ISS and the orthostatic positions was not significant in any of these parameters. Thus, the severity ofRTT did not affect how the individuals with RTT reacted to the different orthostatic positions, as indicated by the ISS.

3.3. Specific orthostatic reactions during position change

There was a significant difference between participants with RTT and controls for the 30:15 ratio (p = 0.014) and for theduration of initial decrease in SBP when getting up from a sitting position (p = 0.009). No significant difference was foundwhen comparing the two groups regarding: signs of POTS (p = 0.592) or the maximum decrease in SBP, when rising to astanding position (p = 0.059). Nor was there any difference in the duration of recovery of SBP, both ‘‘short time’’ and ‘‘longtime’’ (p = 0.267) and (p = 0.815), respectively, or in orthostatic changes in DBP (OH) (p = 0.138) (Table 3).

Table 3

The median (min–max) of the different HR and blood pressure values for the participants with Rett syndrome and the controls during the 3 positions, sitting

�3 min, changes upon standing up and changes after standing upright for 3 min. The significance level of the differences between the groups is also shown

(Mann–Whitney U-test).

Rett syndrome (n = 21) Controls (n = 14) p-Value

30:15 ratio 1.13 (1.03 to 1.58)a 1.30 (1.16 to 1.59) 0.014

POTS (bpm) 11.15 (�4.30 to 46.00)a 10.75 (1.50 to 20.60) 0.592

Diastolic reaction at standing (mmHg) 1.85 (�15.80 to 25.60)b �2.10 (�9.00 to 5.00) 0.138

SBP fall at rising (mmHg) �21.10 (�52.50 to 10.30)c �14.70 (�40.70 to 1.00) 0.059

Initial fall SBP (s) 5.00 (2.00 to 10.00)d 8.00 (6.00 to 10.00) 0.009

‘‘Short time of recovery of SBP’’ (s) 8.50 (5.00 to 19.00)d 7.50 (6.00 to 12.00) 0.267

‘‘Long time of recovery of SBP’’ (s) 16.00 (7.00 to 27.00)d 15.50 (13.00 to 20.00) 0.815

POTS: postural orthostatic tachycardia syndrome; bpm: beats per minute; SBP: systolic blood pressure; s: seconds.a n = 20.b n = 18.c n = = 17.d n = 19.

G. Larsson et al. / Research in Developmental Disabilities 34 (2013) 1897–1905 1903

4. Discussion

The overall results of this study showed that the general orthostatic reactions in participants with RTT did not differ fromthose of the normally developed controls. The RTT participants had normal orthostatic reactions indicated by the heart andblood pressure responses when getting up from a sitting position and standing erect for 3 min. There were individualvariations in the people with RTT, but no one had problems standing. The HR during the three different positions exhibitedthe same pattern for those with RTT as for the controls. Only one person with RTT increased her HR by more than 30 bpmduring standing for 3 min. Thus, this person exhibited POTS (Low et al., 2008). The majority of those with RTT were within thelimits for normal variation of the 30:15 ratio (Ewing & Clarke, 1982; Julu & Hondo, 1992). When comparing groups, the RTTgroup had lower values than the controls for the 30:15 ratio. Thus, individuals with RTT had a weaker response of the heart toorthostatic challenge. There is a tendency of higher than normal HR in RTT, as a consequence of low cardiac vagal tone due tothe immature brain (Julu et al., 1997a).

Even if the participants with RTT showed the same pattern when getting up and standing, they started with lower SBP beforegetting up, and when they got up the SBP had a tendency to drop more, compared with the controls. The average fall of SBP was25.62 mmHg for the participants with RTT and 16.71 for the controls. A normal drop in SBP when getting up and standing for3 min is generally stated as 20 mmHg, although a value of 30 mmHg is also suggested (Low & Singer, 2008; Schatz et al., 1996).The initial decrease in SBP was faster for those with RTT as a group, but the time for recovery of SBP from standing erect was verysimilar in both groups. The distribution of ‘‘long time’’ for recovery or overshoot of SBP was seven to 27 s for participants withRTT, and 13 to 20 s for controls (Wieling, Krediet, van Dijk, Linzer, & Tschakovsky, 2007; Wieling & van Lieshout, 2008). Althoughthe mean values were almost the same, there was more variation within the group with RTT. Thus some people with RTT takelonger to recover SBP. This emphasizes the importance of waiting somewhat before starting to walk, for example.

Both when rising to a standing position and after standing for 3 min, the mean decrease in DBP varied considerably withinthe group with RTT, but no significant difference between groups was found. This result was probably influenced by a largedrop for one of the controls, making the difference smaller between groups. When groups are small, as in this study,individual deviations generally have a greater impact on results. When comparing DBP after standing for 3 min and whensitting before getting up (OH), there was no statistical difference between the groups; 17 out of 20 people with RTT werewithin normal limits, and the controls were all within the normal limits. Thus most individuals with RTT reacted in the sameway as the normally developed controls when standing for 3 min (Low & Singer, 2008; Schatz et al., 1996). MAP, the truearithmetic mean of pressures, is used as the indication for the sympathetic system and the perfusion pressure, and even ifparticipants with RTT started with lower values than controls, the levels were restored within the same time.

