Tests Of Sudomotor Function Research Articles

CIDP variants in diabetes: measuring treatment response with a small nerve fiber test

IntroductionChronic inflammatory demyelinating polyneuropathy (CIDP) is eleven times more common among people with diabetes than the general population and is treatable with appropriate immunotherapy. Treatment response is usually measured clinically (symptomatic and functional improvement). We present a case of a patient with type 2 diabetes (T2D) and CIDP whose treatment response was measurable with the Sudoscan sudomotor function test. This test may represent a new objective evaluation of the treatment of CIDP. Case DescriptionThe patient is a 60year old male initially referred to our center in August 2012, at which time he was diagnosed with CIDP based on AAN electrodiagnostic criteria (NCS). Autonomic functions were significant for low heart rate variability response to expiration/inspiration (E/I), Valsalva maneuver and the ratio of the RR interval for the 30th to the 15th beat upon standing (1.08, 1.12, 1.05 respectively), and frequency analysis of the total spectral power, the standard deviation of the normal RR intervals (sdNN) and their root mean squared (rmsSD). Sudoscan electrochemical skin conductances (ESC), measuring small nerve fiber function on the palms and soles, were very low: 23 μS in the feet and 32 μS in the hands. After one cycle of intravenous immunoglobulin (IVIG: 6 doses total, 75g each) the patient had no change in symptoms of burning, numbness, shooting pains, and gait impairment. However, E/I, Valsalva, and 30:15 ratios (1.19, 1.36, 1.39 respectively) were improved, as were NCS. Sudoscan scores for feet and hands were unchanged (23 μS and 32 μS). In March 2013, the patient's autonomic functions worsened (E/I, Valsalva, and 30:15 ratios 1.1, 1.07, 1.12 respectively), but feet and hand ESC started to show improvement (35 μS and 52 μS respectively). Azathioprine was started. Eight days after a second cycle of IVIG in January 2014, the patient reported for the first time less burning, shooting pains and tingling. E/I, Valsalva, and 30:15 ratios remained low (1.03, 1.07, and not analyzable, respectively), while foot and hand ESC scores continued to improve (43 μS and 55 μS respectively). DiscussionCIDP diagnosis and treatment response are difficult in the diabetic patient. We found that NCS and autonomic function tests did not correlate well with clinical status while numerical Sudoscan scores matched closely symptomatic changes. ESC have been found to correlate well with peripheral small fiber function and neuropathic symptoms in DPN. The findings in this patient warrant further investigation of the use of Sudoscan to monitor CIDP response to therapy.

Axon-reflex based nerve fiber function assessment in the detection of autonomic neuropathy

Axon-reflex-based tests of peripheral small nerve fiber function including techniques to quantify vasomotor and sudomotor responses following acetylcholine iontophoresis are used in the assessment of autonomic neuropathy. However, the established axon-reflex-based techniques, laser Doppler flowmetry (LDF) to assess vasomotor function and quantitative sudomotor axon-reflex test (QSART) to measure sudomotor function, are limited by technically demanding settings as well as interindividual variability and are therefore restricted to specialized clinical centers. New axon-reflex tests are characterized by quantification of axon responses with both temporal and spatial resolution and include "laser Doppler imaging (LDI) axon-reflex flare area test" to assess vasomotor function, the quantitative direct and indirect test of sudomotor function (QDIRT) to quantify sudomotor function, as well as the quantitative pilomotor axon-reflex test (QPART), a technique to measure pilomotor nerve fiber function using adrenergic cutaneous stimulation through phenylephrine iontophoresis. The effectiveness of new axon-reflex tests in the assessment of neuropathy is currently being investigated in clinical studies.

