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To determine the sensitivity and specificity of cutaneous amyloid deposition in relation to patient-reported measures in the earliest disease stage of hereditary ATTR amyloidosis (ATTRv).In a cross-sectional study, we analyzed 88 individuals with TTR mutations, 47 of whom were in the earliest disease stage and without clinically evident neuropathy, 12 healthy controls, and 13 disease controls with diabetes. All participants' neuropathy symptoms and signs were assessed using validated patient and clinician-reported measures and 3-mm skin punch biopsies were immunostained using protein gene product 9.5 and Congo Red.Amyloid can be detected in the earliest disease stages in up to 86% of patients with ATTRv amyloidosis. Amyloid was not detected in healthy individuals or individuals with diabetic peripheral neuropathy supporting a sensitivity of 86% and a specificity of 100%. The cutaneous deposition of amyloid correlates with neuropathy sensory symptoms, measured with the Neuropathy Total Symptom Score-6 (R = 0.46, p 0.01); pain measured with the Brief Pain Symptom Inventory (R = 0.44, p 0.05); autonomic symptoms, measured with the Boston Autonomic Symptom Questionnaire (R = 0.38, p 0.05); and quality of life measured with the Norfolk Diabetic Neuropathy Quality of Life Questionnaire (R = 0.44, p 0.05). Individuals with amyloid deposition were more likely to have sensory symptoms, pain, autonomic impairment, and reduced quality of life than ATTRv patients without amyloid deposition.These findings have implications for understanding the earliest manifestations of the clinical phenotype of ATTRv-associated neuropathy, for the pathophysiological construct of disease staging, and for timing the introduction of disease-modifying therapy.

Finding an easily accessible and reliable tool to diagnose the diseases collectively defined as ‘synucleinopathies’ is an urgent, unmet priority. The synucleinopathies include Parkinson's disease, multiple system atrophy, pure autonomic failure and dementia with Lewy bodies. There are millions of people who have a diagnosis of a synucleinopathy, with more diagnosed every year. With accessibility, ease of implementation, consistently high sensitivity (>80%) and specificity approaching 100%, skin biopsy has great potential as the clinical test of choice for the diagnosis of synucleinopathies. The large, multi-center Synuclein-One study will determine the sensitivity, specificity, accuracy and precision of α-synuclein detection within punch skin biopsies in patients with clinically established synucleinopathies using standardized, robust methods suitable for large-scale analysis. Clinical Trial Registration: NCT04700722 ( ClinicalTrials.gov )

The nucleus tractus solitarius (NTS) is a key brainstem structure relaying interoceptive peripheral information to the interrelated brain centres for eliciting rapid autonomic responses and for shaping longer-term neuroendocrine and motor patterns. Structural and functional NTS' connectivity has been extensively investigated in laboratory animals. But there is limited information about NTS' connectome in humans. Using MRI, we examined diffusion and resting state data from 20 healthy participants in the Human Connectome Project. The regions within the brainstem (n = 8), subcortical (n = 6), cerebellar (n = 2) and cortical (n = 5) parts of the brain were selected via a systematic review of the literature and their white matter NTS connections were evaluated via probabilistic tractography along with functional and directional (i.e. Granger causality) analyses. The underlying study confirms previous results from animal models and provides novel aspects on NTS integration in humans. Two key findings can be summarized: (1) the NTS predominantly processes afferent input and (2) a lateralization towards a predominantly left-sided NTS processing. Our results lay the foundations for future investigations into the NTS' tripartite role composed of interoreceptors' input integration, the resultant neurochemical outflow and cognitive/affective processing. The implications of these data add to the understanding of NTS' role in specific aspects of autonomic functions.

Background and ObjectivesMultiple system atrophy (MSA) is a progressive neurodegenerative disorder caused by the abnormal accumulation of α-synuclein in the nervous system. Clinical features include autonomic and motor dysfunction, which overlap with those of Parkinson disease (PD), particularly at early disease stages. There is an unmet need for accurate diagnostic and prognostic biomarkers for MSA and, specifically, a critical need to distinguish MSA from other synucleinopathies, particularly PD. The purpose of the study was to develop a unique cutaneous pathologic signature of phosphorylated α-synuclein that could distinguish patients with MSA from patients with PD and healthy controls.MethodsWe studied 31 patients with MSA and 54 patients with PD diagnosed according to current clinical consensus criteria. We also included 24 matched controls. All participants underwent neurologic examinations, autonomic testing, and skin biopsies at 3 locations. The density of intraepidermal, sudomotor, and pilomotor nerve fibers was measured. The deposition of phosphorylated α-synuclein was quantified. Results were compared with clinical rating assessments and autonomic function test results.ResultsPatients with PD had reduced nerve fiber densities compared with patients with MSA (p< 0.05, all fiber types). All patients with MSA and 51/54 with PD had evidence of phosphorylated α-synuclein in at least one skin biopsy. No phosphorylated α-synuclein was detected in controls. Patients with MSA had greater phosphorylated α-synuclein deposition (p< 0.0001) and more widespread peripheral distribution (p< 0.0001) than patients with PD. These results provided >90% sensitivity and specificity in distinguishing between the 2 disorders.Discussionα-synuclein is present in the peripheral autonomic nerves of patients with MSA and when combined with synuclein distribution accurately distinguishes MSA from PD.Classification of EvidenceThis study provides Class II evidence that measurement of phosphorylated α-synuclein in skin biopsies can differentiate patients with MSA from those with PD.

