Eccrine glands that are responsible for sweat response receive a rich supply of blood vessels and are innervated by sympathetic C nerve fibers (autonomic nervous system). These fibers are thin and long and so can be impaired at the early stage of different metabolic diseases. “Sweat response may be the most sensitive test in detecting distal small fiber neuropathy” (see publications by Low et al. and Gibbons et al).
EZSCAN evaluates sudomotor function on the palm of the hands and sole of the feet where the density of sweat glands is maximal.
The method is based on an electrochemical reaction between the sweat chloride and the electrodes. A low DC voltage ≤ 4 volts is applied generating a current relative to chloride (ion) flow supplied by the sweat glands and ducts. An Electro Skin Conductance (ESC) is calculated for the hands and feet on this basis of the current and the voltage that is generated.
Similarly to the cardiologic stress test for which the exercise is used as a stimulus to capture specific information that is not assessable in resting state, EZSCAN too relies on an electrical stimulus of sweat chloride to capture information about the sweat dysfunction that cannot be diagnosed in usual conditions. For a better understanding see animation on the web site.
Because the skin’s stratum corneum acts like an electrical capacitor allowing only the conduction of chloride to pass to the surface hands and feet electrodes via the sweat duct when a low voltage stimulation is applied, we can be certain that we’re targeting the underlying sweat gland and its sympathetic innervations.
This underlying theory has been confirmed in a comparative study performed on patients with Cystic Fibrosis (who have high sweat chloride concentration) and controls (see publication by Hubert et al).
Small fiber neuropathy has been associated with many medical conditions including glucose dysmetabolism (diabetes or prediabetes). Several recent studies have found a high prevalence of impaired glucose tolerance in patients with peripheral neuropathies with a rate up to 42% in cases initially thought to be idiopathic compared with 14% in the general population (see article on small fiber neuropathy). Further, peripheral neuropathies are not always diagnosed. Depending on certain population and diagnostic methods, up to 90% of patients with diabetes have confirmed peripheral neuropathies.
Another study showed that patients with metabolic syndrome were twice as likely to present with neuropathy as those without.
However there are other causes for polyneuropathies: alcoholism, chemotherapy drug induced neurotoxicity. In all these cases neuropathies are symmetrical as opposed to mononeuropathies which are asymmetrical.
If sweat dysfunction is detected by EZSCAN, the possibility is high that a lesion of peripheral autonomic nervous system exists. The cause must be investigated with further clinical assessment and the precise diagnosis confirmed by a more specific (but less sensitive) test typical with glucose based measurements (fasting or post charge test i.e. oral glucose tolerance test, OGTT) or HbA1C and lipid metabolism.
Reproducibility is critical for any screening test to be useful. EZSCAN has been tested for reproducibility in several clinical studies on large groups of patients with 5% coefficient of variation for feet ESC and 10% for hands ESC, which is excellent in an en-vivo environment. The reproducibility between measurements performed before and after an exercise is also excellent (see below).
Analyzing dynamic chloride-ionic flow of the sweat glands when stimulated by current that are high comparatively to physiologic current (between 1 and 4 V vs mV) provides better information as compared to methods based on sweat volume since chloride concentrations do not change with sweat rate (see article by Quinton et al on web site)
Also noteworthy is that the reproducibility of EZSCAN is significantly better than HbA1c (especially finger methods) or the oral glucose tolerance test (both HbA1c and OGTT have an effective reproducibility rate of about 20%).
For more information about the reproducibility and robustness of these tests, refer to the article of P Schwarz and et al (accepted for publication in British Journal of Diabetes and Vascular Diseases).
The effect of treatments is a key point and is under investigation.
A preliminary study comparing a small group of patients comparable for age and BMI with or without pioglitazone has shown that patients receiving pioglitazone had higher feet ESC although a longer diabetes duration. This preliminary study will be extended on a larger group of patients with measures performed before pioglitazone administration and after 3 or 6 months with pioglitazone. The effect of other diabetes treatments will be tested.
