Sensory signs in complex regional pain syndrome and peripheral nerve injury

Transcription

1 PAIN Ò 153 (2012) Sensory signs in complex regional pain syndrome and peripheral nerve injury Janne Gierthmühlen a,,1, Christoph Maier b,1,2, Ralf Baron a,2, Thomas Tölle c,2, Rolf-Detlef Treede d,2, Niels Birbaumer e, Volker Huge f, Jana Koroschetz a, Elena K. Krumova b, Meike Lauchart f, Christian Maihöfner g, Helmut Richter b, Andrea Westermann b, the German Research Network on Neuropathic Pain (DFNS) study group 3 a Division of Neurological Pain Research and Therapy, Department of Neurology, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany b Department of Pain Management, BG Universitätsklinikum Bergmansheil, Ruhr-University Bochum, Bochum, Germany c Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany d Chair of Neurophysiology, Center of Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, Heidelberg University, Germany e Institute of Medical Psychology and Behavioral Neurobiology, University of Tübingen, Tübingen, Germany f Department of Anaesthesiology, Ludwig Maximilians-Universität München, Munich, Germany g Department of Neurology, University of Erlangen-Nuremberg, Germany Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. article info abstract Article history: Received 7 March 2011 Received in revised form 1 October 2011 Accepted 7 November 2011 Keywords: Complex regional pain syndrome CRPS Peripheral nerve injury Quantitative sensory testing Somatosensory Pain This study determined patterns of sensory signs in complex regional pain syndrome (CRPS) type I and II and peripheral nerve injury (PNI). Patients with upper-limb CRPS-I (n = 298), CRPS-II (n = 46), and PNI (n = 72) were examined with quantitative sensory testing according to the protocol of the German Research Network on Neuropathic Pain. The majority of patients (66% 69%) exhibited a combination of sensory loss and gain. Patients with CRPS-I had more sensory gain (heat and pressure pain) and less sensory loss than patients with PNI (thermal and mechanical detection, hypoalgesia to heat or pinprick). CRPS-II patients shared features of CRPS-I and PNI. CRPS-I and CRPS-II had almost identical somatosensory profiles, with the exception of a stronger loss of mechanical detection in CRPS-II. In CRPS-I and -II, cold hyperalgesia/allodynia (28% 31%) and dynamic mechanical allodynia (24% 28%) were less frequent than heat or pressure hyperalgesia (36% 44%, 67% 73%), and mechanical hypoesthesia (31% 55%) was more frequent than thermal hypoesthesia (30% 44%). About 82% of PNI patients had at least one type of sensory gain. QST demonstrates more sensory loss in CRPS-I than hitherto considered, suggesting either minimal nerve injury or central inhibition. Sensory profiles suggest that CRPS-I and CRPS-II may represent one disease continuum. However, in contrast to recent suggestions, small fiber deficits were less frequent than large fiber deficits. Sensory gain is highly prevalent in PNI, indicating a better similarity of animal models to human patients than previously thought. These sensory profiles should help prioritize approaches for translation between animal and human research. Ó 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. Corresponding author. Address: Division of Neurological Pain Research and Therapy, Department of Neurology, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Arnold-Heller-Strasse 3, Haus 41, Kiel 24105, Germany. Tel.: ; fax: address: j.gierthmuehlen@neurologie.uni-kiel.de (J. Gierthmühlen). 1 These authors contributed equally to this work. 2 These authors are on the German Research Network on Neuropathic Pain (DFNS) Steering Committee. 3 German Research Network on Neuropathic Pain (DFNS) study group: Prof. Dr. med. Ralf Baron, Dr. med. Janne Gierthmühlen, Dr. med. Andreas Binder, Jana Koroschetz, Division of Neurological Pain Research and Therapy, Department of Neurology, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Germany; Prof. Dr. med. Christoph Maier, Helmut Richter, Dr. med. Elena K. Krumova, Dr. med. Andrea Westermann, Department of Pain Management, BG Universitätsklinikum Bergmansheil, Ruhr-University Bochum, Germany; Prof. D. med. Thomas Tölle, PD Dr. med. Achim Berthele, PD Dr. med. Till Sprenger, Dr. med. Michael Valet, Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Prof. Dr. med. Rolf-Detlef Treede, PD Dr. rer. biol. hum. Walter Magerl, Dr. med. Thomas Klein, Chair of Neurophysiology, Center of Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, Heidelberg University, Germany; Prof. Dr. med. Frank Birklein, Dr. med. Christian Geber, Dr. med. Roman Rolke, Department of Neurology, Johannes Gutenberg-University, Mainz, Germany; PD Dr. med. Christian Maihöfner, Department of Neurology, University of Erlangen - Nuremberg, Germany; PD Dr. med. Shahnaz Christina Azad, Dr. med. Antje Beyer, Dr. med. Volker Huge, Dr. med. Meike Lauchart, Department of Anaesthesiology, Ludwig Maximilians-Universität München, Munich, Germany; Prof. Dr. med. Niels Birbaumer, Dipl.-Psych Anja Schwarz, Institute of Medical Psychology and Behavioral Neurobiology, University of Tübingen, Tübingen, Germany; Prof. Dr. G.B. Landwehrmeyer, Department of Neurology, University of Ulm, Ulm, Germany /$36.00 Ó 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi: /j.pain

2 766 J. Gierthmühlen et al. / PAIN Ò 153 (2012) Introduction Complex regional pain syndromes (CRPS) are characterized by sensory [38], motor [53], and autonomic [46,54] abnormalities. In general, 2 types of CRPS can be distinguished: CRPS type I (CRPS- I) without and type II (CRPS-II) with electrophysiological evidence of a major nerve lesion [16]. The pathogenesis of CRPS is still unclear. Recently, a small fiber neuropathy has been suggested to be one possible underlying mechanism in CRPS-I [39]. The diagnosis of peripheral nerve injury (PNI) rests primarily on a history of nerve lesion in conjunction with somatosensory alterations within the innervation territory of the injured nerve and when the nerve is accessible electrophysiological evidence for the nerve lesion. The reason why some patients develop CRPS-II after a peripheral nerve injury, whereas others do not, is still unclear. The generalized distal distribution of signs and symptoms in CRPS as well as the recently published Budapest diagnostic criteria for CRPS [17] help to clinically distinguish between CRPS and PNI. However, in some patients, differentiation between these 2 syndromes remains complex. The German Research Network on Neuropathic Pain (DFNS) has developed a standardized quantitative sensory testing (QST) battery that investigates different afferent nerve fiber functions [44] in order to address the hypothesis that different clinical signs reflect different underlying mechanisms [4]. Regarding somatosensory findings in CRPS and PNI, multicenter QST studies with large groups of patients and investigating all kinds