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Astrid Juhl Terkelsen,1 Frank Birklein2 1Department of Neurology, Aarhus University Hospital and Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 2University Medical Centre Mainz, Department of Neurology, Mainz, GermanyCorrespondence: Astrid Juhl Terkelsen, Tel +45 78 46 33 80, Fax +45 78 45 42 54, Email astrterk@rm.dkAbstract: Most frequently, complex regional pain syndrome (CRPS) develops after a trauma and affects distal parts of the limbs. Early recognition and initiation of adequate treatment is crucial for a favorable outcome. On the other hand, misdiagnosing other disorders as CRPS is detrimental because more appropriate treatment may be withheld from the patients. Despite intensive research, a specific biomarker or paraclinical measure for CRPS diagnosis is still lacking. Instead, clinical criteria approved by the International Association for the Study of Pain (IASP) and latest adapted in 2019 are central for diagnosing CPRS. Thus, the CRPS diagnosis remains challenging with the risk of a “deliberate diagnosis” for unexplained pain, while at the same time a delayed CRPS diagnosis prevents early treatment and full recovery. CRPS is a diagnosis of exclusion. To clinically diagnose CRPS, a vigorous exclusion of “other diseases that would better explain the signs and symptoms” are needed before the patients should be referred to tertiary centers for specific pain treatment. We highlight red flags that suggest “non-CRPS” limb pain despite clinical similarity to CRPS. Clinical and neurological examination and paraclinical evaluation of a probably CRPS patient are summarized. Finally, we pinpoint common differential diagnoses for CRPS. This perspective might help CRPS researchers and caregivers to reach a correct diagnosis and choose the right treatment, regardless whether for CRPS mimics or CRPS itself.Keywords: diagnostic criteria, differential diagnoses, paraclinical evaluation, misdiagnoses

BACKGROUND: Complex regional pain syndrome is a painful condition of unknown etiology. Clinical and experimental observations suggest that limb immobilization may induce symptoms and signs characteristic of complex regional pain syndrome. This study examined the effect of forearm immobilization on regional sensory and autonomic functions in healthy subjects. METHODS: Thermal and mechanical sensitivity, skin temperature, and vasoconstrictor responses were measured in 30 healthy subjects before and 0, 3, and 28 days after scaphoid cast immobilization. Fifteen subjects served as nonimmobilized controls. RESULTS: At cast removal, 27 subjects experienced pain at joint movement. Cast immobilization induced cold hyperalgesia in glabrous and hairy skin on the immobilized hand and induced significant skin temperature differences between the control and the immobilized hand at cast removal and after 3 days. Immobilization also reduced pain threshold at skin fold testing at all time points after cast removal. All measures except pain threshold at skin fold testing were normalized after 28 days. Immobilization did not affect thermal detection, heat pain, and pressure pain thresholds; resting skin perfusion; or vasoconstrictor responses induced by mental stress or deep inspirations. CONCLUSIONS: Four weeks of forearm immobilization caused transient changes in skin temperature, mechanosensitivity, and thermosensitivity, without alteration in the sympathetically mediated vascular tone. [ABSTRACT FROM AUTHOR]

Background and Purpose: Centers for training in autonomic nervous system (ANS) disorders are not widely available and the recent coronavirus 2019 pandemic temporarily reduced training opportunities in autonomic medicine across European countries. Here we evaluated the current state of education, clinical skills and postgraduate educational preferences on ANS disorders of European neurology residents and consultants., Methods: A 23-item questionnaire was developed and distributed online amongst European neurology residents and consultants via mailing lists of the European Academy of Neurology. The questions assessed demographics, current training opportunities and learning preferences in ANS disorders. Six multiple-choice questions were used to self-evaluate knowledge of ANS disorders., Results: In all, 285 individuals answered the survey (60% female, mostly 25-34 years of age). All respondents considered clinical autonomic skills necessary for good clinical neurological practice, and 92% would like to increase their ANS knowledge. Female respondents and those who trained in Southern/Eastern/Greater Europe more frequently judged ANS skills important for clinical practice than male respondents (p = 0.012) and respondents from Northern/Western Europe (p = 0.011). Female and younger respondents felt less confident in managing ANS disorders (p = 0.001 and p < 0.001, respectively). Respondents below 45 years of age (p < 0.001) and those with lower confidence in managing ANS disorders (p = 0.004) were more likely to recommend that ANS education is embedded in the residency curriculum., Conclusions: Most European neurology residents and consultants reported a need for more autonomic education, with additional gender, age and regional differences. These findings underscore the importance of increasing the educational content on autonomic medicine in European medical and postgraduate curricula., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: It is increasingly significant that adults with diabetes experience lower urinary tract symptoms, however, there has been limited research in younger individuals with type 1 diabetes., Objective: To investigate bladder function using non-invasive urodynamics as a potential indicator of autonomic neuropathy in adolescents with type 1 diabetes. This involved examining the association between urinary flow disturbances, reported symptoms, and results from other autonomic tests., Study Design: Cross-sectional study enrolling 49 adolescents with type 1 diabetes and 18 control subjects. All participants underwent uroflowmetry and ultrasound scanning, completed the Composite Autonomic Symptom Score (COMPASS)-31 questionnaire, and were instructed to record their morning urine volume and voiding frequencies and report them back. Cardiovascular reflex tests (CARTs) and the quantitative sudomotor axon reflex test (QSART) were performed., Results: The main results are shown in the Summary figure., Discussion: In this study, urological abnormalities were not significantly more frequent in adolescents with diabetes, however, urological issues were observed. This is supported by previous findings of Szabo et al. who found that adolescents with type 1 diabetes had reduced flow acceleration and time to maximum flow compared to control subjects. In our study, we observed cases with reduced acceleration and prolonged uroflow curves, possibly indicating detrusor underactivity. People with diabetes had a higher risk of nocturia than healthy controls, which our results supported. Some adolescents reported urination twice per night. Based on these findings, it is considered beneficial to ask about urological symptoms annually to determine if more examinations (frequency-volume charts and uroflowmetry) are necessary and/or if any opportunities for treatment optimization exist. However, uroflowmetry has limitations, as bladder filling and emptying is a complex process involving multiple pathways and neurological centers, making it difficult to standardize and evaluate. Another limitation of this study was that our control group was smaller and consisted of fewer males than females, which could affect the results due to differences in anatomy and physiology in the lower urinary tract system., Conclusion: In conclusion, adolescents with type 1 diabetes, as well as healthy adolescents, frequently experience urological symptoms. Although urological abnormalities were not significantly more frequent in adolescents with diabetes in this study, the focus on nocturia and risk for bladder dysfunction seems relevant, even in adolescents without any other tests indicating autonomic dysfunction., Competing Interests: Conflict of interest No potential conflicts are relevant to this article., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: To assess the agreement between clinical cardiovascular adrenergic function and cardiac adrenergic innervation in type 2 diabetes patients (T2D)., Methods: Thirty-three patients with T2D were investigated bimodally through (1) a standardized clinical cardiovascular adrenergic assessment, evaluating adequacy of blood pressure responses to the Valsalva maneuver and (2) 123 I-meta-iodobenzylguanidine (MIBG) scintigraphy assessing myocardial adrenergic innervation measured as early and delayed heart heart/mediastinum (H/M) ratio, and washout rate (WR)., Results: T2D patients had significantly lower early and delayed H/M-ratios, and lower WR, compared to laboratory specific reference values. Thirteen patients had an abnormal adrenergic composite autonomic severity score (CASS > 0). Patients with abnormal CASS scores had significantly higher early H/M ratios (1.76 [1.66-1.88] vs. 1.57 [1.49-1.63], p < 0.001), higher delayed H/M ratios (1.64 [1.51:1.73] vs. 1.51 [1.40:1.61] (p = 0.02)), and lower WR (-0.13(0.10) vs -0.05(0.07), p = 0.01). Lower Total Recovery and shorter Pressure Recovery Time responses from the Valsalva maneuver was significantly correlated to lower H/M early (r = 0.55, p = 0.001 and r = 0.5, p = 0.003, respectively) and lower WR for Total Recovery (r = -0.44, p = 0.01)., Conclusion: The present study found impairment of sympathetic innervation in T2D patients based on parameters derived from MIBG cardiac scintigraphy (low early H/M, delayed H/M, and WR). These results confirm prior studies. We found a mechanistically inverted relationship with favourable adrenergic cardiovascular responses being significantly associated unfavourable MIBG indices for H/M early and delayed. This paradoxical relationship needs to be further explored but could indicate adrenergic hypersensitivity in cardiac sympathetic denervated T2D patients., Competing Interests: Declaration of competing interest We report no potential conflicts of interest in relation to this manuscript., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Neurosarcoidosis is a rare and serious condition. Rapid diagnosis and treatment are crucial to prevent morbidity and mortality. When neurological symptoms are not present at the time of diagnosis, CNS involvement can be undetected. We present a case of neurosarcoidosis complicating Löfgren's syndrome and discus the challenges in diagnostics and treatment, that can be encountered.