Glucocorticoid use is the most common cause of secondary osteoporosis. Poor skeletal health related to glucocorticoid use is thought to involve inhibition of the Wnt/β-catenin signaling pathway, a key pathway in osteoblastogenesis. Sclerostin, a peptide produced primarily by osteocytes, is an antagonist of the Wnt/β-catenin signaling pathway, raising the possibility that sclerostin is involved in glucocorticoids’ adverse effects on bone. The aim of this study was to determine whether an acute infusion of cosyntropin (i.e. ACTH(1–24)), which increases endogenous cortisol, increases serum sclerostin levels as compared to a placebo infusion. This study was performed using blood samples obtained from a previously published, double-blind, placebo-controlled, randomized, cross-over study among healthy men and women who received infusions of placebo or cosyntropin after being supine and fasted overnight (ClinicalTrials.gov NCT02339506). A total of 17 participants were analyzed. There was a strong correlation (R2 = 0.65, P < 0.0001) between the two baseline sclerostin measurements measured at the start of each visit, and men had a significantly higher average baseline sclerostin compared to women. As anticipated, cosyntropin significantly increased serum cortisol levels, whereas cortisol levels fell during placebo infusion, consistent with the diurnal variation in cortisol. There was no significant effect of cosyntropin as compared to placebo infusions on serum sclerostin over 6–24 h (P = 0.10). In conclusion, this randomized, placebo-controlled study was unable to detect a significant effect of a cosyntropin infusion on serum sclerostin levels in healthy men and women.

Abnormalities in orthostatic blood pressure changes upon active standing are associated with morbidity, mortality, and reduced quality of life. However, over the last decade, several population-based cohort studies have reported a remarkably high prevalence (between 25 and 70%) of initial orthostatic hypotension (IOH) among elderly individuals. This has raised the question as to whether the orthostatic blood pressure patterns in these community-dwelling elderly should truly be considered as pathological. If not, redefining of the systolic cutoff values for IOH (i.e., a value ≥ 40 mmHg in systolic blood pressure in the first 15 s after standing up) might be necessary to differ between normal aging and true pathology. Therefore, in this narrative review, we provide a critical analysis of the current reference values for the changes in systolic BP in the first 60 s after standing up and discuss how these values should be applied to large population studies. We will address factors that influence the magnitude of the systolic blood pressure changes following active standing and the importance of standardization of the stand-up test, which is a prerequisite for quantitative, between-subject comparisons of the postural hemodynamic response.

Objective: MR (mineralocorticoid receptor) activation associates with increased risk of cardiovascular ischemia while MR inhibition reduces cardiovascular-related mortality and plaque inflammation in mouse atherosclerosis. MR in myeloid cells (My-MR) promotes inflammatory cell infiltration into injured tissues and atherosclerotic plaque inflammation by unclear mechanisms. Here, we examined the role of My-MR in leukocyte trafficking and the impact of sex. Approach and Results: We confirm in vivo that My-MR deletion (My-MR-KO) in ApoE-KO mice decreased plaque size. Flow cytometry revealed fewer plaque macrophages with My-MR-KO. By intravital microscopy, My-MR-KO significantly attenuated monocyte slow-rolling and adhesion to mesenteric vessels and decreased peritoneal infiltration of myeloid cells in response to inflammatory stimuli in male but not female mice. My-MR-KO mice had significantly less PSGL1 (P-selectin glycoprotein ligand 1) mRNA in peritoneal macrophages and surface PSGL1 protein on circulating monocytes in males. In vitro, MR activation with aldosterone significantly increased PSGL1 mRNA only in monocytes from MR-intact males. Similarly, aldosterone induced, and MR antagonist spironolactone inhibited, PSGL1 expression in human U937 monocytes. Mechanistically, aldosterone stimulated MR binding to a predicted MR response element in intron-1 of the PSGL1 gene by ChIP-qPCR. Reporter assays demonstrated that this PSGL1 MR response element is necessary and sufficient for aldosterone-activated, MR-dependent transcriptional activity. Conclusions: These data identify PSGL1 as a My-MR target gene that drives leukocyte trafficking to enhance atherosclerotic plaque inflammation. These novel and sexually dimorphic findings provide insight into increased ischemia risk with MR activation, cardiovascular protection in women, and the role of MR in atherosclerosis and tissue inflammation. Graphic Abstract: A graphic abstract is available for this article.

Background X-linked dystonia parkinsonism (XDP) or "Lubag" is a genetic dystonia syndrome observed among Filipinos that can present with levodopa-responsive parkinsonism and abnormal dopamine transporter (DAT) imaging. Objective The aim of this study is to describe the results of skin biopsies for phosphorylated α-synuclein (P-SYN) in XDP. Method This study used the retrospective chart review. Results We report 6 patients who carried the XDP gene mutation with DAT imaging and skin biopsies to detect P-SYN. Five had segmental or multifocal dystonia and parkinsonism: 4 were levodopa-responsive and 1 non-levodopa-responsive. One patient was asymptomatic but had mild bradykinesia. Cutaneous P-SYN and abnormal DAT scans were noted in the 4 levodopa-responsive patients and 1 asymptomatic patient. Conclusion We report for the first time the presence of cutaneous P-SYN in XDP. Our findings suggest that XDP may be a hitherto-undescribed synucleinopathy or that some XDP patients may have concurrent Parkinson's disease.