of afferent nerve fiber functions are rare, in particular for CRPS-II. Thus, the aims of this study were to investigate somatosensory signs in CRPS-I, CRPS-II, and PNI using the QST battery of the DFNS in order to (1) find out whether CRPS-I and CRPS-II show differences in somatosensory profiles that go beyond the nerve lesion differentiating CRPS-I and -II by definition, (2) analyze whether CRPS-II and PNI can be distinguished by certain sensory signs that might help to facilitate differentiation between these syndromes, (3) find out whether CRPS-I, CRPS-II, and PNI are associated with dysfunction of certain sensory pathways, for example, a small-fiber neuropathy. Based on previous clinical reports, CRPS-I should be characterized by hyperalgesia/allodynia and PNI by sensory loss, whereas animal models predict hyperalgesia also in PNI. 2. Methods 2.1. Patients Four hundred sixteen in- and outpatients with neuropathic pain with unilateral CRPS or PNI who had been entered into the nationwide multicenter database of the DFNS between October 2002 and November 2007 were included in the analysis (Tables 1 3). Diagnosis, inclusion, and examination of the patients was made in the different centers exclusively by physicians specialized in diagnosis and treatment of neuropathic pain (authors). A diagnosis of CRPS was made by the corresponding centers when current International Association for the Study of Pain criteria were fulfilled [16]. In addition, the recently published but previously known and more specific Budapest criteria for the diagnosis of CRPS [17] were used by the centers in Kiel and Bochum (n = 121). A diagnosis of CRPS-I was made when no overt nerve lesion was detectable [16], whereas electrophysiological or other definite evidence of a major nerve lesion led to the diagnosis of CRPS-II. Patients with CRPS after an entrapment surgery were classified as CRPS-II because all patients showed an electroneurographically verified nerve lesion/affection prior to surgery. Detailed information of all individual signs and symptoms was, unfortunately, not requested upon inclusion into the database. Therefore, clinical data could not be obtained in all patients (Table 4). Diagnosis of painful PNI was made according to the individual procedures in the different centers using medical history, clinical examinations with presence of sensory (including pain) and motor signs, and symptoms referring exclusively to the innervation territory of the injured nerve and electroneurography. The differentiation between CRPS-II and PNI was left to the different centers own clinical algorithms because all centers come with long experience in diagnosing and treatment of neuropathic pain. Medical history, glove-like distal distribution of pain, and sensory, motor, and autonomic signs and symptoms that spread beyond the innervation territory of the injured nerve were used as differentiation criteria between CRPS-II and PNI in all centers. However, Kiel and Bochum, that together included about 90% of patients with PNI, additionally used long-term skin temperature measurements [26] and 3-phase bone scintigraphy to differentiate between CRPS-II and PNI [21,25,42,55]. Patients with a traumatic plexus root transection or those where a plexus root transection could not be excluded, impaired vigilance, dementia/cognitive impairment, inadequate knowledge of the German language (inability to understand the standardized instruction), patients with skin lesions or dermatological disorders in the areas to be tested, or with any comorbidity that could otherwise influence testing results such as polyneuropathy, diabetes, vascular disease, etc. were removed from analysis. Inclusion was restricted to patients with upper-limb CRPS or PNI to make the investigated patient sample as homogenous as possible. Table 1 Characteristics of patients. CRPS-I [n = 298] CRPS-II [n = 46] PNI [n = 72] P value Females (%) 233 (78.2%) 38 (82.6%) 37 (51.4%) <0.01 a,b Mean age (years) 53.0 ± ± ± 13.2 <0.05 a Mean duration of symptoms ± SD (range) [months] 21.2 ± 35.5 ( ) 25.1 ± 33.3 ( ) 44.1 ± 48.6 ( ) <0.01 a,b <6 months 133 (44.6%) 23 (50.0%) 11 (15.3%) <1 year 22 (7.4%) 3 (6.5%) 11 (15.3%) 1 2 years 48 (16.1%) 2 (4.3%) 12 (16.7%) 2 5 years 64 (21.5%) 10 (21.7%) 22 (30.6%) 5 10 years 12 (4.0%) 4 (8.7%) 6 (8.3%) >10 years 4 (1.3%) 1 (2.2%) 9 (12.5%) Missing data 15 (5.0%) 3 (6.5%) 1 (1.4%) Mean pain (range) [NRS] 5.7 ± 2.3 (0.5 10) 6.3 ± 2.1 (0.5 10) 6.5 ± 2.3 (1 10) <0.05 a Data ± SD. CRPS, complex regional pain syndrome; PNI, peripheral nerve injury; mean pain was defined as average pain within the last 4 weeks; NRS, numerical rating scale where 0 = no pain and 10 = most imaginable pain; Line 1, the ratio of females was higher in CRPS-I and CRPS-II vs PNI (v 2 test). a CRPS-I vs PNI. b CRPS-II vs PNI.

3 J. Gierthmühlen et al. / PAIN Ò 153 (2012) Table 2 Numbers of patients recruited from the different centers of the DFNS. DFNS center CRPS-I CRPS-II PNI Bochum 63 (21.1%) 7 (15.2%) 62 (86.1%) Kiel 45 (15.1%) 6 (13%) 3 (4.2%) Erlangen 47 (15.8%) 14 (30.4%) 4 (5.6%) LMU Munich 118 (39.6%) 11 (23.9%) Mainz 1 (2.2%) 1 (1.4%) TU Munich 3 (1%) 2 (4.3%) 2 (2.8%) Tübingen 19 (6.4%) 4 (8.7%) Ulm 3 (1%) 1 (2.2%) Total 298 (100%) 46 (100%) 72 (100%) DFNS, German Research Network on Neuropathic Pain; CRPS, complex regional pain syndrome; PNI, peripheral nerve injury; LMU, Ludwig Maximilians-Universität; TU, Technische Universität Quantitative sensory testing Investigators from 8 university departments specialized in diagnosis and treatment of neuropathic pain were educated in QST testing procedure [13] and conducted the QST. All patients were examined in the most painful area on the hand. All patients gave written, informed consent. The study was in accordance with the local Ethics Committees and the declaration of Helsinki. The QST battery included the investigation of mechanical detection (MDT) and vibration detection threshold (VDT) representing the function of large myelinated Ab fibers or central pathways, cold detection (CDT), cold pain (CPT), warm detection (WDT) and heat pain threshold (HPT), presence of paradoxical heat sensations (PHS), thermal sensory limen (TSL), mechanical pain threshold (MPT), mechanical pain sensitivity (MPS), wind-up ratio (WUR), and pressure pain threshold (PPT) representing small-fiber function (Ad or C fibers) or central pathways. Additionally, dynamic mechanical allodynia (DMA) was investigated. Table 3 Initiating events of CRPS-I, CRPS-II and PNI. CRPS-I [n = 298] CRPS-II [n = 46] PNI [n = 72] Without surgery before onset Entrapment syndrome 11 (15.3%) Fracture 78 (26.2%) 2 (4.4%) 1 (1.4%) Joint injury/affection 9 (3.0%) 3 (6.5%) Nerve injury/affection 13 (18.1%) Soft tissue disease/trauma 41(13.8%) 2 (4.4%) Without any initiating 5 (1.7%) event All 133 (44.6%) 7 (15.2%) 25 (34.7%) With surgery before onset Entrapment syndrome 25 (54.4%) 27 (37.5%) Fracture 102 (34.2%) 11 (23.9%) 