Electrochemical skin conductance

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Electrochemical skin conductance (ESC) is an objective, non-invasive and quantitative electrophysiological measure of skin conductance through the application of a pulsating direct current on the skin. It is based on reverse iontophoresis and steady chronoamperometry (more specifically chronovoltametry). ESC is intended to provide insight into and assess sudomotor (or sweat gland) function and small fiber peripheral neuropathy. The measure was principally developed by Impeto Medical (patent 20130053673/US 20130053673 A1/2013-02-28 [1] ) to diagnose cystic fibrosis from historical research at the Mayo Clinic and then tested on others diseases with peripheral neuropathic alterations in general. [2] It was later [3] integrated into health connected scales by Withings.

Contents

Biology

Anatomy: the eccrine sweat gland

See also sweat gland, eccrine sweat gland and Autonomic nervous system.

The ESC measurement relies on the particularities of the outer-most layer of the human skin, the stratum corneum (SC), which consists of a lipid corneocyte matrix crossed by skin appendages (sweat glands and their follicles) as described in Electrical properties of skin at moderate voltages: contribution of appendageal macropores. [4] According to the authors the stratum corneum is electrically insulating against DC voltages under 10V and only its appendageal pathways are conductive.

In the hairless skin, such as the palms of the hands and soles of the feet, in contact with the electrodes, the eccrine sweat glands are the principal conductive pathways this is why the ESC measurement technologies focus only on those skin parts.

These sweat glands are innervated by the sympathetic autonomic peripheral nervous system. According to Sato, [5] both adrenergic and cholinergic-muscarinic neurons participate, in the following physiological proportions: adrenergic 2/7 and cholinergic 5/7.

Particularities of the autonomic sympathetic nerve fibers that innervate sweat glands are that they are long (the postganglionic nerves start at the spinal cord and may end at the palm or sole), thin, unmyelinated or thinly myelinated C fibers. Because of these characteristics, they are prone to damage early in many neuropathic processes; assessing sweat gland nerve function, or dysfunction, therefore, can be used as a surrogate for the damage imparted to small caliber sensory nerves in neuropathy.

Physiology: Stimulation of sweat function

See Sudomotor function.

During normal physiological function, activation of eccrine sweat glands starts with a “chemical” stimulus. For instance, in the cholinergic pathway (the dominant pathway), this leads to the following sequence, or activation cascade: [6]

  1. The neurotransmitter acetylcholine binds to its corresponding muscarinic cholinergic receptor on the membrane cells of the sweat gland wall;
  2. This activates the G proteins coupled to the neuroreceptor;
  3. The G proteins, or their intracellular messengers, then modulate ion channels, creating an ion flux through the membrane;
  4. This polarizes the gland to voltages around 10 mV and always less than 100mV electrical potential difference between the two sides of the gland wall [7]

Technology

Impeto medical: Sudoscan

Summary

For the purposes of measuring Electrochemical Skin Conductance Sudoscan technology activates the sweat gland with an “electrical” stimulus. The applied voltage directly polarizes the gland with voltages between 100 mV to 1000 mV. This induces ion fluxes across the gland wall, depending on the electrochemical gradient of the ions. Because the current applied is high compared to the physiological current, the test could be compared to a “stress test” for sweat glands.

In fact, firm application of the hands and feet against the electrodes blocks physiological sweating, and the active measure extracts electro-active ions (i. e., chloride near the anode, proton near the cathode) and pulls them towards the electrodes.

The resulting conductance is then given for each foot and hand in µS (micro-Siemens).

Details

Currently, ESC measurement can be obtained with the use of a medical device, called Sudoscan. [8] [9] No specific patient preparation or medical personnel training is required. The measure lasts less than 3 minutes, and is innocuous and non-invasive. [10]

The apparatus consists of stainless-steel electrodes for the hands and the feet which are connected to a computer for recording and data management purposes. To conduct an ESC test, the patients place their hands and feet on the electrodes. Sweat glands are most numerous on the palms of the hands and soles of the feet, and thus well suited for sudomotor function evaluation. [11]

The electrodes are used alternatively as anode or cathode. A direct current (DC) incremental voltage under 4 volts is applied on the anode. This DC, through reverse iontophoresis, induces a voltage on the cathode and generates a current (of an intensity less than 0.3 mA) between the anode and the cathode, related to electro-active ions from sweat reacting with the electrodes. The electrochemical phenomena are measured by the two active electrodes (the anode and the cathode) successively in the two active limbs (either hands or feet), whilst the two passive electrodes allow retrieval of the body potential. [9]

During the test, 4 combinations of 15 different low DC voltages are applied. The resulting Electrochemical Skin Conductances (ESC) for each hand and foot are expressed in µS (micro-Siemens). The test also evaluates the percentage of asymmetry between the left and right side, for both hands and feet ESC, providing an assessment of whether one side is more affected than the other. [12]

Withings: scales

Summary

Withings integrated Sudoscan [13] technology into its scale (FDA clearance [14] ) in order to provide large adoption of the measurement and allow for at home follow-up of patients with neuropathies.

