Alpha-lipoic acid reduces nociception by reducing oxidative stress and neuroinflammation in a model of complex regional pain syndrome type I in mice.

Complex regional pain syndrome type I (CRPS-I) is a disabling pain condition without adequate treatment. Chronic post-ischemia pain injury (CPIP) is a model of CRPS-I that causes allodynia, spontaneous pain, inflammation, vascular injury, and oxidative stress formation. Antioxidants, such as alpha lipoic acid (ALA), have shown a therapeutic potential for CRPS-I pain control. Thus, we aim to evaluate if ALA repeated treatment modulates neuroinflammation in a model of CRPS-I in mice. We used male C57BL/6 mice to induce the CPIP model (O-ring torniquet for 2 h in the hindlimb). For the treatment with ALA or vehicle (Veh) mice were randomly separated in four groups and received 100 mg/kg orally once daily for 15 days (CPIP-ALA, CPIP-Veh, Control-ALA, and Control-Veh). We evaluated different behavioral tests including von Frey (mechanical stimulus), acetone (cold thermal stimulus), rotarod, open field, hind paw edema determination, and nest-building (spontaneous pain behavior). Also, hydrogen peroxide (H2O2) levels, NADPH oxidase and superoxide dismutase (SOD) activity in the sciatic nerve and spinal cord, and Iba1, Nrf2, and Gfap in spinal cord were evaluated at 16 days after CPIP or sham induction. Repeated ALA treatment reduced CPIP-induced mechanical and cold allodynia and restored nest-building capacity without causing locomotor or body weight alteration. ALA treatment reduced SOD and NADPH oxidase activity, and H2O2 production in the spinal cord and sciatic nerve. CPIP-induced neuroinflammation in the spinal cord was associated with astrocyte activation and elevated Nfr2, which were reduced by ALA. ALA repeated treatment prevents nociception by reducing oxidative stress and neuroinflammation in a model of CRPS-I in mice.

Novel Presentation of Pediatric Complex Regional Pain Syndrome with Concurrent Chromhidrosis: A Case Report.

CASE: An 11-year-old female patient presented to our clinic with a low-grade lateral ankle sprain that was subsequently treated with a lace-up ankle brace. On the reintroduction of weight bearing, the patient developed recurrent ankle pain and symptoms consistent with complex regional pain syndrome (CRPS) Type 1. On physical examination, the patient was found to have a concurrent chromhidrosis in the injured area, which is a novel presentation of CRPS. CONCLUSION: Patients with CRPS found to have superficial skin discoloration should be evaluated further to investigate for chromhidrosis. Early diagnosis can improve the treatment of CRPS and allow for appropriate management of varying manifestations, such as chromhidrosis.

Socioeconomic Disparities in the Utilization of Spinal Cord Stimulation Therapy in Patients with Chronic Pain.

OBJECTIVES: Spinal cord stimulation (SCS) therapies are used in the management of patients with complex regional pain syndrome I (CRPS I) and failed back surgery syndrome (FBSS). The purpose of this study was to investigate the racial and health insurance inequalities with SCS therapy in patients with chronic pain who had CRPS I and FBSS. METHODS: Patients with chronic pain who had a discharge diagnosis of FBSS and CRPS I were identified using the National Inpatient Sample database. Our primary outcome was defined as the history of SCS utilization by race/ethnicity, income quartile, and insurance status. Multivariable logistic regression was used to determine the variables associated with utilization of SCS therapy. RESULTS: Between 2011 and 2015, 40,858 patients who were hospitalized with a primary diagnosis of FBSS and/or CRPS I were identified. Of these patients, 1,082 (2.7%) had a history of SCS therapy. Multivariable regression analysis revealed that compared to White patients, Black and Hispanic patients had higher odds of having SCS therapy (Black patients: odds ratio [OR] = 1.41; 95% confidence interval [CI], 1.12 to 1.77; P = 0.003; Hispanic patients: OR = 1.41; 95% CI, 1.10 to 1.81; P = 0.007). Patients with private insurance had significantly higher odds of having SCS therapy compared with those with Medicare (OR = 1.24; 95% CI, 1.08 to 1.43; P = 0.003). Compared to patients with Medicare, Medicaid patients had lower odds of having SCS therapy (OR = 0.50; 95% CI, 0.36 to 0.70; P < 0.001). CONCLUSIONS: Our study suggests that socioeconomic disparities may exist in the utilization of SCS among hospitalized patients with CRPS I and FBSS the United States. However, confirming these data from other administrative databases, in the outpatient setting, may shed more insight.