Rates of autonomic dysfunction in HIV patients receiving antiretroviral therapy

We read the work by Robinson-Papp et al. with interest. The authors report that 61 % of participants had autonomic dysfunction (AD) as defined by a composite autonomic severity score (CASS) >3, with peripheral nerve dysfunction being the strongest predictor, affecting 90 % of participants who have HIV-associated distal symmetric polyneuropathy. Eighty-six percent of individuals with AD were symptomatic on survey of autonomic symptoms (SAS). The Composite Autonomic Scoring Scale (CASS) is a validated scale designed to quantify autonomic failure. CASS is derived from three areas of autonomic function: adrenergic, cardiovagal, and sudomotor (1996; Weimer 2010; Low et al. 2008). A CASS of 6 is indicative of severe autonomic failure (Low et al. 2008). CASS has been correlated with cardiovascular disease events and mortality (Gehrking et al. 2013). A CASS of 4–6 has been associated with orthostatic hypotension, abnormal sweating, and gastrointestinal abnormalities and is usually seen in autonomic failure (Low 1993). The authors report a median CASS of 3, suggesting that 50 % of subjects had a CASS of >3. The study reported on the CASS upper range of 6. A CASS this high would implicate major clinical outcomes and mortality which frankly have not been seen in large epidemiologic studies. The rates and severity of AD may have been overestimated in this study. In a convenience sample of 48 virologically suppressed HIV-infected individuals with and without polyneuropathy, we reported on a median CASS of 1 (IQR 1), and 40 % of subjects were symptomatic. We utilized the Composite Autonomic Symptom Scale to measure autonomic symptoms, a better instrument to detect and quantitate AD compared to the SAS used in the study. We wonder whether using the Q-sweat test for evaluating the sudomotor response used in the study may have overestimated AD. The qualitative sudomotor axon reflex test (QSART) has been a routine postganglionic sudomotor function test of the Mayo Clinic since 1983. The Q-sweat test is a commercial quantitative sweat measurement test modeled on QSART, but can overestimate sudomotor dysfunction (Sletten et al. 2010). In the era of combination antiretroviral therapy (cART), dramatic improvements in morbidity and mortality have been witnessed. However, autonomic symptoms such as light-headedness, dry mouth and eyes, cold feet, and constipation, as noted in the study and ours, have become common complaints among HIV-infected patients. AD has been correlated with HIV disease progression (Becker et al. 1997; Chow et al. 2011). Individuals with AIDS receiving cART have better measures of autonomic function compared to individuals that are not on cART (Correia et al. 2006). Forty-two percent of the study participants had a detectable viral load. Early and lifelong suppression of HIV infection and avoidance of medications that cause peripheral neuropathy and metabolic disorders needs to be considered for HIV-infected individuals (Askgaard et al. 2011). AD is a common condition. The rate and severity of autonomic dysfunction may not appear as elevated as suggested by the authors. Nonetheless, we commend Robinson-Papp et al. for bringing attention to AD which we agree is an underappreciated condition that is becoming increasingly common among our aging HIV-infected patients. Further investigation is needed to explain the prevalence and nature of AD, and its potential treatment.

Neurovascular Function and Sudorimetry in Health and Disease

In this review of thermoregulatory function in health and disease, we review the basic mechanisms controlling skin blood flow of the hairy and glabrous skin and illustrate the major differences in blood flow to glabrous skin, which is, in essence, sympathetically mediated, while hairy skin is dependent upon neuropeptidergic signals, nitric oxide, and prostaglandin, among others. Laser Doppler methods of quantification of blood flow--in response to iontophoresis of acetylcholine or heat--and nociceptor-mediated blood flow have relatively uniformly demonstrated an impaired capacity to increase blood flow to the skin in diabetes and in its forerunners, prediabetes and the metabolic syndrome. This reduced capacity is likely to be a significant contributor to the development of foot ulcerations and amputations in diabetes, and means of increasing blood flow are clearly needed. Understanding the pathogenic mechanisms is likely to provide a means of identifying a valuable therapeutic target. Thermoregulatory control of sweating is intimately linked to the autonomic nervous system via sympathetic C fibers, and sweat glands are richly endowed with a neuropeptidergic innervation. Sweating disturbances are prevalent in diabetes and its precursors, and quantification of sweating may be useful as an index of diagnosis of somatic and, probably, autonomic dysfunction. Moreover, quantifying this disturbance in sweating by various methods may be useful in identifying the risk of progression from prediabetes to diabetes, as well as responses to therapeutic intervention. We now have the technological power to take advantage of this physiological arrangement to better understand, monitor, and treat disorders of small nerve fibers and the somatic and autonomic nervous system (ANS). Newer methods of sudomotor function testing are rapid, noninvasive, not technically demanding, and accessible to the outpatient clinic. Whether the potential applications are screening for diabetes, following poorly controlled diabetes subjects during alteration of their treatment regimen, or simply monitoring somatic and autonomic function throughout the course of treatment, sudorimetry can be an invaluable tool for today's clinicians.