Chronic pain clinical trials have historically assessed benefit and risk outcomes separately. However, a growing body of research suggests that a composite metric that accounts for benefit and risk in relation to each other can provide valuable insights into the effects of different treatments. Researchers and regulators have developed a variety of benefit-risk composite metrics, although the extent to which these methods apply to randomized clinical trials (RCTs) of chronic pain has not been evaluated in the published literature. This article was motivated by an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting and is based on the expert opinion of those who attended. In addition, a review of the benefit-risk assessment tools used in published chronic pain RCTs or highlighted by key professional organizations (ie, Cochrane, European Medicines Agency, Outcome Measures in Rheumatology, and U.S. Food and Drug Administration) was completed. Overall, the review found that benefit-risk metrics are not commonly used in RCTs of chronic pain despite the availability of published methods. A primary recommendation is that composite metrics of benefit-risk should be combined at the level of the individual patient, when possible, in addition to the benefit-risk assessment at the treatment group level. Both levels of analysis (individual and group) can provide valuable insights into the relationship between benefits and risks associated with specific treatments across different patient subpopulations. The systematic assessment of benefit-risk in clinical trials has the potential to enhance the clinical meaningfulness of RCT results.

Patients with chronic pain syndromes, such as those with painful peripheral neuropathy due to diabetes mellitus, have limited treatment options and suffer ongoing attrition of their quality of life. Safer and more effective treatment options are needed. One therapeutic approach encompasses phenotypic characterization of the neuropathic pain subtype, combined with the selection of agents that act on relevant mechanisms. ISC 17536 is a novel, orally available inhibitor of the widely expressed pain receptor, transient receptor potential ankyrin 1, which mediates nociceptive signaling in peripheral small nerve fibers. In this randomized, placebo-controlled, proof-of-concept trial, we assessed the safety and efficacy of 28-day administration of ISC 17536 in 138 patients with chronic, painful diabetic peripheral neuropathy and used quantitative sensory testing to characterize the baseline phenotype of patients. The primary end point was the change from baseline to end of treatment in the mean 24-hour average pain intensity score based on an 11-point pain intensity numeric rating scale. The study did not meet the primary end point in the overall patient population. However, statistically significant and clinically meaningful improvement in pain were seen with ISC 17536 in an exploratory hypothesis-generating subpopulation of patients with preserved small nerve fiber function defined by quantitative sensory testing. These results may provide a mechanistic basis for targeted therapy in specific pain phenotypes in line with current approaches of "precision medicine" or personalized pain therapeutics. The hypothesis is planned to be tested in a larger phase 2 study.

Purpose of the review Pure autonomic failure (PAF) is a peripheral autonomic neurodegenerative disease caused by alpha-synuclein deposition that is predominantly confined to peripheral autonomic neurons. Patients present with insidious features of autonomic failure that have a chronic course.In this review, we highlight the features of PAF, the differentiating features from other autonomic neuropathies, the diagnostic tests, and the predictors for conversion to a central synucleinopathy. Recent findings Natural history studies have defined the predictors for and rate of conversion to a central alpha-synucleinopathy. Skin immunohistochemistry techniques and demonstration of length-dependent neuronal loss of both somatic and autonomic small fiber nerves, and intraneural phosphorylated synuclein deposition provide diagnostic biomarkers. In the future, diagnosis maybe supported by measuring cerebrospinal fluid alpha-synuclein oligomers using techniques, such as protein misfolding cyclic amplification assay and real-time quaking-induced conversion. Summary PAF is a sporadic peripheral autonomic neurodegenerative disease that belongs to the group of disorders known as alpha-synucleinopathies. Peripheral autonomic manifestations are similar to those seen in other autonomic neuropathies, particularly, diabetic autonomic neuropathy, amyloid polyneuropathy, and autoimmune autonomic neuropathies. Novel diagnostic procedures like skin immunohistochemistry for alpha-synuclein, and protein amplification techniques are being investigated to provide an earlier and more specific diagnosis. A substantial number of PAF patients' phenoconvert to a central alpha-synucleinopathy.

ObjectiveTo present standardized diagnostic criteria for idiopathic distal sensory polyneuropathy (iDSP) and its subtypes: idiopathic mixed fiber sensory neuropathy (iMFN), idiopathic small fiber sensory neuropathy (iSFN), and idiopathic large fiber sensory neuropathy (iLFN) for use in research.MethodsThe Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities and Networks (ACTTION) public-private partnership with the Food and Drug Administration convened a meeting to develop consensus diagnostic criteria for iMFN, iSFN, and iLFN. After background presentations, a collaborative, iterative approach was used to develop expert consensus for new criteria.ResultsAn iDSP diagnosis requires at least 1 small fiber (SF) or large fiber (LF) symptom, at least 1 SF or LF sign, abnormalities in sensory nerve conduction studies (NCS) or distal intraepidermal nerve fiber density (IENFD), and exclusion of known etiologies. An iMFN diagnosis requires that at least 1 of the above clinical features is SF and 1 clinical feature is LF with abnormalities in sensory NCS or IENFD. Diagnostic criteria for iSFN require at least 1 SF symptom and at least 1 SF sign with abnormal IENFD, normal sensory NCS, and the absence of LF symptoms and signs. Diagnostic criteria for iLFN require at least 1 LF symptom and at least 1 LF sign with normal IENFD, abnormal sensory NCS, and absence of SF symptoms and signs.ConclusionAdoption of these standardized diagnostic criteria will advance research and clinical trials and spur development of novel therapies for iDSPs.

