Complex Regional Pain Syndrome: Evidence-Based Advances in Concepts and Treatments.

PURPOSE OF REVIEW: This review presents the most current information about the epidemiology of complex regional pain syndrome (CRPS), classification and diagnostic criteria, childhood CRPS, subtypes, pathophysiology, conventional and less conventional treatments, and preventive strategies. RECENT FINDINGS: CRPS is a painful disorder with multifactorial pathophysiology. The data describe sensitization of the central and peripheral nervous systems, inflammation, possible genetic factors, sympatho-afferent coupling, autoimmunity, and mental health factors as contributors to the syndrome. In addition to conventional subtypes (type I and type II), cluster analyses have uncovered other proposed subtypes. Prevalence of CRPS is approximately 1.2%, female gender is consistently associated with a higher risk of development, and substantial physical, emotional, and financial costs can result from the syndrome. Children with CRPS seem to benefit from multifaceted physical therapy leading to a high percentage of symptom-free patients. The best available evidence along with standard clinical practice supports pharmacological agents, physical and occupational therapy, sympathetic blocks for engaging physical restoration, steroids for acute CRPS, neuromodulation, ketamine, and intrathecal baclofen as therapeutic approaches. There are many emerging treatments that can be considered as a part of individualized, patient-centered care. Vitamin C may be preventive. CRPS can lead to progressively painful sensory and vascular changes, edema, limb weakness, and trophic disturbances, all of which substantially erode healthy living. Despite some progress in research, more comprehensive basic science investigation is needed to clarify the molecular mechanisms of the disease so that targeted treatments can be developed for better outcomes. Incorporating a variety of standard therapies with different modes of action may offer the most effective analgesia. Introducing less conventional approaches may also be helpful when traditional treatments fail to provide sufficient improvement.

The Sigma Enigma: A Narrative Review of Sigma Receptors.

The sigma-1 and sigma-2 receptors were first discovered in the 1960s and were thought to be a form of opioid receptors initially. Over time, more was gradually learned about these receptors, which are actually protein chaperones, and many of their unique or unusual properties can contribute to a range of important new therapeutic applications. These sigma receptors translocate in the body and regulate calcium homeostasis and mitochondrial bioenergetics and they also have neuroprotective effects. The ligands to which these sigma receptors respond are several and dissimilar, including neurosteroids, neuroleptics, and cocaine. There is controversy as to their endogenous ligands. Sigma receptors are also involved in the complex processes of cholesterol homeostasis and protein folding. While previous work on this topic has been limited, research has been conducted in multiple disease states, such as addiction, aging. Alzheimer's disease, cancer, psychiatric disorders, pain and neuropathic pain, Parkinson's disease, and others. There is currently increasing interest in sigma-1 and sigma-2 receptors as they provide potential therapeutic targets for many disease indications.

Single CT-guided chemodenervation of the anterior scalene muscle with botulinum toxin for neurogenic thoracic outlet syndrome.

OBJECTIVE: To examine pain relief in patients with neurogenic thoracic outlet syndrome (NTOS) after a single, low dose injection of botulinum toxin A (Botox) into the anterior scalene muscle (ASM) under computed tomographic (CT) guidance. DESIGN: Prospective longitudinal study. SETTING: Academic medical institution. PATIENTS: Patients 18 years of age and older were evaluated for potential scalenectomy and first rib resection using the transaxillary approach at the study institution between 2005 and 2008. All patients had failed physical therapy. A total of 29 procedures on 27 participants were studied. INTERVENTIONS: A single, 20-unit injection of Botox into the ASM under CT-guidance. OUTCOME MEASURES: Short-form McGill Pain Questionnaire (SF-MPQ) prior to and at 1, 2, and 3 months post-Botox toxin injection. RESULTS: There was a decline in pain during the 3 months subsequent to Botox injection as noted by the following components of the SF-MPQ: sensory (P = 0.02), total (P = 0.05), visual analog scale (VAS [P = 0.04]), and present pain intensity (PPI) score (P = 0.06). The proportion of patients reporting more intense pain scores did not return to the pre-intervention level at 3 months post-Botox injection. CONCLUSION: Patients experienced substantial pain relief in months 1 and 2 following a single Botox injection into the ASM under CT guidance. Significant pain reduction was noted for 3 months after Botox injection with respect to both sensory and VAS scores, and the total and PPI scores approximated statistical significance. After 3 months, patients experienced a 29% decrease in the sensory component of their pain as well as an approximate 15% reduction in their VAS score. A single, CT-guided Botox injection into the ASM may offer an effective, minimally invasive treatment for NTOS.