Purpose: To quantify sweat gland nerve fiber density in adolescents with diabetes. Additionally, to investigate associations between sudomotor innervation, sweat responses, and possible risk factors for sudomotor neuropathy., Methods: Cross-sectional study where 60 adolescents with type 1 diabetes (duration > 5 years) and 23 control subjects were included. Clinical data, quantitative sudomotor axon reflex test, and skin biopsies were obtained. Skin tissue was immunostained and imaged by confocal microscopy. Quantification of the sweat gland volume and three-dimensional reconstruction of the nerve fibers was performed using a design-unbiased technique., Results: Adolescents with diabetes had a significant reduction of maximum and mean values of nerve fiber length and nerve fiber density in sweat glands compared to controls (p values < 0.05). No association between nerve fiber density and sweat responses was found (p = 0.21). In cases with reduced sweat gland nerve fiber length, nerve fiber density, and volume, the sweat response was reduced or absent. Height, systolic blood pressure, time in hypoglycemia, and total daily and basal/total insulin dose were positively correlated to sweat response, while low-density lipoprotein, and HbA1c were negatively correlated with sweat response (p values < 0.05). Other microvascular complications and high cholesterol levels increased the relative risk for reduced sweat gland nerve fiber density., Conclusion: Our findings of reduced sweat gland innervation in a selected group of adolescents add new knowledge about the structural changes that occur in autonomic nerves due to diabetes. Evaluating both the sweat gland innervation and sweat gland volume was important for understanding the association with sweat responses. Further research is needed to understand its clinical relevance., (© 2023. The Author(s).)

Aims: To estimate the prevalence of large fiber (LFN), small fiber (SFN), and autonomic neuropathy in adolescents with type 1 diabetes using confirmatory tests known from adults and to identify risk factors and bedside methods for neuropathy., Methods: Sixty adolescents with type 1 diabetes (diabetes duration > five years) and 23 control subjects underwent neurological examination and confirmatory diagnostic tests for neuropathy, including nerve conduction studies, skin biopsies determining intraepidermal nerve fiber density, quantitative sudomotor axon reflex test (QSART), cardiovascular reflex tests (CARTs), and tilt table test. Possible risk factors were analyzed. Bedside tests (biothesiometry, DPNCheck®, Sudoscan, and Vagus®device) were compared with the confirmatory tests using ROC analysis., Results: The prevalence of neuropathies in the adolescents with diabetes (mean HbA1c 7.6% (60 mmol/mol)) was as follows: 14% confirmed/26% subclinical LFN, 2% confirmed/25% subclinical SFN, 20% abnormal QSART, 8% abnormal CARTs, and 14% orthostatic hypotension. Higher age, higher insulin dose, previous smoking, and higher triglycerides level were found to increase the relative risk for neuropathy. The bedside tests showed poor to acceptable concordance with the confirmatory tests (all, AUC ≤ 0.75)., Conclusions: The diagnostic tests confirmed the presence of neuropathy in adolescents with diabetes and underscore the importance of prevention and screening., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Thyroid [ 123 I]MIBG uptake is proposed as a tool for differentiating between Parkinson's disease (PD) and diabetes mellitus (DM) on [ 123 I]MIBG scintigraphies since both patient groups show decreased cardiac uptake. One study compared thyroid [ 123 I]MIBG uptake in DM and PD patients and reported reduced [ 123 I]MIBG uptake only in the PD group. Here, we investigated thyroid [ 123 I]MIBG uptake in patients with PD and DM and found severely reduced thyroid [ 123 I]MIBG uptake in DM. Larger studies are needed to substantiate whether DM patients are more or less likely to exhibit decreased thyroid MIBG uptake compared to controls and PD patients., Competing Interests: None, (© 2023 The Authors.)

Background: To assess the prevalence of objective signs of gastrointestinal (GI) autonomic neuropathy (AN) in adolescents with type 1 diabetes (T1D). In addition, to investigate associations between objective GI findings and self-reported symptoms or other findings of AN., Methods: Fifty adolescents with T1D and 20 healthy adolescents were examined with a wireless motility capsule to assess the total and regional GI transit times and motility index. GI symptoms were evaluated with the GI Symptom Rating Scale questionnaire. AN was evaluated with cardiovascular and quantitative sudomotor axon reflex tests., Results: There was no difference in GI transit times in adolescents with T1D and healthy controls. Adolescents with T1D had a higher colonic motility index and peak pressure than the controls, and GI symptoms were associated with low gastric and colonic motility index (all p < 0.05). Abnormal gastric motility was associated with the duration of T1D, while a low colonic motility index was inversely associated with "time in target range" for blood glucose (all p < 0.01). No associations were found between signs of GI neuropathy and other measures of AN., Conclusions: Objective signs of GI neuropathy are common in adolescents with T1D and it seems to require early interventions in patients at high risk of developing GI neuropathy.