9 (12.5%) Joint injury/affection 19 (6.4%) 2 (2.8%) Nerve injury/affection 3 (6.6%) 6 (8.4%) Soft tissue disease/trauma 42 (14.1%) 3 (4.2%) Other disease 1 (0.3%) Unknown disease/trauma 1 (0.3%) All 165 (55.4%) 39 (84.8%) 47 (65.3%) Affected nerve Median nerve 18 (39.1%) 28 (38.9%) Ulnar nerve 8 (17.4%) 27 (37.5%) Radial nerve 14 (30.4%) 10 (13.9%) Brachial plexus 4 (8.7%) 5 (6.9%) Multiple nerves 1 (2.2%) 2 (2.8%) Interdigital nerve 1 (2.2%) CRPS, complex regional pain syndrome; PNI, peripheral nerve injury. Soft tissue diseases/traumata include soft tissue diseases such as tendovaginitis, tendon contractions on the hand (Morbus Dupuytren) or minor soft tissue traumas (eg, distortion). Note that a spontaneous onset of CRPS was rare Thermal detection and thermal pain thresholds, paradoxical heat sensations Thermal thresholds were determined using a TSA 2001-II (ME- DOC, Ramat Yishai, Israel) thermal sensory testing device with a thermode of Peltier elements (contact area mm; 32 C baseline temperature; ramped stimuli with 1 C/s; method of limits). First, thresholds of cold and warm detection (CDT, WDT) were measured in triplicate. The number of paradoxical heat sensations (PHS, ie, reports of hot or burning sensations to innocuous cold stimuli) was determined during the TSL procedure (the difference limen for alternating warm and cold stimuli), followed by determination of CPTs and HPTs measured in triplicate. The mean threshold temperature of the 3 consecutive measurements was calculated Mechanical detection threshold MDT was assessed using a standardized set of modified von Frey hairs (Optihair2-Set, Marstock Nervtest, Schreisheim, Germany) exerting forces between 0.25 and 512 mn. The contact area of the von Frey hairs with the skin was a rounded tip (0.5 mm in diameter) to avoid sharp edges that would facilitate nociceptor activation. Threshold determinations were made using series of alternating ascending and descending stimulus intensities yielding 5 just suprathreshold and 5 just subthreshold estimates. The final threshold was the geometric mean of the 10 determinations Mechanical pain threshold MPT was assessed using custom-made weighted pinprick stimuli with fixed stimulus intensities (8, 16, 32, 64, 128, 256, 512 mn; flat contact area of 0.25 mm diameter; the PinPrick; MRC Systems GmbH, Heidelberg, Germany). These punctate stimuli adequately excite cutaneous nociceptors [15,50]. Again, threshold determinations were made by a series of alternating ascending and descending stimulus intensities yielding 5 just suprathreshold and 5 just subthreshold estimates. The final threshold was the geometric mean of the 10 estimates Mechanical pain sensitivity and dynamic mechanical allodynia In a separate test, a stimulus-response function for MPS was determined using the same weighted pinprick stimuli as for mechanical pain threshold. Additionally, pain in response to light touch (DMA) was tested by gentle/light stroking with a cotton wisp (3 mn), a cotton wool tip fixed to an elastic strip (100 mn), and a brush ( mn). Each of the 7 intensities of pinpricks and of the 3 intensities of light stroking was applied 5 times in a balanced sequence. Subjects were asked to give a pain rating for each stimulus on a numerical rating scale (0 indicating no pain, and 100 indicating most intense pain imaginable ). Mechanical pain sensitivity was calculated as the geometric mean of all numerical ratings for pinprick stimuli, and allodynia was quantified as the geometric mean of all numerical ratings across all 3 different types of light touch stimulators Wind-up ratio temporal pain summation for repetitive pinprick stimuli Wind-up is a frequency-dependent increase in excitability of spinal cord neurons evoked by electrical stimulation of afferent C fibers [20]. The perceptual correlate of wind-up in humans can be described by the so called wind-up ratio obtained in this test. Therefore, the perceived magnitude of pain to a series of pinprick stimuli (pinprick force: 256 mn, repeated 10 times at a 1/s rate on separate spots within a small area of about 1 cm 2 ) was compared to a single pinprick stimulus of the same force. The patient was asked to assign a pain rating for the single stimulus and for the pain reached at the end of the train. This procedure was applied 5 times at different skin sites within the marked area. The mean pain rating of trains divided by the mean pain rating to single stimuli was

4 768 J. Gierthmühlen et al. / PAIN Ò 153 (2012) Table 4 Clinical characteristics of CRPS-I and CRPS-II patients. CRPS-I n = 298 CRPS-II n = 46 Pain Pain at rest 164 (55.0%) 35 (76.1%) Pain upon movement 195 (65.4%) 29 (63.0%) Continuous pain 121 (40.6%) 30 (65.2%) Pain at orthostatic conditions 89 (29.9%) 12 (26.0%) Autonomic abnormalities Autonomic disturbances (at least 1 sign) [CRPS-I: n = 246; CRPS-II: n = 40] 210 (85.4%) 34 (85.0%) Edema at rest [CRPS-I: n = 235; CRPS-II: n = 38] 158 (67.2%) 23 (60.5%) Intermittent edema [CRPS-I: n = 235; CRPS-II: n = 38] 63 (26.8%) 16 (42.1%) Hyperhidrosis [CRPS-I: n = 236; CRPS-II: n = 38] 77 (32.6%) 15 (39.5%) Sudomotor dysfunction [CRPS-I: n = 236; CRPS-II: n = 38] 111 (47.0%) 21 (55.3%) Disturbances of hair/nail growth [CRPS-I: n = 234; CRPS-II: n = 38] 132 (56.4%) 17 (44.7%) Changes of skin color [CRPS-I: n = 211; CRPS-II: n = 38] 152 (72%) 29 (76.3%) Reduced skin perfusion [CRPS-I: n = 234; CRPSI: n = 38] 62 (26.5%) 8 (21.1%) Disturbed perfusion [CRPS-I: n = 244; CRPS-II: n = 40] 193 (79.1%) 33 (82.5%) Skin temperature difference >1 C [CRPS-I: n = 206; CRPS-II: n = 38] 86 (41.7%) 17 (44.7%) Motor disturbances n = 209 n = 29 No disturbances 54 (25.8%) 2 (6.9%) Mild disturbances 42 (20.1%) 9 (31.0%) Moderate disturbances 100 (47.8%) 18 (62.1%) Severe disturbances 12 (5.7%) Fixed position 1 (0.5%) 1 (3.4%) CRPS, complex regional pain syndrome. Data are given as mean ± SD. Numerical rating scale where 0 = no pain and 10 = strongest pain imaginable. If not specifically mentioned, data are shown for all (n = 298) patients. Otherwise, the number of patients where data were available is mentioned separately. The Table presents signs (objective findings upon clinical examination) and symptoms (subjective report of patients): Pain characteristics were based upon subjective reports of patients, autonomic abnormalities were based upon signs or symptoms: Edema at rest, disturbances of hair/nail growth and skin temperature difference >1 C was based upon clinical findings (signs), whereas all other autonomic characteristics were based either on signs or symptoms or both. The line autonomic disturbances refers to the number of patients with at least one autonomic sign upon clinical examination. Motor disturbances were based on clinical examination: Mild disturbances = finger palmar distance at fist closure <2 cm or disturbances of fine motor skills or reduced movement ability or movement-induced tremor without paresis; moderate