Effect duration of lumbar sympathetic ganglion neurolysis in patients with complex regional pain syndrome: a prospective observational study.

Lumbar sympathetic ganglion neurolysis (LSGN) has been used for long-term pain relief in patients with complex regional pain syndrome (CRPS). However, the actual effect duration of LSGN has not been accurately measured. This prospective observational study measured the effect duration of LSGN in CRPS patients and investigated the relationship between temperature change and pain relief. After performing LSGN, the skin temperatures of both the maximum pain site and the plantar area in the affected and unaffected limbs were measured by infrared thermography, and pain intensity was assessed before and at 2 weeks, 1 month, and 3 months. The median time to return to baseline temperature was calculated using survival analysis. The skin temperature increased significantly at all-time points relative to baseline in both regions (maximum pain site: 1.4 °C ± 1.0 °C, plantar region: 1.28 °C ± 0.8 °C, all P < 0.001). The median time to return to baseline temperature was 12 weeks (95% confidence interval [CI] 7.7-16.3) at the maximum pain site and 12 weeks (95% CI 9.4-14.6) at the plantar area. Pain intensity decreased significantly relative to baseline, at all-time points after LSGN. In conclusion, the median duration of the LSGN is estimated to be 12 weeks.

A decision tree algorithm to identify predictors of post-stroke complex regional pain syndrome.

This prospective cohort study aimed to identify the risk factors for post-stroke complex regional pain syndrome (CRPS) using a decision tree algorithm while comprehensively assessing upper limb and lower limb disuse and physical inactivity. Upper limb disuse (Fugl-Meyer assessment of upper extremity [FMA-UE], Action Research Arm Test, Motor Activity Log), lower limb disuse (Fugl-Meyer Assessment of lower extremity [FMA-LE]), balance performance (Berg balance scale), and physical inactivity time (International Physical Activity Questionnaire-Short Form [IPAQ-SF]) of 195 stroke patients who visited the Kishiwada Rehabilitation Hospital were assessed at admission. The incidence of post-stroke CRPS was 15.4% in all stroke patients 3 months after admission. The IPAQ, FMA-UE, and FMA-LE were extracted as risk factors for post-stroke CRPS. According to the decision tree algorithm, the incidence of post-stroke CRPS was 1.5% in patients with a short physical inactivity time (IPAQ-SF < 635), while it increased to 84.6% in patients with a long inactivity time (IPAQ-SF ≥ 635) and severe disuse of upper and lower limbs (FMA-UE score < 19.5; FMA-LE score < 16.5). The incidence of post-stroke CRPS may increase with lower-limb disuse and physical inactivity, in addition to upper-limb disuse. Increasing physical activity and addressing lower- and upper-limb motor paralysis may reduce post-stroke CRPS.

Bilateral deficiency of Meissner corpuscles and papillary microvessels in patients with acute complex regional pain syndrome.

ABSTRACT: Complex regional pain syndrome (CRPS) presents postinjury with disproportionate pain and neuropathic, autonomic, motor symptoms, and skin texture affection. However, the origin of these multiplex changes is unclear. Skin biopsies offer a window to analyze the somatosensory and vascular system as well as skin trophicity with their protecting barriers. In previous studies, barrier-protective exosomal microRNAs were altered in CRPS. We here postulated that tissue architecture and barrier proteins are already altered at the beginning of CRPS. We analyzed ipsilateral and contralateral skin biopsies of 20 fully phenotyped early CRPS patients compared with 20 age- and sex-matched healthy controls. We established several automated unbiased methods to comprehensively analyze microvessels and somatosensory receptors as well as barrier proteins, including claudin-1, claudin-5, and claudin-19. Meissner corpuscles in the skin were bilaterally reduced in acute CRPS patients with some of them lacking these completely. The number of Merkel cells and the intraepidermal nerve fiber density were not different between the groups. Dermal papillary microvessels were bilaterally less abundant in CRPS, especially in patients with allodynia. Barrier proteins in keratinocytes, perineurium of dermal nerves, Schwann cells, and papillary microvessels were not affected in early CRPS. Bilateral changes in the tissue architecture in early CRPS might indicate a predisposition for CRPS that manifests after injury. Further studies should evaluate whether these changes might be used to identify risk patients for CRPS after trauma and as biomarkers for outcome.