Details

The Withings technology is based on the same principle but only measure the ESC on foot from its BodyComp [15] and BodyScan [16] scales. A clinical trial (agreement study) demonstrated the correlation between the BodyScan scale and Sudoscan measurements. [17] More generally the adoption of a technology going from only hospital measurements to home measurements allow the building of Real World Evidence (RWE) time series profile for patients.

Alternative methods and technologies

There are several other clinical tests available to assess sudomotor and/or small fiber function [18] [19] and/or peripheral or cardiac neuropathy. [20] These may employ a measurement target other than the sweat glands, and/or alternate methodologies.

For sudomotor tests specific clinical assessments include:

Applications

From a physiological standpoint, the pattern of innervation of the sweat gland—namely, the postganglionic sympathetic nerve fibers—allows clinicians and researchers to use sudomotor function testing to assess dysfunction of the autonomic nervous systems (ANS).

To ensure optimal use and interpretation of the ESC, normative values were defined in adults [24] and children. [25] In addition, reproducibility of the method was assessed under clinical conditions, including both healthy controls and patients with common chronic conditions. [26]

ESC has clinical utility in the evaluation and follow-up of dysautonomia and small fiber peripheral neuropathy which may occur in diseases such as:

Diabetes

General

See diabetes

Diabetes and two of its main complications: diabetic neuropathy [27] [8] [28] and autonomic neuropathy. [29] Sensorimotor polyneuropathy (DSPN) is the most common type of polyneuropathy in community-dwelling patients with diabetes, affecting about 25% of them.  The course of DSPN is insidious, though, and up to 50% of patients with neuropathy may be asymptomatic, often resulting in delayed diagnosis. Advanced or painful DSPN may result not only in reduced quality of life, but has been statistically associated with retinopathy and nephropathy, and leads to considerable morbidity and mortality. [30]   The autonomic nervous system (ANS), of which sudomotor nerves are an integral part, is the primary extrinsic control mechanism regulating heart rate, blood pressure, and myocardial contractility. Cardiac autonomic neuropathy (CAN) describes a dysfunction of the ANS and its regulation of the cardiovascular system. CAN is the strongest predictor for mortality in diabetes. [31] [32]   Because early symptoms of CAN tend to be nonspecific, its diagnosis is frequently delayed and screening for CAN should be routinely considered in diabetic patients. Assessment of sudomotor function provides a measure of sympathetic cholinergic function in the workup of CAN.

Diabetic foot ulcer

See Diabetic foot ulcer (DFU).

In diabetic wounds, issues like tissue ischemia, hypoxia, high glucose microenvironment and skin dryness disrupt the healing process, leading to delayed or nonhealing wounds and clinical complications. In some cases it led to amputations and in the worst cases to the death. [33] [34] [35] [36] In that context being able to detect earlier the diabetic neuropathies and skin dryness with electrochemical conductance to avoid complication has been proposed for DFU management. [37] [38]

Amyloidosis

Amyloidosis such as familial amyloid neuropathy, [39] [40] AL amyloidosis, [41] and AA amyloidosis [publication pending]. During the course of AL amyloidosis, peripheral neuropathy occurs in 10–35% of patients; dysautonomia itself is an independent prognostic factor, and assessment of sweat disturbances is routine in the evaluation of amyloidosis.  ESC may provide a measure of subclinical autonomic involvement, which is not systematically assessed with more sophisticated equipment.

Cystic fibrosis

The effects of cystic fibrosis on sweat glands were described by Quinton. [42] The performance and potential utility of ESC were assessed in this disease. [43]

Parkinson's disease

Assessment of dysautonomia is important for patient follow-up and assessment of sudomotor function can be helpful in daily practice. [44] [45]

Chemotherapy-induced peripheral neuropathy (CIPN)

Chemotherapy-induced peripheral neuropathy is a common, potentially severe and dose-limiting adverse effect of multiple chemotherapeutic agents.  CIPN can persist long after the completion of chemotherapy and imposes a significant quality of life and economic burden to cancer survivors.  ESC allows for an objective quantification of small fiber impairment and is easy to implement in the clinic. [46] [47]

Sjögren syndrome

ESC may help in the diagnosis process. [48] [49]

Neuropathic pain

Neuropathic pain usually manifests in the setting of small fiber neuropathy. Small fiber neuropathy is common and may arise from a number of conditions such as diabetes, metabolic syndrome, infectious diseases, toxins, and autoimmune disorders. The gold standard for diagnosing small fiber neuropathy as the etiology of neuropathic pain is skin biopsy. Sudomotor assessment, an accurate objective technique, could be considered as a good screening tool to limit skin biopsy in patients in whom it is not suitable. [19] [50]

ESC has been evaluated for both early diagnosis of small fiber neuropathy and follow-up of treatment efficacy in each of these conditions. [51] [52] [53] [54]

Related Research Articles

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Microangiopathy is a disease of the microvessels, small blood vessels in the microcirculation. It can be contrasted to macroangiopathies such as atherosclerosis, where large and medium-sized arteries are primarily affected.