Clinical Features of Pediatric Complex Regional Pain Syndrome: A 5-Year Retrospective Chart Review.

OBJECTIVES: Complex regional pain syndrome (CRPS) is a painful condition of a limb characterized by a constellation of symptoms. Little is known about the clinical features of pediatric CRPS, with fewer than a dozen studies published to date. The aim of this study was to explore the clinical course of pediatric CRPS, with emphasis on clinical features and disease outcomes. A secondary aim was to discern differences in clinical features of pediatric CRPS with and without related movement disorders, and between children who had a favorable and unfavorable outcome. MATERIALS AND METHODS: We carried out a retrospective chart review of children with CRPS who presented to a pediatric Chronic Pain Clinic in Canada over a 5-year period (2012 to 2016). RESULTS: The study identified 59 children with CRPS (mean age: 12.7±2.5; 74.6% female; 72.9% lower extremity). In total, 87% (n=48) of children experienced complete resolution or significant improvement of CRPS, with a relapse rate of 15%. Overall, 25% (n=15) had a CRPS-related movement disorder. There were no differences in the clinical features of pediatric CRPS with or without related movement disorders. Children who experienced a favorable outcome had a significantly shorter symptom duration at the initial visit in comparison with children who experienced an unfavorable outcome. DISCUSSION: In this cohort, pediatric CRPS was most common in girls around the age of 12, usually in the lower extremity, and most experienced a favorable outcome. Further research is needed to better understand the prognosis and relapse rate of pediatric CRPS.

Nociceptive mechanisms involved in the acute and chronic phases of a complex regional pain syndrome type 1 model in mice.

Complex regional pain syndrome I (CRPS-I) is a chronic painful pathology still undertreated. CTK 01512-2 is a recombinant version of the spider peptide Phα1ß, and it functions as a voltage-gated calcium channel blocker and a transient receptor potential ankyrin 1 (TRPA1) antagonist with antinociceptive effect in different pain models. Here, we investigate the mechanisms involved in the acute and chronic nociceptive phases of a model of CPRS-I in mice and assess the antinociceptive effect of CTK 01512-2 using this model. Adult male and female mice C57BL/6 (20-30 g) were used to determine mechanical (von Frey test) or cold (acetone test) allodynia induction. Inflammatory parameters (serum and tibial nerve lactate levels, hind paw temperature and edema, or tissue cell infiltration) were evaluated after chronic post-ischemia pain (CPIP, a model of CPRS-I) induction. Anti-inflammatory and anti-neuropathic drugs or CTK 01512-2 were tested. First, we detected that CPIP-induced mechanical and cold allodynia in male and female mice in a similar way. In the acute phase (1 day after CPIP), an increase in inflammatory parameters were observed, as well as the anti-allodynic effect of anti-inflammatory compounds. In the chronic phase (17 days after CPIP), mice exhibited mechanical and cold allodynia, and anti-neuropathic drugs induced antinociception, while no inflammatory alterations were found. CTK 01512-2 reversed the CPIP allodynic effect in both nociceptive phases. Thus, this CPRS-I model can be used to understand the mechanisms involved in CPRS-I induced pain and inflammation. Besides, we observed that CTK 01512-2 has a valuable antinociceptive effect in this pain model.

Photophobia and neuropathic pain in Sudecks syndrome. / Fotofobia y dolor neuropático en el síndrome de Sudeck.

