Edited by: Ossama Yassin Mansour, Freiburg University Hospital, Germany
Reviewed by: Yi Pan, Saint Louis University, USA; Edgard Pereira, JFK Medical Center, USA
Specialty section: This article was submitted to Endovascular and Interventional Neurology, a section of the journal Frontiers in Neurology
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Achieving perceptual gains in healthy individuals or facilitating rehabilitation in patients is generally considered to require intense training to engage neuronal plasticity mechanisms. Recent work, however, suggested that beneficial outcome similar to training can be effectively acquired by a complementary approach in which the learning occurs in response to mere exposure to repetitive sensory stimulation (rSS). For example, high-frequency repetitive sensory stimulation (HF-rSS) enhances tactile performance and induces cortical reorganization in healthy subjects and patients after stroke. Patients with complex regional pain syndrome (CRPS) show impaired tactile performance associated with shrinkage of cortical maps. We here investigated the feasibility and efficacy of HF-rSS, and low-frequency rSS (LF-rSS) to enhance tactile performance and reduce pain intensity in 20 patients with CRPS type I. Intermittent high- or low-frequency electrical stimuli were applied for 45 min/day to all fingertips of the affected hand for 5 days. Main outcome measures were spatial two-point-discrimination thresholds and mechanical detection thresholds measured on the tip of the index finger bilaterally. Secondary endpoint was current pain intensity. All measures were assessed before and on day 5 after the last stimulation session. HF-rSS applied in 16 patients improved tactile discrimination on the affected hand significantly without changes contralaterally. Current pain intensity remained unchanged on average, but decreased in four patients by ≥30%. This limited pain relief might be due to the short stimulation period of 5 days only. In contrast, after LF-rSS, tactile discrimination was impaired in all four patients, while detection thresholds and pain were not affected. Our data suggest that HF-rSS could be used as a novel approach in CRPS treatment to improve sensory loss. Longer treatment periods might be required to induce consistent pain relief.
The complex regional pain syndrome (CRPS) is a chronic pain syndrome, which is characterized by sensory, autonomic, and motor disturbances (
Changes of tactile abilities can be reliably induced not only by training and practice but also by brief, training-independent sensory learning through repetitive somatosensory stimulation (rSS) (
A recent investigation demonstrated enhanced cortical excitability of the somatosensory and motor cortex in patients with CPRS (
We therefore here explored the feasibility and efficacy of both a high-frequency rSS (HF-rSS) and a low-frequency rSS (LF-rSS) protocol over 45 min on five consecutive days to all fingertips of the affected hand in patients with CRPS. Primary outcome criteria were the two-point-discrimination (2PD) threshold and the mechanical detection threshold (MDT) of the index finger as measures of tactile performance. As additional secondary endpoint the potential impact on the current pain intensity was investigated.
The study was approved by the Ethics Committee of the Ruhr-University Bochum, Germany (4236-12) and was performed in accordance with the Declaration of Helsinki from October 2008. All patients gave their written informed consent. A total of 26 consecutive in-patients of the Department of Pain Medicine of the University Hospital Bergmannsheil Bochum who fulfilled the Budapest diagnostic criteria for CRPS (
A total of six patients were excluded (CRPS II:
Patient | Age (years) | Gender | Handedness | Affected hand | Inciting event | With/without surgery before onset | Disease duration (months) | Positive scintigraphy | Finger-palm-distance (cm) | Current pain |
Average pain (last 4 weeks) |
Sensory signs | Vasomotor signs | Sudormotor signs/edema | Motor/trophic signs | Current medication |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | 49 | F | R | R | Fract. | − | 9 | + | 3 | 7 | 7 | + | + | + | + | Metamizol, AC, TCA |
2 | 46 | M | R | R | Fract. | + | 5 | + | 0 | 0 | 7 | + | + | + | + | Metamizol |
3 | 57 | F | R | L | Surg. | + | 12 | + | 0 | 5 | 6 | + | − | + | + | Metamizol, AC |
4 |
28 | F | R | L | Trau. | + | 4 | n/a | 11 | 3 | 5 | + | + | − | + | Metamizol, AC, Opioids-III |
5 | 59 | F | R | R | Trau. | + | 6 | + | 4 | 3 | − | + | − | − | + | Opioids-II, NSAID |
6 | 70 | F | R | R | Surg. | + | 11 | + | 5 | 3 | 4 | + | + | + | + | Paracetamol |
