Search

Objective: 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)., Methods: 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., Results: 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., Interpretation: 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., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Neuropathy is a major cause of morbidity and mortality in individuals with diabetes, with no effective therapy to alter the inevitable progression of nerve damage. We hypothesized that mesenchymal stroma cell-like populations, that are characterized as immune modulators also have the potential of inducing angiogenesis and neurite outgrowth, might be useful in treating diabetic peripheral neuropathy (DPN). The aims of this study were to investigate the efficacy and safety of mesenchymal stem cell-like product (PDA-002) in treating DPN. A phase-2 randomized placebo-controlled trial was conducted in 26 patients with DPN. Treatment consisted of three rounds of intramuscular injections in one lower limb using one of the three randomized treatment arms PDA-002 (low-dose 3 × 10 6 cells), PDA-002 (high-dose 30 × 10 6 cells), or placebo. Three treatments per patient occurred on days 1, 29, and 57. Study endpoints included efficacy and safety of PDA-002 in treating DPN in both lower extremities following unilateral local injection. Outcome measures included intra-epidermal nerve fiber density (IENFD) up to 1 year from the day of treatment with 6-month as the primary outcome measurement. In this phase 2 study of DPN, PDA-002 was well tolerated in both doses. No significant changes were noted in IENFD in both the treated and untreated leg in the NIS-LL, NTSS-6, or UENS. Mesenchymal stem cells represent a novel mechanism for treating diabetic neuropathy and are well tolerated. Preliminary results highlight the need of further investigation of PDA-001 as a disease modifying agent for treatment of DPN., (© 2021 Peripheral Nerve Society.)

Purpose of Review: This article provides an up-to-date review of the manifestations of neuropathy seen in the setting of diabetes and other metabolic disorders., Recent Findings: Although a number of metabolic disorders cause or are associated with peripheral neuropathy, the neuropathies associated with glucose dysregulation make up the vast majority of cases. Recent investigations have determined major differences in the neuropathies associated with type 1 and type 2 diabetes. Neuropathy in type 1 diabetes is closely linked to glycemic control, whereas neuropathy in type 2 diabetes is linked to dyslipidemia, central obesity, hypertension, insulin resistance, and glucose control. Although length-dependent axonal distal symmetric polyneuropathy is the most common clinical presentation, diabetes is also associated with acute, asymmetric, painless, and autonomic neuropathies., Summary: The prevalence of diabetes and metabolic syndrome is increasing across the globe. The need to recognize and treat the wide array of clinical manifestations of neuropathy detected in individuals with metabolic disorders will continue to grow. As a consequence, an increasing number of well-trained physicians who can manage these patients is needed. At present, treatment is largely focused on prevention and symptomatic management. Investments into funding for both basic and clinical science are necessary to bring novel therapeutic interventions into clinical practice.

Introduction: To develop a new method to quantify the density of nerves, vessels, and the neurovascular contacts, we studied skin biopsies in diabetes and control subjects., Methods: Skin biopsies with dual immunofluorescent staining were used to visualize nerves and blood vessels. The density of nerves, vessels, and their neurovascular contacts were quantified with unbiased stereology. Results were compared with examination findings, validated questionnaires, and autonomic function., Results: In tissue from 19 controls and 20 patients with diabetes, inter-rater and intra-rater intraclass correlation coefficients were high (>0.85; P < .001) for all quantitative methods. In diabetes, the nerve densities (P < .05), vessel densities (P < .01), and the neurovascular densities (P < .01) were lower compared with 20 controls. Results correlated with autonomic function, examination and symptom scores., Discussion: We report an unbiased, stereological method to quantify the cutaneous nerve, vessel and neurovascular density and offer new avenues of investigation into cutaneous neurovascular innervation in health and disease., (© 2020 Wiley Periodicals, Inc.)