disturbances = slight paresis (max. III/V) or finger palmar distance at fist closure <5 cm or mild disturbances + tremor/dystonia; severe disturbances = paresis more severe than II/V or finger palmar distance at fist closure >5 cm. The methods for evaluation of clinical characteristics were within the decision of the examining physicians of the individual centers. calculated as WUR [34]. WUR was not calculated if the first (single) stimulus was rated on a numeric rating scale 0/100 in more than 3 assessments, and in this case was handled as missing data Vibration detection threshold VDT was assessed with a Rydel Seiffert tuning fork (64 Hz, 8/8 scale; for example available at Arno Barthelmes & Co. GmbH, Tuttlingen, Germany) applied with suprathreshold vibration intensity left on the skin until the sensation of vibration had ceased. The final vibration detection threshold was the arithmetic mean of 3 consecutive measurements Pressure pain threshold PPT was assessed by using a pressure gauge device (FDN200, Wagner Instruments, Greenwich, CT, USA) with a probe area of 1cm 2 that exerts pressure up to 2000 kpa. The pressure pain threshold was determined by 3 series of ascending stimulus intensities with a slowly increasing stimulus ramp (50 kpa/s). The final threshold was the arithmetic mean of the 3 consecutive measurements Data evaluation Statistical comparison was made to a reference database of healthy controls of the DFNS with the dorsum of the hand as reference site [44]. For calculation of z-values, all patient data were normalized to the respective gender and age group of the healthy controls [z = (individual value mean database )/SD database ]. The resulting z-scores are independent of the original units of measurement and can be used to create somatosensory profiles. z-score values indicate hypo- or hyperfunction of the subject s sensitivity for each parameter as compared with the mean of age- and gender-matched controls. The 95% confidence interval of controls is between 1.96 and z-values above 0 indicate hyperfunction, that is, patients are more sensitive to the tested parameter compared to controls (lower thresholds), whereas z-scores below 0 indicate hypofunction and therefore a loss of or lower sensitivity of the patient compared to controls (higher thresholds, [44]). Both z-values out of the 95% confidence interval (absolute abnormal value) and a difference of more than 2 SDs in the z-scores between affected and corresponding unaffected extremity (abnormal side-to-side difference) were considered as abnormal. All calculations were performed using the z-values. Significance of differences from healthy controls was estimated according to Magerl et al. [32]. Univariate analysis of variance (ANOVA) was used for intergroup differences with Bonferroni or Dunnett T3 test for post hoc analysis, depending on existence of homogeneity. Linear relationships between gender/age/pain intensity and duration of symptoms with the analyzed QST parameters were assessed by Pearson s correlation coefficient. In cases where correlation coefficient R was >0.15 between gender or age or pain intensity or duration of symptoms and the analyzed QST parameter, a univariate ANOVA was calculated considering the corresponding factors as covariates. Single-tailed v 2 test was used to test whether abnormal values were more frequent in patients than in healthy controls. P < 0.05 was considered statistically significant, in case of multiple variables, results were Bonferroni corrected. 3. Results 3.1. Somatosensory alterations in CRPS and PNI compared to healthy controls Mean QST parameters (Table 5) showed that CRPS and PNI patients were more sensitive to painful stimuli, but showed a sensory

5 J. Gierthmühlen et al. / PAIN Ò 153 (2012) Table 5 QST values of the affected extremity in CRPS-I, CRPS-II, and PNI. QST parameter CRPS-I n P value CRPS-II n P value PNI n P value CDT ( C) 0.38 ± < ± < ± <0.01 WDT ( C) 0.49 ± < ± < ± <0.01 TSL ( C) 0.72 ± < ± < ± <0.01 CPT ( C) 16.9 ± < ± < ± <0.01 HPT ( C) 41.4 ± < ± < ± ns PPT (kpas) 2.36 ± < ± < ± <0.01 MPT (mn) 1.68 ± < ± ns 1.73 ± <0.05 MPS 0.21 ± < ± ns 0.06 ± <0.05 WUR 0.40 ± < ± ns 0.31 ± ns MDT (mn) 0.32 ± < ± < ± <0.01 VDT (x/8) 7.20 ± < ± < ± <0.01 DMA 1.6 ± a 2.2 ± a 0.9 ± a PHS 6% (41/894 tests) 298 a Not present 46 a 7% (9/216 tests) 72 a QST, quantitative sensory testing; CRPS, complex regional pain syndrome; PNI, peripheral nerve injury; CDT, cold detection threshold; WDT, warm detection threshold; TSL, thermal sensory limen; CPT, cold pain threshold; HPT, heat pain threshold; PPT, pressure pain threshold; MPT, mechanical pain threshold; MPS, mechanical pain sensitivity; WUR, wind-up ratio; MDT, mechanical detection threshold; VDT, vibration detection threshold; DMA, dynamic mechanical allodynia; PHS, paradoxical heat sensations. Data are given as log-transformed values (mean ± SD) except PHS, HPT, CPT, VDT, and DMA which are listed as absolute values according to [44]. P-values are given compared to healthy controls. a, P values for PHS and DMA vs controls cannot be given as DMA and PHS do not usually occur in healthy controls. For PHS, frequencies instead of mean values are shown. loss of nonpainful detection compared to normative data [32]. Data analysis on the individual level for frequencies of abnormal values showed similar results (Tables 6 and 7). In short, 24% 55% of patients showed an abnormal loss of sensitivity to nonpainful stimuli. Increased sensitivity to painful stimuli occurred more frequently (28% 73%) than decreased sensitivity to painful stimuli (4% 21%) in both CRPS and PNI. Notably, for HPT, MPT, and MPS, both gain and loss of function occurred in the different diseases, indicating that mean QST values without looking at individual abnormalities give an incomplete picture of abnormalities [5] Somatosensory profiles Patients with CRPS-I and CRPS-II had almost identical somatosensory profiles, with the exception of a more pronounced loss of mechanical detection in CRPS-II, which was similar to PNI (Fig. 1), that is, CRPS-II patients showed the same gain as in CRPS-I and the same loss as PNI. Compared to PNI, both groups of CRPS patients were characterized by an increased pressure pain and a more or less increased heat pain sensitivity, whereas compared to CRPS-I, patients with PNI showed a trend towards a stronger loss of thermal and mechanical detection. Correlations between gender/age/duration of symptoms or pain and QST parameters were overall only mild (R = maximal 0.24). Considering all linear relationships (correlation coefficients R > 0.15) as covariates in a univariate ANOVA did not reveal different results compared to the group differences shown in Fig Frequencies of abnormal QST values On the individual level, the majority of patients had absolute abnormal values on the affected extremity, only a minority had merely abnormal side-to-side differences (dark vs light bars in Fig. 2). The