7 | 58 | F | R | L | Fract. | − | 12 | n/s | 5 | 5 | 5 | + | − | − | + | Metamizol |
8 | 58 | M | R | L | Surg. | + | 4 | + | 4 | 1 | 6 | + | − | + | + | Metamizol, AC, Opioids-III, NSAID |
9 | 60 | F | R | L | Fract. | + | 2 | + | 5 | 1 | 10 | + | + | + | + | Metamizol, NSAID |
10 |
60 | F | R | R | Fract. | + | 15 | + | 4 | 4 | 6 | + | + | + | + | AC, Opioids-III |
11 | 63 | F | R | L | Fract. | − | 5 | + | 3.5 | 7 | 8 | + | − | + | + | Metamizol, SNRI |
12 | 52 | M | R | R | Fract. | − | 14 | n/s | 2.5 | 6 | 3 | + | + | + | + | NSAID |
13 | 52 | M | R | L | Fract. | + | 27 | + | 11 | 5 | 5 | + | + | + | + | Metamizol, AC, Flupirtin |
14 | 51 | M | R | L | Fract. | − | 4 | + | 6 | 3 | 4 | + | + | + | + | NSAID, TCA |
15 | 60 | M | R | R | Fract. | + | 8 | + | 2 | 2 | 9 | + | + | + | + | Metamizol, AC |
16 |
41 | M | R | R | Trau. | + | 5 | + | 2 | 2 | 2 | + | − | + | + | Metamizol |
17 | 71 | M | R | L | Fract. | + | 6 | + | 6 | 6 | 6 | + | + | + | + | AC, Opioids-III, NSAID |
18 | 53 | M | R | L | Fract. | − | 12 | + | 1 | 4 | 5 | + | − | + | + | Opioids-II, NSAID |
19 | 58 | F | R | R | Surg. | + | 9 | − | 3 | 3 | 7 | + | − | + | + | AC, Opioids-III, NSAID, Flupirtin |
20 | 58 | M | L | L | Fract. | + | 4 | + | 3 | 0 | 5 | + | + | + | + | NSAID |
In this non-randomized open pilot study, 16 of the 20 CRPS patients were stimulated with high-frequency electrical pulses (HF-rSS). The application of the LF-rSS protocol was terminated after four patients, as impairment of the primary outcome parameter (2PD) was observed.
Two-point-discrimination threshold (2PDTH) as primary outcome measure and additionally MDT as a second component of tactile performance as well as current pain intensity were assessed immediately before the start of the intervention and 1–4 h after the termination of the last rSS application.
Repetitive sensory stimulation was applied on five consecutive days. Each single session lasted 45 min. Electrical stimuli were generated by a two-channel stimulation-device (ELPHA II 3000, danmeter, Denmark) and were conveyed to the fingertips of all fingers of the affected hand by a custom-made hand pad. In case of one patient (patient 4, Table
Tactile 2PD of the index finger of the affected and unaffected hand was assessed using a method of constant stimuli, as described previously (
The MDT was assessed bilaterally on the palmar tip of the index finger using a standardized set of modified von Frey filaments (VF1 OptiHair2, Marstocknervtest, Marburg, Germany) exerting forces between 0.25 and 512 mN in five ascending and descending stimulus intensities. The final threshold was calculated as the geometric mean of the resulting five suprathreshold and five subthreshold values.
Patients were asked to rate their current pain intensity at rest on an 11-point numerical rating scale (NRS 0–10), with NRS = 0 meaning no pain and NRS = 10 meaning the worst pain imaginable.
All data are expressed as mean ± SEM. In case of the calculation of the mean current pain intensity, the data of patients who rated 0 for no pain (
Before treatment, the mean 2PDTH of the index finger of the affected hand was significantly higher than on the non-affected hand (3.52 ± 0.25 vs. 2.59 ± 0.21 mm,
Before the intervention, the mean MDT of the affected hand was higher than on the non-affected hand (2.26 ± 0.63 vs. 1.59 ± 0.43 mN,
The mean level of current pain at rest before the start of the treatment was 3.8 ± 0.49. The mean pain intensity after 5 days of stimulation was 3.4 ± 0.52. Differences in pain intensity before and after the intervention were not statistically significant. However, four patients showed a reduction in pain of at least 30% (Table
Two-point-discrimination threshold before and after the intervention, MDT before and after the intervention, as well as current pain intensity before and after the intervention were significantly correlated (2PDTH:
Parameter | Disease duration | 2PDTH affected hand, pre | 2PDTH affected hand, post | Δ 2PDTH affected hand | MDT affected hand, pre | MDT affected hand, post | Δ MDT affected hand | Current pain, pre | Current pain, post | Δ current pain |
---|---|---|---|---|---|---|---|---|---|---|
Disease duration | 0.219 | −0.146 | −0.512 | −0.086 | 0.477 | 0.733 | 0.463 | 0.429 | −0.028 | |
2PDTH affected hand, pre | 0.219 | 0.840 | 0.082 | −0.161 | 0.224 | 0.465 | 0.276 | −0.065 | −0.323 | |
2PDTH affected hand, post | −0.146 | 0.597 | 0.133 | 0.214 | 0.048 | 0.203 | −0.091 | −0.263 | ||
Δ 2PDTH affected hand | −0.512 | 0.082 | 0.597 | 0.558 | 0.182 | −0.505 | 0.009 | −0.027 | −0.010 | |
MDT affected hand, pre | −0.086 | −0.161 | 0.133 | 0.558 | 0.695 | −0.257 | 0.118 | −0.112 | −0.373 | |