Introduction/aims: Autonomic dysfunction is a common complication of small-fiber neuropathy (SFN). In this study we aimed to assess the applicability of autonomic microvascular indices as a potential marker for SFN assessment., Methods: Fifteen patients with confirmed SFN (idiopathic neuropathy [n = 10], chemotherapy-induced peripheral neuropathy [n = 2], impaired glucose tolerance [n = 1], hereditary transthyretin amyloidosis (hATTR) [n = 1], pulmonary sarcoidosis [n = 1]) and 15 matched control subjects underwent assessment of vascular skin responses assessed through laser Doppler flowmetry and evaluation of microvascular vessel and nerve density in skin biopsies. All participants underwent peripheral autonomic evaluation by quantitative sudomotor axon reflex testing (QSART)., Results: We found no significant differences in vascular skin responses, or in any microvascular skin biopsy markers, when comparing SFN with control subjects. We found no correlation between vascular skin responses and skin biopsy indices. We saw no significant difference in any microvascular indices when comparing subjects with and without impaired sudomotor function., Discussion: Our findings suggest markers of peripheral microvascular innervation and function are not associated with the diagnosis of SFN. Furthermore, we saw no association between microvascular markers and sudomotor function, suggesting that these are independent and unrelated components of the autonomic nervous system., (© 2022 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)

Objective: Cardiovascular autonomic neuropathy is a known complication in type 2 diabetes (T2D). However, the extent of sympathetic dysfunction and its relation to blood pressure (BP) dysregulation is insufficiently studied. We therefore assessed the cardiovascular sympathetic function using a standardized autonomic test-battery., Research Design and Methods: Forty T2D patients (mean age and duration of diabetes ±SD, 65.5 ± 7.3 and 9.5 ± 4.2 years) and 40 age- and gender-matched controls were examined through autonomic testing, assessing cardiovascular responses to deep breathing, Valsalva maneuver and tilt-table testing. Additionally, 24-hour oscillometric BP and self-reported autonomic symptoms on COMPASS-31 questionnaire was recorded., Results: Patients with T2D had reduced parasympathetic activity with reduced deep breathing inspiratory:expiratory-ratio (median [IQR] T2D 1.11 [1.08-1.18] vs. controls 1.18 [1.11-1.25] (p = 0.01)), and reduced heart rate variability (p < 0.05). We found no differences in cardiovascular sympathetic function measured through BP responses during the Valsalva maneuver (p > 0.05). 24-hour-BP detected reduced night-time systolic BP drop in T2D (9.8 % ± 8.8 vs. controls 15.8 % ± 7.7 (p < 0.01)) with more patients having reverse dipping. Patients with T2D reported more symptoms of orthostatic intolerance on the COMPASS-31 (p = 0.04)., Conclusions: Patients with T2D showed reduced parasympathetic activity but preserved short-term cardiovascular sympathetic function, compared to controls, indicating autonomic dysfunction with predominantly parasympathetic impairment. Despite this, T2D patients reported more symptoms of orthostatic intolerance in COMPASS-31 and had reduced nocturnal BP dipping, indicating that these are not a consequence of cardiovascular sympathetic dysfunction., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: To estimate the prevalence of neuropathy in adolescents with type 1 diabetes., Methods: Systematic collection of published studies exploring the prevalence of large fibre neuropathy (LFN), small fibre neuropathy (SFN), and autonomic neuropathy in adolescents with type 1 diabetes. Following prospective registration (Prospero CRD42020206093), PubMed, EMBASE, and Cochrane Library were searched for studies from 2000 to 2020. PICO framework was used in the selection process (Population: adolescents aged 10-19 years with type 1 diabetes; Intervention: diagnostic methods for neuropathy; Comparison: reference data; Outcome: data on prevalence or comparison). Data were extracted concerning study quality based on available data and established methods for determining and diagnosing various neuropathy types., Results: From 2,017 initial citations, 27 studies (7589 participants) fulfilled eligibility criteria. The study population (47% males) had a diabetes duration between 4.0 and 10.6 years, and HbA1c level between 7.3 and 10.8%, 56-95 mmol/mol. The prevalence of LFN, based on nerve conduction studies, was 10-57%. Based on other tests for neuropathy, the prevalence of LFN and SFN was 12-62%, and that of cardiac autonomic neuropathy was 12-75%., Conclusion: The described prevalence of neuropathy in adolescents with type 1 diabetes varied, which can be methodological due to different screening methods and classifications of neuropathy., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Complex regional pain syndrome (CRPS) is a debilitating pain condition often resistant to standard treatment modalities. In these cases, spinal cord stimulation (SCS) can be an option, but the effect on CRPS remains disputed. We aimed to assess the long-term effect of SCS on CRPS., Methods: We retrospectively analysed 51 CRPS patients implanted with an SCS system at the University Hospitals in Aarhus or Odense, Denmark, with a median follow-up time of 4.4 years. Primary outcomes were pain intensity on a numeric rating scale (NRS) and the Patients' Global Impression of Change (PGIC). Secondary outcomes were patient satisfaction, work status, consumption of pain medication, the Major Depression Inventory (MDI), Pain Catastrophizing Scale (PCS) and quality of life (QoL) measured using the Short-Form Health Survey (SF-36). For each outcome measure, baseline data were compared to the latest collected data point., Results: A significant pain relief was found with a mean reduction in NRS score of 2.4 (95% CI: 1.7-3.0, p < 0.0001). 68.8% reported 'much improved' or 'very much improved' on the PGIC scale. 87.5% would choose SCS again for the same outcome. A significant beneficial impact was found on MDI score, PCS, SF-36 summary scores and consumption of tricyclic antidepressants, antiepileptic drugs and opioids. No statistical effect was found on work status., Conclusion: Pain intensity, depression, pain catastrophizing, pain medication use and QoL were significantly improved after SCS implantation, with high patient satisfaction rates in CRPS patients. This study supports the continued use of SCS in the treatment of severe CRPS., Significance: This study presents detailed data from a large, well-characterized cohort of Danish CRPS patients treated with SCS, analyzing several outcome measures. The results serve to document SCS as an effective treatment for severe CRPS and expands the cumulative level of evidence in favor of its use. Additionally, analysis of preoperative patient characteristics suggests that SCS treatment should not be withheld in patients with a high degree of psychological distress or high consumption of analgesics., (© 2021 European Pain Federation - EFIC®.)