Investigating Object Affordance in People with Complex Regional Pain Syndrome: No Alterations in the Automatic Activation of Motor Plans.

Complex Regional Pain Syndrome (CRPS) is a condition of chronic pain, predominantly affecting one limb. CRPS is characterised by motor changes including slowed or uncoordinated movements. Cognitive processes that drive movement planning and/or execution might contribute to these changes. We aimed to investigate the potential alterations to such cognitive mechanisms using an 'object affordance' paradigm. Object affordance refers to the observation that viewing an object modulates associated motor responses, presumably due to the automatic activation of a motor plan. We hypothesised that people with CRPS would show reduced object affordance effects for their affected compared to unaffected hand, and compared to pain-free controls. First, we validated an online object affordance task involving button press responses to everyday objects with handles, in pain-free participants (n = 63; Experiment 1). Object affordance was reflected by faster and more accurate responses when the object handle was aligned to the responding hand ("aligned") compared to when the handle was aligned to the other hand ("non-aligned"). These results were similar for the online task as when administered in person. Second, in a case-control study, we administered the online object affordance task to people with CRPS predominantly affecting the upper limb (n = 25), and age-matched pain-free controls (n = 68; Experiment 2). People with CRPS responded faster and more accurately in the aligned versus non-aligned condition (ie, an object affordance effect), both for the affected and unaffected hands. There were no differences to pain-free participants. Therefore, object affordance effects were seen in people with CRPS, providing no evidence for altered motor planning. PERSPECTIVE: This article presents research investigating cognitive processes related to motor planning in Complex Regional Pain Syndrome (CRPS). Using an online object affordance paradigm, validated in pain-free controls, the authors found that people with CRPS showed intact object affordance effects in the affected and unaffected hand, suggesting unaltered motor planning. DATA AVAILABILITY: The experiment materials, data, pre-processing scripts, and analysis scripts can be found via Open Science Framework (https://osf.io/nc825/files/osfstorage).

Pupillary Reflexes in Complex Regional Pain Syndrome: Asymmetry to Arousal Stimuli Suggests an Ipsilateral Locus Coeruleus Deficit.

Converging lines of evidence suggest that autonomic and nociceptive pathways linked with the locus coeruleus are disrupted in complex regional pain syndrome (CRPS). To investigate this, pupillary dilatation to arousal stimuli (which reflects neural activity in the locus coeruleus) and pupillary reflexes to light were assessed in a cross-sectional study of 33 patients with CRPS. Moderately painful electrical shocks were delivered to the affected or contralateral limb and unilateral 110 dB SPL acoustic startle stimuli were delivered via headphones. To determine whether the acoustic startle stimuli inhibited shock-induced pain, startle stimuli were also administered bilaterally 200 ms before or after the electric shock. The pupils constricted briskly and symmetrically to bright light (500 lux) and dilated symmetrically in dim light (5 lux). However, the pupil on the CRPS-affected side was smaller than the contralateral pupil before and after the delivery of painless and painful arousal stimuli. Auditory sensitivity was greater on the affected than unaffected side but acoustic startle stimuli failed to inhibit shock-induced pain. Together, these findings suggest that neural activity in pathways linked with the locus coeruleus is compromised on the affected side in patients with CRPS. This may contribute to autonomic disturbances, auditory discomfort and pain. PERSPECTIVE: The locus coeruleus is involved not only in modulation of pain but also regulates sensory traffic more broadly. Hence, fatigue of neural activity in the ipsilateral locus coeruleus might not only exacerbate pain and hyperalgesia in CRPS but could also contribute more generally to hemilateral disturbances in sensory processing.

Normal manual straight ahead pointing in Complex Regional Pain Syndrome.