Single nucleotide polymorphisms in obesity-related genes and all-cause and cause-specific mortality: a prospective cohort study.

BACKGROUND: The aim of this study was to examine the associations between 16 specific single nucleotide polymorphisms (SNPs) in 8 obesity-related genes and overall and cause-specific mortality. We also examined the associations between the SNPs and body mass index (BMI) and change in BMI over time. METHODS: Data were analyzed from 9,919 individuals who participated in two large community-based cohort studies conducted in Washington County, Maryland in 1974 (CLUE I) and 1989 (CLUE II). DNA from blood collected in 1989 was genotyped for 16 SNPs in 8 obesity-related genes: monoamine oxidase A (MAOA), lipoprotein lipase (LPL), paraoxonase 1 and 2 (PON1 and PON2), leptin receptor (LEPR), tumor necrosis factor-alpha (TNFalpha), and peroxisome proliferative activated receptor-gamma and -delta (PPARG and PPARD). Data on height and weight in 1989 (CLUE II baseline) and at age 21 were collected from participants at the time of blood collection. All participants were followed from 1989 to the date of death or the end of follow-up in 2005. Cox proportional hazards regression was used to obtain the relative risk (RR) estimates and 95% confidence intervals (CI) for each SNP and mortality outcomes. RESULTS: The results showed no patterns of association for the selected SNPs and the all-cause and cause-specific mortality outcomes, although statistically significant associations (p < 0.05) were observed between PPARG rs4684847 and all-cause mortality (CC: reference; CT: RR 0.99, 95% CI 0.89, 1.11; TT: RR 0.60, 95% CI 0.39, 0.93) and cancer-related mortality (CC: reference; CT: RR 1.01, 95% CI 0.82, 1.25; TT: RR 0.22, 95% CI 0.06, 0.90) and TNFalpha rs1799964 and cancer-related mortality (TT: reference; CT: RR 1.23, 95% CI 1.03, 1.47; CC: RR 0.83, 95% CI 0.54, 1.28). Additional analyses showed significant associations between SNPs in LEPR with BMI (rs1137101) and change in BMI over time (rs1045895 and rs1137101). CONCLUSION: Findings from this cohort study suggest that the selected SNPs are not associated with overall or cause-specific death, although several LEPR SNPs may be related to BMI and BMI change over time.

Single nucleotide polymorphisms in inflammation-related genes and mortality in a community-based cohort in Washington County, Maryland.

The purpose of this study was to examine the associations between single nucleotide polymorphisms (SNPs) in genes controlling inflammatory processes and mortality. Data were analyzed from 9,933 individuals who participated in two large community-based cohort studies conducted in Washington County, Maryland, in 1974 and 1989, designated "CLUE I" and "CLUE II," respectively. DNA from blood collected in 1989 was genotyped for 47 SNPs in 23 inflammation-related genes, including interferon-gamma (IFNgamma), lymphotoxin-alpha (LTalpha), tumor necrosis factor-alpha (TNFalpha), C-reactive protein (CRP), peroxisome proliferator-activated receptor (PPAR), and the human endothelial nitric oxide synthase (eNOS). All participants were followed from 1989 to the date of death or to June 20, 2005. The results showed no observable patterns of association for the SNPs and the all-cause and cause-specific mortality outcomes, although statistically significant associations were observed between at least one mortality outcome and SNPs in eNOS (reference SNP (rs) 1799983), PPARG (rs4684847), CRP (rs2794521), IFNgamma (rs2069705), TNFalpha (rs1799964), and LTalpha (rs2229094). Additionally, three of the four examined CRP SNPs were strongly associated with CRP serum concentration among those with CRP measurements. The authors' findings from this community-based prospective cohort study suggest that the selected SNPs are not associated with overall or cause-specific death, although CRP genotypes may be associated with systemic inflammation.