<span class="mw-page-title-main">Dysautonomia</span> Any disease or malfunction of the autonomic nervous system

Dysautonomia, autonomic failure or autonomic dysfunction is a condition in which the autonomic nervous system (ANS) does not work properly. This may affect the functioning of the heart, bladder, intestines, sweat glands, pupils, and blood vessels. Dysautonomia has many causes, not all of which may be classified as neuropathic. A number of conditions can feature dysautonomia, such as Parkinson's disease, multiple system atrophy, dementia with Lewy bodies, Ehlers–Danlos syndromes, autoimmune autonomic ganglionopathy and autonomic neuropathy, HIV/AIDS, mitochondrial cytopathy, pure autonomic failure, autism and postural orthostatic tachycardia syndrome.

Diabetic neuropathy is various types of nerve damage associated with diabetes mellitus. Symptoms depend on the site of nerve damage and can include motor changes such as weakness; sensory symptoms such as numbness, tingling, or pain; or autonomic changes such as urinary symptoms. These changes are thought to result from a microvascular injury involving small blood vessels that supply nerves. Relatively common conditions which may be associated with diabetic neuropathy include distal symmetric polyneuropathy; third, fourth, or sixth cranial nerve palsy; mononeuropathy; mononeuropathy multiplex; diabetic amyotrophy; and autonomic neuropathy.

<span class="mw-page-title-main">Amyloidosis</span> Metabolic disease involving abnormal deposited amyloid proteins

Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. There are several non-specific and vague signs and symptoms associated with amyloidosis. These include fatigue, peripheral edema, weight loss, shortness of breath, palpitations, and feeling faint with standing. In AL amyloidosis, specific indicators can include enlargement of the tongue and periorbital purpura. In wild-type ATTR amyloidosis, non-cardiac symptoms include: bilateral carpal tunnel syndrome, lumbar spinal stenosis, biceps tendon rupture, small fiber neuropathy, and autonomic dysfunction.

<span class="mw-page-title-main">Peripheral neuropathy</span> Nervous system disease affecting nerves beyond the brain and spinal cord

Peripheral neuropathy, often shortened to neuropathy, is a general term describing damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerves are affected. Neuropathy affecting motor, sensory, or autonomic nerves result in different symptoms. More than one type of nerve may be affected simultaneously. Peripheral neuropathy may be acute or chronic, and may be reversible or permanent.

<span class="mw-page-title-main">Polyneuropathy</span> Medical condition

Polyneuropathy is damage or disease affecting peripheral nerves in roughly the same areas on both sides of the body, featuring weakness, numbness, and burning pain. It usually begins in the hands and feet and may progress to the arms and legs and sometimes to other parts of the body where it may affect the autonomic nervous system. It may be acute or chronic. A number of different disorders may cause polyneuropathy, including diabetes and some types of Guillain–Barré syndrome.

Neuropathic pain is pain caused by a lesion or disease of the somatosensory nervous system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia). It may have continuous and/or episodic (paroxysmal) components. The latter resemble stabbings or electric shocks. Common qualities include burning or coldness, "pins and needles" sensations, numbness and itching.

<span class="mw-page-title-main">Nerve conduction velocity</span> Speed at which an electrochemical impulse propagates down a neural pathway

In neuroscience, nerve conduction velocity (CV) is the speed at which an electrochemical impulse propagates down a neural pathway. Conduction velocities are affected by a wide array of factors, which include age, sex, and various medical conditions. Studies allow for better diagnoses of various neuropathies, especially demyelinating diseases as these conditions result in reduced or non-existent conduction velocities. CV is an important aspect of nerve conduction studies.

<span class="mw-page-title-main">Compensatory hyperhidrosis</span> Medical condition

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<span class="mw-page-title-main">Familial amyloid polyneuropathy</span> Medical condition

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Small fiber peripheral neuropathy is a type of peripheral neuropathy that occurs from damage to the small unmyelinated and myelinated peripheral nerve fibers. These fibers, categorized as C fibers and small Aδ fibers, are present in skin, peripheral nerves, and organs. The role of these nerves is to innervate some skin sensations and help control autonomic function. It is estimated that 15–20 million people in the United States have some form of peripheral neuropathy.

