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.

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.

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 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). 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.

Diabetic neuropathy.

Diabetic neuropathy (DN) is the most common and troublesome complication of diabetes mellitus, leading to the greatest morbidity and mortality and resulting in a huge economic burden for diabetes care. The clinical assessment of diabetic peripheral neuropathy and its treatment options are multifactorial. Patients with DN should be screened for autonomic neuropathy, as there is a high degree of coexistence of the two complications. A review of the clinical assessment and treatment algorithms for diabetic neuropathy, painful neuropathy, and autonomic dysfunction is provided.