Large variability in the individual response to even the most-efficacious pain treatments is observed clinically, which has led to calls for a more personalized, tailored approach to treating patients with pain (i.e., "precision pain medicine"). Precision pain medicine, currently an aspirational goal, would consist of empirically-based algorithms that determine the optimal treatments, or treatment combinations, for specific patients (i.e., targeting the right treatment, in the right dose, to the right patient, at the right time). Answering this question of "what works for whom" will certainly improve the clinical care of patients with pain. It may also support the success of novel drug development in pain, making it easier to identify novel treatments that work for certain patients and more accurately identify the magnitude of the treatment effect for those subgroups. Significant preliminary work has been done in this area, and analgesic trials are beginning to utilize precision pain medicine approaches such as stratified allocation on the basis of pre-specified patient phenotypes using assessment methodologies such as quantitative sensory testing. Current major challenges within the field include: (1) identifying optimal measurement approaches to assessing patient characteristics that are most robustly and consistently predictive of inter-patient variation in specific analgesic treatment outcomes, (2) designing clinical trials that can identify treatment-by-phenotype interactions, and (3) selecting the most promising therapeutics to be tested in this way. This review surveys the current state of precision pain medicine, with a focus on drug treatments (which have been most-studied in a precision pain medicine context). It further presents a set of evidence-based recommendations for accelerating the application of precision pain methods in chronic pain research. PERSPECTIVE: : Given the considerable variability in treatment outcomes for chronic pain, progress in precision pain treatment is critical for the field. An array of phenotypes and mechanisms contribute to chronic pain; this review summarizes current knowledge regarding which treatments are most effective for patients with specific biopsychosocial characteristics.

Idiopathic small fiber neuropathy (iSFN) lacks broadly accepted diagnostic criteria, which hinders its timely diagnosis and treatment. A systematic literature review was performed to assess the published screening and diagnostic criteria for iSFN, excluding studies where SFN was of well-established etiology. Eighty-four clinical studies and seven guideline/review publications were included in this systematic review. Substantial heterogeneity existed in iSFN diagnostic criteria. The most common set of criteria to diagnose iSFN [presence of any symptoms of iSFN, absence of large fiber involvement, and reduced intraepidermal nerve fiber density (IENFD)] was used in only 14% of studies. Mandatory individual criteria to confirm iSFN included any sensory symptoms (60% of studies), pain (19% of studies), small fiber signs (20% of studies), absence of large fiber signs (62% of studies), reduced IENFD (38% of studies), and autonomic symptoms (1% of studies). This review highlights a clear need for standardized, evidence-based guidelines for diagnosing iSFN.

The detection of cutaneous phosphorylated alpha-synuclein (P-syn) in patients with Parkinson’s disease (PD) has ranged from 30% to 100% across different studies. We hypothesize that part of the variability in P-syn detection is due to methodological differences using sections of different tissue thickness. Three skin biopsies were obtained from 29 individuals with PD and 21 controls. Tissues were cut into 10-, 20-, and 50-µm-thick sections and double-stained with protein gene product (PGP) 9.5 and P-syn. We quantified the deposition of P-syn with and without PGP 9.5 in sweat glands, pilomotor muscle, and blood vessels using confocal digital images of autonomic structures. Overall, the P-syn-positive rates with PGP 9.5 colocalization in subjects with PD were 100% using 50 µm sections, 90% using 20 µm sections, and 73% using 10 µm sections with 100% specificity. (No P-syn was detected within control subjects.) Without PGP 9.5, colocalization of the P-syn-positive rates was 100% for all samples, but specificity dropped below 70%. In this study, double-immunostained 50 µm skin biopsy tissue sections are superior to 20 and 10 µm tissue sections at detecting P-syn in subjects with PD. The increased sensitivity is likely secondary to a combination of greater volume of tissue analyzed and improved visualization of nerve fiber architecture.

The estimated probability of progressing from phase 3 analgesic clinical trials to regulatory approval is approximately 57%, suggesting that a considerable number of treatments with phase 2 trial results deemed sufficiently successful to progress to phase 3 do not yield positive phase 3 results. Deficiencies in the quality of clinical trial conduct could account for some of this failure. An Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting was convened to identify potential areas for improvement in trial conduct in order to improve assay sensitivity (ie, ability of trials to detect a true treatment effect). We present recommendations based on presentations and discussions at the meeting, literature reviews, and iterative revisions of this article. The recommendations relate to the following areas: 1) study design (ie, to promote feasibility), 2) site selection and staff training, 3) participant selection and training, 4) treatment adherence, 5) data collection, and 6) data and study monitoring. Implementation of these recommendations may improve the quality of clinical trial data and thus the validity and assay sensitivity of clinical trials. Future research regarding the effects of these strategies will help identify the most efficient use of resources for conducting high quality clinical trials. PERSPECTIVE: Every effort should be made to optimize the quality of clinical trial data. This manuscript discusses considerations to improve conduct of pain clinical trials based on research in multiple medical fields and the expert consensus of pain researchers and stakeholders from academia, regulatory agencies, and industry.

