
==== Front
Eur J Phys Rehabil Med
Eur J Phys Rehabil Med
EJPRM
European Journal of Physical and Rehabilitation Medicine
1973-9087
1973-9095
Edizioni Minerva Medica

38197628
7625
10.23736/S1973-9087.23.07625-6
Article
Mirror visual feedback as therapeutic modality in unilateral upper extremity complex regional pain syndrome type I: randomized controlled trial
MACHAČ Stanislav 1 *
CHASÁKOVÁ Ludmila 1
KAKAWAND Soroush 2
KOZÁK Jiří 3
ŠTĚPÁNEK Lubomír 4 5
VEJVALKA Jan 6
KOLÁŘ Pavel 1
ČERNÝ Rudolf 7
1Department of Rehabilitation and Sports Medicine, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic; 2Department of Neurology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; 3Department of Pain Research and Treatment, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic; 4Institute of Biophysics and Informatics, First Faculty of Medicine, Charles University, Prague, Czech Republic; 5Department of Statistics and Probability, Faculty of Informatics and Statistics, Prague University of Economics and Business, Prague, Czech Republic; 6Department of Information Systems, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic; 7Department of Neurology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
* Corresponding author: Stanislav Machač, Department of Rehabilitation and Sports Medicine, Second Faculty of Medicine, Charles University and University Hospital Motol, V Úvalu 84, 150 06 Prague 5, Czech Republic. E-mail: stanislav.machac@lfmotol.cuni.cz
Authors’ contributions: Stanislav Machač: development of research plan, project coordination, data collection, literature search, manuscript writing; Ludmila Chasáková: development of research plan, manufacture of mirror boxes, collection of a significant part of the data within master thesis, literature search; Soroush Kakawand: proposing a research topic, help with study design, expert consultation in neuroscience, language proofreading, communication with the Journal Editor; Jiří Kozák: consultation in pain neuroscience, help with patient recruitment, text correction; Lubomír Štěpánek and Jan Vejvalka: statistical data processing, text correction; Pavel Kolář: specialist consultation; Rudolf Černý: development of research plan, supervision of the selection of examination methods, consultation in the field of neurology, patient recruitment, text correction. All authors read and approved the final version of the manuscript.

22 1 2024
4 2024
60 2 280291
21 11 2023
30 10 2023
28 6 2022
2023 THE AUTHORS
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (CC BY-NC-ND) 4.0 License.
BACKGROUND

There is growing evidence for the effectiveness of mirror therapy (MT) on pain reduction in patients with type I complex regional pain syndrome (CRPS I).

AIM

To evaluate the efficacy of MT on pain reduction and hand function in subjects with unilateral upper extremity CRPS I.

DESIGN

Randomized controlled trial with control group cross-over (half cross-over design).

SETTING

Subjects with CRPS I were outpatients of a university hospital and cooperating centers. All patients carried out the daily exercise at home.

POPULATION

Subjects with unilateral upper extremity CRPS I meeting the Budapest diagnostic criteria.

METHODS

Subjects were randomly divided into two groups. Group A (N.=13) carried out a ten-minute MT exercise daily, for a total duration of six weeks. Group B (N.=14) acted as a control group for six weeks followed by six weeks of MT with the same characteristics as Group A. Upper extremity active range of motion, strength, dexterity, limb volume, affected-to-unaffected hand temperature difference, and health-related quality of life were evaluated before and after each period. Daily records on the visual analogue scale were used for pain evaluation. Effectiveness was calculated using mixed-effects modelling for between-group comparisons and within-group variability, and identification of significant predictors.

RESULTS

Twenty-three females and four males with an average age of 56.1±9.6 years completed the study. Except for the affected-to-unaffected hand temperature difference, both groups consistently demonstrated significant or near-significant improvements in measured parameters after MT period. The improvements were evident upon an intergroup comparison of Group A and the control period of Group B as well as longitudinally within Group B. No significant improvement was found during the control period.

CONCLUSIONS

Principles focused on mirror visual feedback to the central nervous system can sustain promising therapeutic potential as part of the treatment for pain reduction and hand function in CRPS I patients.

CLINICAL REHABILITATION IMPACT

MT can be considered as part of the therapeutic regimen employed for the treatment of CRPS I.