Background: Treatment induced neuropathy of diabetes (TIND) is an iatrogenic painful sensory and autonomic neuropathy. Although the prevalence is not known, it is seen in up to 10% of tertiary cases referred for evaluation of diabetic neuropathy., Evidence: TIND is associated with a decrease in the glycosylated hemoglobin A1C in individuals with longstanding hyperglycemia. TIND is more common in individuals with type 1 diabetes, but can occur in anyone with diabetes through the use of insulin, oral hypoglycemic medications or diet control. There is an acute or subacute onset of neuropathy that is linked to the change in glucose control. Although the primary clinical manifestation is neuropathic pain there is a concurrent development of autonomic dysfunction, retinopathy and nephropathy., Conclusion: TIND is more common than previously suspected. The number of cases reported over the past 10 years is much greater than historical literature predicted. Increased attention to target glucose control as a physician metric could suggest a possible explanation for the increased in TIND cases reported in recent years. At present, supportive care is the only recommended treatment. Future research is necessary to define the underlying mechanism, prevent development and to guide treatment recommendations., Competing Interests: Declaration of competing interest Christopher H. Gibbons has received research funding from Grifols, and has served as a scientific advisor for Lundbeck, Biohaven, and Cutaneous NeuroDiagnostics., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose of Review: Treatment-induced neuropathy of diabetes (TIND) is an under-recognized iatrogenic painful sensory and autonomic neuropathy. This review highlights the clinical symptoms and signs, raises awareness of the cause, and provides education about prevention of TIND., Recent Findings: TIND may be triggered by a rapid decline in the blood glucose levels following the use of insulin, oral hypoglycemic medications, or even diet only to control diabetes. This may be seen in up to 10% of patients with diabetic neuropathy and has the potential for significant long-term complications that could be avoided through careful disease management. Based on the available evidence, a decrease in the glycosylated hemoglobin A1C of more than 3 points in 3 months in individuals with chronic hyperglycemia increases the risk of developing TIND. TIND is more common than previously suspected, and is tied to rates of glycemic control. Slower changes to glucose control are suggested, although there is no prospective data on disease prevention. Future research is necessary to guide treatment recommendations.

Aims/hypothesis: Aggressive glucose control can result in treatment induced neuropathy of diabetes (TIND) if glycemic control is achieved too quickly. The aim of the present study is to describe the 8-year follow-up data on a cohort of individuals with type 1 diabetes who developed TIND., Methods: Twenty-six individuals with type 1 diabetes and TIND were followed longitudinally for 8years with regular quantitative measurement of pain, neurological examinations and evaluation of microvascular complications. Comprehensive neurological testing was performed after TIND and 7-8years later., Results: Among the 26 individuals with TIND, 19/26 had stable glycemic control and 7/26 had unstable glycemic control in long-term follow up. Those 19/26 with stable glycemic control had improvement in neuropathy, pain and microvascular complications while the 7/26 with unstable glycemic control had significant worsening of neuropathy, pain and microvascular complications (P<0.01, all tests)., Conclusion/interpretation: TIND is a poorly understood iatrogenic complication of aggressive glycemic control, although individuals with stable glycemic control tended to improve, while those with unstable glycemic control worsened. Additional studies of TIND are required to understand potential outcomes in an era of medical 'metrics' where physician reimbursement may be tied to achievement of excessively rapid glycemic control., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: No treatments for axonal peripheral neuropathy are approved by the United States Food and Drug Administration (FDA). Although patient- and clinician-reported outcomes are central to evaluating neuropathy symptoms, they can be difficult to assess accurately. The inability to identify efficacious treatments for peripheral neuropathies could be due to invalid or inadequate outcome measures., Methods: This systematic review examined the content validity of symptom-based measures of diabetic peripheral neuropathy, HIV neuropathy, and chemotherapy-induced peripheral neuropathy., Results: Use of all FDA-recommended methods to establish content validity was only reported for 2 of 18 measures. Multiple sensory and motor symptoms were included in measures for all 3 conditions; these included numbness, tingling, pain, allodynia, difficulty walking, and cramping. Autonomic symptoms were less frequently included., Conclusions: Given significant overlap in symptoms between neuropathy etiologies, a measure with content validity for multiple neuropathies with supplemental disease-specific modules could be of great value in the development of disease-modifying treatments for peripheral neuropathies. Muscle Nerve 55: 366-372, 2017., (© 2016 Wiley Periodicals, Inc.)