Neuronal aggregates of misfolded alpha-synuclein protein are found in the brain and periphery of patients with Parkinson's disease. Braak and colleagues have hypothesized that the initial formation of misfolded alpha-synuclein may start in the gut, and then spread to the brain via peripheral autonomic nerves hereby affecting several organs, including the heart and intestine. Age is considered the greatest risk factor for Parkinson's disease, but the effect of age on the formation of pathology and its propagation has not been studied in detail. We aimed to investigate whether propagation of alpha-synuclein pathology from the gut to the brain is more efficient in old versus young wild-type rats, upon gastrointestinal injection of aggregated alpha-synuclein. Our results demonstrate a robust age-dependent gut-to-brain and brain-to-gut spread of alpha-synuclein pathology along the sympathetic and parasympathetic nerves, resulting in age-dependent dysfunction of the heart and stomach, as observed in patients with Parkinson's disease. Moreover, alpha-synuclein pathology is more densely packed and resistant to enzymatic digestion in old rats, indicating an age-dependent maturation of alpha-synuclein aggregates. Our study is the first to provide a detailed investigation of alpha-synuclein pathology in several organs within one animal model, including the brain, skin, heart, intestine, spinal cord and autonomic ganglia. Taken together, our findings suggest that age is a crucial factor for alpha-synuclein aggregation and complete propagation to heart, stomach and skin, similar to patients. Given that age is the greatest risk factor for human Parkinson's disease, it seems likely that older experimental animals will yield the most relevant and reliable findings. These results have important implications for future research to optimize diagnostics and therapeutics in Parkinson's disease and other age-associated synucleinopathies. Increased emphasis should be placed on using aged animals in preclinical studies and to elucidate the nature of age-dependent interactions., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Peripheral neuropathy is one of the most common complications of both type 1 and type 2 diabetes. Up to half of patients with diabetes develop neuropathy during the course of their disease, which is accompanied by neuropathic pain in 30-40% of cases. Peripheral nerve injury in diabetes can manifest as progressive distal symmetric polyneuropathy, autonomic neuropathy, radiculo-plexopathies, and mononeuropathies. The most common diabetic neuropathy is distal symmetric polyneuropathy, which we will refer to as DN, with its characteristic glove and stocking like presentation of distal sensory or motor function loss. DN or its painful counterpart, painful DN, are associated with increased mortality and morbidity; thus, early recognition and preventive measures are essential. Nevertheless, it is not easy to diagnose DN or painful DN, particularly in patients with early and mild neuropathy, and there is currently no single established diagnostic gold standard. The most common diagnostic approach in research is a hierarchical system, which combines symptoms, signs, and a series of confirmatory tests. The general lack of long-term prospective studies has limited the evaluation of the sensitivity and specificity of new morphometric and neurophysiological techniques. Thus, the best paradigm for screening DN and painful DN both in research and in clinical practice remains uncertain. Herein, we review the diagnostic challenges from both clinical and research perspectives and their implications for managing patients with DN. There is no established DN treatment, apart from improved glycaemic control, which is more effective in type 1 than in type 2 diabetes, and only symptomatic management is available for painful DN. Currently, less than one-third of patients with painful DN derive sufficient pain relief with existing pharmacotherapies. A more precise and distinct sensory profile from patients with DN and painful DN may help identify responsive patients to one treatment versus another. Detailed sensory profiles will lead to tailored treatment for patient subgroups with painful DN by matching to novel or established DN pathomechanisms and also for improved clinical trials stratification. Large randomized clinical trials are needed to identify the interventions, i.e. pharmacological, physical, cognitive, educational, etc., which lead to the best therapeutic outcomes., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Noradrenergic neurotransmission may play an important role in tremor modulation through its innervation of key structures of the central tremor circuits. Here, Parkinson's disease (PD) patients with (PD T+ ) or without (PD T- ) rest tremor had 11 C-methylreboxetine( 11 C-MeNER) positron emission tomography (PET) to test the hypothesis that noradrenaline terminal function was relatively preserved in PD T+ compared to PD T- ., Methods: Sixty-five PD patients and 28 healthy controls (HC) were scanned with 11 C-MeNER PET. Patients were categorized as PD T+ if subscores in UPDRS-III item 3 or MDS-UPDRS-III item 17 was ≥2; remaining were categorized as PD T- . Simplified reference tissue model 2 distribution volume ratios (DVR) for 11 C-MeNER were calculated for thalamus, dorsal and median raphe, locus coeruleus (LC) and red nucleus using time activity curves (TACs) obtained from volumes of interest (VOI). Data were statistically interrogated with a general linear mixed model using 'region', and 'group' as factors and the interaction of 'region x group' was examined., Results: Tremor positive PD patients had a significantly higher mean 11 C-MeNER DVR compared to PD T- in LC and thalamus. The PD T+ mean LC DVR was similar to that of HC. PD T+ mean 11 C-MeNER DVRs were significantly lower than HC in the dorsal raphe while the PD T- group showed significantly lower mean 11 C-MeNER DVR across all regions compared to HC., Conclusion: While both PD T+ and PD T- groups showed a significant loss of noradrenaline terminal function compared to controls, noradrenergic neurons were relatively preserved in PD T+ in LC and thalamus. The greater loss of noradrenergic transporters in PD T- in LC and thalamus compared with PD T+ is in line with earlier in-vitro studies and could potentially contribute to their tremor negative phenotype., (Copyright © 2021. Published by Elsevier Inc.)

The autonomic nervous system delicately regulates the function of several target organs, including the gastrointestinal tract. Thus, nerve lesions or other nerve pathologies may cause autonomic dysfunction (AD). Some of the most common causes of AD are diabetes mellitus and α-synucleinopathies such as Parkinson's disease. Widespread dysmotility throughout the gastrointestinal tract is a common finding in AD, but no commercially available method exists for direct verification of enteric dysfunction. Thus, assessing segmental enteric physiological function is recommended to aid diagnostics and guide treatment. Several established assessment methods exist, but disadvantages such as lack of standardization, exposure to radiation, advanced data interpretation, or high cost, limit their utility. Emerging methods, including high-resolution colonic manometry, 3D-transit, advanced imaging methods, analysis of gut biopsies, and microbiota, may all assist in the evaluation of gastroenteropathy related to AD. This review provides an overview of established and emerging assessment methods of physiological function within the gut and assessment methods of autonomic neuropathy outside the gut, especially in regards to clinical performance, strengths, and limitations for each method.

Treatment-induced neuropathy of diabetes is an iatrogenic acute painful sensory and autonomic neuropathy. The condition is caused by rapid downregulation of blood glucose after a long period of hyperglycaemia. In this case report, a 43-year-old man with Type 1 diabetes and severe metabolic dysregulation had downregulated his blood glucose level with 3.8% over ten weeks through optimised insulin treatment and weight loss. He developed severe neuropathic pain due to small fiber neuropathy and neurogenic autonomic dysfunction with erectile dysfunction, urine retention and cardiovagal and enteric dysfunction.

Introduction: The Composite Autonomic Symptom Score (COMPASS 31) is a validated self-assessment questionnaire quantifying the severity and distribution of autonomic symptoms across six domains (orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder and pupillomotor functions) by scoring 31 clinically selected questions. The aim of this study was to translate into Danish and validate the Danish version of COMPASS 31., Methods: The original (US) English version of the COMPASS 31 questionnaire was translated into Danish via forward/backward translation and validated in accordance with a protocol set forth by the Autonomic Group at the Mayo Clinic. Ten healthy controls and 20 patients with disorders associated with a variable degree of autonomic dysfunction were enrolled - all bilingual (Danish mother tongue, proficiency in English)., Results: A total of 20 patients (16 women, aged 48 + 17 years) and ten healthy controls (six women, aged 40 + 19 years) were included. Test-retest reliability was high with no consistent bias, and the Danish version of the COMPASS 31 significantly correlated with the English version of the COMPASS 31 in both total score and all sub-scores. Patients scored significantly higher on the COMPASS 31 questionnaire than healthy controls (34.0 (26.5-49.2) versus 2.3 (1.6-24.3) (median (interquartile ranges); p = 0.01)., Conclusions: We present a Danish version of the COMPASS 31 - a validated self-reported questionnaire allowing for the quantification of autonomic dysfunction. We hope this Danish version will be implemented in both clinical practice and research settings in Denmark., Funding: none., Trial Registration: not relevant., (Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