Key words:

Complex regional pain syndromes
Mirror movement therapy
Feedback, sensory
Movement without help Foundation
==== Body
pmcComplex regional pain syndrome (CRPS) is a chronic pain condition primarily targeting one limb. Patients commonly report prolonged or excessive pain often described as burning or throbbing. Accompanying this pain, there can be notable changes in skin color, temperature, and texture. Additional manifestations include swelling, heightened sensitivity to touch, and motor dysfunctions such as muscle spasms, weakness, and decreased range of motion. These symptoms can pose significant challenges, often impairing the patient’s daily activities and overall quality of life. Since the diagnosis is clinical, the incidence varies widely from study to study and is estimated to be between five and 26 per 100,000 per year.1 Complex Regional Pain Syndrome type I (CRPS I) and type II exhibit the same symptoms. However, the distinguishing feature of type II is its association with a confirmed peripheral nerve injury.2 CRPS I represents the majority of CRPS. Pathogenesis of CRPS I typically involves an exaggerated inflammatory response following diverse injuries to the extremities.3 It can also develop following a central nervous system (CNS) lesion or as a response to any visceral trauma. The pain associated with CPRS is typically projected to deep tissue and is not referred to any particular dermatome.4 Other possible signs include swelling, changes to the skin colour, right-left limb temperature difference, altered diaphoresis and importantly altered motor functions such as loss of strength, decreased range of motion and tremor.5 During the acute stage of the CRPS I the affected limb is usually extremely painful, warm, red, swollen and mobility very limited as a result. During the chronic stage, the oedema is resolved and muscle atrophy often occurs.6 Pain is the cardinal symptom of CRPS I and is present in both stages. CRPS I is also associated with an increased risk of suicide,7 functional disability and increased long-term social and health care costs.

However, despite the associated burden on the quality of life, an effective therapy with strong supporting evidence lacks in this patient cohort according to the most recent Cochrane review.8 Treatment strategies including pharmacotherapy and physical therapy have traditionally focused on pain reduction in the affected limb at the peripheral level. However, the pathophysiology of CPRS I is yet to be fully elucidated and the clinical symptoms appear to be related to abnormalities at both PNS and CNS level.5, 9, 10 It was hypothesised that significant peripheral factor is sympathetic nervous system dysfunction. Other peripheral factors include altered cutaneous innervation, peripheral sensitisation, and exaggerated catecholamine responsiveness. Furthermore, a pro-inflammatory shift in the system of cytokines and neuropeptides is also usually present.5

There is growing evidence for functional abnormalities at CNS level in subjects with CRPS.11-18 Seifert et al. have proposed a disruption in endogenous pain modulation. Specifically a shift from inhibition to stimulation of peripheral nociceptive stimuli may possibly play a role in the experience of pain in this patient group.11 Important evidence for central changes includes functional reorganisation of the cortex and thalamus, which has been demonstrated by using PET and magnetoencephalography.15, 16 In the resting state, subjects with CRPS showed greater and more diffuse connections to various regions of the brain, mainly to the cingulate cortex, precuneus, thalamus and prefrontal cortex. It has also been proposed the higher activation of regions in the frontal area to be associated with more intense emotional processing in patients with CRPS. This notion highlights the importance of focusing therapeutic interventions on pain processing rather than on the sensory input.17 Furthermore, high rates of neglect-like symptoms in patients with CRPS I are also of important clinical significance.13, 19, 20 These findings indicate the need for CNS-focused therapeutic interventions as an important component of complex healthcare management for subjects with CRPS.

The principle of visual feedback may offer a potential therapeutic modality in patients with CPRS. The principles of visual feedback intervention utilise the superimposition of an image of the unaffected extremity onto the affected side using a mirror.21-23 It is believed that mirror therapy (MT) has the potential to correct an inter-sensory interaction between vision, tactile and proprioceptive stimuli. It can also recover so called “learned pain” and neglect-like symptoms.22, 24 MT was originally used in subjects after limb amputation suffering from phantom pain.25 Interestingly, typical phantom abnormal feelings have certain common attributes with the sensations described by individuals with CRPS, such as intractability, burning sensation, the presence of referred pain or vivid feeling of unnatural shape, size or limb position.22 Following the pioneering works of McCabe et al.,21 other studies have been carried out using MT in subjects with CRPS I.26-29 However, the majority of these studies were case reports or they have concentrated on a small number of subjects with an emphasis on the pain scoring. There is a need for thorough evaluation of the effects of MT on fine motor function, strength, and range of motion of the affected limb, its effects on inflammation, as well as health-related quality of life in subjects with CRPS I. The current study reports on the effects of MT on the above-mentioned modalities.

Materials and methods

Setting

Subjects with CRPS I were outpatients of University Hospital Motol and its cooperating centers. The first meeting and further evaluation took place at the University Hospital Motol. All patients carried out the daily exercise at home.

Study design

Following the confirmation of the diagnosis of CRPS I using the Budapest criteria, those not meeting this criteria were excluded from study. Subjects with unilateral upper extremity CRPS I were considered for participation in the study. Exclusion criteria:

failure to meet the diagnostic clinical criteria for CRPS I;30

previous use of MT prior to the commencement of this study;

substantial difficulties in cooperation;

a significant change to the subjects’ treatment regimen, outside of the study design.

The CONSORT Flow diagram is available as Supplementary Digital Material 1, Supplementary Figure 1. The project was approved by the Ethics Committee of University Hospital Motol with protocol number EK-1288/14 and was registered under ClinicalTrials.gov ID NCT06100107. Relevant informed consents were obtained.