ContextHypoglycemia attenuates cardiovascular homeostatic autonomic control. This attenuation, known as the cardiovascular component of hypoglycemia-associated autonomic failure (HAAF), is characterized most notably by decreased baroreflex sensitivity (BRS) that begins during hypoglycemia and persists until at least the next day, despite return to euglycemia. Understanding the mechanisms underlying this reduction in BRS is important because BRS attenuation is associated with increased morbidity and mortality.ObjectiveThe objective of this work is to investigate the role of the adrenocorticotropin (ACTH)-adrenal axis in decreasing BRS. We tested the hypothesis that infusion of ACTH 1–24 (cosyntropin), as compared to placebo, would acutely suppress BRS, and that this decrease in BRS would be present the next day.DesignA double-blind, placebo-controlled, random-order, cross-over study was conducted.SettingThis study took place in a clinical research center.ParticipantsParticipants included healthy men and women.InterventionsInterventions included an intravenous infusion of cosyntropin (70 μg/hour for 2.5 hours in the morning and again in the early afternoon) vs normal saline placebo.Main Outcome MeasuresOutcome measures included BRS during and 16 hours after cosyntropin vs placebo infusions.ResultsCosyntropin infusion attenuated BRS (mm Hg/ms) as compared to placebo (baseline 17.8 ± 1.38 vs 17.0 ± 2.07; during 14.4 ± 1.43 vs 17.3 ± 1.65; and next day 14.8 ± 1.42 vs 18.9 ± 2.04; P ConclusionsACTH attenuates BRS, raising the possibility that hypoglycemia-induced increases in ACTH may contribute to the cardiovascular component of HAAF.

BackgroundThe second consensus criteria for the diagnosis of multiple system atrophy (MSA) are widely recognized as the reference standard for clinical research, but lack sensitivity to diagnose the disease at early stages.ObjectiveTo develop novel Movement Disorder Society (MDS) criteria for MSA diagnosis using an evidence-based and consensus-based methodology.MethodsWe identified shortcomings of the second consensus criteria for MSA diagnosis and conducted a systematic literature review to answer predefined questions on clinical presentation and diagnostic tools relevant for MSA diagnosis. The criteria were developed and later optimized using two Delphi rounds within the MSA Criteria Revision Task Force, a survey for MDS membership, and a virtual Consensus Conference.ResultsThe criteria for neuropathologically established MSA remain unchanged. For a clinical MSA diagnosis a new category of clinically established MSA is introduced, aiming for maximum specificity with acceptable sensitivity. A category of clinically probable MSA is defined to enhance sensitivity while maintaining specificity. A research category of possible prodromal MSA is designed to capture patients in the earliest stages when symptoms and signs are present, but do not meet the threshold for clinically established or clinically probable MSA. Brain magnetic resonance imaging markers suggestive of MSA are required for the diagnosis of clinically established MSA. The number of research biomarkers that support all clinical diagnostic categories will likely grow.ConclusionsThis set of MDS MSA diagnostic criteria aims at improving the diagnostic accuracy, particularly in early disease stages. It requires validation in a prospective clinical and a clinicopathological study. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

An expert committee was formed to reach consensus on the use of tilt table testing (TTT) in the diagnosis of disorders that may cause transient loss of consciousness (TLOC) and to outline when other provocative cardiovascular autonomic tests are needed. While TTT adds to history taking, it cannot be a substitute for it. An abnormal TTT result is most meaningful if the provoked event is recognised by patients or eyewitnesses as similar to spontaneous events. The minimum requirements to perform TTT are a tilt table, a continuous beat-to-beat blood pressure monitor, at least one ECG lead, protocols for the indications stated below and trained staff. This basic equipment lends itself to the performance of (1) additional provocation tests, such as the active standing test, carotid sinus massage and autonomic function tests; (2) additional measurements, such as video, EEG, transcranial Doppler, NIRS, end-tidal CO2 or neuro-endocrine tests; and (3) tailor-made provocation procedures in those with a specific and consistent trigger of TLOC. TTT and other provocative cardiovascular autonomic tests are indicated if the initial evaluation does not yield a definite or highly likely diagnosis, but raises a suspicion of (1) reflex syncope, (2) the three forms of orthostatic hypotension (OH), i.e. initial, classic and delayed OH, as well as delayed orthostatic blood pressure recovery, (3) postural orthostatic tachycardia syndrome or (4) psychogenic pseudosyncope. A therapeutic indication for TTT is to teach patients with reflex syncope and OH to recognise hypotensive symptoms and to perform physical counter manoeuvres.

Abnormalities in orthostatic blood pressure changes upon active standing are associated with morbidity, mortality, and reduced quality of life. However, over the last decade, several population-based cohort studies have reported a remarkably high prevalence (between 25 and 70%) of initial orthostatic hypotension (IOH) among elderly individuals. This has raised the question as to whether the orthostatic blood pressure patterns in these community-dwelling elderly should truly be considered as pathological. If not, redefining of the systolic cutoff values for IOH (i.e., a value ≥ 40 mmHg in systolic blood pressure in the first 15 s after standing up) might be necessary to differ between normal aging and true pathology. Therefore, in this narrative review, we provide a critical analysis of the current reference values for the changes in systolic BP in the first 60 s after standing up and discuss how these values should be applied to large population studies. We will address factors that influence the magnitude of the systolic blood pressure changes following active standing and the importance of standardization of the stand-up test, which is a prerequisite for quantitative, between-subject comparisons of the postural hemodynamic response.