Background: Patients with Parkinson's disease (PD) often show peripheral autonomic dysfunction and depositions of pathological alpha-synuclein aggregates in the skin. However, functional consequences of this skin involvement have received little attention., Objective: To determine thermographic differences in the skin between healthy controls (HCs) and PD patients on hands, feet, and trunk and to correlate findings with symptoms and signs of dysautonomia. Between-group differences in autonomic parameters and questionnaires were explored., Methods: Twenty-one PD patients and 19 HCs were examined by thermographic infrared imaging of standardized anatomical locations on the trunk and upper and lower extremities at baseline and after exposure to cold stress test (CST). Thermal recovery rates (RRs) were determined on the basis of thermograms. Correlation analyses between alterations in skin temperature and autonomic dysfunction were performed., Results: The most significant RR difference between PD patients and HCs was seen on the fifth distal phalanx 10 minutes post-CST (mean RR ± SD: 51 ± 18% vs. 70 ± 23%, p  = 0.003). No between-group differences were seen in baseline or post-CST values of the feet. No correlations were seen between thermal parameters and clinical and autonomic data. In the HC group, a positive, moderate correlation was seen between post-CST recovery values on the 3 rd and 5 th phalanx and body mass index (BMI) ( r  = 0.661, p  = 0.002)., Conclusions: The PD patients exhibited significant reduction in RR compared to HC and patients also displayed altered thermal responses in multiple anatomical locations. Thus, infrared thermography could become an important future tool in investigation of autonomic deficiency in PD., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Mathias Møller Purup et al.)

Complex regional pain syndrome (CRPS) can be a debilitating, persistent, and treatment-resistant pain condition. This report presents a case of severe CRPS affecting multiple limbs, resistant to standard treatment modalities. Treatment with spinal cord stimulation (SCS) had an initial good effect. Nevertheless, the CRPS continued to progress, eventually affecting all 4 extremities. A lead fracture resulted in a rapidly developing recurrence of CRPS in the patient's arm, necessitating amputation. SCS may be an effective modality for treatment of severe CRPS. However, mechanical problems should always be considered when an SCS-implanted patient experiences rapid symptom progression or abrupt cessation of stimulation.

Purpose: Although autonomic features are part of the diagnostic criteria for complex regional pain syndrome (CRPS), the role of the autonomic nervous system in CRPS pathophysiology has been downplayed in recent years. The purpose of this review is to redress this imbalance., Methods: We focus in this review on the contribution of the autonomic nervous system to CRPS pathophysiology. In particular, we discuss regional sympathetic and systemic autonomic disturbances in CRPS and the mechanisms which may underlie them, and consider links between these mechanisms, immune disturbances and pain., Results: The focused literature research revealed that immune reactions, alterations in receptor populations (e.g., upregulation of adrenoceptors and reduced cutaneous nerve fiber density) and central changes in autonomic drive seem to contribute to regional and systemic disturbances in sympathetic activity and to sympathetically maintained pain in CRPS., Conclusions: We conclude that alterations in the sympathetic nervous system contribute to CRPS pathology. Understanding these alterations may be an important step towards providing appropriate treatments for CRPS.

Aims: To investigate the region-specific effects of painful trigeminal capsaicin stimulation in healthy participants., Methods: Twenty healthy participants (10 men and 10 women) participated in four sessions in which they received application of 0.05 mL Vaseline (placebo) or capsaicin cream (0.1%) to a different area innervated by the three branches of the trigeminal nerve: the supraorbital area (V1), the nasal mucosa (V1/V2), and the maxillary (V2) and mandibular (V3) oral mucosa. The participants rated their perceived sensations on a 0-50-100 numeric rating scale (NRS). Thermal (5°C, 23°C, and 50°C) and mechanical (32 mN and 256 mN) sensitivities were assessed. The Schirmer tearing test was used to monitor the lacrimation level as a local measure of autonomic activity, and the Task Force Monitor was used to record systemic autonomic activity. Data were analyzed using repeated measures analysis of variance., Results: Capsaicin application evoked significantly higher overall NRS scores (P < .001) and induced significantly higher ratings to the heat stimuli (P < .009) in all sessions compared to control. For lacrimation level, capsaicin stimulation resulted in a significant increase compared to control (P < .0002) only in the nasal mucosa session., Conclusion: Topical application of capsaicin cream to the different branches of the trigeminal nerve caused higher NRS scores along with an altered somatosensory sensitivity. Furthermore, in the nasal mucosa session, a robust local and generalized parasympathetic activation appeared following capsaicin application.

Introduction: In this study we assessed the value of genetic screening for Fabry disease (FD) and hereditary ATTR amyloidosis in patients with idiopathic small-fiber neuropathy (SFN) or mixed neuropathy in a clinical setting., Methods: This was a Nordic multicenter study with 9 participating centers. Patients with idiopathic SFN or mixed neuropathy were included. Genetic sequencing of the TTR and GLA genes was performed., Results: There were 172 patients enrolled in the study. Genetic screening was performed in 155 patients. No pathogenic mutations in the TTR gene were found. A single patient had a possible pathogenic variant, R118C, in the GLA gene, but clinical investigation showed no firm signs of FD., Discussion: Screening for hereditary ATTR amyloidosis and FD in patients with idiopathic SFN or mixed neuropathy without any additional disease-specific symptoms or clinical characteristics in a Nordic population appears to be of little value in a clinical setting. Muscle Nerve 59:354-357, 2019., (© 2018 Wiley Periodicals, Inc.)

Objective: Findings regarding small nerve fiber damage in complex regional pain syndrome type I (CRPS-I) are not uniform, and studies have not included a matched healthy control group. The aim was to assess intraepidermal nerve fiber density (IENFD) in relation to thermal sensitivity of the same skin areas in CRPS-I patients and a gender- and age-matched healthy control group., Methods: IENFD was investigated in skin biopsies from the CRPS-affected and contralateral limbs of eight CRPS-I patients and from an equivalent site in eight gender- and age-matched healthy controls (HCs). Thermal thresholds (cold/warm detection, cold- and heat-pain detection) were assessed on the affected limb, the matching contralateral limb, and on the equivalent limbs of HCs, and participants rated the intensity of cold/heat and pain to static thermal stimuli (5 °C and 40 °C)., Results: IENFD was significantly lower in both the affected and contralateral limbs of CRPS-I patients than HCs, but IENFD did not differ between the affected and contralateral limbs of patients. The heat pain threshold was lower in the affected CRPS-I limb than in HCs, but all other thermal thresholds were similar in both groups. CRPS-I patients rated the cold stimulus as colder and more painful in the affected limb, and the warm stimulus as hotter, bilaterally, than the HCs., Conclusions: CRPS-I may be associated with bilateral small fiber damage, and perhaps small fiber neuropathy and bilateral disturbances in thermo-sensory perception. These disturbances could stem from a systemic response to injury or might increase the risk of developing CRPS-I after physical trauma.