The study employed a half cross-over design. Group A began with the intervention, while Group B started with a control period of equal length, followed by the MT intervention. This design facilitated comparisons both between the groups and also within Group B across the two periods. Two-sample t-tests were applied to the variables’ values for a pilot subselection of six individuals from the intervened and control groups before and after the MT. Assuming that point estimates of the variables’ differences before and after MT and the differences’ variances are constant even for large samples, that a minimal sufficient sample size was calculated for difference proof on a confidence level of 0.05. Depending on the outcome variable, it was clear that to achieve static significance in at least some of the variables evaluated, it was necessary to include at a minimum of 12 individuals who undergo the intervention period and 12 individuals who undergo the control period. An effort was made to recruit all available outpatients of the University Hospital and its collaborating centers who met the inclusion criteria to participate in the study.

All subjects were assigned randomly to two groups by a blinded researcher. This researcher, who conducted the randomization, had access only to anonymous demographic data, such as age and gender, without access to additional medical information. A formal randomization list was not established prior to study inclusion. The rationale for this randomization approach was to ensure a well-balanced distribution of age and gender between the two groups. Additionally, it was necessary to consider that three individuals would be unavailable for the entire 12-week study period, precluding their assignment to Group B. Subjects in Group A were given a mirror box (Figure 1) personally by a physiotherapist for home use and were asked to carry out a ten-minute exercise on a daily basis, for a total duration of six weeks.

Figure 1 —Mirror box.

The first meeting and further evaluation took place at the University Hospital. The duration and total period of MT were based on the pilot work of McCabe et al.21 The current study utilized a once daily MT exposure.

Group B acted as a control group for six weeks followed by six weeks of MT with the same characteristics as for group A. In order to avoid a nocebo effect during the control period, the subjects were not told that this period does not include the “treatment of interest”. This special study design allowed for between-group comparison (Group B’s control period vs. Group A) as well as longitudinal, within group comparison after switching the Group B to the MT, i.e. control period switched to MT intervention. The study design is shown in Figure 2.

Figure 2 —Study design (black line shows subjects’ participation in a given period).

All subjects in both groups were asked not to change their long-term ongoing medication and therapeutic regime and to report possible changes. Main components of their medication are listed in Supplementary Digital Material 2, Supplementary Table I.

The design of the study resulted in three sets of data which were subsequently analyzed:

1) Group A: the intervention period consisting of six weeks of MT without prior control period;

2) control period of Group B: acting as control period for group A;

3) intervention period of Group B: all participants in Group B who finished the control period switched into six weeks of MT intervention.

Intervention

All patients performed exercise training and in the presence of a physiotherapist at the visit immediately preceding the intervention period. The principle and purpose of the exercise was explained. The exercise included a combination of pronation, supination, clapping, opening and clenching the fist, finger walking, etc., depending on the ability and preferences of each subject. Importantly, the movements were made with the unaffected hand superimposed onto the affected hand by the mirror. The individuals were asked not to move with the affected hand for the first five minutes of MT while slight movements were allowed (but not requested) in the other five-minute interval. During the whole session, the subjects observed the hand reflection in the mirror with an assumption of a vivid illusion of affected hand movement. The subjects were asked to carry out a ten-minute exercise on a daily basis at home, for a total duration of six weeks.

Outcomes

The primary outcomes included the level of pain perception and hand function. Hand function was assessed using the following parameters: active range of motion, muscular strength, dexterity, hand and forearm volume combined, and the temperature difference between the right and left hand. Health-related quality of life was evaluated as a secondary outcome.

The participants in both groups made daily accounts of their pain level using 10 cm long numbered Visual Analog Scale (VAS) at rest as well as typical pain level during hand movement. Pain assessment was also performed as a follow-up 30 days after the MT period based on a telephone interview. For this purpose, a verbal numerical pain rating with a range of 1-10 was used.

The evaluation of hand function and health-related quality of life were conducted both immediately before and after each designated time period. These evaluations were performed by a researcher who was not blinded to the study’s details and were conducted at the University Hospital, with each assessment taking approximately 30 minutes. These measurements resulted in two and three separate assessments in Group A and in Group B, respectively.

Active Range of Motion was evaluated, rather than a passive range of motion, which could be painful and can exaggerate CRPS symptoms. Three attributes were measured: maximal active range of wrist flexion and extension (°) determined with goniometer measuring the angle between forearm and metacarpal bones, and minimal distance (cm) between fingertip and palm while actively trying to clench the fist (FP distance). The strength of the hand grip was determined with a balloon dynamometer (Riester Dynatest, Germany). The outcome parameter is the highest pressure (bar) performed during one maximal grip. Dexterity was evaluated by using a nine-hole PegBoard.31, 32 The subjects were asked to put all nine pegs into the board holes as quickly as possible. The time taken to complete this task was measured. The times for affected and unaffected hand were measured separately. The combined volume of hand and forearm was evaluated due to frequent oedema or possible muscle atrophy in subjects with CRPS I. The volumetric measurement was based on the principle of water displacement.33 All the above-described measurements were evaluated bilaterally with respect to the affected vs. unaffected extremity. Temperature was measured bilaterally in the thenar area using an infrared thermometer (Tecnimed Thermofocus, Italy). Temperature measurements were taken just before determination of extremity volume to minimise the effects of water temperature influence.