Treatment-induced neuropathy in diabetes (also referred to as insulin neuritis) is considered a rare iatrogenic small fibre neuropathy caused by an abrupt improvement in glycaemic control in the setting of chronic hyperglycaemia. The prevalence and risk factors of this disorder are not known. In a retrospective review of all individuals referred to a tertiary care diabetic neuropathy clinic over 5 years, we define the proportion of individuals that present with and the risk factors for development of treatment-induced neuropathy in diabetes. Nine hundred and fifty-four individuals were evaluated for a possible diabetic neuropathy. Treatment-induced neuropathy in diabetes was defined as the acute onset of neuropathic pain and/or autonomic dysfunction within 8 weeks of a large improvement in glycaemic control-specified as a decrease in glycosylated haemoglobin A1C (HbA1c) of ≥2% points over 3 months. Detailed structured neurologic examinations, glucose control logs, pain scores, autonomic symptoms and other microvascular complications were measured every 3-6 months for the duration of follow-up. Of 954 patients evaluated for diabetic neuropathy, 104/954 subjects (10.9%) met criteria for treatment-induced neuropathy in diabetes with an acute increase in neuropathic or autonomic symptoms or signs coinciding with a substantial decrease in HbA1c. Individuals with a decrease in HbA1c had a much greater risk of developing a painful or autonomic neuropathy than those individuals with no change in HbA1c (P < 0.001), but also had a higher risk of developing retinopathy (P < 0.001) and microalbuminuria (P < 0.001). There was a strong correlation between the magnitude of decrease in HbA1c, the severity of neuropathic pain (R = 0.84, P < 0.001), the degree of parasympathetic dysfunction (R = -0.52, P < 0.01) and impairment of sympathetic adrenergic function as measured by fall in blood pressure on tilt-table testing (R = -0.63, P < 0.001). With a decrease in HbA1c of 2-3% points over 3 months there was a 20% absolute risk of developing treatment-induced neuropathy in diabetes, with a decrease in HbA1c of >4% points over 3 months the absolute risk of developing treatment-induced neuropathy in diabetes exceeded 80%. Treatment-induced neuropathy of diabetes is an underestimated iatrogenic disorder associated with diffuse microvascular complications. Rapid glycaemic change in patients with uncontrolled diabetes increases the risk of this complication., (© 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.)

This study aimed to investigate prospective changes to neurophysiologic function over 3 years in patients with well-controlled diabetes. Sixty-two subjects had neurologic examinations, symptom scores, autonomic testing, nerve conduction studies, quantitative sensory testing, and laser-Doppler flowmetry at 18-month intervals for 3 years. During the study, there was a 1 µV decrease in sural amplitude (p < 0.05), an increase in monofilament detection threshold of 0.36 g (p < 0.001), and a decrease in the axon-reflex vasodilation in the foot (p < 0.005) and forearm (p < 0.05). There was an increase in symptoms of distal hypersensitivity (p < 0.005) but no change in neuropathy frequency or severity. Our findings suggest that laser-Doppler flowmetry, a test of small fiber function, can detect the largest neurophysiologic change over time in groups of patients with diabetes. Sural nerve amplitude and monofilament thresholds may be more effective at detecting change in individual patients. Other tests of neurophysiologic function may require longer periods of time and greater numbers of participants to detect a difference. We conclude that patients with well-controlled diabetes and optimal medical management of comorbid risk factors have low rates of neuropathy development and progression although the clinical relevance of this finding to the general population of individuals with diabetes is unknown., (© 2013 Peripheral Nerve Society.)

Objective: To determine the relationships among large, small, and autonomic fiber neurophysiological measures in a cross-sectional study of patients with diabetes., Research Design and Methods: We assessed 130 individuals: 25 healthy subjects and 105 subjects with diabetes. Subjects were classified by the presence or absence of neuropathy by physical examination. All subjects underwent autonomic testing, nerve conduction studies, quantitative sensory testing, and nerve-axon reflex vasodilation in addition to quantifiable neurological examination and symptom scores. Correlation and cluster analysis were used to determine relationships between and among different neurophysiological testing parameters., Results: Results of neurophysiological tests were abnormal in patients with clinical evidence of diabetic neuropathy compared with results in healthy control subjects and in those without neuropathy (P < 0.01, all tests). The correlations among individual tests varied widely, both within (r range <0.5->0.9, NS to <0.001) and between test groups (r range <0.2->0.5, NS to <0.01). A two-step hierarchical cluster analysis revealed that neurophysiological tests do not aggregate by typical "small," "large," or "autonomic" nerve fiber subtypes., Conclusions: The modest correlation coefficients seen between the different testing modalities suggest that these techniques measure different neurophysiological parameters and are therefore not interchangeable. However, the data suggest that only a small number of neurophysiological tests are actually required to clinically differentiate individuals with neuropathy from those without. The natural clustering of both patients and healthy control subjects suggests that variations in the population will need to be considered in future studies of diabetic neuropathy.