Neurogenic autonomic dysfunction (NAD) is underdiagnosed, and it is likely in patients, who have orthostatic hypotension and symptoms from multiple organ systems as well as abnormal results from a neurological examination. A clinical and neurophysiological examination of the autonomic nervous system combined with a standardised paraclinical evaluation should be performed. NAD may be present in neurodegenerative disorders, vitamin deficiency, toxicity, infection, and in paraneoplastic, metabolic, hereditary and immune-mediated conditions.

Background: The deep breathing test (DB) and Valsalva maneuver (VM) are used to detect autonomic dysfunction. The VM induces sympathetically mediated changes in blood pressure (phase II late, phase IV, and recovery time) and both tests induce vagally mediated heart rate changes. There is limited information on effects of key variables, compliance with testing and the effects of non-compliance This study has twin goals of evaluating compliance with standard instructions and the effects of changes in key variables. We also evaluated the effect of position on the VM., Material and Methods: Forty healthy males performed DB at air exchange volumes of 50, 80, and 100% of vital lung capacity (VLC). The VM was performed at 40 and 30mmHg expiratory pressure for 15 and 10s in sitting and supine position, respectively., Results: Participants performed DB at lower volumes than intended and were not able to maintain 100% VLC for the duration of the test. The DB heart rate response decreased 6.3beats/min per liter below VLC. During the VM, subjects blew at lower pressures than instructed. The VM responses were significantly larger with longer expiration durations, higher expiratory pressures and when performed sitting. Performing the VM at 40mmHg for 10s in supine position increased the odds ratio of experiencing flat-top responses., Conclusion: The ability of subjects to strictly comply with methodological guidelines significantly improves results. Recording of both test parameters and ensuing results is suggested., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Small fibre neuropathies are a heterogeneous group of disorders affecting thinly myelinated Aδ-fibres and unmyelinated C-fibres. Although multiple causes of small nerve fibre degeneration have been reported, including via genetic mutations, the cause of small fibre neuropathy remains unknown in up to 50% of cases. The typical clinical presentation of small fibre neuropathy is that of a symmetrical, length-dependent polyneuropathy associated with sensory or autonomic symptoms. More rarely, the clinical presentation is characterised by non-length-dependent, focal, or multifocal symptoms. The diagnostic tests to identify small fibre neuropathy include skin biopsy, quantitative sensory, and autonomic testing. Additional tests, such as those measuring small fibre-related evoked potentials and corneal confocal microscopy, might contribute to a better understanding of these neuropathies. Biochemical markers can also help in screening patients for the presence of small fibre neuropathy and to assess disease progression., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

To characterise self-reported levels of stress and autonomic responses in healthy humans evoked by different rates of the Paced Auditory Serial Addition Task (PASAT). Fifteen participants performed PASATs with different rates (3·6-, 2·4-, 1·6- or 1·2-s intervals) and a control task, in random order. Correct responses, self-reported levels of stress and autonomic responses to the PASATs were estimated. Increased PASAT rates were associated with decreases in correct responses (P < 0·001) and increases in self-reported levels of stress (P < 0·001). For autonomic responses, significant changes were seen in 10 variables during 2·4-s PASAT compared with the respective baseline; however, significant differences in relative changes from baseline were found between the 2·4-s PASAT and control task only for mean RR-intervals (P < 0·001), systolic and diastolic blood pressure (P = 0·002 and P = 0·006) and cardiac output (P < 0·001). Regarding comparison between the four PASATs, significant differences in the relative changes from baseline were seen between the 3·6-s PASAT and faster PASATs, for example mean RR-intervals, high-frequency power and respiration rate; however, there were no differences between the faster PASATs. The autonomic responses during the PASATs with different rates were quite similar for the faster PASATs (intervals < 2·4 s); however, the slowest 3·6-s PASAT evoked significantly less self-reported stress and autonomic arousal compared with the faster PASATs. Standardization of the PASAT rate may be important for studies on autonomic nervous system function and self-reported measures of stress. Future studies may test more complex interactions between stress, autonomic responses and pain responses., (© 2014 John Wiley & Sons Ltd.)

Background: A maladaptation of the autonomic nervous system may been seen in patients with chronic pain that includes persistent changes in the autonomic tone, increased heart rate, and reduced heart rate variability and baroreflex sensitivity. Baroreflex sensitivity and acute pain intensity have been reported to be inversely correlated. However, it is unknown whether the same correlation applies with regard to post-operative pain. In the present study, autonomic function was measured in patients scheduled for minor hand surgery and correlated with early and persistent pain after the procedure. Thus, the cause (autonomic imbalance) was present before the effect (post-operative pain). Our primary hypothesis was that a lower level of pre-operative baroreflex sensitivity is correlated with increased early post-operative pain., Methods: There were 30 patients included and scheduled for open carpal tunnel surgery. Baroreflex sensitivity and heart rate variability were measured before surgery. Efferent cardiac parasympathetic activity was estimated by power spectral analysis of heart rate variability. Post-operative pain was recorded daily for 6 weeks (early post-operative pain) and for 1 week 1 year after surgery (persistent post-operative pain)., Results: Pre-operative baroreflex sensitivity correlated negatively with early (P=0.05) and persistent (P=0.04) post-operative pain. Efferent cardiac parasympathetic activity correlated negatively with early (P=0.03) but not persistent post-operative pain (P=0.12)., Conclusions: The findings suggest that a low pre-operative level of baroreflex sensitivity is associated with higher post-operative pain intensity. To our knowledge, this is the first study to show the correlation between baroreflex sensitivity and post-operative pain., (© 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Diabetic neuropathy is associated with disturbances in endoneurial metabolism and microvascular morphology, but the roles of these factors in the aetiopathogenesis of diabetic neuropathy remain unclear. Changes in endoneurial capillary morphology and vascular reactivity apparently predate the development of diabetic neuropathy in humans, and in manifest neuropathy, reductions in nerve conduction velocity correlate with the level of endoneurial hypoxia. The idea that microvascular changes cause diabetic neuropathy is contradicted, however, by reports of elevated endoneurial blood flow in early experimental diabetes, and of unaffected blood flow when early histological signs of neuropathy first develop in humans. We recently showed that disturbances in capillary flow patterns, so-called capillary dysfunction, can reduce the amount of oxygen and glucose that can be extracted by the tissue for a given blood flow. In fact, tissue blood flow must be adjusted to ensure sufficient oxygen extraction as capillary dysfunction becomes more severe, thereby changing the normal relationship between tissue oxygenation and blood flow. This review examines the evidence of capillary dysfunction in diabetic neuropathy, and whether the observed relation between endoneurial blood flow and nerve function is consistent with increasingly disturbed capillary flow patterns. The analysis suggests testable relations between capillary dysfunction, tissue hypoxia, aldose reductase activity, oxidative stress, tissue inflammation and glucose clearance from blood. We discuss the implications of these predictions in relation to the prevention and management of diabetic complications in type 1 and type 2 diabetes, and suggest ways of testing these hypotheses in experimental and clinical settings.