Health-related Quality of Life was determined using second part of the EQ-5D-3L questionnaire.34 The second part of the questionnaire is a visual analog scale from 0% to 100%, where 0% is the lowest and 100% is the highest possible quality of life as experienced by the subject.

Statistical analysis

A number of the measured variables were preprocessed before the analysis in order to ensure these variables would follow normal distribution and to make comparability of the variables easier. Values of the measured variables such as dexterity, strength, palmar and dorsal wrist flexion of the affected side (numerator) were divided by corresponding values of the healthy side (denominator). Subsequently, the results were converted to a percentage (%). In the case of temperature difference, the variable was calculated in terms of the absolute magnitude of the temperature difference between the affected and healthy side (°C). The FP distance variable was considered without its right-left comparison because this distance is physiologically 0 cm, which was checked on the healthy side.

The categorical independent variables were: group affiliation, evaluation before and after each period, duration of CRPS I since diagnosis, age and dominance of the affected hand.

The dependent variables were: pain levels, palmar and dorsal wrist flexion, strength, dexterity, absolute volume difference, absolute temperature difference, and quality of life

The mean values of dependent variables as well as the combinations of categorical independent variables are reported as 95% confidence intervals (CI) of the means. A mixed effects model that treats the assigning of subjects into groups as a random factor and the rest of variables as fixed factors was used to evaluate whether there were statistically significant differences between the mean values of the variables in both Group A and Group B. This was performed both at the beginning and at the end of each period. This approach allows the identification of independent, statistically significant predictors associated with a mean change of the dependent variables.

Histograms and residual plots were used in order to check the validity of the linear models. All statistical analyses were performed using R language for statistical computing and graphics.35

Results

Thirty subjects with unilateral upper extremity CRPS I were initially randomized for the study. However, two subjects declined participation after being randomized. So a total of 28 subjects started the study. All eligible subjects available at the time of the study were included, resulting in 4 more subjects (approximately 15%) than the minimal sample size determined as necessary from the pilot study. Fourteen subjects were initially enrolled in Group A. However, one subject was excluded during the study due to substantial cooperation difficulties, resulting in 13 subjects in Group A who completed the study. In Group B, initially, fourteen subjects served as controls for six weeks before crossing over to a six-week MT intervention. The characteristics of the subjects are shown in Table I.

Table I —Subject characteristics.

Group A	
Subject N.		Affected Hand	Age (years)	CRPS duration (months)	Onset	
1	♀	Dx	Dom	55	144†	Elbow fracture	
2	♀	Sin	Non-dom	57	2	Distal radius fracture	
3	♀	Sin	Non-dom	65	6	Distal radius fracture	
4	♀	Dx	Dom	42	2.5	Distal radius fracture	
5	♀	Sin	Non-dom	57	24	Digitus saltans surgery	
6	♀	Sin	Non-dom	61	1	Wrist fracture	
7	♀	Dx	Dom	62	2.5	Distal radius fracture	
8	♀	Sin	Dom	56	3	Wrist fracture	
9	♂	Sin	Non-dom	31	3	Metacarpal fracture	
10	♀	Dx	Dom	54	2	Distal radius fracture	
11	♀	Dx	Dom	70	5	NA	
12	♀	Sin	Non-dom	66	1.5	Distal radius fracture	
13	♀	Sin	Non-dom	65	12	Proximal humerus fracture	
Mean±SD				57.0±10.1	16.4±37.4		
Median				57	3.0		
Group B	
Subject N.		Affected Hand	Age (years)	CRPS duration (months)	Onset	
14	♂	Dx	Dom	50	120†	Chest contusion	
15	♂	Dx	Dom	40	120†	Wrist contusion	
16	♀	Sin	Non-dom	60	1.5	Digitus saltans surgery	
17	♀	Dx	Dom	63	1	Distal radius fracture	
18	♀	Sin	Non-dom	66	3	Distal radius fracture	
19	♀	Sin	Dom	55	96	NA	
20	♀	Dx	Dom	53	36	Cervical spine surgery	
21	♀	Dx	Dom	56	4	MC joint luxation	
22	♀	Dx	Dom	58	3.5	Distal radius fracture	
23	♂	Dx	Dom	60	3	Distal radius fracture	
24	♀	Sin	Non-dom	37	2	Distal radius+ulna fracture	
25	♀	Sin	Non-dom	45	1.5	Distal radius fracture	
26	♀	Sin	Dom	66	4	Bitten by a dog	
27	♀	Sin	Non-dom	65	3	Distal radius fracture	
Mean±SD				55.3±9.0	28.5±44.8		
Median				57	3.3		
Dx: dexter (right); sin: sinister (left); dom: dominant; non-dom: non-dominant; NA: not available. †Three subjects reported “10 or 12 years of the symptoms duration”.