Relationship of Limited Joint Mobility and Foot Deformities with Neurological Examination in Patients with Diabetes

The aim is to define the association of forefoot deformity and limited joint mobility in the ankle and hallux joints in patients with diabetes mellitus subject to different diagnostic tests for diabetic neuropathy. Prospective study with 118 type 2 diabetic patients (68 men, mean age of 65.6±9.9 years) enrolled consecutively from the Diabetic Foot Unit of the Complutense University of Madrid subject to evaluation of plantar surface sensitivity by 10-g Semmes-Weinstein Monofilament, vibratory threshold by biothesiometer, and sudomotor dysfunction by Neuropad®. The patients presented with limited joint mobility of the ankle and the first metatarsophalangeal joints, and forefoot deformities were registered. Statistical analysis was done through a univariate model to test the association between neurological and biomechanical alteration. There was an association of abnormal Monofilament (p=0.01; OR=3.9) and biothesiometer tests (p=0.01; OR=2.6) with the presence of forefoot deformity. Furthermore, a relation was found between abnormal Monofilament (p=0.02; OR=4.8) and biothesiometer (p<0.00; OR=12.8) tests with limited mobility of the first metatarsophalangeal joint both in loading and off-loading. Abnormal sudomotor function test was related with limited joint mobility of the ankle joint with the knee flexed (p=0.04; OR=2.8). The results of this study show discordance between biomechanical abnormalities and neuropathy depending on the diagnostic test used. Tests that assess large myelinated nerve fibers are associated with the presence of deformities. Abnormal sudomotor function test is associated with limited joint mobility and this test has a greater capacity for selecting patients at risk.

Evaluation of the Neuropad sudomotor function test as a screening tool for polyneuropathy in the elderly population with diabetes and pre‐diabetes: the KORA F4 survey

Neuropad is a novel indicator test for sudomotor dysfunction, which has not been validated as a screening tool in a population-based study. This study aimed to evaluate the utility of Neuropad as a screening tool for distal symmetric polyneuropathy among elderly subjects with diabetes and pre-diabetes in the general population. Eligible subjects aged 61-82 years (n = 940) from the KORA F4 survey were examined, 201 of whom had diabetes and 231 had pre-diabetes (WHO 1999 criteria). Polyneuropathy was defined by the Michigan Neuropathy Screening Instrument (MNSI) score >3. Polyneuropathy was diagnosed in 60 (29.9%) subjects with diabetes and in 45 (19.5%) subjects with pre-diabetes, respectively (p = 0.013). The sensitivity and negative predictive value of Neuropad (reading time: 10 min) for the diagnosis of polyneuropathy were moderately high, reaching 76.7% and 78.1% in subjects with diabetes and 57.8% and 76.5% in those with pre-diabetes, respectively. Conversely, the specificity and positive predictive value for the diagnosis of polyneuropathy were rather low: 35.5% and 33.6% in diabetic individuals and 33.3% and 17.3% in subjects with pre-diabetes, respectively. Use of the >2 cut-off and MNSI combined with monofilament examination did not improve the diagnostic performance of Neuropad. In the elderly general population with diabetes and pre-diabetes, Neuropad has reasonable sensitivity but rather low specificity for the diagnosis of polyneuropathy. It is a useful simple and inexpensive tool to screen for and to exclude polyneuropathy as desired, while its low specificity implies that a longer reading time merits consideration.

Autonomic Testing

Laboratories able to test autonomic function are increasingly available and rely on batteries of well-accepted, noninvasive tests. Tests of parasympathetic cardiovagal, sympathetic vasoconstriction, and sudomotor (sweating) function are most commonly employed. Common examples include heart rate variability to various challenges, Valsalva maneuver, standing and tilt-table studies, and various sudomotor methods. New techniques and technical refinements continue to be described. Most studies rely on perturbations of complex systems and not direct assessment. Testing has helped to improve disease recognition and prompted advances in classification, pathophysiology, and treatment. Major areas impacted include hereditary and immune-mediated autonomic neuropathy, diabetic autonomic neuropathy, distal symmetric polyneuropathy, Parkinson disease and other autonomic failure syndromes, orthostatic intolerance, and unexplained syncope.

Methods of evaluation of autonomic nervous system function

Disturbances of the autonomic nervous system play a crucial role in the pathogenesis and clinical course of many diseases. Recently, rapid development has occurred in the clinical assessment of autonomic function. Various procedures have been described as diagnostic tools to monitor autonomic dysfunction. Some of them are mostly used for research purposes. Many, however, have found their place in routine clinical evaluation. Our paper presents selected methods of assessment of the autonomic nervous system with particular emphasis on those that are useful in diagnosis and treatment of diseases of the cardiovascular system. We discuss multiple tests based on cardiovascular reflexes, methods of studying heart rate variability as well as direct catecholamine measurements. Moreover, we outline tests of sudomotor function and microneurography.