The case is presented of a 14 year-old patient diagnosed with Sudeck's syndrome secondary to uneventful foot trauma. The patient complained of decreased visual acuity along with photophobia and intense ocular pain not correlated with the exploratory findings. Sudeck's syndrome is an idiopathic neuropathic inflammatory disease characterised by disproportionate pain, unrelated to a previous traumatic event, which can evolve to severe and generalised pain. A new explanation has recently described this as "neuropathic eye pain" for those patients with severe eye pain that do not correlate with clinical signs. In the case presented here, the pain became widespread and led to photophobia and very intense ocular neuropathic pain. It is believed that this was the cause of the visual decrease presented by this patient. It is proposed that the Sudeck syndrome should become part of the differential diagnosis of neuropathic eye pain.

Spinal epidural abscess associated with an epidural catheter in a woman with complex regional pain syndrome and selective IgG3 deficiency: A case report.

RATIONALE: Continuous epidural infusion of local anesthetic may be an alternative to sympathetic blocks in refractory cases of complex regional pain syndrome (CRPS). Spinal epidural abscess (SEA) is a well-known complication associated with this technique, especially in patients with immune deficiencies. We herewith report a cervical SEA associated with an epidural catheter in a woman with CRPS and selective IgG3 subclass deficiency. PATIENT CONCERNS: Severe pain interfering with activities of daily living. DIAGNOSIS: Complex regional pain syndrome type-1 with involvement of upper extremity. INTERVENTIONS: The patient underwent inpatient epidural infusion for management of left upper extremity CRPS. Her history was notable for previous left shoulder injury requiring numerous surgical revisions complicated by recurrent shoulder infections, and selective IgG3 deficiency. She received antibiotic prophylaxis and underwent placement of a C6-C7 epidural catheter. On day 5, she became febrile. Neurological examination remained unchanged and an MRI demonstrated acute fluid collection from C3-T1. The following day she developed left arm weakness and was taken for emergent cervical decompression. Intraoperative abscess cultures were positive for Pseudomonas aeruginosa. OUTCOMES: Postoperatively, the patient's neurological symptoms and signs improved. LESSONS: Patients with selective IgG3 deficiency who are being considered for epidural catheterization may benefit from expert consultation with infectious diseases specialist. A history of recurrent device- or tissue-related infections should alert the clinician to the possible presence of a biofilm or dormant bacterial colonization. Close monitoring in an ICU setting during therapy is recommended. In case of early signs of infection, clinicians should have a high suspicion to rule out a SEA in immunocompromised patients.

Complex regional pain syndrome type 1 in the medico-legal setting: High rates of somatoform disorders, opiate use and diagnostic uncertainty.

Objective The aim of this study was to review demographic and clinical characteristics of patients with complex regional pain syndrome type 1 (CRPS) seen in a UK medico-legal setting - particularly the relationship between CRPS and somatoform disorders. Methods Fifty consecutive cases of CRPS (interviewed 2005-2016) undergoing psychiatric assessment were reviewed. A systematic assessment of mental states was conducted via interview and examination of medical/psychiatric records. Thirty patients also completed the Brief Illness Perception Questionnaire (BIPQ). Results Sixty per cent of patients ( n = 30) were female, and the mean age was 43 years. Twenty-two per cent ( n = 11) were employed, and 60% ( n = 30) received disability benefits. Symptoms were reported in the upper limb (62%; n = 31), lower limb (30%; n = 15), both (6%; n = 3) or elsewhere (2%; n = 1). Eighty-four per cent ( n = 42) satisfied DSM-5 criteria for current somatoform disorder. A history of more than two pain-related functional somatic syndromes (e.g. non-cardiac chest pain) was found in 42% ( n = 21) and functional neurological symptoms (e.g. 'claw-hand') in 42% ( n = 21). BIPQ scores resembled those associated with somatoform disorders and disorders mediated by psychological factors (e.g. irritable bowel syndrome). In 38% ( n = 19), the CRPS diagnosis was disputed among experts. A history of depression was noted in 60% ( n = 30), panic attacks in 20% ( n = 10) and alcohol/substance misuse in 18% ( n = 9). Opiates were prescribed to 64% ( n = 32). Conclusions Patients diagnosed with CRPS involved in litigation have high rates of prior psychopathology (mainly somatoform disorders) and pain-related disability for which opiate use is common. They risk an adverse reaction to limb pain 'shaped' by maladaptive illness beliefs. The CRPS diagnosis lacks reliability in medico-legal settings and may cause iatrogenic harm.