Figure 3, 4 show the resting pain rate from day to day during the control period and during the intervention period, respectively.

Figure 3 —Level of rest pain in the control period (Group B).

Figure 4 —Level of rest pain in the intervention period (Group A + Group B).

Table II shows mean values of pain and Table III provides mean values of the other monitored variables as measured at the defined evaluation points during the whole study design. Monitored variables other than pain are expressed as percent values relative to the contralateral, i.e. healthy, upper limb. No significant differences were observed between mean values of the variables before and after the control period. On the other hand, there were significant or near-significant differences between mean values before and after the MT intervention period (with an exception for absolute temperature differences).

Table II —95% confidence intervals of pain evaluation at rest or at motion during MT.

Pain evaluation	95% CI	
Group A	Group B	
Day 1	Day 42	Day 72	Day “-42”	Day 1	Day 42	Day 72	
At rest	4.1 (2.9; 5.3)	1.2 (0.4; 2.1)	0.9 (0.1; 1.6)	4.4 (3.4; 5.4)	3.6 (2.6; 4.5)	2.3 (1.2; 3.3)	2.6 (1.6; 3.6)	
At motion	5.9 (5.0; 6.7)	2.3 (1.0; 3.6)	2.0 (0.7; 3.4)	6.7 (5.6; 7.8)	5.6 (4.2; 6.9)	3.3 (1.7; 4.9)	4.0 (3.1; 4.9)	
CI: confidence intervals. Day 1 stands for the first and day 42 for the last day of the mirror therapy; day 72 stands for one-month follow-up; day “-42” stands for the first day of control period preceding the mirror therapy.

Table III —95% confidence intervals of independent variable means.

Independent variable [units]	95% CI	
Group A before 6 weeks of MT	Group A after 6 weeks of MT	Group B before control period	Group B before 6 weeks of MT	Group B after 6 weeks of MT	
Palmar wrist flexion (% of healthy side)	37.7 (18.5; 56.9)	71.9 (53.6; 90.3)	47.1 (30.7; 63.6)	49.0 (31.5; 66.6)	60.5 (44.9; 76.2)	
Dorsal wrist flexion (% of healthy side)	52.6 (32.3; 72.9)	76.6 (59.3; 93.9)	48.2 (34.2; 62.1)	49.5 (35.7; 63.3)	80.5 (64.5; 96.6)	
Dactylion-palm distance (cm)	4.9 (3.6; 6.3)	1.2 (0.1; 2.3)	3.9 (2.2; 5.6)	3.9 (2.3; 5.5)	2.2 (0.5; 3.9)	
Strength (% of healthy side)	18.7 (4.0; 33.4)	46.9 (31.1; 62.6)	32.5 (20.7; 44.3)	35.2 (23.4; 47.1)	65.1 (54.7; 75.4)	
Dexterity (% of healthy side)	129.4 (109.9; 148.8)	105.2 (93.6; 116.8)	138.0 (100.3; 175.6)	129.5 (110.3; 148.7)	116.5 (104.9; 128.0)	
Volume difference (% of healthy side)	11.6 (5.4; 17.9)	2.7 (1.3; 4.1)	9.1 (4.6; 13.7)	10.2 (5.2; 15.2)	6.4 (3.4; 9.3)	
Temperature difference (°C)	0.8 (0.4; 1.2)	0.4 (0.2; 0.5)	0.6 (0.3; 0.9)	0.5 (0.3; 0.7)	0.6 (0.3; 0.9)	
Quality of life (%)	66.8 (58.2; 75.4)	79.2 (68.0; 90.4)	61.1 (51.9; 70.2)	61.1 (53.1; 69.0)	75.0 (65.5; 84.5)	
CI: confidence intervals.

MT effectiveness

Mixed effect model

Table IV and Supplementary Digital Material 3, Supplementary Table II demonstrate the mixed effects model which illustrates individual (fixed) effects of both continuous and categorical predictors.

Table IV —Multiple predictors associated with pain.

		Rest	Motion	
Estimate	P value	Estimate	P value	
Fixed effects	(Intercept)	1.33	<0.001	0.96	0.001	
Day	-0.01	0.004	-0.03	<0.001	
Group=“intervention”	-0.95	<0.001	-1.68	<0.001	
Dominance=“dominant”	0.96	<0.001	-0.01	0.951	
Age	0.05	<0.001	0.10	<0.001	
Duration	<0.01	0.037	0.01	<0.001	
Day: Group=intervention	-0.03*	<0.001*	-0.03*	<0.001*	
Random effects	SD of Intercept	1.44		1.63		
SD of Day	2.93		2.28		
SD of residuals	1.44		1.63		
Mixed effects model of different levels of multiple predictors associated with pain at rest or motion. Positive values of estimators stand for levels of predictors associated with increased value of a dependent variable of interest, negative estimators stand for levels of predictors associated with decreased value of a dependent variable of interest. The crucial variable for assessing the effect of MT intervention is Day: Group=”intervention,” which is therefore marked with *. SD: standard deviation.