frequency of patients with unremarkable values upon QST was <6% in all 3 diagnoses. Hyperalgesia/allodynia without loss of detection (only gain) was more frequent in CRPS-I than in CRPS-II and PNI, but similar in CRPS-II and PNI (Table 8). Loss of detection was more frequent in PNI than in CRPS-I. Most of the patients showed a combination of loss of detection and hyperalgesia/ allodynia (57% 68%). In Table 9, these findings are differentiated according to thermal (small fibers) or mechanical (large fibers) QST tests. For all 3 diagnoses, mixed loss in combination with hyperalgesia/allodynia (L3G3) was more frequent than isolated mechanical loss with hyperalgesia/allodynia (L2G2), which in turn was more prevalent than thermal loss in combination with hyperalgesia/allodynia (L1G1). Hypoalgesia without loss of detection was rare in each group (<5%, P ns). Hypoalgesia in combination with loss of detection Table 6 Frequencies of abnormal values (including abnormal side-to-side differences) in CRPS-I, CRPS-II, and PNI. Gain Healthy controls [n = 180] CRPS-I [n = 298] CRPS-II [n = 46] PNI [n = 72] P [vs healthy controls] CDT 4 (2.3%) 9 (3.2%) 2 (4.4%) 1 (1.4%) n.s. WDT 11 (6.1%) 6 (2.1%) 1 (2.3%) 1 (1.4%) n.s. TSL 9 (5%) 9 (3.1%) 1 (2.2%) 1 (1.4%) n.s. CPT 8 (4.5%) 94 (31.7%) 13 (28.3%) 25 (34.8%) <0.01 HPT 7 (3.9%) 130 (43.7%) 16 (35.7%) 24 (33.4%) <0.01 PPT 10 (5.6%) 195 (66.6%) 33 (73.4%) 32 (47.9%) <0.01 MPT 6 (3.3%) 82 (28.8%) 17 (37%) 24 (33.9%) <0.01 MPS 9 (5%) 127 (42.8%) 19 (41.4%) 25 (35.3%) <0.01 WUR 13 (7.2%) 39 (14.6%) 4 (9.6%) 8 (13%) <0.05 (CRPS-I) MDT 11 (6.2%) 33 (11.3%) 2 (4.4%) 10 (14.2%) <0.05 (PNI) VDT 12 (6.7%) 5 (1.7%) 0 (0%) 0 (0%) n.s. PHS 0 (0%) 19 (6.4%) 0 (0%) 5 (7%) <0.01 (CRPS-I, PNI) DMA 2 (1.1%) 71 (23.9%) 13 (28.3%) 14 (19.5%) <0.01 CRPS, complex regional pain syndrome; PNI, peripheral nerve injury; CDT, cold detection threshold; WDT, warm detection threshold; TSL, thermal sensory limen; CPT, cold pain threshold; HPT, heat pain threshold; PPT, pressure pain threshold; MPT, mechanical pain threshold; MPS, mechanical pain sensitivity; WUR, wind-up ratio; MDT, mechanical detection threshold; VDT, vibration detection threshold; PHS, paradoxical heat sensations; DMA, dynamic mechanical allodynia. Both, abnormal values and abnormal side-to-side differences were considered for frequencies of abnormal values. If not specifically mentioned, values of significance are given for all three diseases.

6 770 J. Gierthmühlen et al. / PAIN Ò 153 (2012) Table 7 Frequencies of abnormal values (including abnormal side-to-side differences) in CRPS-I, CRPS-II, and PNI. Loss Healthy controls [n = 180] CRPS-I [n = 298] CRPS-II [n = 46] PNI [n = 72] P value [vs healthy controls] CDT 12 (6.7%) 88 (29.6%) 20 (43.6%) 25 (34.8%) <0.01 WDT 13 (7.2%) 74 (24.9%) 14 (31.2%) 26 (36.2%) <0.01 TSL 10 (5.5%) 71 (24%) 13 (28.3%) 26 (36.2%) <0.01 CPT 8 (4.4%) 11 (3.7%) 4 (8.7%) 4 (5.6%) n.s. HPT 5 (2.8%) 19 (6.4%) 5 (11.2%) 11 (15.3%) <0.05 (CRPS-II, PNI) PPT 6 (3.4%) 10 (3.5%) 2 (4.6%) 4 (6%) n.s. MPT 9 (5%) 26 (8.9%) 6 (13.1%) 15 (21.2%) <0.01 (PNI) MPS 4 (2.2%) 27 (9.2%) 4 (8.7%) 14 (19.8%) <0.01 (CRPS-I, PNI), <0.05 (CRPS-II) WUR 5 (2.8%) 6 (2.3%) 1 (2.4%) 1 (1.7%) n.s. MDT 11 (6.1%) 91 (30.9%) 25 (54.5%) 38 (53.6%) <0.01 VDT 2 (1.1%) 96 (32.5%) 19 (41.4%) 35 (48.7%) <0.01 CRPS, complex regional pain syndrome; PNI, peripheral nerve injury; CDT, cold detection threshold; WDT, warm detection threshold; TSL, thermal sensory limen; CPT, cold pain threshold; HPT, heat pain threshold; PPT, pressure pain threshold; MPT, mechanical pain threshold; MPS, mechanical pain sensitivity; WUR, wind-up ratio; MDT, mechanical detection threshold; VDT, vibration detection threshold. Both abnormal values and abnormal side-to-side differences were considered for frequencies of abnormal values. If not specifically mentioned, values of significance are given for all 3 diseases. was more often observed in PNI than in CRPS-I (14% vs 4.3%, P < 0.01) and was not observed in CRPS-II Positive signs Increased sensitivity to pressure pain was the most peculiar finding in CRPS, which was present in more than 60% of patients significantly more often than in PNI (Fig. 2). However, pressure pain hyperalgesia was also observed in around 45% of the PNI patients. Heat hyperalgesia in combination with pressure pain hyperalgesia was shown in 94 (31.5%) patients with CRPS-I, 12 (26%) patients with CRPS-II, and 14 (19.4%) patients with PNI Negative signs Negative sensory signs were more frequent in PNI than in CRPS- I(Table 7; Fig. 2). Frequencies for negative sensory signs in CRPS-II lay between CRPS-I and PNI and did not reach the level of significance, except for loss of mechanical detection that occurred more often in CRPS-II than CRPS-I. Despite an absence of an obvious nerve lesion, 63% of patients with CRPS-I demonstrated a loss of detection. In these, an isolated dysfunction of small fiber afferent pathways was less frequent (14%) than an isolated large fiber (23%) or mixed fiber afferent pathway dysfunction (25%; numbers noted with in Table 9). CRPS-I patients with (n = 185) loss of detection of nonpainful stimuli had a less pronounced gain in heat pain sensitivity (0.94 ± 1.71 vs 1.6 ± 1.54, F = 11.04) and mechanical pain sensitivity (MPT: 0.29 ± 1.45 vs 0.94 ± 1.32; F = 14.71) than patients without (n = 110) loss of detection. However, correlation coefficients between MDT and HPT (r = 0.23, P < 0.001) or MDT and MPT (r = 0.32, P < 0.001) that is, the better mechanical detection, the stronger mechanical and heat hyperalgesia were significant but small. In CRPS-I and PNI there was a trend towards increased thermal and mechanical detection thresholds in patients with more severe pain (numerical rating scale P7), but no significant differences Fig. 1. Somatosensory profiles (A) and occurrence of dynamic mechanical allodynia (DMA) and paradoxical heat sensations (PHS) (B) in complex regional pain syndrome (CRPS)-I, CRPS-II and peripheral nerve injury (PNI). z-values ± SEM. To obtain z-values, all patient data were normalized to the respective region, gender and age group of healthy controls [z = (individual value mean database )/SD database ]. The 95% confidence interval of z-values of controls is between 1.96 and z-values above 0 indicate hyperfunction, whereas z-scores below 0 indicate hypofunction [44]. For threshold differences compared to healthy controls, see Table 5. P < 0.01 for CRPS-I vs PNI, ## P < 0.01 for CRPS-II vs PNI, $ P < 0.05 for CRPS-I vs CRPS-II. NRS, numeric rating scale; CDT, cold detection threshold; WDT, warm detection threshold; TSL, thermal sensory limen; CPT, cold pain threshold; HPT, heat pain threshold; PPT, pressure pain threshold; MPT, mechanical pain threshold; MPS, mechanical pain sensitivity; WUR, wind-up ratio; MDT, mechanical detection threshold; VDT, vibration detection threshold; DMA, dynamic mechanical allodynia; PHS, paradoxical heat sensations.