Intrapartum electronic fetal heart rate monitoring and the prevention of perinatal brain injury.

OBJECTIVE: Electronic fetal heart rate monitoring (EFM) is the most widely used method of intrapartum surveillance, and our objective is to review its ability to prevent perinatal brain injury and death. DATA SOURCES: Studies that quantified intrapartum EFM and its relation to specific neurologic outcomes (seizures, periventricular leukomalacia, cerebral palsy, death) were eligible for inclusion. MEDLINE was searched from 1966 to 2006 for studies that examined the relationship between intrapartum EFM and perinatal brain injury using these MeSH and text words: "cardiotocography," "electronic fetal monitoring," "intrapartum fetal heart rate monitoring," "intrapartum fetal monitoring," and "fetal heart rate monitoring." METHODS OF STUDY SELECTION: This search strategy identified 1,628 articles, and 41 were selected for further review. Articles were excluded for the following reasons: in case reports, letters, commentaries, and review articles, intrapartum EFM was not quantified, or specific perinatal neurologic morbidity was not measured. Three observational studies and a 2001 meta-analysis of 13 randomized controlled trials were selected for determination of the effect of intrapartum EFM on perinatal brain injury. TABULATION, INTEGRATION, AND RESULTS: Electronic fetal monitoring was introduced into widespread clinical practice in the late 1960s based on retrospective studies comparing its use to historical controls where auscultation was performed in a nonstandardized manner. Case-control studies have shown correlation of EFM abnormalities with umbilical artery base excess, but EFM was not able to identify cerebral white matter injury or cerebral palsy. Of 13 randomized controlled trials, one showed a significant decrease in perinatal mortality with EFM compared with auscultation. Meta-analysis of the randomized controlled trials comparing EFM with auscultation have found an increased incidence of cesarean delivery and decreased neonatal seizures but no effect on the incidence of cerebral palsy or perinatal death. CONCLUSION: Although intrapartum EFM abnormalities correlate with umbilical cord base excess and its use is associated with decreased neonatal seizures, it has no effect on perinatal mortality or pediatric neurologic morbidity.

Breast carcinoma chemoprevention in the community setting. Estimating risks and benefits.

BACKGROUND: The United States Preventive Services Task Force recommends that women who are at both high risk for breast carcinoma and low risk for adverse events should receive counseling regarding tamoxifen for chemoprevention. Estimates of the risks and benefits of tamoxifen based on results from clinical trials may not reflect the real-world experience. The authors determined the prevalence of women in a community-based cohort who would meet the definition of high risk for breast carcinoma and calculated the number of women needed to screen to determine one for whom the benefits of tamoxifen would outweigh the risks. Baseline incidence also was examined for adverse health events in this community-based cohort compared with participants in the Breast Cancer Prevention Trial. METHODS: The study participants were women ages 40-70 years (n = 6048 women) who were members of the CLUE II cohort, which started in 1989, and who responded to questionnaire surveys in 1996 and 2000. RESULTS: Eighteen percent of all women had a 5-year risk of invasive breast carcinoma > or = 1.66%. The number of women needed to screen to find 1 woman for whom the benefits outweighed the risks of tamoxifen ranged from 26 women ages 40-49 years to 142 women ages 60-70 years. For women who had undergone a hysterectomy, the numbers needed to screen were lower. Baseline incidence rates of fracture and thromboembolic disease were higher in the community-based cohort compared with the rates observed among prevention trial participants; thus, fewer women had to be treated with tamoxifen to prevent one fracture. However, fewer women in the community also had to be treated to observe harm with a thromboembolic event. CONCLUSIONS: Clinicians who counsel women about tamoxifen should take into consideration community-level risks and benefits.