Small C fibers innervating sweat glands are sympathetic fibers, and rely on acetylcholine to support neurotransmitter function. The effect of treatment that could act on sympathetic nervous system (i.e. beta-blockers that are not specific for the heart) has not been yet tested. In the same way the effect of atropinic agents has not yet be tested. These agents are known to decrease sweat rate and have been shown to negatively influence other sudomotor function tests such as QSART (Quantitative Sudomotor Axon Reflex Testing) that are based on sweat rate, as opposed to EZSCAN which do not depend on sweat rate.
Clinical tests run at different temperatures (changes of more than 5°C) demonstrate that temperature variance do not have impact on test results. Hands and feet that are poorly involved in thermoregulation due to their small area and thus are less temperature dependant than other parts of the body for their sweat rate. The role of sweat on hands and feet is to increase friction between skin and substrate, to increase the toughness of the skin, and to increase tactile sensitivity.
Theoretically, extreme cold temperature on the electrodes could result in vasoconstriction, whose effect has not been yet studied.
Therefore, avoid performing test measurements if the electrodes are too cold.
Given sweat rate changes with exercise it was important to evaluate the effects of exercise on EZSCAN tests. Measurements were performed before and after high level exercise on more than 100 subjects. They evidenced a coefficient of variation of 13 % for the hands and of 4% for the feet between these two measurements. These results confirm that EZSCAN measurements performed by don’t depend on sweat rate.
Evaluation of sudomotor function using other tests such as QSART has shown generally lower measures (in sweat output) in women compared with those on men. This can be explained by lower sweat rates in women. Measurements performed by EZSCAN don’t depend on sweat rate. A study performed on more than 500 women and more than 200 men show no significant differences in hands’ and feet’ ESC. This will be confirmed in future pending studies on larger group populations.
Sweat rate vary with ethnicity. EZSCAN measurements do not depend on sweat rates. Studies that have been performed in India, China, Germany, France and other European countries show no notable differences in hands and feet ESC in Asian subjects as compared with European subjects. Larger studies are necessary to confirm this hypothesis.
Blood pressure influences local vascularisation. Chronic high blood pressure levels induce micro vascular lesions potentially affecting the renal function. Sweat glands representing small nephrons and comparable lesions could be observed in both apparatus. In addition high chronic levels of blood pressure are a risk factor and impact sudomotor function as evidenced by several methods (QSART, skin biopsies….) (see article by Low et al).
With high chronic levels of blood pressure, a decrease in ESC is expected given the relationship with sweat dysfunction.
High acute blood pressure levels should not affect EZSCAN measurements as EZSCAN does not depend on sweat rate.
EZSCAN is an objective measurement unlike the use of questionnaires which depend on a patient’s understanding of the questions and subjectivity. Questionnaires need to be adapted to target the screened population. The EZSCAN risk score (classified into at-risk/moderate risk/no-risk color coded quadrants) can greatly help the patient and physician visualize the results.
EZSCAN is quantitative so it can be used for the follow-up of the subject to evaluate their improvement when involved in a prevention program. EZSCAN provide a simple and easy user interface (e.g., using color classification) that can make for a useful tool – for example in displaying an improve change in risk score/health status could be highly motivating for a patient undergoing intervention/treatment.
For patients involved in a training program, usual tools or the follow-up, weight, waist the only parameters that will change in a questionnaire need time to go down that can decrease motivation of the subject.
The EZSCAN score, calculated from hands and feet ESC values relies on the following parameters:
- comparison between hands and feet patterns
- demographic data (age and BMI)
The algorithm was developed and refined through numerous clinical studies and is continuously improved with new data.
Electrodes are made of stainless steel with high Nickel grade, so they are more resistant to corrosive influences. Their shelf-life depends on how often they are used and how good their cleaning is done. Cleaning must be performed after each patient using the proper ANIOS cleaner product. This cleaning is necessary
- to respect hygiene and safety standards
- to stop the corrosion process being initiated by electrochemical reaction
In one French hospital in which the EZSCAN system has experienced moderately heavy use, the electrodes are still functional and performing satisfactorily even after 5 years.
A large study is ongoing in Netherlands with more than 15000 people tested with 4 devices (electrodes are still in service).