Objective: To describe the natural history, clinical, neurophysiological, and histological features, and outcomes of diabetic patients presenting with acute painful neuropathy associated with glycemic control, also referred to as insulin neuritis., Methods: Sixteen subjects presenting with acute painful neuropathy had neurological and retinal examinations, laboratory studies, autonomic testing, and pain assessments over 18 months. Eight subjects had skin biopsies for evaluation of intraepidermal nerve fiber density., Results: All subjects developed severe pain within 8 weeks of intensive glucose control. There was a high prevalence of autonomic cardiovascular, gastrointestinal, genitourinary, and sudomotor symptoms in all subjects. Orthostatic hypotension and parasympathetic dysfunction were seen in 69% of subjects. Retinopathy worsened in all subjects. Reduced intraepidermal nerve fiber density (IENFD) was seen in all tested subjects. After 18 months of glycemic control, there were substantial improvements in pain, autonomic symptoms, autonomic test results, and IENFD. Greater improvements were seen after 18 months in type 1 versus type 2 diabetic subjects in autonomic symptoms (cardiovascular p < 0.01; gastrointestinal p < 0.01; genitourinary p < 0.01) and autonomic function tests (p < 0.01, sympathetic and parasympathetic function tests)., Interpretation: Treatment-induced neuropathy is characterized by acute, severe pain, peripheral nerve degeneration, and autonomic dysfunction after intensive glycemic control. The neuropathy occurred in parallel with worsening diabetic retinopathy, suggesting a common underlying pathophysiological mechanism. Clinical features and objective measures of small myelinated and unmyelinated nerve fibers can improve in these diabetic patients despite a prolonged history of poor glucose control, with greater improvement seen in patients with type 1 diabetes.

Objective: To evaluate a novel method to quantify the density of nerve fibers innervating sweat glands in healthy control and diabetic subjects, to compare the results to an unbiased stereologic technique, and to identify the relationship to standardized physical examination and patient-reported symptom scores., Methods: Thirty diabetic and 64 healthy subjects had skin biopsies performed at the distal leg and distal and proximal thigh. Nerve fibers innervating sweat glands, stained with PGP 9.5, were imaged by light microscopy. Sweat gland nerve fiber density (SGNFD) was quantified by manual morphometry. As a gold standard, three additional subjects had biopsies analyzed by confocal microscopy using unbiased stereologic quantification. Severity of neuropathy was measured by standardized instruments including the Neuropathy Impairment Score in the Lower Limb (NIS-LL) while symptoms were measured by the Michigan Neuropathy Screening Instrument., Results: Manual morphometry increased with unbiased stereology (r = 0.93, p < 0.01). Diabetic subjects had reduced SGNFD compared to controls at the distal leg (p < 0.001), distal thigh (p < 0.01), and proximal thigh (p < 0.05). The SGNFD at the distal leg of diabetic subjects decreased as the NIS-LL worsened (r = -0.89, p < 0.001) and was concordant with symptoms of reduced sweat production (p < 0.01)., Conclusions: We describe a novel method to quantify the density of nerve fibers innervating sweat glands. The technique differentiates groups of patients with mild diabetic neuropathy from healthy control subjects and correlates with both physical examination scores and symptoms relevant to sudomotor dysfunction. This method provides a reliable structural measure of sweat gland innervation that complements the investigation of small fiber neuropathies.

Diabetic polyneuropathy (DPN) and cold-induced nerve injury share several pathogenic mechanisms. This study explores whether cold exposure contributes to the development of DPN. Streptozotocin-induced diabetic rats and controls were exposed to a room temperature (23 degrees C) or cold environment (10 degrees C). H-reflex, tail and sciatic motor, and sensory nerve conduction studies were performed. Analyses of sural nerve, intraepidermal nerve fibers, and skin and nerve nitrotyrosine ELISAs were performed. Diabetic animals exposed to a cold environment had an increased H-reflex four weeks earlier than diabetic room temperature animals (P = .03). Cold-exposed diabetic animals also had greater reduction in motor conduction velocities at 20 weeks (P = .017), decreased skin nerve fiber density (P = .037), and increased skin nitrotyrosine levels (P = .047). Cold exposure appears to hasten the development of DPN in the rat STZ model of diabetes. These findings support that further study into the relationship between ambient temperature and DPN is warranted.