In the current study, the interaction term of Group=“intervention” & Time = “after” illustrates the effect after MT period, acting as a statistically significant predictor for improvements in pain, dorsal wrist flexion, FP distance, grip strength, and quality of life. Assuming also random effects, i. e. individually unique intercepts and slopes of the interaction term for each individual, there can be seen that standard deviations of the random effects are usually much lower than point estimates of the corresponding interecepts.

In the evaluation of the pain score most predictors are significantly associated with the reduction of pain variable, confirming the beneficial effect of MT. Based on the observation presented in Table IV, it is noted that the pain level increases with age and the duration of CRPS. Most importantly, pain relief was associated with the number of days which the MT intervention was carried out (see Day: Group=“intervention”). There is an association between the number of days subjects underwent MT and the reduction in their respective pain levels which was statistically significant. As a result of this, subjects who underwent MT experienced reduced pain levels compared to the controls. This effect is evident in the pain score associated with rest as well as with limb movement. A follow-up telephone interview conducted 30 days after the end of the interval confirmed the long-term effects of MT on pain reduction. Three subjects in Group B did not complete pain diaries, so the missing pain data were not included in the statistical analysis.

After undergoing MT, subjects demonstrated improved palmar and dorsal wrist flexion by 20.5% and 26.3% with respective to unaffected side flexion range, but only dorsal wrist flexion had a statistically significant gain (P=0.16; P=0.02). Functional ROM (FP distance) also improved after MT, demonstrating a mean decrease of 2.6 cm (P=0.04). As demonstrated in Supplementary Table II, subjects who underwent MT showed an average of 25.5% increase in the strength of the affected hand as compared with the healthy hand, P=0.02 (Figure 5).

Figure 5 —Hand grip strength level.

The time required to complete the PegBoard task as a measure of dexterity was reduced by 10.1% compared to the values of the unaffected side after the MT period. Although this reduction did not achieve statistical significance (P=0.59), it may still be of clinical relevance. Furthermore, a near-significant reduction of 7.3% was observed in the affected-to-unaffected hand volume difference following MT when compared to the control group, P=0.056. No significant association was noted with respect to the temperature difference in the affected hand compared to the unaffected hand in both the intervention and control groups. Most importantly, participants reported an increase of 13.3% in their quality of life after using MT (P=0.04) (Figure 6).

Figure 6 —Level of quality of life.

Influence of affected hand dominance, age, and CRPS I duration on the monitored variables

It was determined that age, hand dominance and duration of CPRS had the most influence on the level of pain and the quality of life. Using mixed effects models, certain associations can be identified. In other words, these categorical variables can help to predict values of dependent variables if the other input variables were fixed (“ceteris paribus”).

For example the strength of the affected hand is significantly higher if the lesion is on the dominant side, P=0.025, especially if the person had already completed the MT. On the other hand, strength is inversely proportional to age, P=0.017, and duration of CRPS, P=0.003 (see Supplementary Digital Material 3: Supplementary Table II).

Dominance of the affected hand, age or CRPS I duration as predictors of the MT effectiveness?

The influence of the three potential predictors (dominance of the affected hand, age and CRPS I duration) on the MT’s effectiveness is difficult to analyze properly due to the high amount of potential interactions between input variables. Indicative analysis of these predictors of the MT’s effectiveness as expressed by Cohen’s d values are shown in Table V and Table VI.

Table V —Cohen’s d for pain evaluation at rest and at motion.

Predictor	Level of predictor	Pain at rest	Pain at motion	
Dominance	Dominant	-1.21	-1.01	
Nondominant	-1.28	-2.06	
Age	≥60 years	-2.08	-2.26	
<60 years	-0.65	-0.93	
Duration	≥12 months	-0.32	-0.39	
<12 months	-1.67	-2.17	
Each Cohen’s d coefficient was calculated as a difference between “after therapy” and “before therapy” average value of a dependent variable in each of subgroups defined by cut offs, and divided by a pooled standard deviation. The cut off are displayed in the rows.

Table VI —Cohen’s d for independent variables.

Predictor	Level of predictor	Palmar wrist flexion	Dorsal wrist flexion	Dactylion-palm distance	Strength	Dexterity	Volume difference	Temperature difference	Quality of life	
Dominance	Dominant	0.84	0.98	-0.73	1.08	-1.03	-1.07	-0.37	0.54	
Nondominant	0.52	0.86	-1.37	1.67	-0.46	-0.48	-0.34	1.76	
Age	≥60 years	0.93	1.09	-1.28	1.41	-0.77	-0.93	-0.52	1.23	
<60 years	0.48	0.77	-0.77	0.97	-0.53	-0.75	-0.21	0.50	
Duration	≥12 months	0.10	0.47	-0.16	0.88	0.37	-0.21	0.37	0.05	
<12 months	0.94	1.21	-1.51	1.22	-0.84	-1.02	-0.61	1.27	
Each Cohen’s d coefficient was calculated as a difference between “after therapy” and “before therapy” average value of a dependent variable in each of subgroups defined by cut offs, and divided by a pooled standard deviation. The cut off are displayed in the rows.