Study Objectives To define the clinical implications of cutaneous phosphorylated α-synuclein (p-syn) and its association with subjective and objective measures of autonomic impairment and clinical features including antidepressant use in isolated rapid eye movement (REM) sleep behavior disorder (iRBD). Methods Twenty-five iRBD patients had quantified neurological and cognitive examinations, olfactory testing, questionnaires, autonomic function testing, and 3 punch skin biopsies (distal thigh, proximal thigh, neck). Skin biopsies were stained for the pan-axonal marker PGP 9.5 and co-stained with p-syn, and results were compared to 28 patients with Parkinson’s disease (PD) and 18 healthy controls. Equal numbers of iRBD patients on and off antidepressants were recruited. The composite autonomic severity scale (CASS) was calculated for all patients. Results P-syn was detected in 16/25 (64%) of iRBD patients, compared to 27/28 (96%) of PD and 0/18 controls. The presence of p-syn at any biopsy site was correlated with both sympathetic (CASS adrenergic r = 0.6, p < 0.05) and total autonomic impairment (CASS total r = 0.6, p < 0.05) on autonomic reflex testing in iRBD patients. These results were independent of the density of p-syn at each site. There was no correlation between p-syn and antidepressant use. Conclusions In patients with iRBD, the presence of cutaneous p-syn was detected in most patients and was associated with greater autonomic dysfunction on testing. Longitudinal follow-up will aid in defining the predictive role of both skin biopsy and autonomic testing in determining phenoconversion rates and future disease status.

Autonomic synucleinopathies feature deposition of the protein alpha-synuclein (AS) in neurons [e.g., Lewy body neurogenic orthostatic hypotension (nOH)] or glial cells (multiple system atrophy, MSA). AS in skin biopsies might provide biomarkers of these diseases; however, this approach would be complicated or invalidated if there were substantial loss of AS-containing nerves. We report AS content in arrector pili muscles in skin biopsies after adjustment for local innervation in patients with Lewy body nOH or MSA. Cardiac sympathetic neuroimaging by myocardial 18F-dopamine positron emission tomography (PET) was done to examine pathophysiological correlates of innervation-adjusted AS. Thirty-one patients (19 Lewy body nOH, 12 MSA) underwent thoracic 18F-dopamine PET and skin biopsies. AS signal intensity analyzed by immunofluorescence microscopy was adjusted for innervation by the ratio of AS to protein gene product (PGP) 9.5, a pan-axonal marker (Harvard lab site), or the ratio of AS to tyrosine hydroxylase (TH), an indicator of catecholaminergic neurons (NIH lab site). The Lewy body nOH group had higher ratios of AS/PGP 9.5 or log AS/TH than did the MSA group (0.89 ± 0.05 vs. 0.66 ± 0.04, −0.13 ± 0.05 vs. −1.60 ± 0.33; p 0.8 or log AS/TH > 1.2 and had myocardial 18F-dopamine-derived radioactivity

Human papillomavirus (HPV) vaccination has been anecdotally connected to the development of dysautonomia, chronic fatigue, complex regional pain syndrome and postural tachycardia syndrome. To critically evaluate a potential connection between HPV vaccination and the above-noted conditions. We reviewed the literature containing the biology of the virus, pathophysiology of infection, epidemiology of associated cancers, indications of HPV vaccination, safety surveillance data and published reports linking HPV vaccination to autonomic disorders. At this time, the American Autonomic Society finds that there are no data to support a causal relationship between HPV vaccination and CRPS, chronic fatigue, and postural tachycardia syndrome to other forms of dysautonomia. Certain conditions are prevalent in the same populations that are vaccinated with the HPV vaccine (peri-pubertal males and females). This association, however, is an insufficient proof of causality.

Purpose: The average adult stands approximately 50–60 times per day. Cardiovascular responses evoked during the first 3 min of active standing provide a simple means to clinically assess short-term neural and cardiovascular function across the lifespan. Clinically, this response is used to identify the haemodynamic correlates of patient symptoms and attributable causes of (pre-)syncope, and to detect autonomic dysfunction, variants of orthostatic hypotension, postural orthostatic tachycardia syndrome and orthostatic hypertension. Methods: This paper provides a set of experience/expertise-based recommendations detailing current state-of-the-art measurement and analysis approaches for the active stand test, focusing on beat-to-beat BP technologies. This information is targeted at those interested in performing and interpreting the active stand test to current international standards. Results: This paper presents a practical step-by-step guide on (1) how to perform active stand measurements using beat-to-beat continuous blood pressure measurement technologies, (2) how to conduct an analysis of the active stand response and (3) how to identify the spectrum of abnormal blood pressure and heart rate responses which are of clinical interest. Conclusion: Impairments in neurocardiovascular control are an attributable cause of falls and syncope across the lifespan. The simple active stand test provides the clinician with a powerful tool for assessing individuals at risk of such common disorders. However, its simplicity belies the complexity of its interpretation. Care must therefore be taken in administering and interpreting the test in order to maximise its clinical benefit and minimise its misinterpretation.