7 J. Gierthmühlen et al. / PAIN Ò 153 (2012) Fig. 2. Frequencies of abnormal values in complex regional pain syndrome (CRPS)-I (n = 298), CRPS-II (n = 46), and peripheral nerve injury (PNI) (n = 72). Black columns: absolute abnormal values for loss of function; light grey columns: abnormal side-to-side difference with loss of function on the affected extremity; dark grey columns: absolute abnormal values for gain of function; white columns: abnormal side-to-side difference with gain of function on the affected extremity. Abnormal side-to-side differences were evaluated only if the value on the contralateral unaffected extremity was within the 95% confidence interval for healthy controls. 1: CRPS-I, 2: CRPS-II, 3: PNI. Frequency of loss and gain of abnormal values was significantly different from controls (not shown in the figure, P < 0.01 for CRPS-I, CRPS-II, and PNI compared to controls except WUR, which did not differ from controls in PNI and CRPS-II and where P < 0.05 for CRPS-I compared to controls; PHS did not occur in CRPS-II). P < 0.05 and P < 0.01 for CRPS-I vs PNI, ## P < 0.01 for CRPS-II vs PNI, $$ P < 0.01 for CRPS-I vs CRPS-II. CDT, cold detection threshold; WDT, warm detection threshold; TSL, thermal sensory limen; CPT, cold pain threshold; HPT, heat pain threshold; PPT, pressure pain threshold; MPT, mechanical pain threshold; MPS, mechanical pain sensitivity; WUR, wind-up ratio; MDT, mechanical detection threshold; VDT, vibration detection threshold; PHS, paradoxical heat sensations; DMA, dynamic mechanical allodynia. were found and correlation coefficients between detection thresholds and pain were overall only marginal (maximum r = 0.23). 4. Discussion Main findings of the present study are: (a) In all syndromes, the majority of patients (66% 69%) exhibited a combination of sensory loss and hyperalgesia/allodynia. For some QST parameters (heat pain and mechanical pain), some patients exhibited increased and other patients decreased sensitivity. Hence, mean values do not represent sensory findings in these diseases. (b) Patients with CRPS-I had more sensory gain (heat and pressure pain) and less sensory loss than patients with PNI. CRPS-II shared features of CRPS-I and PNI: Somatosensory abnormalities of CRPS-I and CRPS-II were almost identical except for a stronger loss of mechanical detection (MDT) in CRPS-II, which was similar to PNI. (c) There was significantly more pressure pain hyperalgesia in CRPS than in PNI. However, this sign was also present in about 50% of PNI patients. (d) Approximately 80% of CRPS-II and PNI patients and 63% of CRPS-I patients demonstrated loss of detection, where loss of large or mixed fiber afferent pathways was more common than loss of small fiber afferent pathways Sensory signs in PNI PNI patients were characterized by loss of sensitivity to nonpainful stimuli and moderate gain in sensitivity to painful stimuli. Negative sensory signs due to nerve lesions leading to degeneration and loss of function have been frequently reported in PNI [28,47] and may add to nerve conduction studies by covering also small fiber functions. We found that hyperalgesia was more frequent than hypoalgesia for all thermal and mechanical painful stimuli. The overall frequency of hyperalgesia was much higher than in another study where heat and pinprick hyperalgesia were found in no more than 22% [28]. However, categorization of pathological/unremarkable QST in this study was based on clinical decision-making with the corresponding healthy side as control area. Our results show that in addition to heat and pinprick hyperalgesia, cold and pressure pain hyperalgesia are also frequent in PNI. In animal experiments Table 8 Loss and gain in CRPS-I, CRPS-II, and PNI. CRPS-I CRPS-II PNI P value No loss, no gain 7 (2.4%) 2 (4.4%) 4 (5.6%) ns Only gain (hyperalgesia/allodynia) 103 (34.6%) 7 (15.4%) 11 (15.4%) <0.01 a,b Only loss (hypoesthesia) 18 (6.0%) 5 (11%) 10 (13.9%) <0.05 a Gain and loss of detection 168 (56.4%) 31 (67.4%) 47 (65.3%) ns CRPS, complex regional pain syndrome; PNI, peripheral nerve injury. Loss was defined as loss of thermal and/or mechanical detection. Gain was defined as presence of thermal and/or mechanical hyperalgesia/allodynia. No loss, no gain = L0G0; only gain = L0G1-3; only loss = L1-3G0; gain and loss of detection (L1-3G1-3, see Table 9). a CRPS-I vs PNI. b CRPS-I vs CRPS-II.

