Marie-Laure Nevoret

The New Age of Sudomotor Function Testing: A Sensitive and Specific Biomarker for Diagnosis, Estimation of Severity, Monitoring Progression, and Regression in Response to Intervention

Sudorimetry technology has evolved dramatically, as a rapid, non-invasive, robust, and accurate biomarker for small fibers that can easily be integrated into clinical practice. Though skin biopsy with quantitation of intraepidermal nerve fiber density is still currently recognized as the gold standard, sudorimetry may yield diagnostic information not only on autonomic dysfunction but also enhance the assessment of the small somatosensory nerves, disease detection, progression, and response to therapy. Sudorimetry can be assessed using Sudoscan™, which measures electrochemical skin conductance (ESC) of hands and feet. It is based on different electrochemical principles (reverse iontophoresis and chronoamperometry) to measure sudomotor function than prior technologies, affording it a much more practical and precise performance profile for routine clinical use with potential as a research tool. Small nerve fiber dysfunction has been found to occur early in metabolic syndrome and diabetes and may also be the only neurological manifestation in small fiber neuropathies, beneath the detection limits of traditional nerve function tests. Test results are robust, accomplished within minutes, require little technical training and no calculations, since established norms have been provided for the effects of age, gender, and ethnicity. Sudomotor testing has been greatly under-utilized in the past, restricted to specialized centers capable of handling the technically demanding and expensive technology. Yet, evaluation of autonomic and somatic nerve function has been shown to be one of the best estimates of cardiovascular risk. Evaluation of sweating has the appeal of quantifiable non-invasive determination of the integrity of the peripheral autonomic nervous system, and can now be accomplished rapidly at point of care clinics with the determination of ESC, allowing intervention for morbid complications prior to permanent structural nerve damage. We review here sudomotor function testing technology, the research evidence accumulated supporting the clinical utility of measuring ESC, the medical applications of sudorimetry now available to physicians with this device, and clinical vignettes illustrating its use in the clinical decision-making process.

Accuracy of a Rapid and Non-Invasive Method for the Assessment of Small Fiber Neuropathy Based on Measurement of Electrochemical Skin Conductances

Peripheral nerves (PN) consist of small and large fibers (1). The small fibers represent 80% of PN and are long, thin, with little or no myelin. They are, therefore, more fragile and the first to be damaged in many pathological processes (2–5). The current clinical diagnostic methods mainly assess large fibers (6). Similarly the gold standard neurophysiological tool, namely nerve conduction studies or NCS, is also limited to measuring large fiber function. These recommended methodologies, therefore, only examine 20% of PN, those that are largest and degenerate late or not at all in certain diseases. Small fibers can be sensory or autonomic and there are several methods to assess small fiber function or structure (7). Laser-evoked potentials assess A-delta fiber function (sensory nerves) but these instruments are not widely available (8). Quantitative sensory testing (QST) measures sensitivity to cold, heat, and vibration (sensory small and large fibers) and is more widely available but time-consuming and subjective for routine clinical practice (9). Skin biopsies can assess small fiber structure but are relatively invasive (3 mm in diameter, 1 month for full healing) and, thus, are ill suited for longitudinal assessments (10). Sudomotor function assessing small fibers of the sympathetic autonomic system can be evaluated by the quantitative sudomotor axon reflex test (QSART); though considered the reference method, QSART remains mostly limited to research centers due to the technical complexity and relative discomfort of the examination (11). Other sudomotor methodologies include the Neuropad, which is semi-quantitative and not highly sensitive (12), quantitative direct and indirect testing (QDIRT) and the dynamic sweat test (DST). QDIRT and DST both induce sweating with iontophoresis of acetylcholine or pilocarpine; they are relatively tedious and not particularly suited to the outpatient clinic and there are no data validating the diagnostic utility of these newer technologies (13, 14). Specific stains can be used to evaluate sweat gland nerve fiber density (SGNFD), but there is currently no standardized methodology or normative reference ranges for SGNFD (15). The SUDOSCAN® device was developed to allow the quantitative measurement of sweat gland function using a simple and rapid process (16, 17). Results are immediately available and expressed as electrochemical skin conductances (ESCs). This technique has been compared to reference neurological tests, is not operator dependent, and could be used in the follow-up of patients and in multi-center studies (18–21). The aim of this study was to assess repeatability and reproducibility of the method in healthy volunteers (HV) and diabetic patients with a range of glycemic control.