Six subgroups were created according to the dominance of the affected hand, age or CRPS I duration. It is noted that MT has an overall beneficial impact on most of the monitored variables in persons with chronic CRPS I (duration ≥12 months). There was also no significant difference in the quality of life in the same subject group (Table VI).

Side effects

There were no side effects reported.

Discussion

The 2016 Cochrane review identified graded motor imagery (GMI) and MT as the most promising strategies for reducing the pain and disability associated with CRPS I after traumatic events, surgery or a stroke.36 The concept of Graded Motor imagery assumes a cumulative therapeutic effect if the therapeutic process sequentially includes: 1) Laterality training with right-left discrimination to correct the cortical representation of the body schema, 2) imagined hand movements; and lastly 3) MT.37 Nevertheless, no effect was seen for laterality training with right-left discrimination, and conflicting results were found for motor imagery used as stand-alone techniques, but positive effects were observed for both MT and the whole GMI.38 Therefore, it can be assumed that MT also plays a crucial role in GMI. In the present study, it is shown that MT has a positive effect not only on the pain score as reported in previous studies21, 26-29 but also on measurable parameters of upper extremity function and quality of life in subjects with CRPS I.

MT effect on pain

The effects of MT on pain reduction in subjects with CPRS I reported in this paper is in line with previous reports on the effects of MT on pain modulation.21, 26-29 The number of days patients receiving MT was a significant predictor for the amount of pain relief, P<0.001. A follow-up with patients in the study, confirmed long-term effects of MT on pain reduction.

We hypothesize that the reduction of pain can possibly be due to the elimination of neglect-like symptoms. Since it was described that neglect-like dysfunction in persons with CRPS can be present before the onset of pain complaints,24 it is possible that the restoration of somatosensory CNS functions may contribute to the therapeutic effects of MT on the primary pathology. The present study noted beneficial improvement in pain reduction in subjects with long-standing CPRS as opposed the proposals by McCabe et al. The proposed reason for the low effectiveness of MT in subjects with long-lasting CRPS was chronic dystrophy of the affected limb and substantial loss of neuroplasticity potential.21 Nevertheless, the observation provided in the current study seems to be promising also for subjects with long-lasting CRPS I. After MT intervention, one such subject for instance described significantly lower analgesic consumption, enhanced sleep, higher stability of hand vasomotor changes and greater pain-free wrist movement.

In line with the study by McCabe et al.,21 participants in the current study typically experienced the most distinctive changes two weeks following the initiation of MT. The subjects commonly described their hand having “started to behave differently” with respect to perception of pain (reduced pain sensation), touch tolerance and vasomotor changes. We hypothesize that neuroplastic changes manifest soon after the initiation of MT, with its greatest impact on pain modulation in the first two weeks as shown in Figure 4. Interestingly, this effect on pain reduction slightly plateaus during the third- and fourth-week following MT initiation. This plateau is followed by a further reduction in pain intensity as the MT continues in the fifth and sixth week. This observation signifies the need to continue MT despite an eventual lack of efficacy during the initial phases of MT initiation.

MT effect on hand function

There are insufficient studies addressing MT’s effects on upper limb function and they have mainly focused on post-stroke subjects.26, 39

The present study clearly demonstrated improvements in functional parameters after MT including active range of motion, strength, and hand volume. We propose that these functional attributes were mainly improved as a result of central pain reduction and correction of neglect-like symptoms. There is higher prevalence of neglect-like symptoms in subjects with CRPS I, than in other chronic pain conditions affecting upper extremity.14 These symptoms are believed to be mainly a result of limb disuse for prolonged periods of time.13 It has been reported that symptoms of distorted body image can precede pain in subjects with CRPS I, which indicates that the disturbance of somatomotor circuits may be the primary contributor to this syndrome, and pain, a consequence of this disturbance.24

There are further reports that have suggested a correlation with distorted self-perception of the hand and the development of symptoms of CRPS I and the sensation of foreignness which can contribute to distorted body image.40 Further support for this hypothesis is provided by Juottonen et al. which postulates a correlation between a foreign feeling and the pain intensity which is independent of the affected side.15 Inability to identify correct fingers upon tactile stimulation in the affected patients raises the possibility of a correlation between finger agnosia and CRPS I. Finger agnosia in Gertsmann syndrome is the result of a lesion in the dominant hemisphere, and the finger agnosia reported in CRPS patients has no correlation with hand dominance.40 Juottonen et al. reports that the alterations in cortical representation of the hand in the primary sensory cortex, contributes to this clinical finding.15