Distal sudomotor findings in postural tachycardia syndrome

Postural tachycardia syndrome (POTS) is a heterogeneous disorder characterized by excessive orthostatic tachycardia in the absence of orthostatic hypotension and by sympathetic nervous system activation. Postganglionic sudomotor deficits have been used to define a neurogenic postural tachycardia POTS subtype. Norepinephrine levels above 600 pg/ml have also been used to delineate patients with a hyperadrenergic state. This study aims to determine the relationship of sudomotor abnormalities to other aspects of dysautonomia in POTS. Autonomic function was quantified in thirty women through tests of cardiovagal, adrenergic, and sudomotor function including quantitative sudomotor axon reflex testing (QSART) and spectral indices. Differences between patients with and without sudomotor dysfunction as defined by QSART and between patients with and without hyperadrenergic POTS were assessed with Mann-Whitney U test and Mantel-Haenszel Chi-Square test using a p value of 0.01 for significance. Spearman correlation coefficients were used to test raw sweat volume correlations with other variables. Of 30 women (ages 20-58), 17 patients (56%) had an abnormal QSART which was typically patchy and involved the lower extremity, while 13 patients had normal QSART results. Other autonomic tests, catecholamines or spectral indices did not correlate with QSART results. No differences in autonomic tests or spectral indices were observed between hyperadrenergic and non-hyperadrenergic POTS. Our findings confirm that a large subset of POTS patients have sudomotor abnormalities which are typically patchy in distribution but do not correlate with other tests of autonomic function. Further studies are needed to determine the best method of endophenotyping patients with POTS.

QDIRT

To develop a novel assessment of sudomotor function. Postganglionic sudomotor function is currently evaluated using the quantitative sudomotor axon reflex test (QSART) or silicone impressions. We hypothesize that high-resolution digital photography has advanced sufficiently to allow quantitative direct and indirect reflex testing of sudomotor function (QDIRT) with spatial and temporal resolution comparable to these techniques. Sweating in 10 humans was stimulated on both forearms by iontophoresis of 10% acetylcholine. Silicone impressions were made and topical indicator dyes were digitally photographed every 15 seconds for 7 minutes after iontophoresis. Sweat droplets were quantified by size, location, and percent surface area. Each test was repeated eight times in each subject on alternating arms over 2 months. Another 10 subjects had silicone impressions, QDIRT, and QSART performed on the dorsum of the right foot. The percent area of sweat photographically imaged correlated with silicone impressions at 5 minutes on the forearm (r = 0.92, p < 0.01) and dorsal foot (r = 0.85, p < 0.01). The number of sweat droplets assessed with QDIRT correlated with the silicone impression, although the droplet number was lower (162 +/- 28 vs 341 +/- 56, p < 0.01, r = 0.83, p < 0.01). The sweat response and sweat onset latency assessed by QDIRT correlated with QSART measured at the dorsum of the foot (r = 0.63, p < 0.05; r = 0.52, p < 0.05). The quantitative direct and indirect reflex test of sudomotor function (QDIRT) measured both the direct and the indirect sudomotor response with spatial resolution similar to that of silicone impressions, and with temporal resolution similar to that of the quantitative sudomotor axon reflex test (QSART). QDIRT provides a novel tool for the evaluation of postganglionic sudomotor function.

Idiopathic pure sudomotor failure

Acquired idiopathic generalized anhidrosis (AIGA) represents a heterogeneous clinical syndrome including sudomotor neuropathy and failure of the sweat glands. However, most AIGA cases comprise idiopathic pure sudomotor failure (IPSF), a distinct subgroup without sudomotor neuropathy or sweat gland failure. Eight patients with IPSF (mean +/- SD age 20 +/- 5 years) were assessed by thermoregulatory and pilocarpine-induced sweating tests, as well as emotional sweating using sudorometer (4 cases), microneurography of skin sympathetic nerve activity (2 cases), and skin biopsies from the forearm or axilla (3 cases). Clinical features of IPSF comprise early onset; acute or sudden onset; concomitant sharp pain or cholinergic urticaria over the entire body; lack of autonomic dysfunction other than generalized anhidrosis; elevated serum IgE levels; and marked response to steroid. Sudomotor function testing revealed complete absence of thermoregulatory sweating, but well-preserved emotional sweating; pilocarpine did not induce sweating, and microneurography revealed that bursts of skin sympathetic nerve activity were not decreased; and skin biopsy displayed no morphologic abnormalities in sweat glands. The first two findings suggest lesions on the postsynaptic side of the nerve-sweat gland junction. The lesions in IPSF may be in the muscarinic cholinergic receptors of sweat glands. Allergic mechanisms are probably involved in its pathophysiology.