There is evidence to suggest that people with Complex Regional Pain Syndrome (CRPS) can have altered body representations and spatial cognition. One way of studying these cognitive functions is through manual straight ahead (MSA) pointing, in which participants are required to point straight ahead of their perceived body midline without visual feedback of the hand. We therefore compared endpoint errors from MSA pointing between people with CRPS (n = 17) and matched controls (n = 18), and examined the effect of the arm used (Side of Body; affected/non-dominant, non-affected/dominant). For all participants, pointing errors were biased towards the hand being used. We found moderate evidence of no difference between Groups on endpoint errors, and moderate evidence of no interaction with Side of Body. The differences in variability between Groups were non-significant/inconclusive. Correlational analyses showed no evidence of a relationship between MSA endpoint errors and clinical parameters (e.g. CRPS severity, duration, pain) or questionnaire measures (e.g. body representation, "neglect-like symptoms", upper limb disability). This study is consistent with earlier findings of no difference between people with CRPS and controls on MSA endpoint errors, and is the first to provide statistical evidence of similar performance of these two groups. Our results do not support a relationship between clinical or self-reported measures (e.g. "neglect-like symptoms") and any directional biases in MSA. Our findings may have implications for understanding neurocognitive changes in CRPS.

Low mechano-afferent fibers reduce thermal pain but not pain intensity in CRPS.

BACKGROUND: Human hairy (not glabrous skin) is equipped with a subgroup of C-fibers, the C-tactile (CT) fibers. Those do not mediate pain but affective aspects of touch. CT-fiber-activation reduces experimental pain if they are intact. In this pilot study we investigated pain modulating capacities of CT-afferents in CRPS. METHODS: 10 CRPS-patients (mean age 33 years, SEM 3.3) and 11 healthy controls (mean age 43.2 years, SEM 3.9) participated. CT-targeted-touch (brush stroking, velocity: 3 cm/s) was applied on hairy and glabrous skin on the affected and contralateral limb. Patients rated pleasantness of CT-targeted-touch (anchors: 1 "not pleasant"-4 "very pleasant") twice daily on 10 days. Pain intensity (NRS: 0 "no pain" - 10 "worst pain imaginable") was assessed before, 0, 30, 60 and 120 min after each CT-stimulation. To assess sensory changes, quantitative-sensory-testing was performed at the beginning and the end of the trial period. RESULTS: CT-targeted-touch was felt more pleasant on the healthy compared to the affected limb on hairy (p < 0.001) and glabrous skin (p 0.002), independent of allodynia. In contrast to healthy controls patients felt no difference between stimulating glabrous and hairy skin on the affected limb. Thermal pain thresholds increased after CT-stimulation on the affected limb (cold-pain-threshold: p 0.016; heat-pain-threshold: p 0.033). CONCLUSIONS: CT-stimulation normalizes thermal pain thresholds but has no effect on the overall pain in CRPS. Therefore, pain modulating properties of CT-fibers might be too weak to alter chronic pain in CRPS. Moreover, CT-fibers appear to lose their ability to mediate pleasant aspects of touch in CRPS.

Neuroanatomical correlates of poststroke complex regional pain syndrome: a voxel-based lesion symptom-mapping study.

Complex regional pain syndrome (CRPS) is a common poststroke complication. However, the neural substrates associated with CRPS remain unclear. We investigated the neural correlates associated with poststroke CRPS using voxel-based lesion‒symptom mapping (VLSM) analysis. Among 145 patients with ischemic stroke, 35 were diagnosed with CRPS and categorized into the poststroke CRPS group, and the remaining 110 into the control group. We compared the clinical characteristics between the groups. VLSM analysis was performed to identify the brain region associated with the development of poststroke CRPS. The clinical findings suggested that the poststroke CRPS group had lower muscle strength; lower scores on Fugl‒Meyer assessment, Manual Function Test, Mini-Mental Status Examination; and higher incidence of absent somatosensory evoked potentials in the median nerve than the control group. The head of the caudate nucleus, putamen, and white matter complexes in the corona radiata were significantly associated with poststroke CRPS development in ischemic stroke patients. These results facilitate an understanding of poststroke CRPS pathophysiology. Monitoring patients with lesions in these structures may aid the prevention and early treatment of poststroke CRPS.

Functional dystonia in the foot and ankle.