Distal symmetrical axonal polyneuropathy (DSP) is due to injury to peripheral sensory, motor, and autonomic nerve fibers, resulting in distal predominant sensory loss, pain, and gait instability. DSP occurs as a complication of multiple medical conditions including diabetes or HIV, or following exposure to various toxins such as chemotherapy. It affects at least 10% of the United States population. Few treatments for DSP are approved by regulatory agencies. Reliable and responsive outcome measures are integral to developing new DSP treatments. Multiple clinician-rated measures that incorporate neuropathy signs exist, however, it is not clear which of these measures performs best for various DSP phenotypes. This systematic review summarizes the content of 18 published measures of DSP identified using PubMed and from personal archives of the authors. The relative percentage of scoring dedicated to motor, reflex, large and small fiber sensory, and autonomic domains varied considerably among measures. The most common neurologic examination items included in the scales were (1) vibration perception (n = 18, 100%), (2) reflexes (n = 16, 89%), (3) pinprick perception (n = 14, 78%), (4) muscle strength (n = 11, 61%), (5) touch–pressure perception (n = 9, 50%), and (6) joint position perception (n = 8, 44%). This review can be used to inform decisions regarding which of the available clinician-rated sign outcome measures would be most appropriate for use in a particular DSP population, based on the domains most affected by that neuropathy or on the domains most likely to be affected by a particular experimental therapy.

The Peripheral Neuropathy Research Registry (PNRR) is a prospective cohort of peripheral neuropathy (PN) patients focused on idiopathic axonal peripheral neuropathy. Patients with diabetic, human immunodeficiency virus-, and chemotherapy-induced peripheral neuropathies are enrolled as comparison groups. The PNRR is a multi-center collaboration initiated and funded by the Foundation for Peripheral Neuropathy (FPN) with the objective to recruit a well characterized cohort of patients with different phenotypes and symptoms in each diagnostic category, and to advance research through development of biomarkers and identification of previously unknown causes of PN. The overall goal of the initiative is to find disease-altering treatments and better symptom relief for patients. We present the study design, types of data collected, and characteristics of the first 1150 patients enrolled. We also discuss ongoing analyses on this dataset, including untargeted-omics methodologies.

Stress can be classified as either psychosocial or physiologic. Physiologic stress refers to stresses due to acute illness, trauma, pain, hypoglycemia, and sleep deprivation-much less is known regarding its health consequences. This review focuses on hypoglycemia as a model to further investigate physiological stress. Experimental mild to moderate hypoglycemia is a paradigmatic physiological stress that evokes autonomic, neuroendocrine, and immune responses. Hypoglycemic stress is an ideal model to examine the interactions and consequences of physiological stress on the autonomic nervous system. Acute hypoglycemia has been demonstrated to increase inflammatory markers, prolong QTc, and impair cardiac-vagal baroreflex sensitivity. Some of these consequences may not reverse completely when euglycemia is restored. For example, there is attenuation of the cardiac-vagal baroreflex, attenuation of the vascular sympathetic baroreflex (muscle sympathetic nerve activity response to transient hypotension), and attenuation of the catecholamine response to lower body negative pressure that is present the next day after hypoglycemia has resolved.

Postural orthostatic tachycardia syndrome (POTS) is a chronic and often disabling disorder characterized by orthostatic intolerance with excessive heart rate increase without hypotension during upright posture. Patients often experience a constellation of other typical symptoms including fatigue, exercise intolerance and gastrointestinal distress. A typical patient with POTS is a female of child-bearing age, who often first displays symptoms in adolescence. The onset of POTS may be precipitated by immunological stressors such as a viral infection. A variety of pathophysiologies are involved in the abnormal postural tachycardia response; however, the pathophysiology of the syndrome is incompletely understood and undoubtedly multifaceted. Clinicians and researchers focused on POTS convened at the National Institutes of Health in July 2019 to discuss the current state of understanding of the pathophysiology of POTS and to identify priorities for POTS research. This article, the first of two articles summarizing the information discussed at this meeting, summarizes the current understanding of this disorder and best practices for clinical care. The evaluation of a patient with suspected POTS should seek to establish the diagnosis, identify co-morbid conditions, and exclude conditions that could cause or mimic the syndrome. Once diagnosed, management typically begins with patient education and non-pharmacologic treatment options. Various medications are often used to address specific symptoms, but there are currently no FDA-approved medications for the treatment of POTS, and evidence for many of the medications used to treat POTS is not robust.

Objective Acute neuropathic pain is a significant diagnostic challenge, and it is closely related to our understanding of both acute pain and neuropathic pain. Diagnostic criteria for acute neuropathic pain should reflect our mechanistic understanding and provide a framework for research on and treatment of these complex pain conditions. Methods The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public–private partnership with the U.S. Food and Drug Administration (FDA), the American Pain Society (APS), and the American Academy of Pain Medicine (AAPM) collaborated to develop the ACTTION-APS-AAPM Pain Taxonomy (AAAPT) for acute pain. A working group of experts in research and clinical management of neuropathic pain was convened. Group members used literature review and expert opinion to develop diagnostic criteria for acute neuropathic pain, as well as three specific examples of acute neuropathic pain conditions, using the five dimensions of the AAAPT classification of acute pain. Results AAAPT diagnostic criteria for acute neuropathic pain are presented. Application of these criteria to three specific conditions (pain related to herpes zoster, chemotherapy, and limb amputation) illustrates the spectrum of acute neuropathic pain and highlights unique features of each condition. Conclusions The proposed AAAPT diagnostic criteria for acute neuropathic pain can be applied to various acute neuropathic pain conditions. Both the general and condition-specific criteria may guide future research, assessment, and management of acute neuropathic pain.