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

INTRODUCTION Chronic 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 DESCRIPTION The 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 patients 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). DISCUSSION CIDP 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.

Neuropathy in Prediabetes and the Metabolic Syndrome

The issue of neuropathy in prediabetes and the metabolic syndrome has been controversial, the major reasons being the difficulty in defining neuropathy and the failure to recognize that a substantial proportion of patients with prediabetes have a sensory neuropathy without evidence of abnormalities in nerve conduction studies—the hallmark of the neurologists’ definition of what constitutes neuropathy. Secondly, there is a large cadre of people with neuropathy or neuropathic pain in whom careful studies of the criteria for prediabetes including impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) as well as the lipid abnormalities of the metabolic syndrome (MS) such as elevated triglycerides and a low HDL-cholesterol have not been carried out. Taking these into consideration has vastly changed the appreciation of the relationship between neuropathy and the metabolic entities. Thus, it has been estimated that 24.6–62% of patients with chronic idiopathic symmetrical sensorimotor polyneuropathy (SPN) have prediabetes; as a corollary, of subjects with prediabetes, 11.2–24.3% exhibit SPN and 12.9–20.5% exhibit neuropathic pain. Population-based studies suggest a gradient for the prevalence of SPN, with the highest being in patients with diabetes, followed by IGT, IFG, and the lowest in normal glucose tolerance. The most sensitive test to evaluate glucose homeostasis is the oral glucose tolerance test (OGTT). The pathogenesis of neuropathy may be hyperglycemia, microvascular abnormalities, dyslipidemia, and the metabolic syndrome, with increasing evidence that oxidative and nitrosative stress may play a role. The characteristics of the neuropathy in prediabetes and the metabolic syndrome suggest that it may be a less severe neuropathy than in diabetes. Sensory modality findings prevail compared with motor, and small nerve fiber structure and function abnormalities may be the earliest findings. Diagnosis should rely on careful history and clinical examination, with emphasis on the evaluation of small fibers. A skin biopsy may be necessary to quantify intraepidermal nerve fiber density. An OGTT and fasting serum lipids should be performed in patients with idiopathic SPN to screen for prediabetes and the metabolic syndrome. Treatment should include hygienic measures such as diet and exercise. The only drug with potential for reversal of the neuropathy is Topiramate.

Cardiac Autonomic Neuropathy in Diabetes: A Predictor of Cardiometabolic Events

Autonomic nervous system (ANS) imbalance manifesting as cardiac autonomic neuropathy in the diabetic population is an important predictor of cardiovascular events. Symptoms and signs of ANS dysfunction, such as resting heart rate elevations, diminished blood pressure responses to standing, and altered time and frequency domain measures of heart rate variability in response to deep breathing, standing, and the Valsalva maneuver, should be elicited from all patients with diabetes and prediabetes. With the recognition of the presence of ANS imbalance or for its prevention, a rigorous regime should be implemented with lifestyle modification, physical activity, and cautious use of medications that lower blood glucose. Rather than intensifying diabetes control, a regimen tailored to the individual risk of autonomic imbalance should be implemented. New agents that may improve autonomic function, such as SGLT2 inhibitors, should be considered and the use of incretins monitored. One of the central mechanisms of dysfunction is disturbance of the hypothalamic cardiac clock, a consequence of dopamine deficiency that leads to sympathetic dominance, insulin resistance, and features of the metabolic syndrome. An improvement in ANS balance may be critical to reducing cardiovascular events, cardiac failure, and early mortality in the diabetic population.