Mental load during cognitive performance in complex regional pain syndrome I.

BACKGROUND: Complex regional pain syndrome (CRPS) is associated with deficits in limb recognition. The purpose of our study was to determine whether mental load during this task affected performance, sympathetic nervous system activity or pain in CRPS patients. METHODS: We investigated twenty CRPS-I patients with pain in the upper extremity and twenty age- and sex-matched healthy controls. Each participant completed a limb recognition task. To experimentally manipulate mental load, the presentation time for each picture varied from 2 s (greatest mental load), 4, 6 to 10 s (least mental load). Before and after each run, pain intensity was assessed. Skin conductance was recorded continuously. RESULTS: Patients with CRPS did not differ from controls in terms of limb recognition and skin conductance reactivity. However, patients with CRPS reported an increase in pain during the task, particularly during high mental load and during the latter stages of the task. Interestingly, state anxiety and depressive symptoms were also associated with increases in pain intensity during high mental load. CONCLUSIONS: These findings indicate that high mental load intensifies pain in CRPS. The increase of pain in association with anxiety and depression indicates a detrimental effect of negative affective states in situations of high stress and mental load in CRPS. SIGNIFICANCE: The effects of mental load need to be considered when patients with CRPS-I are investigated for diagnostic or therapeutic reasons.

Bone SPECT/CT Localizes Increased Bone Metabolism and Subsequent Bone Resorption in Reflex Sympathetic Dystrophy.

A 64-year-old man with lung cancer with a history of revascularization of the occluded right femoral artery underwent bone scintigraphy, which showed intense uptake in the distal side of the right leg. The additional SPECT/CT clarified that the uptake was predominantly increased in the epiphyses of the right ankle and foot with possible osteopenia. One month later, follow-up SPECT/CT showed the manifestation of periosteal resorption in the hypermetabolic sites with slight decrease in bone metabolism. Radiological correlation between bone metabolism and subsequent bone resorption in addition to clinical symptoms in this patient suggested the diagnosis of reflex sympathetic dystrophy.

Perioperative Management of a Parturient with Complex Regional Pain Syndrome for Elective C-Section.

A 33 year-old female at 38 weeks gestation with a history of Complex Regional Pain Syndrome (CRPS) Type 1 of the upper extremities, diagnosed 13 years prior to this admission, was scheduled for an elective cesarean section (C-Section). She refused neuraxial anesthesia and requested general anesthesia. This abstract discusses the general anesthesia steps taken to pre-empt recurrence of CRPS symptoms.

Activation of cannabinoid receptor 2 attenuates mechanical allodynia and neuroinflammatory responses in a chronic post-ischemic pain model of complex regional pain syndrome type I in rats.

Complex regional pain syndrome type 1 (CRPS-I) remains one of the most clinically challenging neuropathic pain syndromes and its mechanism has not been fully characterized. Cannabinoid receptor 2 (CB2) has emerged as a promising target for treating different neuropathic pain syndromes. In neuropathic pain models, activated microglia expressing CB2 receptors are seen in the spinal cord. Chemokine fractalkine receptor (CX3CR1) plays a substantial role in microglial activation and neuroinflammation. We hypothesized that a CB2 agonist could modulate neuroinflammation and neuropathic pain in an ischemia model of CRPS by regulating CB2 and CX3CR1 signaling. We used chronic post-ischemia pain (CPIP) as a model of CRPS-I. Rats in the CPIP group exhibited significant hyperemia and edema of the ischemic hindpaw and spontaneous pain behaviors (hindpaw shaking and licking). Intraperitoneal administration of MDA7 (a selective CB2 agonist) attenuated mechanical allodynia induced by CPIP. MDA7 treatment was found to interfere with early events in the CRPS-I neuroinflammatory response by suppressing peripheral edema, spinal microglial activation and expression of CX3CR1 and CB2 receptors on the microglia in the spinal cord. MDA7 also mitigated the loss of intraepidermal nerve fibers induced by CPIP. Neuroprotective effects of MDA7 were blocked by a CB2 antagonist, AM630. Our findings suggest that MDA7, a novel CB2 agonist, may offer an innovative therapeutic approach for treating neuropathic symptoms and neuroinflammatory responses induced by CRPS-I in the setting of ischemia and reperfusion injury.