It has been hypothesised that subjects with CRPS can mimic the same pathological processes of sensorimotor function, as in patients following limb amputation. Functional cortical reorganisation has been shown to be present in subjects with CRPS by positron emission tomography scan.15, 16 A distorted representation of the limb in the cortex has been proposed as causing discrepancies between motor intention, proprioception, and vision. This distortion, in turn, can be perceived as pain.41 Pain level, active range of motion, strength, and side-to-side volume difference showed significant or near-significatnt improvements following MT intervention. A 10.1% reduction in time on the PegBoard task toward unaffected side values as a dexterity evaluation can be considered clinically significant even though it did not reach statistical significance. The statistical insignificance for dexterity was affected by a worse outcome in the chronic subjects, while the beneficial effect was strong in the others (Table VI). Nevertheless, all the changes enable more frequent usage of the hand followed by beneficial trophic changes. No significant difference in temperature was noted to be present between the affected limb pre and post treatment possibly due to a relatively low average right-to-left temperature difference (<1 °C) prior to the MT intervention. The infrared thermometer may have been insufficient to capture minute differences.

MT effect on quality of life

Improved quality of life as a result of pain relief as well as improved functionality is one of the primary goals of MT intervention. To our knowledge, there are no published studies assessing the effects of MT on the enhancement in quality of life. This study demonstrated that pain reduction and improvement in hand function were in line with a positive impact on the subjects’ quality of life. It is hypothesized that prior psychological influences may also play a role in the development of CPRS I. This is in line with clinical observations and is supported by prospective studies by Bean et al.42 The study suggests that anxiety, pain-related fear, and disability are associated with adverse outcomes.

Predictors of MT effectiveness

It remains inconclusive if MT has a more significant effect in patients with the dominant hand affected or in those with the involvement of their non-dominant hand. Indicative analysis showed that MT was more effective in subjects older than 60 years, as shown in Table V. However, this simplistic analysis, based on cut-off groups, was influenced by a higher number of chronic subjects in the younger group. The most significant predictor of the effectiveness of MT was, however, the duration of CRPS I since diagnosis. Despite of that, some improvements were also observed in patients with chronic CRPS I (duration over 12 months). This observation provides a more optimistic outlook for these long term patients than that proposed by McCabe.21 Interestingly, these improvements in the subgroup with chronic CRPS I were associated with only a small change in the quality of life. We propose this is possibly influenced by changes in the psychological domain associated with long standing CRPS. This notion necessitates psychological support and assessment as part of the complex treatment strategy, as well as the importance of early initiation of MT in newly diagnosed cases.

Treatment costs

It must be emphasized that the beneficial changes described in the current study were achieved using a low cost methods. This is in sharp contrast to currently employed treatment strategies in the management of CPRS patients which include a combination pharmacotherapy, multimodal physiotherapy, electrotherapy and manual lymphatic drainage, which are usually associated with a much higher financial burden and with an uncertain therapeutic efficacy.8, 36

Limitations of the study

The limitations of the current study are non-blinded evaluators, limited placebo options and relatively small sample size. Further consideration must also be given to the fact that these interventions were on a home-based regime where full control over the MT frequency and duration could not be monitored. The allocation method, conducted by a blinded researcher based on age and gender without additional medical information, posed also a limitation. Moreover, three participants were unavailable for the entire 12-week study, impacting group assignment into Group A.

Nevertheless, at the same time, the specific study design (Randomized Controlled Trial with Control Group Cross-Over), where the original control group changed the regimen to the intervention group after six weeks, is robust to possible moderate discrepancies in randomization.

Conclusions

Principles focused on neural feedback to CNS, including MT, can sustain promising therapeutic potential in individuals with CRPS I. Certain beneficial effects can also be applicable to those patients with long-standing CRPS I. The current study provides a new quality of evidence for MT’s effectiveness not only in pain reduction but also in hand function restoration and improvements in the quality of life of patients with CRPS I, with minimal financial costs.

Supplementary Digital Material 1

Supplementary Text File 1

CONSORT 2010 Flow Diagram

Supplementary Digital Material 2

Supplementary Table I

Pharmacotherapy.

Supplementary Digital Material 3

Supplementary Table III

Mixed effects model of different levels of multiple predictors associated with the dependent variables of interest. Positive values of estimators stand for levels of predictors associated with increased value of a dependent variable of interest, negative estimators stand for levels of predictors associated with decreased value of a dependent variable of interest. the interaction term of (Group = “intervention” & Time = “after”) illustrates the effect of MT, acting as statistically significant predictor for improvements in dorsal wrist flexion, FP distance, grip strength, and quality of life. The crucial variable for assessing the effect of MT intervention is Day : Group = "intervention", which is therefore highlighted in bold. SD = standard deviation.

Conflicts of interest: The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.

Funding: The authors would like to thank the Movement without help Foundation for supporting this publication.

Congresses: Part of this research was presented as a poster at the 75th Annual Meeting of the American Academy of Neurology, under number P9-6.001, in Boston, MA, USA, on April 22-27, 2023.
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