Das Horner-Syndrom - Ein Update zur Neuroanatomie, topographischen Differenzialdiagnostik und Ätiologie

Due to the complex neuroanatomy of the sympatho-excitatory pathway, Horner's syndrome represents a clinical sign that may result from a variety of lesions in the central and peripheral nervous system. The purpose of the present communication is to help the reader to localize the site of the lesion and to demonstrate the most common etiologic mechanisms resulting in Horner's syndrome. The functional anatomy of the sympathetic supply to the iris, eyelids, facial sweat glands and blood vessels is reviewed and in particular the structure of the central pathway updated. Moreover, pharmacological testing and tests of sudomotor function are described that may help to guide the decision regarding useful additional diagnostic, especially neuroimaging procedures. Finally, a schematic overview is given on the most common pathology, considering additional clinical signs and symptoms.

Idiopathic Painful Sensory Neuropathy

Unexplained painful burning feet are common complaints among the elderly. Conventional elettrodiagnostic testing may be normal or only minimally abnormal and the lack of a universally accepted diagnostic test for small fiber dysfunction has posed a significant impediment to evaluation of these patients. The increasing application of newer diagnostic techniques, including quantitative sensory testing, tests of sudomotor function, and skin biopsy for intrnepidermal nerve fiber quantification, has permitted recognition and characterization of the idiopathic painful sensory neuropathies This article reviews the clinical features, evaluation, and management of this syndrome.

AAEM minimonograph #48: autonomic nervous system testing.

The autonomic nervous system maintains internal homeostasis by regulating cardiovascular, thermoregulatory, gastrointestinal, genitourinary, exocrine, and pupillary function. Testing and quantifying autonomic nervous system function is an important but difficult area of clinical neurophysiology. Tests of parasympathetic cardiovagal regulation include heart rate analysis during standing (the 30:15 ratio), heart rate variation with deep breathing, and the Valsalva ratio. Tests of sympathetic adrenergic vascular regulation include blood pressure analysis while standing, the Valsalva maneuver, sustained handgrip, mental stress, and cold water immersion. Tests of sympathetic cholinergic sudomotor function include the sympathetic skin response, quantitative sudomotor axon reflex test, sweat box testing, and quantification of sweat imprints. Pupil function is tested pharmacologically and with pupiilographic techniques. Tests of gastrointestinal and genitourinary function do not satisfactorily isolate autonomic regulation from their other functions. The available tests have various sensitivities and ease of administration. They are typically administered in a battery of multiple tests, which improves sensitivity and reliability, and allows probing of various autonomic functions.

Sudomotor functional dissection of neurodegenerative diseases

We performed a quantitative sudomotor function test using thermal stimulation (40°C) and thyrotropin-releasing hormone (TRH) in 14 patients with multiple system atrophy (MSA), 10 patients with Parkinson's disease (PD), 11 patients with amyotrophic lateral sclerosis (ALS) and in 11 age-matched control subjects. There was thermal sudomotor dysfunction in the lower extremities of the MSA patients. The PD patients failed to increase their local sweating and frequency of sweat expulsions with TRH infusion, in spite of the fact that they still had normal thermal sweating. ALS patients had mild thermoregulatory sweat dysfunction in their lower extremities. These results suggest that in MSA the lesion most responsible for sudomotor dysfunction is the intermediolateral column cells of the spinal cord and postganglionic sympathetic neurons. There may be an impairment of TRH-induced sympathetic responses in PD, and there is a mild postganglionic sympathetic lesion in the lower extremities of ALS patients.

Assessment of Sudomotor Dysfunction in Early Parkinson’s Disease

We performed a quantitative sudomotor function test on 10 patients with early Parkinson's disease (PD) and 11 age-matched control subjects. Thermal warming increased the sweat rate in both PD and controls. There was no difference in sweat rate between the forearm and the thigh in either PD or controls. In PD, thyrotropin-releasing hormone (TRH) did not increase the sweat rate, whereas it did so in the controls. These results suggest that sudomotor dysfunction in early PD is minor but that there may be an impairment of TRH-induced sympathetic response in the early stages of PD.

Comparison of microscope and loupe magnification: assistance for the repair of median and ulnar nerves

A retrospective study of the results of repair of complete divisions of median and ulnar nerves in 31 patients was carried out to compare those operations in which microscope magnification had been used with those in which loupe magnification had been used. A comprehensive set of clinical parameters was applied to assess the patients. It included motor performance of the intrinsic muscles of the hand, tests of protective sensation, discriminatory sensation, sudomotor function and vibration sensation. The results are comparable with previously published series with children notably showing a greater degree of recovery of function than adults. Because this is a relatively small retrospective series, it does not lend itself to statistical analysis. However, the results suggest that the type of magnification assistance used in peripheral nerve repair is not as significant in the achievement of good results as other factors which should be considered.