Bone abnormalities of the knee: MRI features.

The knee is one of the most studied anatomical structures by magnetic resonance imaging (MRI). Bone abnormalities are very frequently detected, whether or not related to the symptoms for which imaging was indicated. The aim of this pictorial study is to review the most commonly observed bone abnormalities of the knee, bearing in mind that the interpretation of MR images should always take into consideration both clinical and laboratory data, as well as the results of conventional X-ray imaging.

Effects of Mirror Therapy in Stroke Patients With Complex Regional Pain Syndrome Type 1: A Randomized Controlled Study.

OBJECTIVE: To investigate the effects of mirror therapy on upper limb motor functions, spasticity, and pain intensity in patients with hemiplegia accompanied by complex regional pain syndrome type 1. DESIGN: Randomized controlled trial. SETTING: Training and research hospital. PARTICIPANTS: Adult patients with first-time stroke and simultaneous complex regional pain syndrome type 1 of the upper extremity at the dystrophic stage (N=30). INTERVENTIONS: Both groups received a patient-specific conventional stroke rehabilitation program for 4 weeks, 5 d/wk, for 2 to 4 h/d. The mirror therapy group received an additional mirror therapy program for 30 min/d. MAIN OUTCOME MEASURES: We evaluated the scores of the Brunnstrom recovery stages of the arm and hand for motor recovery, wrist and hand subsections of the Fugl-Meyer Assessment (FMA) and motor items of the FIM-motor for functional status, Modified Ashworth Scale (MAS) for spasticity, and visual analog scale (VAS) for pain severity. RESULTS: After 4 weeks of rehabilitation, both groups had significant improvements in the FIM-motor and VAS scores compared with baseline scores. However, the scores improved more in the mirror therapy group than the control group (P<.001 and P=.03, respectively). Besides, the patients in the mirror therapy arm showed significant improvement in the Brunnstrom recovery stages and FMA scores (P<.05). No significant difference was found for MAS scores. CONCLUSIONS: In patients with stroke and simultaneous complex regional pain syndrome type 1, addition of mirror therapy to a conventional stroke rehabilitation program provides more improvement in motor functions of the upper limb and pain perception than conventional therapy without mirror therapy.

Extent of recovery in the first 12 months of complex regional pain syndrome type-1: A prospective study.

BACKGROUND: The literature concerning the outcomes of complex regional pain syndrome (CRPS) is contradictory, with some studies suggesting high rates of symptom resolution, whilst others demonstrate that CRPS symptoms can persist and lead to significant disability. The aim of the present study was to carefully document the extent of recovery from each of the signs and symptoms of CRPS. METHODS: A sample of 59 patients with recently onset (<12 weeks) CRPS-1 were followed prospectively for 1 year, during which time they received treatment-as-usual. At baseline, 6 and 12 months, the following were measured: CRPS severity scores (symptoms and signs of CRPS), pain, disability, work status and psychological functioning. RESULTS: Analyses showed that rates of almost all signs and symptoms of CRPS reduced significantly over 1 year. Reductions in symptom severity were clinically relevant and were greatest in the first 6 months and plateaued thereafter. However, at 1 year, nearly 2/3 of patients continued to meet the IASP-Orlando criteria for CRPS and 1/4 met the Budapest research criteria for CRPS. Only 5.4% of patients were symptom-free at 12 months. CONCLUSIONS: Overall the results were less optimistic than several previously conducted prospective studies and suggest that few cases of CRPS resolve completely within 12 months of onset. Improvements were generally greater in the first 6 months, and suggest that it may be worth exploring early interventions to prevent long-term disability in CRPS.