<span class="mw-page-title-main">Epalrestat</span> Chemical compound

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Sudomotor function refers to the autonomic nervous system control of sweat gland activity in response to various environmental and individual factors. Sweat production is a vital thermoregulatory mechanism used by the body to prevent heat-related illness as the evaporation of sweat is the body’s most effective method of heat reduction and the only cooling method available when the air temperature rises above skin temperature. In addition, sweat plays key roles in grip, microbial defense, and wound healing.

<span class="mw-page-title-main">Axon reflex</span>

The axon reflex is the response stimulated by peripheral nerves of the body that travels away from the nerve cell body and branches to stimulate target organs. Reflexes are single reactions that respond to a stimulus making up the building blocks of the overall signaling in the body's nervous system. Neurons are the excitable cells that process and transmit these reflex signals through their axons, dendrites, and cell bodies. Axons directly facilitate intercellular communication projecting from the neuronal cell body to other neurons, local muscle tissue, glands and arterioles. In the axon reflex, signaling starts in the middle of the axon at the stimulation site and transmits signals directly to the effector organ skipping both an integration center and a chemical synapse present in the spinal cord reflex. The impulse is limited to a single bifurcated axon, or a neuron whose axon branches into two divisions and does not cause a general response to surrounding tissue.

Complications of diabetes are secondary diseases that are a result of elevated blood glucose levels that occur in diabetic patients. These complications can be divided into two types: acute and chronic. Acute complications are complications that develop rapidly and can be exemplified as diabetic ketoacidosis (DKA), hyperglycemic hyperosmolar state (HHS), lactic acidosis (LA), and hypoglycemia. Chronic complications develop over time and are generally classified in two categories: microvascular and macrovascular. Microvascular complications include neuropathy, nephropathy, and retinopathy; while cardiovascular disease, stroke, and peripheral vascular disease are included in the macrovascular complications.

<span class="mw-page-title-main">Diabetic foot</span> Medical condition

A diabetic foot disease is any condition that results directly from peripheral artery disease (PAD) or sensory neuropathy affecting the feet of people living with diabetes. Diabetic foot conditions can be acute or chronic complications of diabetes. Presence of several characteristic diabetic foot pathologies such as infection, diabetic foot ulcer and neuropathic osteoarthropathy is called diabetic foot syndrome. The resulting bone deformity is known as Charcot foot.

Chemotherapy-induced peripheral neuropathy (CIPN) is a nerve-damaging side effect of antineoplastic agents in the common cancer treatment, chemotherapy. CIPN afflicts between 30% and 40% of patients undergoing chemotherapy. Antineoplastic agents in chemotherapy are designed to eliminate rapidly dividing cancer cells, but they can also damage healthy structures, including the peripheral nervous system. CIPN involves various symptoms such as tingling, pain, and numbness in the hands and feet. These symptoms can impair activities of daily living, such as typing or dressing, reduce balance, and increase risk of falls and hospitalizations. They can also give cause to reduce or discontinue chemotherapy. Researchers have conducted clinical trials and studies to uncover the various symptoms, causes, pathogenesis, diagnoses, risk factors, and treatments of CIPN.

Idiopathic pure sudomotor failure (IPSF) is the most common cause of a rare disorder known as acquired idiopathic generalized anhidrosis (AIGA), a clinical syndrome characterized by generalized decrease or absence of sweating without other autonomic and somatic nervous dysfunctions and without persistent organic cutaneous lesions.

<span class="mw-page-title-main">Diabetic foot ulcer</span> Medical condition

Diabetic foot ulcer is a breakdown of the skin and sometimes deeper tissues of the foot that leads to sore formation. It may occur due to a variety of mechanisms. It is thought to occur due to abnormal pressure or mechanical stress chronically applied to the foot, usually with concomitant predisposing conditions such as peripheral sensory neuropathy, peripheral motor neuropathy, autonomic neuropathy or peripheral arterial disease. It is a major complication of diabetes mellitus, and it is a type of diabetic foot disease. Secondary complications to the ulcer, such as infection of the skin or subcutaneous tissue, bone infection, gangrene or sepsis are possible, often leading to amputation.

<span class="mw-page-title-main">Diabetic foot infection</span> Medical condition

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  13. ↑ "Withings Acquires Impeto Medical to Strengthen and Grow Its Research and Development of Medical Technologies" (Press release).
  14. ↑ https://media.withings.com/press/press-releases/body-scan/withings-body-scan-us-fda-clearance-082423.pdf?
  15. ↑ "Get a complete body assessment - Body Comp | Withings".
  16. ↑ "Get a health check-up - Body Scan | Withings".
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