AIMS: To assess the characteristic clinical features, management, and outcome of patients who present to orthopaedic surgeons with functional dystonia affecting the foot and ankle. METHODS: We carried out a retrospective search of our records from 2000 to 2019 of patients seen in our adult tertiary referral foot and ankle unit with a diagnosis of functional dystonia. RESULTS: A total of 29 patients were seen. A majority were female (n = 25) and the mean age of onset of symptoms was 35.3 years (13 to 71). The mean delay between onset and diagnosis was 7.1 years (0.5 to 25.0). Onset was acute in 25 patients and insidious in four. Of the 29 patients, 26 had a fixed dystonia and three had a spasmodic dystonia. Pain was a major symptom in all patients, with a coexisting diagnosis of chronic regional pain syndrome (CRPS) made in nine patients. Of 20 patients treated with Botox, only one had a good response. None of the 12 patients who underwent a surgical intervention at our unit or elsewhere reported a subjective overall improvement. After a mean follow-up of 3.2 years (1 to 12), four patients had improved, 17 had remained the same, and eight reported a deterioration in their condition. CONCLUSION: Patients with functional dystonia typically presented with a rapid onset of fixed deformity after a minor injury/event and pain out of proportion to the deformity. Referral to a neurologist to rule out neurological pathology is advocated, and further management should be carried out in a movement disorder clinic. Response to treatment (including Botulinum toxin (Botox) injections) is generally poor. Surgery in this group of patients is not recommended and may worsen the condition. The overall prognosis remains poor. Cite this article: Bone Joint J 2021;103-B(6):1127-1132.

Sensory Function and Psychological Factors in Children With Complex Regional Pain Syndrome Type 1.

OBJECTIVE: To assess thermal-sensory thresholds and psychosocial factors in children with Complex Regional Pain Syndrome Type 1 (CRPS-I) compared to healthy children. METHODS: We conducted quantitative sensory testing on 34 children with CRPS-I and 56 pain-free children. Warm, cool, heat, and cold stimuli were applied to the forearm. Children with CRPS-I had the protocol administered to the pain site and the contralateral-pain site. Participants completed the self-report Behavior Assessment System for Children. RESULTS: Longer pain durations (>5.1 months) were associated with decreased sensitivity to cold pain on the pain site (P = .04). Higher pain-intensity ratings were associated with elevated anxiety scores (P = .03). Anxiety and social stress were associated with warmth sensitivity (both P < .05) on the contralateral-pain site. CONCLUSIONS: Pain duration is an important factor in assessing pediatric CRPS-I. Hyposensitivity in the affected limb may emerge due to degeneration of nociceptive nerves. Anxiety may contribute to thermal-sensory perception in childhood CRPS-I.

Local and Systemic Expression Pattern of MMP-2 and MMP-9 in Complex Regional Pain Syndrome.

Matrix metalloproteinases (MMP)-2 and MMP-9 play important roles in inflammation as well as in pain processes. For this reason, we compared the concentrations of these enzymes in skin and serum of patients with complex regional pain syndrome (CRPS), other pain diseases and healthy subjects. We analyzed ipsi- and contralateral skin biopsies of 18 CRPS patients, as well as in 10 pain controls and 9 healthy subjects. Serum samples were analyzed from 20 CRPS, 17 pain controls and 17 healthy subjects. All samples were analyzed with ELISA. Concentrations were then compared to clinical data as well as to quantitative sensory testing data.MMP-2 was increased in both ipsi- and contralateral skin biopsies of CRPS patients compared to healthy subjects. While low ipsilateral MMP-2 was associated with trophic changes, contralateral MMP-2 inversely correlated with the CRPS severity. MMP-9 was also locally increased in ipsilateral CRPS skin, and higher ipsi- and contralateral MMP-9 levels correlated with CRPS severity. We conclude that MMP-2 and MMP-9 are differently expressed depending on the clinical phenotype in CRPS. PERSPECTIVE: This article describes an upregulation of MMPs in CRPS and pain controls and shows different expression of MMP-2 and -9 depending on clinical phenotype in CRPS. These results provide evidence that MMP-2 and -9 play a key role in CRPS pathophysiology.

Review of complex regional pain syndrome and the role of the neuroimmune axis.