Resolution of hypothyroidism after correction of somatovisceral reflex dysfunction by refusion of the cervical spine.

Psychosis is a rare initial presentation of new-onset hypothyroidism. The author describes the case of a 29-year-old woman who presented with psychosis caused by hypothyroidism, or myxedema madness. Although the patient's psychosis resolved after standard monotherapy using levothyroxine sodium, her hypothyroidism persisted. Imaging of the patient's cervical spine showed that previous C5-C6 and C6-C7 fusions had failed. The failed fusions were corrected, and the patient's hypothyroidism resolved, suggesting that the somatovisceral reflex was the cause of the patient's hypothyroidism. Although somatovisceral reflex dysfunctions are rare, physicians should consider them as potential underlying causes of their patients' presenting medical conditions.

[Bone resorption in posttraumatic dystrophy. Root cause analysis based on the literature]. / Knochenresorption bei posttraumatischer Dystrophie. Ursachenanalyse anhand der Literatur.

BACKGROUND: In posttraumatic dystrophy the resorption of cancellous bone remains an unsolved phenomenon. OBJECTIVES: The possible effects of arteriovenous (av) anastomoses, hypoxia and acidosis in posttraumatic dystrophy on cancellous bone structures should be elucidated. MATERIAL AND METHODS: In posttraumatic dystrophy of the hand after distal radius fracture, hand fractures and elective hand surgery [20] the results suggest that persistent av anastomoses could be the reason for this syndrome. Possible pathways for the occurrence of cancellous bone resorption are discussed in context with the literature. RESULTS AND CONCLUSION: Intraosseous av anastomoses with acidosis and hypoxia of the tissues are probably responsible for the excessive activity of osteoclasts in acute posttraumatic dystrophy. Even enhancements in the late static phase of the three phase bone scan (TPBS) are in agreement with this hypothesis. In cancellous bone these enhancements are induced by the bone seeking tracers. The nomenclature for these tracer molecules is in line with the recommendations of International Union of Pure and Applied Chemistry (IUPAC) as methylene bisphosphonate and hydroxymethylene bisphosphonate. From this, therapeutic recommendations for posttraumatic dystrophy can be derived. The term diphosphonates should be changed to bisphosphonates.

Thoracic sympathetic block for the treatment of complex regional pain syndrome type I: a double-blind randomized controlled study.

Pain relief in complex regional pain syndrome (CRPS) remains a major challenge, in part due to the lack of evidence-based treatment trials specific for this condition. We performed a long-term randomized, double-blinded active-control study to evaluate the efficacy of thoracic sympathetic block (TSB) for upper limb type I CRPS. The study objective was to evaluate the analgesic effect of TSB in CRPS. Patients with CRPS type I were treated with standardized pharmacological and physical therapy and were randomized to either TSB or control procedure as an add-on treatment. Clinical data, pain intensity, and interference (Brief Pain Inventory), pain dimensions (McGill Pain Questionnaire [MPQ]), neuropathic characteristics (Neuropathic Pain Symptom Inventory [NPSI]), mood, upper limb function (Disabilities of Arm, Shoulder and Hand), and quality of life were assessed before, and at 1 month and 12 months after the procedure. Thirty-six patients (19 female, 44.7 ± 11.1 years of age) underwent the procedure (17 in the TSB group). Average pain intensity at 1 month was not significantly different after TSB (3.5 ± 3.2) compared to control procedure (4.8 ± 2.7; P=0.249). At 12 months, however, the average pain item was significantly lower in the TSB group (3.47 ± 3.5) compared to the control group (5.86 ± 2.9; P=0.046). Scores from the MPQ, evoked-pain symptoms subscores (NPSI), and depression scores (Hospital Anxiety and Depression Scale) were significantly lower in the TSB group compared to the control group at 1 and at 12 months. Other measurements were not influenced by the treatment. Quality of life was only slightly improved by TSB. No major adverse events occurred. Larger, multicentric trials should be performed to confirm these original findings.