There is tremendous interpatient variability in the response to analgesic therapy (even for efficacious treatments), which can be the source of great frustration in clinical practice. This has led to calls for “precision medicine” or personalized pain therapeutics (ie, empirically based algorithms that determine the optimal treatments, or treatment combinations, for individual patients) that would presumably improve both the clinical care of patients with pain and the success rates for putative analgesic drugs in phase 2 and 3 clinical trials. However, before implementing this approach, the characteristics of individual patients or subgroups of patients that increase or decrease the response to a specific treatment need to be identified. The challenge is to identify the measurable phenotypic characteristics of patients that are most predictive of individual variation in analgesic treatment outcomes, and the measurement tools that are best suited to evaluate these characteristics. In this article, we present evidence on the most promising of these phenotypic characteristics for use in future research, including psychosocial factors, symptom characteristics, sleep patterns, responses to noxious stimulation, endogenous pain-modulatory processes, and response to pharmacologic challenge. We provide evidence-based recommendations for core phenotyping domains and recommend measures of each domain.

Randomized clinical trials have demonstrated the efficacy of opioid analgesics for the treatment of acute and chronic pain conditions, and for some patients, these medications may be the only effective treatment available. Unfortunately, opioid analgesics are also associated with major risks (eg, opioid use disorder) and adverse outcomes (eg, respiratory depression and falls). The risks and adverse outcomes associated with opioid analgesics have prompted efforts to reduce their use in the treatment of both acute and chronic pain. This article presents Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus recommendations for the design of opioid-sparing clinical trials. The recommendations presented in this article are based on the following definition of an opioid-sparing intervention: any intervention that (1) prevents the initiation of treatment with opioid analgesics, (2) decreases the duration of such treatment, (3) reduces the total dosages of opioids that are prescribed for or used by patients, or (4) reduces opioid-related adverse outcomes (without increasing opioid dosages), all without causing an unacceptable increase in pain. These recommendations are based on the results of a background review, presentations and discussions at an IMMPACT consensus meeting, and iterative drafts of this article modified to accommodate input from the co-authors. We discuss opioid sparing definitions, study objectives, outcome measures, the assessment of opioid-related adverse events, incorporation of adequate pain control in trial design, interpretation of research findings, and future research priorities to inform opioid-sparing trial methods. The considerations and recommendations presented in this article are meant to help guide the design, conduct, analysis, and interpretation of future trials.

We read with interest the publication entitled “In vivo distribution of α-synuclein in multiple tissues and biofluids in Parkinson disease.”1 In the article, Chahine et al.1 discuss the results of the Systemic Synuclein Sampling Study (S4 study). This was an important step toward the in vivo diagnosis of synucleinopathy. Unfortunately, although the detection of phosphorylated alpha-synuclein was highly specific, sensitivity was quite poor, particularly for skin (with a sensitivity of 24.1%). The authors note that there were several explanations for such findings, including the earlier diagnosis of PD in the S4 study compared with the relatively small studies performed at other centers.

Evaluation of disorders of the autonomic nervous system is both an art and a science, calling upon the physician's most astute clinical skills as well as knowledge of autonomic neurology and physiology. Over the last three decades, the development of noninvasive clinical tests that assess the function of autonomic nerves, the validation and standardization of these tests, and the growth of a large body of literature characterizing test results in patients with autonomic disorders have equipped clinical practice further with a valuable set of objective tools to assist diagnosis and prognosis. This review, based on current evidence, outlines an international expert consensus set of recommendations to guide clinical electrodiagnostic autonomic testing. Grading and localization of autonomic deficits incorporates scores from sympathetic cardiovascular adrenergic, parasympathetic cardiovagal, and sudomotor testing, as no single test alone is sufficient to diagnose the degree or distribution of autonomic failure. The composite autonomic severity score (CASS) is a useful score of autonomic failure that is normalized for age and gender. Valid indications for autonomic testing include generalized autonomic failure, regional or selective system syndromes of autonomic impairment, peripheral autonomic neuropathy and ganglionopathy, small fiber neuropathy, orthostatic hypotension, orthostatic intolerance, syncope, neurodegenerative disorders, autonomic hyperactivity, and anhidrosis.

Copyright © 2020 International Association for the Study of Pain., Interpreting randomized clinical trials (RCTs) is crucial to making decisions regarding the use of analgesic treatments in clinical practice. In this article, we report on an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, the purpose of which was to recommend approaches that facilitate interpretation of analgesic RCTs. We review issues to consider when drawing conclusions from RCTs, as well as common methods for reporting RCT results and the limitations of each method. These issues include the type of trial, study design, statistical analysis methods, magnitude of the estimated beneficial and harmful effects and associated precision, availability of alternative treatments and their benefit-risk profile, clinical importance of the change from baseline both within and between groups, presentation of the outcome data, and the limitations of the approaches used.