BACKGROUND: Complex regional pain syndrome (CRPS) is a progressive and painful disease of the extremities that is characterized by continuous pain inconsistent with the initial trauma. CRPS is caused by a multi-mechanism process that involves both the peripheral and central nervous system, with a prominent role of inflammation in CRPS pathophysiology. This review examines what is currently known about the CRPS inflammatory and pain mechanisms, as well as the possible impact of neurostimulation therapies on the neuroimmune axis of CRPS. STUDY DESIGN: A narrative review of preclinical and clinical studies provided an overview of the pain and inflammatory mechanisms in CRPS and addressed the effect of neurostimulation on immunomodulation. METHODS: A systematic literature search was conducted based on the PRISMA guidelines between September 2015 to September 2020. Data sources included relevant literature identified through searches of PubMed, Embase and the Cochrane Database of Systematic Reviews. RESULTS: Sixteen preclinical and eight clinical studies were reviewed. Preclinical studies identified different mechanisms of pain development in the acute and chronic CRPS phases. Several preclinical and clinical studies investigating inflammatory mechanisms, autoimmunity, and genetic profiles in CRPS, supported a role of neuroinflammation in the pathophysiology of CRPS. The immunomodulatory effects of neurostimulation therapy is still unclear, despite clinical improvement in the CRPS patients. CONCLUSIONS: Increasing evidence supports a role for inflammation and neuroinflammation in CRPS pathophysiology. Preliminary neurostimulation findings, together with the role of (neuro)inflammation in CRPS, seems to provide a compelling rationale for its use in CRPS pain treatment. The possible immunomodulatory effects of neurostimulation opens new therapeutic possibilities, however further research is needed to gain a better understanding of the working mechanisms.

Neurological Causes of Chest Pain.

PURPOSE OF REVIEW: Chest pain is a very common presenting complaint among patients in the hospital, a large proportion of whom have non-cardiac chest pain (NCCP). Neurological causes of NCCP have not been previously reviewed although several causes have been identified. RECENT FINDINGS: Chest pain has been reported as a symptom of multiple neurological conditions such as migraine, epilepsy, and multiple sclerosis, with varying clinical presentations. The affected patients are often not formally diagnosed for long periods of time due to difficulties in recognizing the symptoms as part of neurological disease processes. This paper will briefly summarize well-known etiologies of chest pain and, then, review neurological causes of NCCP, providing an overview of current literature and possible pathophysiologic mechanisms.

Dimethyl Fumarate Reduces Oxidative Stress and Pronociceptive Immune Responses in a Murine Model of Complex Regional Pain Syndrome.

BACKGROUND: Complex regional pain syndrome (CRPS) is a highly disabling cause of pain often precipitated by surgery or trauma to a limb. Both innate and adaptive immunological changes contribute to this syndrome. Dimethyl fumarate (DMF) works through the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor and other targets to activate antioxidant systems and to suppress immune system activation. We hypothesized that DMF would reduce nociceptive, functional, and immunological changes measured in a model of CRPS. METHODS: Male C57BL/6 mice were used in the well-characterized tibial fracture model of CRPS. Some groups of mice received DMF 25 mg/kg/d orally, per os for 3 weeks after fracture versus vehicle alone. Homozygous Nrf2 null mutant mice were used as test subjects to address the need for this transcription factor for DMF activity. Allodynia was assessed using von Frey filaments and hindlimb weight-bearing data were collected. The markers of oxidative stress malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) were quantified in the skin of the fractured mice using immunoassays along with the innate immune system cytokines IL-1ß and IL-6. The accumulation of IgM in the fractured limbs and lymph node hypertrophy were used as indexes of adaptive immune system activation, and the passive transfer of serum from wildtype fractured mice to B cell-deficient fractured muMT mice (mice lacking B cells and immunoglobulin) helped to assess the pronociceptive activity of humoral factors. RESULTS: We observed that oral DMF administration strongly prevented nociceptive sensitization and reduced uneven hindlimb weight bearing after fracture. DMF was also very effective in reducing the accumulation of markers of oxidative stress, activation of innate immune mediator production, lymph node hypertrophy, and the accumulation of IgM in fractured limbs. The sera of fractured vehicle-treated but not DMF-treated mice conferred pronociceptive activity to recipient mice. Unexpectedly, the effects of DMF were largely unchanged in the Nrf2 null mutant mice. CONCLUSIONS: Oxidative stress and immune system activation are robust after hindlimb fracture in mice. DMF strongly reduces activation of those systems, and the Nrf2 transcription factor is not required. DMF or drugs working through similar mechanisms might provide effective therapy for CRPS or other conditions where oxidative stress causes immune system activation.

Changes in visual attentional behavior in complex regional pain syndrome: A preliminary study.