Purpose Of Review: Aggressive glycemic control has become the standard clinical approach to diabetes care. Unintended consequences have included the development of microvascular complications that are related to the rapidity of glycemic improvement.Recent Findings: Diabetic neuropathy may develop in up to 10% of individuals secondary to aggressive glycemic control. The neuropathy is predominantly small fiber sensory and autonomic, and the severity of the neuropathy is tied to the change in the glycosylated hemoglobin A1C. Other microvascular complications such as retinopathy and nephropathy are common and may occur in parallel with the neuropathy. Eating disorders are a common comorbid risk factor. Individuals with uncontrolled diabetes for prolonged periods, particularly those with a history of eating disorders involving insulin restriction for calorie purging, are at high risk for developing treatment-induced microvascular complications. Gradual glycemic improvements should be encouraged but future research is needed to optimize treatment and prevention strategies. [ABSTRACT FROM AUTHOR]

Neurogenic orthostatic hypotension (nOH) is common in patients with neurodegenerative disorders such as Parkinson's disease, multiple system atrophy, pure autonomic failure, dementia with Lewy bodies, and peripheral neuropathies including amyloid or diabetic neuropathy. Due to the frequency of nOH in the aging population, clinicians need to be well informed about its diagnosis and management. To date, studies of nOH have used different outcome measures and various methods of diagnosis, thereby preventing the generation of evidence-based guidelines to direct clinicians towards 'best practices' when treating patients with nOH and associated supine hypertension. To address these issues, the American Autonomic Society and the National Parkinson Foundation initiated a project to develop a statement of recommendations beginning with a consensus panel meeting in Boston on November 7, 2015, with continued communications and contributions to the recommendations through October of 2016. This paper summarizes the panel members' discussions held during the initial meeting along with continued deliberations among the panel members and provides essential recommendations based upon best available evidence as well as expert opinion for the (1) screening, (2) diagnosis, (3) treatment of nOH, and (4) diagnosis and treatment of associated supine hypertension. [ABSTRACT FROM AUTHOR]

ASO OBJECTIVE-- To determine the relationships among large, small, and autonomic fiber neurophysiological measures in a cross-sectional study of patients with diabetes. RESEARCH DESIGN AND METHODS-- We assessed 130 individuals: 25 healthy subjects and 105 subjects with diabetes. Subjects were classified by the presence or absence of neuropathy by physical examination. All subjects underwent autonomic testing, nerve conduction studies, quantitative sensory testing, and nerve-axon reflex vasodilation in addition to quantifiable neurological examination and symptom scores. Correlation and cluster analysis were used to determine relationships between and among different neurophysiological testing parameters. RESULTS-- Results of neurophysiological tests were abnormal in patients with clinical evidence of diabetic neuropathy compared with results in healthy control subjects and in those without neuropathy (P < 0.01, all tests). The correlations among individual tests varied widely, both within (r range < 0.5->0.9, NS to <0.001) and between test groups (r range <0.2->0.5, NS to <0.01). A two-step hierarchical cluster analysis revealed that neurophysiological tests do not aggregate by typical "small," "large," or "autonomic" nerve fiber subtypes. CONCLUSIONS-- The modest correlation coefficients seen between the different testing modalities suggest that these techniques measure different neurophysiological parameters and are therefore not interchangeable. However, the data suggest that only a small number of neurophysiological tests are actually required to clinically differentiate individuals with neuropathy from those without. The natural clustering of both patients and healthy control subjects suggests that variations in the population will need to be considered in future studies of diabetic neuropathy. [ABSTRACT FROM AUTHOR]

Neurogenic orthostatic hypotension is a highly prevalent and disabling feature of autonomic failure due to both peripheral and central neurodegenerative diseases. Community-based epidemiological studies have demonstrated a high morbidity and mortality associated with neurogenic orthostatic hypotension. It is due to impairment of baroreflex-mediated vasoconstriction of the skeletal muscle and splanchnic circulation and is caused by damage or dysfunction at central and/or peripheral sites in the baroreflex efferent pathway. Nonpharmacological and pharmacological interventions may be implemented to ameliorate the symptoms of orthostatic intolerance and improve quality of life. Many patients will be adequately treated by education, counseling, removal of hypotensive medications, and other nonpharmacological interventions, whereas more severely afflicted patients require pharmacological interventions. The first stage of pharmacological treatment involves repletion of central blood volume. If unsuccessful, this should be followed by treatment with sympathomimetic agents. [ABSTRACT FROM AUTHOR]