It has been reported that people with RTT spent about two-thirds of their waking hours ‘‘in sedentary behaviour’’,significantly more than normally developed children and adolescents, and their physical activity decreased with advancingage (Downs, Leonard, & Hill, 2012). This can be compared with the statement of the World Health Organization (WHO) in‘‘Global recommendations on physical activity for health’’ that being active according to one’s ability is important for goodhealth. These recommendations apply ‘‘unless specific medical conditions indicate to the contrary’’ (World HealthOrganization (WHO), 2010). Our RTT group displayed no medical conditions limiting their ability to stand up and remainstanding for 3 min. It has been reported that activity could be positive in RTT, as it was shown that a person’s respiratorypattern and heart rate function improved when walking or listening to music – in other words, during activity (Rohdin et al.,2007). There is also a risk of increased orthostatic intolerance due to reduced physical activity (Low et al., 2008). For thosewith disabilities such as RTT, rising to a standing position for transferring, and remaining standing for some time, can beregarded as physical activity and important for their daily life.

Nevertheless, the quicker initial drop in SBP when standing up, found in those with RTT, needs to be taken intoconsideration when helping them to stand up after resting. However, people with RTT also need help to continue to stand,since their SBP recovered in adequate time and orthostatic tolerance can be developed (Borst et al., 1984; Grubb, 2005; Low &Singer, 2008; Wieling, Ganzeboom, & Saul, 2004). When getting up from a sitting position and during standing for 3 min, noparticipant with RTT reported, verbally or interpreted by parents or staff, more than a very short period of discomfort.However, from the video recordings it was evident that most participants with RTT did not stand perfectly still during the3 min. It was common to move the upper body with the feet still, or take small steps back and forth or to the sides. This maybe a way of compensating for dizziness due to lack of balance, or a pattern of behaviour (Dan & Cheron, 2008). In RTT, as wellas in people with other severe disabilities, these reactions are not easy to interpret. It is not always possible to ask them howthey feel in a situation; one must rely on facial reactions, body reactions or signs.

From our results, the plan for lifelong care can and should include standing, weight bearing and activity, since today themajority of individuals with RTT survive into adulthood (Frelinger et al., 2010; Hagberg, Berg, & Steffenburg, 2001; Kirbyet al., 2010). It is evident that loss of abilities tends to be more documented, but with intervention it is may be possible tomaintain and improve gross motor ability in RTT (Foley et al., 2011; Larsson & Witt-Engerstrom, 2001; Lotan, Schenker,Wine, & Downs, 2012).

5. Methodological considerations

Since RTT is still a clinical diagnosis, it should be emphasized that in our study there are individuals with classicRTT and variants, with and without genetically confirmed RTT. In addition, our results can only relate to people with RTT

G. Larsson et al. / Research in Developmental Disabilities 34 (2013) 1897–19051904

who can stand, even if some of the participants with RTT had a pronounced disability and needed support. On someoccasions, artefacts due to hand movements in participants with RTT made it difficult to obtain continuous recordings.This did not cause incorrect readings but meant that fewer were made. Since the controls stood still whereas those withRTT moved somewhat, this may have led to a smaller decrease in SBP for participants with RTT. An advantage in thisstudy was that it was possible to use a method where all parameters were measured simultaneously, heartbeat byheartbeat. Also the time-locked video recordings made it possible to control for events or reactions that could interferewith the results.

6. Conclusion

The results do not indicate any autonomic limitations for people with RTT in getting up from a sitting position or instanding for 3 min. The participants with RTT had normal orthostatic reactions, indicated by the response of the heart andblood pressures (i.e. SBP, DBP and MAP) when standing erect for 3 min. The fast initial fall of systolic blood pressure in someindividuals with RTT must be taken into consideration when helping them in daily life. The authors recommend that lifelongcare should include standing, weight bearing and activity, since the majority of people with RTT today survive intoadulthood.

Future research could include walking on a treadmill to investigate how people with RTT manage their HR and BP duringincreased physical challenge. Subsequent research could address intervention over time to study effects of training onparasympathetic activity and see whether this leads to improved autonomic response for HR and BP. The results couldprovide more knowledge on possible physical activities to help people with RTT to maintain their general health.

Acknowledgements

The authors would like to thank all the participants, those with RTT and those who volunteered as controls, as well as theirfamilies and carers, for taking part in this study. Special thanks to Stig Hansen for describing the equipment, as well ashandling it during assessments, and to Flora Apartopoulos for support during assessments. We also acknowledge statisticianHans Stenlund for his advice on the statistics.

The study was supported by the Swedish Rett Center, Jamtland County Council and by grants from the SavstaholmFoundation and the Linnea and Josef Carlsson Foundation.

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