PURPOSE: The purpose of the present study was to investigate the visual attentional behavior towards a pain-affected area and face/body images using eye tracking in complex regional pain syndrome (CRPS) patients. Moreover, we investigated the relationship between visual attentional behavior and clinical symptoms. PATIENTS AND METHODS: Eight female patients with CRPS type 1 in their upper limbs and 8 healthy adult women participated in this study. First, the participants were asked to watch videoclips in a relaxed manner (Videoclip 1 featured young adults who introduced themselves; Videoclip 2 featured young adults touching the hand of the other person sitting across from them with their hand.) Eye movement data were tracked with eye-tracking glasses. RESULTS: In video clip 1, the fixation duration (FD) and fixation count (FC) on faces tended to be lower in CRPS patients than in healthy controls. This tendency was found in patients with low body cognitive distortions. In video clip 2, CRPS patients displayed significantly lower FD and FC on the unaffected hand while watching a video of the unaffected hand being touched compared with healthy controls. Moreover, patients with low body cognitive distortion displayed significantly longer FD on the affected hand. CONCLUSION: Some CRPS patients differed in visual attentional behavior toward the face and body compared with healthy controls. In addition, our findings suggest that patients with lower body cognitive distortion may have a high visual attention for the affected hand, while patients with higher distortion may be neglecting the affected hand.

Modifications in fMRI Representation of Mental Rotation Following a 6 Week Graded Motor Imagery Training in Chronic CRPS Patients.

Complex regional pain syndrome (CRPS) is a neuropathic pain condition that is difficult to treat. For behavioral interventions, graded motor imagery (GMI) showed relevant effects, but underlying neural substrates in patient groups have not been investigated yet. A previous study investigating differences in the representation of a left/right hand judgment task demonstrated less recruitment of subcortical structures, such as the putamen, in CRPS patients than in healthy controls. In healthy volunteers, the putamen activity increased after a hand judgment task training. In order to test for longitudinal effects of GMI training, we investigated 20 CRPS patients in a wait-list crossover design with 3 evaluation time points. Patients underwent a 6 week GMI treatment and a 6 week waiting period in a randomized group assignment and treatment groups were evaluated by a blinded rater. When compared to healthy matched controls at baseline, CRPS patients showed less functional activation in areas processing visual input, left sensorimotor cortex, and right putamen. Only GMI treatment, but not the waiting period showed an effect on movement pain and hand judgment task performance. Regression analyses revealed positive associations of movement pain with left anterior insula activation at baseline. Right intraparietal sulcus activation change during GMI was associated with a gain in performance of the hand judgment task. The design used here is reliable for investigating the functional representation of the hand judgment task in an intervention study. PERSPECTIVE: Twenty chronic CRPS patients underwent a 6 week GMI intervention in a randomized wait-list crossover design. functional MRI was tested pre and post for the hand lateralization task which improved over GMI but not over WAITING. Performance gain was positively related to right parietal functional MRI activation.

Altered visuomotor integration in complex regional pain syndrome.

During self-guided movements, we optimise performance by combining sensory and self-motion cues optimally, based on their reliability. Discrepancies between such cues and problems in combining them are suggested to underlie some pain conditions. Therefore, we examined whether visuomotor integration is altered in twenty-two participants with upper or lower limb complex regional pain syndrome (CRPS) compared to twenty-four controls. Participants located targets that appeared in the unaffected (CRPS) / dominant (controls) or affected (CRPS) / non-dominant (controls) side of space, using the hand of their unaffected/dominant or affected/non-dominant side of the body. For each side of space and each hand, participants located the target using visual information and no movement (vision only condition), an unseen pointing movement (self-motion only condition), or a visually-guided pointing movement (visuomotor condition). In all four space-by-hand conditions, controls reduced their variability in the visuomotor compared to the vision and self-motion only conditions and in line with a model prediction for optimal integration. Participants with CRPS showed similar evidence of cue combination in two of the four conditions. However, they had better-than-optimal integration for the unaffected hand in the affected space. Furthermore, they did not integrate optimally for the hand of the affected side of the body in unaffected space, but instead relied on the visual information. Our results suggest that people with CRPS can optimally integrate visual and self-motion cues under some conditions, despite lower reliability of self-motion cues, and use different strategies to controls.

Is adhesive capsulitis of the shoulder a form of complex regional pain syndrome type I?

[No Abstract Available].