Parkinson's disease is associated with early parasympathetic dysfunction leading to constipation and gastroparesis. It has been suggested that pathological α-synuclein aggregations originate in the gut and ascend to the brainstem via the vagus. Our understanding of the pathogenesis and time course of parasympathetic denervation in Parkinson's disease is limited and would benefit from a validated imaging technique to visualize the integrity of parasympathetic function. The positron emission tomography tracer 5-[(11)C]-methoxy-donepezil was recently validated for imaging acetylcholinesterase density in the brain and peripheral organs. Donepezil is a high-affinity ligand for acetylcholinesterase-the enzyme that catabolizes acetylcholine in cholinergic synapses. Acetylcholinesterase histology has been used for many years for visualizing cholinergic neurons. Using 5-[(11)C]-methoxy-donepezil positron emission tomography, we studied 12 patients with early-to-moderate Parkinson's disease (three female; age 64 ± 9 years) and 12 age-matched control subjects (three female; age 62 ± 8 years). We collected clinical information about motor severity, constipation, gastroparesis, and other parameters. Heart rate variability measurements and gastric emptying scintigraphies were performed in all subjects to obtain objective measures of parasympathetic function. We detected significantly decreased (11)C-donepezil binding in the small intestine (-35%; P = 0.003) and pancreas (-22%; P = 0.001) of the patients. No correlations were found between the (11)C-donepezil signal and disease duration, severity of constipation, gastric emptying time, and heart rate variability. In Parkinson's disease, the dorsal motor nucleus of the vagus undergoes severe degeneration and pathological α-synuclein aggregations are also seen in nerve fibres innervating the gastro-intestinal tract. In contrast, the enteric nervous system displays little or no loss of cholinergic neurons. Decreases in (11)C-donepezil binding may, therefore, represent a marker of parasympathetic denervation of internal organs, but further validation studies are needed., (© The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Complex regional pain syndrome is multifactorial. Exaggerated inflammatory responses to limb injury may be involved. The authors hypothesized that capsaicin-induced pain and neurogenic inflammation (skin perfusion and flare area) are increased in patients with complex regional pain syndrome compared with that in controls., Methods: Twenty patients with unilateral upper-limb complex regional pain syndrome and 20 age-, sex-, and body mass index-matched controls participated. Topical capsaicin 5% was applied to the back of both hands for 30 min, and pain intensity was assessed on a visual analogue scale. A laser Doppler perfusion imager scanner estimated capsaicin-induced skin perfusion and flare area. Autonomic and small-fiber function was assessed by sensory testing, quantitative sudomotor axon reflex test, and vasoconstrictor responses., Results: The authors found bilateral hypersensitivity to capsaicin (P ≤ 0.02), skin fold (P = 0.001), joint pressure (P < 0.0001), cold (P ≤ 0.01), and heat pain (P ≤ 0.04) in patients compared with that in controls and thermal and mechanical hyperalgesia in the complex regional pain syndrome-affected hand compared with that in the unaffected hand (P ≤ 0.001). The patients had normal capsaicin-induced flare areas, thermal detection thresholds, quantitative sudomotor axon reflex test, and vasoconstrictor responses., Conclusions: The main finding is bilaterally increased capsaicin-induced pain in patients compared with controls. The flare response to capsaicin was normal, suggesting that the increased pain response was not due to increased neurogenic inflammation. The bilateral hypersensitivity to painful chemical, thermal, and mechanical stimuli not confined to the innervation area of a peripheral nerve or root cannot be explained by a regional change and may partly be due to central sensitization.

Complex regional pain syndrome (CRPS) is characterised by autonomic, sensory, and motor disturbances. The underlying mechanisms of the autonomic changes in CPRS are unknown. However, it has been postulated that sympathetic inhibition in the acute phase with locally reduced levels of noradrenaline is followed by an up-regulation of alpha-adrenoceptors in chronic CRPS leading to denervation supersensitivity to catecholamines. This exploratory study examined the effect of cutaneous sympathetic activation and inhibition on cutaneous noradrenaline release, vascular reactivity, and pain in CRPS patients and in healthy volunteers. Seven patients and nine controls completed whole-body cooling (sympathetic activation) and heating (sympathetic inhibition) induced by a whole-body thermal suit with simultaneous measurement of the skin temperature, skin blood flow, and release of dermal noradrenaline. CRPS pain and the perceived skin temperature were measured every 5 min during thermal exposure, while noradrenaline was determined from cutaneous microdialysate collected every 20 min throughout the study period. Cooling induced peripheral sympathetic activation in patients and controls with significant increases in dermal noradrenaline, vasoconstriction, and reduction in skin temperature. The main findings were that the noradrenaline response did not differ between patients and controls or between the CRPS hand and the contralateral unaffected hand, suggesting that the evoked noradrenaline release from the cutaneous sympathetic postganglionic fibres is preserved in chronic CRPS patients., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: Thoracoscopic sympathectomy at levels T2 or T2-T3 is a treatment for focal hyperhidrosis and facial blushing. These levels of the sympathetic trunk innervate the heart, and consequently, the procedure is reported to change the heart rate variability due to changes in efferent cardiac autonomic activity. Our objective was to investigate the effects of thoracoscopic sympathectomy on global autonomic control, including baroreceptor sensitivity., Methods: Eight patients (6 F, median age 28 years [range 20-58 years]) were exposed to the tilt-table test and cardiopulmonary exercise test before, and 3 months after, thoracoscopic sympathectomy. Eight healthy age-, gender- and BMI-matched controls were used as controls and underwent the same tests once. During tilt-table testing electrocardiogram, blood pressure, impedance cardiography and respiration were measured continuously, and efferent cardiac autonomic balance was estimated., Results: The heart rate measured during orthostatic stress test was lowered after thoracoscopic sympathectomy (between-group; P = 0.01) due to a change in autonomic tone, with increased vagal (high-frequency power n.u.; P = 0.001), and reduced sympathetic efferent cardiac activity (low-frequency power n.u.; P < 0.001). Baroreceptor sensitivity measured during rest was increased (26 ± 13 vs 44 ± 19 ms/mmHg; P = 0.01), and diastolic blood pressure reduced after surgery (P = 0.01). The increases in systolic blood pressure and the sympathetic marker CCV-LF in response to orthostatic stress were higher before sympathectomy, with almost no increases post-surgically (condition × group interaction; P = 0.01 and P = 0.001, respectively). We found no change in post-procedure exercise capacity, although patients had a lower peak VO2 and maximal cardiac index than controls., Conclusions: Thoracoscopic sympathectomy changes the autonomic tone towards increased vagal activity; this is potentially cardioprotective. To our knowledge, this is the first study to show increased baroreceptor sensitivity after thoracoscopic sympathectomy.