8 772 J. Gierthmühlen et al. / PAIN Ò 153 (2012) Table 9 Different combinations of gain and loss of detection in CRPS-I, CRPS-II, and PNI. Loss/gain G0 G1 G2 G3 L total L0 CRPS-I 7 (2.4%) 11 (3.7%) 40 (13.4%) 52 (17.5%) 110 (37%) CRPS-II 2 (4.4%) 0 2 (4.4%) 5 (10.9%) 9 (19.6%) PNI 4 (5.6%) 1 (1.4%) 5 (6.9%) 5 (6.9%) 15 (20.8%) L1 CRPS-I 6 (1.8%) 1 (0.3%) 16 (5.4%) 19 (6.4%) 41 (13.8%) * CRPS-II 0 1 (2.2%) 2 (4.4%) 3 (6.5%) 6 (13.0%) PNI 1 (1.4%) 2 (2.8%) 2 (2.8%) 1 (1.4%) 6 (8.3%) L2 CRPS-I 5 (1.7%) 10 (3.4%) 19 (6.4%) 35 (11.7%) 69 (23.2%) * CRPS-II 2 (4.4%) 0 4 (8.7%) 7 (15.2%) 13 (28.3%) PNI 4 (5.6%) 2 (2.8%) 5 (6.9%) 11 (15.3%) 22 (30.6%) L3 CRPS-I 7 (2.4%) 6 (2.0%) 35 (11.7%) 27 (9.1%) 75 (25.2%) * CRPS-II 3 (6.5%) 0 10 (21.7%) 4 (8.7%) 17 (37%) PNI 5 (7%) 3 (4.2%) 10 (13.9%) 11 (15.3%) 29 (40.6%) G total CRPS-I 25 (7.5%) 28 (9.5%) 110 (37%) 133 (45.1%) CRPS-II 7 (15.4%) 1 (2.2%) 18 (40%) 19 (42.2%) PNI 14 (19.6%) 8 (11.3%) 22 (31%) 28 (39.4%) CRPS, complex regional pain syndrome; PNI, peripheral nerve injury. An isolated loss of small fiber function (L1) was diagnosed if the values of cold detection threshold (CDT) or warm detection threshold (WDT) were abnormal on the affected side in combination with unremarkable mechanical detection threshold (MDT) and vibration detection threshold (VDT). Isolated loss of large fiber function (L2) was present if values of MDT or VDT were abnormal on the affected side in combination with unremarkable CDT and WDT. Mixed fiber loss of function (L3) was diagnosed, when both, loss of small and large fiber function were present. Thermal hyperalgesia/allodynia (G1) was diagnosed when gain of function was present solely in cold pain threshold or heat pain threshold. If gain of function was present only in mechanical pain threshold, mechanical pain sensitivity, dynamic mechanical allodynia, or pressure pain threshold; mechanical hyperalgesia/allodynia was diagnosed (G2). When both mechanical and thermal hyperalgesia/allodynia were present, mixed hyperalgesia/allodynia was diagnosed (G3). Data of n = 3 (1%) in CRPS-I, n = 1 (2.2%) in CRPS-II, and n = 1 (1.4%) in PNI were not available due to some missing data. * Total loss of small (L1), large (L2) or mixed fiber afferent pathway function in CRPS-I. Note that an isolated dysfunction of small fiber afferent pathways was less frequent than an isolated loss of large fiber or mixed fiber afferent pathway dysfunction. of different kinds of nerve lesion, increased responses to nociceptive thermal and mechanical stimuli have been frequently observed [6,9,51]. Considering that animal data are overestimated due to selection bias (exclusion of animals without increased responses), the high frequency of increased sensitivity to painful stimuli in our PNI patients indicates a better similarity of animal models to human patients than previously thought Sensory signs in CRPS CRPS patients were characterized by gain in sensitivity to painful stimuli and moderate loss of sensitivity to nonpainful stimuli. The only differentiation between CRPS-I and -II was the stronger loss of mechanical detection in CRPS-II explainable by the nerve lesion. CRPS-I and -II may thus represent one disease continuum with at least in major aspects a similar pathophysiology of pain and hyperalgesia. No study has compared QST in CRPS-I and -II patients. CRPS-II patients reported more cold and dysesthetic pain than patients with CRPS-I, but this was not confirmed by QST [8]. We found cold hyperalgesia/allodynia to a similar degree (30%) in both CRPS-I and -II. In contrast to former reports [8,45,49], we observed heat hyperalgesia in more than 40% of CRPS-I patients. Pressure pain hyperalgesia even occurred in about 70%. According to current concepts of pain mechanisms, there is much evidence that heat hyperalgesia is predominantly due to peripheral sensitization of nociceptors [4,27], although central mechanisms cannot be excluded. The observation that pressure pain hyperalgesia was present only in the primary zone after sensitizing the skin with capsaicin, also implies a peripheral origin [24]. This suggests that peripheral sensitization might play a more important role in CRPS than previously thought [22], particularly in early stages. Loss of detection in CRPS-II can be regarded as a consequence of nerve injury, but is an interesting finding in CRPS-I, where by definition no overt nerve lesion exists. Increased thermal and mechanical detection thresholds have been reported in CRPS [8,23,40,45], but their pathogenesis in CRPS-I is unclear. Loss of detection in combination with spontaneous pain and hyperalgesia/allodynia can be either due to peripheral nerve lesion and consecutive spontaneous activity of rostral afferent pathways [11,31] or it can be secondary to nociceptive stimulation, that is, pain-induced hypoesthesia [12,29,30,37] Is CRPS-I a small fiber neuropathy? Recently, a small fiber neuropathy has been suggested to be a mechanism of CRPS-I [39] because C-fiber degeneration was found in sural nerves of CRPS-I patients [52] and reduced epidermal, sweat gland, and vascular [2], as well as intraepidermal, small fibers were shown [40]. These findings suggest a peripheral nerve lesion in CRPS-I due to, for example, minimal nerve injuries [38,40]. As these minimal nerve injuries include only some, but not all fibers, they could possibly be detected by QST, but remain undetected in clinical settings (cf. spinal cord injury [19]). Since almost all patients with CRPS-I had a preceding trauma, a minor nerve injury is imaginable. In this study, a dysfunction of small fiber afferent pathways was observed in 39% of patients with CRPS-I (isolated: 14%, combined: 25%), whereas dysfunction of large fiber afferent pathways occurred in 48% (isolated: 23%, combined: 25%) and no loss of detection was observed in 37%. Overall, about 60% of patients with CRPS- I had a proper function of small fiber afferent pathways. Therefore, our results demonstrate that an isolated small fiber neuropathy is unlikely to be a major mechanism in CRPS-I Loss of detection in CRPS-I central inhibition? Although CRPS-I patients with loss of detection had less pain sensitivity, suggesting deafferentation, only a mild correlation between loss of mechanical detection and loss for painful stimuli was observed. QST cannot differentiate between a peripheral or central dysfunction, and several reports have also given evidence for an involvement of the central nervous system in CRPS [35,36,43,54]. Loss of function could therefore also be due to central plasticity induced by activation of the nociceptive system as it has been shown in clinical and experimental pain, that is, pain-induced hypoesthesia [10,12,29,30,33,37]. In contrast to chronic pain syndromes [1],