MDT affected hand, post | 0.477 | 0.224 | 0.214 | 0.182 | 0.439 | 0.326 | −0.031 | −0.513 | ||
Δ MDT affected hand | 0.026 | 0.465 | 0.048 | −0.505 | −0.257 | 0.439 | 0.147 | 0.106 | −0.077 | |
Current pain, pre | 0.463 | 0.276 | 0.203 | 0.009 | 0.118 | 0.326 | 0.147 | 0.653 | −0.307 | |
Current pain, post | 0.429 | −0.065 | −0.091 | −0.027 | −0.112 | −0.031 | 0.106 | −0.495 | ||
Δ Current pain | −0.028 | −0.323 | −0.263 | −0.010 | −0.373 | −0.513 | −0.077 | −0.307 | 0.495 |
After 5 days of LF-rSS, performance in 2PD on the affected hand was impaired in all four patients (Figure
After application of HF-rSS to the affected hand of CRPS patients on five consecutive days, performance in 2PD and mechanical detection significantly improved on the affected hand. The average gain in performance was about 10% for the 2PDTH and about 28% for the MDT. The mean current pain intensity was not reduced after HF-rSS, although individual patients showed a pain relief of 30% or more. The few patients receiving LF-rSS showed further deteriorated 2PD on the affected hand.
Following HF-rSS, tactile acuity as measured by 2PD was significantly improved on the affected hand with an average gain in performance of about 10%. In other studies applying HF-rSS in healthy subjects, the gain in tactile acuity was in the range of approximately 10–20%, depending on whether one single digit or all digits of the hand were stimulated and whether HFS-rSS was applied for one single session or for longer periods (
In all of the four patients stimulated with LF-rSS, impaired 2PD performance was detected. This is in line with findings in healthy individuals after LF-rSS (
From imaging as well as from studies measuring somatosensory evoked potentials in healthy persons (
The average current pain intensity of CRPS patients was not affected by the HF-rSS treatment; however, in four patients, pain decreased by at least 30%. Since studies from amputees with phantom limb pain (
In all but two patients rSS applied by means of the hand pad was well feasible. In one patient, the hand pad was not suitable, because one finger could not contact the stimulation area for this finger on the pad due to a flexion contracture. In this case, we used adhesive electrodes to transmit the stimuli. In a second patient, we terminated stimulation with the hand pad after 3 days because this patient experienced the rigid position of the fingers during the third session as unpleasant. None of the patients reported the electric stimulation itself to be painful or unpleasant. Thus, HF-rSS with the stimulation device used in this study is suitable for the use in patients with CRPS of the upper limb. In rare cases where no sufficient contact of all fingers with the stimulation area is possible, adhesive electrodes could be used alternatively to apply HF-rSS pulses. Since an intact somatosensory input is essential for recovery of handfunction (
Our results demonstrate a good feasibility and efficacy of HF-rSS in CRPS patients to improve sensory loss, therefore providing an essential prerequisite for rehabilitation of handfunction. Qualitatively, stimulation effects were similar to those observed in healthy controls, indicating intact cortical processing of rSS stimuli in patients with CRPS type I. The limited impact on pain relief might be due to the short stimulation period. In order to further evaluate this, studies with an extended period of daily stimulation are needed.
Marianne David, Hubert R. Dinse, Martin Tegenthoff and Christoph Maier hold patents about repetitive sensory stimulation applications. The remaining authors have no conflict of interest to declare.
We thank all our patients who participated in this study for their consent and cooperation. We also thank Dr. Elena Krumova for carefully reading earlier versions of the manuscript. MT and HD acknowledge support by the SFB 874 from the German Research Foundation (DFG). MT received research grants from the DFG, DGUV (German Statutory Accident Insurer), BMBF (Federal Ministry of Education and Research), Mercator Research Foundation and intramural funding of the Ruhr-University Bochum (FoRum), MD was supported by intramural funding of the Ruhr-University Bochum (FoRUM: grant number F776N). TM and CM are part of the European Collaboration, which has received support from the Innovative Medicines Initiative Joint Undertaking, under grant agreement no 115007, resources of which are composed of financial contribution from the European Union’s Seventh Framework Program (FP7/2007-2013) and EFPIA companies’ in kind contribution (IMI JU web address:
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