Although the use of prayer as a religious coping strategy is widespread and often claimed to have positive effects on physical disorders including pain, it has never been tested in a controlled experimental setting whether prayer has a pain relieving effect. Religious beliefs and practices are complex phenomena and the use of prayer may be mediated by general psychological factors known to be related to the pain experience, such as expectations, desire for pain relief, and anxiety. Twenty religious and twenty non-religious healthy volunteers were exposed to painful electrical stimulation during internal prayer to God, a secular contrast condition, and a pain-only control condition. Subjects rated expected pain intensity levels, desire for pain relief, and anxiety before each trial and pain intensity and pain unpleasantness immediately after on mechanical visual analogue scales. Autonomic and cardiovascular measures provided continuous non-invasive objective means for assessing the potential analgesic effects of prayer. Prayer reduced pain intensity by 34 % and pain unpleasantness by 38 % for religious participants, but not for non-religious participants. For religious participants, expectancy and desire predicted 56-64 % of the variance in pain intensity scores, but for non-religious participants, only expectancy was significantly predictive of pain intensity (65-73 %). Conversely, prayer-induced reduction in pain intensity and pain unpleasantness were not followed by autonomic and cardiovascular changes.

Aims: To investigate in a randomized, double-blinded, placebo controlled, crossover study the effect of a single dose of the nonselective β-adrenergic receptor antagonist propranolol (40 mg) on hypertonic saline (HS)-evoked masseter muscle pain and autonomic activity during rest and during a mental arithmetic task (Paced Auditory Serial Addition Task, PASAT)., Methods: Sixteen healthy women participated in two sessions in which propranolol or placebo was administered orally prior to two 5-minute infusions (30 minutes apart) of HS in the masseter muscle. The second HS infusion was combined with PASAT. HS-evoked pain intensity was scored on a numeric rating scale (NRS, 0 to 10). Heart rate variability and hemodynamic measures were recorded noninvasively (Task Force Monitor). Data were analyzed with repeated measurements analysis of variance (ANOVA)., Results: Propranolol did not reduce NRS pain scores compared with placebo but did induce significant autonomic changes with reduced heart rate and increased heart rate variability (standard deviations of all normal RR intervals; root mean square successive differences; low-frequency power; high-frequency power; and total power) independent of the mental task., Conclusion: A single dose of propranolol had no effect on acute HS-evoked pain levels during rest or during mental arousal. However, it influenced the tone of the autonomic nervous system, possibly reflecting an anxiolytic effect.

Aims: To test in a randomized controlled trial, if hypertonic saline (HS)-evoked pain and autonomic function are modulated by either a cold pressor test (CPT) or mental arithmetic stress induced by a paced auditory serial addition task (PASAT)., Methods: Fourteen healthy women participated in three sessions. Pain was induced by two 5% HS infusions (5 minutes each, 30 minutes apart) infused into the masseter muscle. During the second HS infusion, pain was modulated by PASAT, CPT, or control (HS alone). HS-evoked pain intensity was scored on a 0 to 10 numeric rating scale (NRS). Heart rate variability (HRV) and hemodynamic measures were recorded noninvasively (Task Force Monitor). Data were analyzed using repeated measurements ANOVAs and Spearman correlation analysis., Results: HS-evoked pain was significantly and similarly reduced by both PASAT (30.8 ± 27.6%; P < .001) and CPT (35.8 ± 26.6%; P < .001) compared with the control session (9.0 ± 30.5%; P > .05). PASAT and CPT increased the heart rate compared with control (P <.001). CPT reduced measures of vagal activity: Root mean square successive difference, high-frequency (HF) power, and coefficient of HF component variance compared with an internal control, ie, the first HS infusion (P < .05), while PASAT did not alter any of these HRV measures (P > .05)., Conclusion: CPT and PASAT reduced HS-evoked masseter muscle pain and altered the autonomic response. The increase in heart rate following CPT and PASAT may be caused by different mechanisms. CPT reduced measures of efferent cardiac vagal (parasympathetic) activity, while the PASAT-induced increase in heart rate, but unchanged HRV, may suggest neurohumoral activation.

Background: Complex regional pain syndrome (CRPS) is a pain condition with regional sensory and autonomic abnormalities in the affected limb. The authors studied systemic autonomic and hemodynamic function in CRPS patients during rest, and during orthostatic and mental arithmetic stress., Methods: Twenty patients with CRPS and 20 age-, sex-, and body mass index-matched control subjects participated. Mean values of heart rate variability, baroreceptor sensitivity, blood pressure, stroke volume, cardiac output, and total peripheral resistance were estimated during supine rest and 60° tilt-table testing. On a separate day, heart rate variability was also measured during mental arithmetic stress testing induced by a paced auditory serial addition task., Results: Heart rate was increased and heart rate variability reduced in patients with CRPS patients compared with control subjects during rest and mental and orthostatic stress, whereas baroreceptor sensitivity was unaffected. When tilted from supine to upright position, patients with CRPS were not able to preserve cardiac output in comparison with control subjects, and they exhibited an exaggerated increase in the total peripheral resistance. The hemodynamic changes correlated to pain duration but not to pain intensity., Conclusion: The increased heart rate and decreased heart rate variability in CRPS suggest a general autonomic imbalance, which is an independent predictor for increased mortality and sudden death. The inability of the patients to protect their cardiac output during orthostatic stress was aggravated with the chronicity of the disease.

Objectives: Examination of the relationship between pain, sensory hypersensitivity, referred sensations and involuntary muscle jerks in patients with brachial plexus injury., Materials and Methods: Fourteen patients with brachial plexus lesions were included. Spontaneous background and paroxysmal pain and mechanically and thermally evoked pain were recorded. Areas with sensory hypersensitivity and referred pain were mapped on a body chart. This was supplemented by electrophysiological analysis in three patients., Results: Sensory hypersensitivity and areas with pinprick-induced referred phantom sensations were present in adjacent dermatomes. There was no clear relationship between chronic neuropathic pain and referred sensations, but there was a correlation between pain paroxysms and sensory hypersensitivity in dermatomes adjacent to deafferented areas. In three patients, simultaneous referred sensations and short latency motor action potentials ipsilateral to the denervated side suggested origin at subcortical sites., Conclusion: The study suggests a possible role of a spinal generator for sensory hypersensitivity and referred sensations following denervation.

In a recent study we found that 4 weeks of human experimental forearm immobilization induced hypersensitivity to mechanical and cold stimuli and a higher skin temperature on the immobilized hand. Identical findings are reported in immobilization studies in rats where increased substance P signaling is suggested to play a central role. Capsaicin releases substance P from axon collaterals in the periphery initiating vasodilatation and plasma extravasation. The effect of immobilization on capsaicin-induced responses is, however, not known. Therefore, the present study examined the effect of experimental forearm immobilization on capsaicin-induced pain and flare responses in healthy subjects. Twenty-seven human volunteers were exposed to 4 weeks of scaphoid cast immobilization of the left forearm. Before and after immobilization, skin temperature and blood flow were measured at the thumbs of both hands during 5 min of rest. Subjects then received topical capsaicin (5%) randomly on the dorsum of the right and left hands. Time to sensory detection of capsaicin and pain onset was significantly increased on the immobilized left hand. Immobilization significantly reduced capsaicin-evoked pain, neurogenic flare area, and skin blood flow (perfusion units), and the reduced capsaicin-evoked pain was significantly correlated to an increase in peripheral skin temperature but not to skin blood flow. The correlation between reduced capsaicin-evoked pain and increased skin temperature suggests an increased substance P release while the delayed onset and diminished magnitude of capsaicin-induced pain may be due to reduced penetration of capsaicin into the epidermis.