9 J. Gierthmühlen et al. / PAIN Ò 153 (2012) pain intensity showed only a marginal correlation with detection thresholds and these did not differ between patients with severe or milder pain. This makes pain-induced hypoesthesia unlikely to be the main cause for loss of detection. Nevertheless, we cannot exclude a more dominant role of pain-induced hypoesthesia in the very beginning of CRPS-I, as pain-induced hypoesthesia has mostly been demonstrated in acute pain Differences between CRPS and PNI Although CRPS patients had more sensory gain and less sensory loss than patients with PNI, no characteristic patterns of gain and loss were found in all 3 entities. The only sign differing between CRPS and PNI was an increased pressure pain and a slightly increased heat pain sensitivity in CRPS. The high frequency of pressure pain hyperalgesia in CRPS is in line with the clinical observation of an involvement of deep somatic tissue in CRPS, for example, occurrence of bone atrophy [7,41] or an increased periarticular uptake in the delayed phase of 3-phase bone scintigraphy [3,14,48,55]. However, neither mechanical nor, in particular, thermal hyperalgesia were significantly more frequent in CRPS than in PNI, although both signs have recently been included in a newly proposed CRPS severity score [18]. Pressure pain hyperalgesia was also present in about 50% of PNI patients. This emphasizes the importance of presence of autonomic signs [46,54] and impairment of motor function [53], as well as the spreading tendency of signs and symptoms in order to accurately diagnose CRPS. QST alone seems inappropriate to discriminate between CRPS or PNI on the individual level Technical considerations Limitations of this study include the use of reference z-values from the dorsum of the hand, although QST measurements were performed in the most painful area of the hand. We are aware that there are small differences between dorsum and palmar site of the hand and cannot exclude that this might have influenced our results. Furthermore, detailed information of fulfillment of diagnostic criteria of CRPS was not entered into the database. However, there is no risk of mixing diagnoses, as all centers of the DFNS are experts in their field. It should be kept in mind that the CRPS groups had a high proportion of patients with short disease duration (approximately 50% <6 months) and that the majority of PNI patients was included by one center (Bochum). Both may have also influenced our results Conclusions This study, for the first time, compared several different somatosensory abnormalities in a large group of CRPS-I, CRPS-II, and PNI patients. Main conclusions are: QST of CRPS-I, CRPS-II, and PNI patients found a spectrum of overlapping, but also somewhat distinct, somatosensory abnormalities. On the individual level, all patterns of gain and loss were found in CRPS and PNI. QST alone cannot discriminate between CRPS and PNI. Sensory profiles suggest that CRPS-I and CRPS-II may represent one disease continuum with comparable underlying mechanisms. More sensory loss was observed in CRPS-I than hitherto considered, suggesting either minimal nerve injury or central inhibition. In contrast to recent suggestions, a small fiber neuropathy seems unlikely to be a major underlying mechanism in CRPS-I. Sensory gain is highly prevalent in PNI, indicating a better similarity of animal models to human patients than previously thought. Conflict of interest statement There were no conflicts of interests. Acknowledgements This work was supported by the Bundesministerium für Bildung und Forschung (BMBF, Grants 01EM EM0512, 01EM EM0904 for the German Research Network on Neuropathic Pain [DFNS]). None of the sponsors was involved in design and conduct of the study, in collection, management, analysis, interpretation and preparation of the data, review, or approval of the manuscript. We are indebted to the subjects who participated in the study for their consent and cooperation. References [1] Agostinho CM, Scherens A, Richter H, Schaub C, Rolke R, Treede RD, Maier C. Habituation and short-term repeatability of thermal testing in healthy human subjects and patients with chronic non-neuropathic pain. Eur J Pain 2009;13: [2] Albrecht PJ, Hines S, Eisenberg E, Pud D, Finlay DR, Connolly MK, Pare M, Davar G, Rice FL. Pathologic alterations of cutaneous innervation and vasculature in affected limbs from patients with complex regional pain syndrome. Pain 2006;120: [3] Atkins RM, Tindale W, Bickerstaff D, Kanis JA. Quantitative bone scintigraphy in reflex sympathetic dystrophy. Br J Rheumatol 1993;32:41 5. [4] Baron R. Mechanisms of disease: neuropathic pain a clinical perspective. Nat Clin Pract Neurol 2006;2: [5] Baumgartner U, Magerl W, Klein T, Hopf HC, Treede RD. Neurogenic hyperalgesia versus painful hypoalgesia: two distinct mechanisms of neuropathic pain. Pain 2002;96: [6] Bennett GJ. An animal model of neuropathic pain: a review. Muscle Nerve 1993;16: [7] Bickerstaff DR, O Doherty DP, Kanis JA. Radiographic changes in algodystrophy of the hand. J Hand Surg 1991;16: [8] Birklein F, Riedl B, Sieweke N, Weber M, Neundorfer B. Neurological findings in complex regional pain syndromes analysis of 145 cases. Acta Neurol Scand 2000;101: [9] Chung JM, Kim HK, Chung K. Segmental spinal nerve ligation model of neuropathic pain. Methods Mol Med 2004;99: [10] De Col R, Maihofner C. Centrally mediated sensory decline induced by differential C-fiber stimulation. Pain 2008;138: [11] Devor M, Wall PD, Catalan N. Systemic lidocaine silences ectopic neuroma and DRG discharge without blocking nerve conduction. Pain 1992;48: [12] Geber C, Magerl W, Fondel R, Fechir M, Rolke R, Vogt T, Treede RD, Birklein F. Numbness in clinical and experimental pain a cross-sectional study exploring the mechanisms of reduced tactile function. Pain 2008;139: [13] Geber C, Scherens A, Pfau D, Nestler N, Zenz M, Tolle T, Baron R, Treede RD, Maier C. Procedure for certification of QST laboratories [German]. Schmerz 2009;23:65 9. [14] Genant HK, Kozin F, Bekerman C, McCarty DJ, Sims J. The reflex sympathetic dystrophy syndrome. A comprehensive analysis using fine-detail radiography, photon absorptiometry, and bone and joint scintigraphy. Radiology 1975;117: [15] Greenspan JD, McGillis SL. Stimulus features relevant to the perception of sharpness and mechanically evoked cutaneous pain. Somatosens Mot Res 1991;8: [16] Harden N, Bruehl S. Diagnostic criteria: the statistical derivation of the four criterion factors. In: Wilson P, Stanton-Hicks M, Harden N, editors. CRPS: current diagnosis and therapy, vol. 32. Seattle: IASP Press; p [17] Harden RN, Bruehl S, Perez RS, Birklein F, Marinus J, Maihofner C, Lubenow T, Buvanendran A, Mackey S, Graciosa J, Mogilevski M, Ramsden C, Chont M, Vatine JJ. Validation of proposed diagnostic criteria (the Budapest Criteria ) for Complex Regional Pain Syndrome. Pain 2010;150: [18] Harden RN, Bruehl S, Perez RS, Birklein F, Marinus J, Maihofner C, Lubenow T, Buvanendran A, Mackey S, Graciosa J, Mogilevski M, Ramsden C, Schlereth T, Chont M, Vatine JJ. Development of a severity score for CRPS. Pain 2010;151: [19] Hayes KC, Wolfe DL, Hsieh JT, Potter PJ, Krassioukov A, Durham CE. Clinical and electrophysiologic correlates of quantitative sensory testing in patients with incomplete spinal cord injury. Arch Phys Med Rehabil 2002;83: [20] Herrero JF, Laird JM, Lopez-Garcia JA. Wind-up of spinal cord neurones and pain sensation: much ado about something? Prog Neurobiol 2000;61: