DECODING Study (Dermal Electrochemical Conductance in Diabetic Neuropathy)

Study Overview
=================
Brief Summary
-----------------
Diabetes mellitus is the leading cause of polyneuropathy in the Western world. Diabetic neuropathy is a frequent complication of diabetes and may have great clinical transcendence due to pain and possible ulceration of the lower extremities. It is also a relevant cause of morbidity and mortality in patients with diabetes. Although the cause of polyneuropathy in patients with diabetes is only partially known, it has been associated with chronic hyperglycaemia suggesting the possible aetiopathogenic implication of advanced glycosylation end-products. The strategy of choice in the medical management of diabetic neuropathy is early detection since glycaemic control and the use of certain drugs may prevent or slow the development of this disease. Diabetic neuropathy most often presents with a dysfunction of unmyelinated C-fibers, manifested as an alteration of the sweat reflex of the eccrine glands. This dysfunction can now be demonstrated using a newly developed technology which measures dermal electrochemical conductivity. This noninvasive test is easy and cost-effective. The aim of the present study is to evaluate the feasibility and effectiveness of dermal electrochemical conductance measurement (quantitative expression of the sudomotor reflex) as a screening test for the diagnosis of diabetic neuropathy in patients in primary care.

Detailed Description
-----------------
The prevalence of diabetes mellitus (DM) is very high in Spain, being nearly 14% according to oral glucose tolerance test (OGTT) results . The management of DM requires a significant consumption of healthcare resources, mainly in relation to the care of vascular complications. Among the late microvascular events which may develop in patients with DM, polyneuropathy (PN) is the most common and disabling, and is the leading cause of morbidity and mortality in these patients. Indeed, in Spain, the leading cause of neuropathy is DM, with its prevalence increasing with the presence of DM and other risk factors such as obesity. PN is defined as the presence of symptoms and/or signs of peripheral nerve dysfunction in people with DM after the exclusion of other possible causes. The Toronto Panel Consensus on PN defined this disorder as symmetrical, depending on large fibers, sensory-motor attributable to metabolic and micro vessel disorders, as a result of chronic hyperglycemia and other risk factors. In patients with PN, thin fibers (autonomic system - sweating) and thermal and tactile sensitivity are first affected, followed by the involvement of large fibers, presenting an altered vibrating sensation which eventually alters electromyography (EMG) patterns. Therefore, dysfunction of sweat reflex in small distal fibers is one of the earliest changes to be detected in these patients. The most common clinical presentation of PN is distal symmetric polyneuropathy (DSPN), being predominantly sensory in 80% of cases. Pain is the most important symptom, being described as burning or flashing, lancinating, deep, and with frequent exacerbations during rest (4). Pain often affects the quality of life of these patients, and it is a frequent cause of depression and/or anxiety. Moreover, some patients may develop hypoesthesia, which may lead to severe foot lesions. The prevalence of DSPN varies greatly according to the population, definition and detection method. The Rochester study, including more than 64,000 patients, reported the prevalence of PN to be between 66% and 59% for type1 DM and type 2 DM, respectively. The 3rd report of the Technical Study Group of Diabetes of the World Health Organization (WHO) described a prevalence of 40% (8), and 50% in patients with more than 25 years of DM evolution. Pirart et al. reported a prevalence ranging from 25 to 48% (7,10-17), while in Spain, Cabezas-Cerrato et al. published a figure of 24.1%. DSPN-related factors are: age, DM duration, metabolic control, male gender, acute myocardial infarction, hyperlipidemia (especially hypertriglyceridemia), smoking, and general cardiovascular risk factors . Puig et al. also included urinary albumin excretion as a risk factor of presenting DSPN. The diagnosis of DSPN is commonly made based on signs and symptoms and usually includes the use of several questionnaires such as the Neuropathy Disability Score (NDS), the Neuropathy Symptoms Score (NSS) and the Michigan Neuropathy Instrument (MNI). These questionnaires are easy to perform and are reproducible, sensitive and adequate for use in a screening program. Additionally, It was included a short scale (UENS - Utah Early Neuropathy Scale) to screen early neuropathy . This sensitive, fast and practical test, has 5 items and their score ranges from 0 to 42 points. There are many confirmatory tests, including measurements of nerve conduction velocity (EMG) and bio-thesiometry or skin biopsy. However, those most commonly used are the measurement of altered sensations using a vibrating tuning fork with 128 Hz and/or pressure with Semmes-Weinstein 5:07 monofilament. Monofilament testing (MFT) is widely accepted and recommended by all scientific societies because of its validity, predictive risk, efficiency and simplicity. Feng et al. reported that MFT has a sensitivity of 57-93%, a specificity of 75-100%, a positive predictive value of 36-94% and a negative predictive value of 84-100% compared to the measurement of nerve velocity by EMG. Although electrophysiological measures are more objective and reproducible, they are limited in that they only detect dysfunction based on the presence of thicker and faster (myelinated) fibers and show their involvement later. Consequently, EMG is a specific, albeit very insensitive, test. Recently developed noninvasive techniques are more reproducible and reliable for the detection of early dysfunction of small fibers. One of these new techniques involves the measurement of dermal electrochemical conductance (DEC) or sudomotor dysfunction index and has been evaluated by well-designed studies (Calvet, Dupin, Winiecki, Black, 2013; Casellini 2013; Devigili 2008; Peltier 2009) which support its use as a screening test . Ramachandran et al studied the use of DEC to detect diabetes and other disorders of glucose metabolism. In a study on the use of DEC Casellini et al (5) applied a PN test which showed a low sensitivity of 78% and a specificity of 92% in diabetic patients without neuropathy compared to other subjects with neuropathy and a control group. In this latter study, correlation with clinical parameters showed adequate reproducibility of the results, particularly in regard to the measurements of the feet . Several other studies also obtained significantly lower DEC values on comparing diabetic patients and controls. In a study of patients following a 12-month program of intense physical activity, Raisanen et al (23) observed a greater improvement in DEC compared to weight, waist circumference or maximum oxygen volume (VO2 max). Therefore, taking into account the large number of methods used and the learning curve required to correctly implement these techniques as well as the absence of consensus as to which method is the most adequate to diagnose DSPN, the aim of this study is to validate the usefulness of DEC measurement in the early diagnosis of DSPN compared with traditional techniques in the Primary Care setting.

Official Title
-----------------
Feasibility and Effectiveness of Electrochemical Dermal Conductance Measurement for the Screening of Diabetic Neuropathy in Primary Care.

Conditions
-----------------
Neuropathy, Diabetic, Diabetes Mellitus, Type 2

Intervention / Treatment
-----------------
* Diagnostic Test: dermal electrochemical conductance (DEC)
* Diagnostic Test: Monofilament testing


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: patients with type 2 DM patients with pre-diabetes patients without glucose alterations Three main diagnostic categories (normal, pre-diabetes and diabetes) were defined using the WHO criteria based on 2-h postload glucose [<7.8 (140 mg/dL), 7.8-11.0 mmol/L (140-200 mg/dL) and / or fasting plasma glucose (6.1-6.9 mmol/L; 110-126 mg/dL) and >11.1 mmol/L (>200 mg/dL), respectively. Exclusion Criteria: Type 1 DM upper or lower limb amputation (except phalanges), diagnosis of neuropathy not related to diabetes neuropathy by entrapment use of psychoactive substances chronic alcoholism malnutrition treatment with beta-blockers presence of terminal disease or life expectancy less than 3 years Pregnancy will be ruled out in women (negative pregnancy test) and a possible history of gestational diabetes will also be taken into account.

Ages Eligible for Study
-----------------
Minimum Age: 40 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Screening
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: consecutively there will be included patients with type 2 DM over 40 years of age, with or without symptoms of neuropathy, attended in Primary Care. We will also include the following two groups of patients matched by age and gender: one including patients with prediabetes (intermediate alterations of glucose metabolism defined as impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) determined by OGTT after 2-hour 75 g oral glucose administration and another including patients without glucose alterations (normal glucose tolerance) (control group)
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: patients with type 2 DM<br>Patients with type 2 DM over 40 years of age, with or without symptoms of neuropathy, attended in Primary Care. Intervention(s) to be administered:After verifying the inclusion criteria and receiving written informed consent to participate, during the first visit to the Primary Care centres the medical history of the patient will be obtained and a physical examination will be performed using the Monofilament testing -MFT and the Neuropathy Disability Score-NDS and Utah Early Neuropathy Scale-UENS questionnaires will be given to screen for polyneuropathy-PN. The patient will also undergo dermal electrochemical conductance- DEC quantification using the Sudoscan® device. | Diagnostic Test: dermal electrochemical conductance (DEC)<br>* The patient will undergo DEC quantification using the Sudoscan® device.(Sudoscan®, Impeto Medical, France)<br>Diagnostic Test: Monofilament testing<br>* Monofilament testing by Semmes-Weinstein 5:07 MFT (10 g),<br>|
| Experimental: prediabetes<br>Patients with intermediate alterations of glucose metabolism defined as impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) determined by OGTT after 2-hour 75 g oral glucose administration. Intervention(s) to be administered:After verifying the inclusion criteria and receiving written informed consent to participate, during the first visit to the Primary Care centres the medical history of the patient will be obtained and a physical examination will be performed using the Monofilament testing -MFT and the Neuropathy Disability Score-NDS and Utah Early Neuropathy Scale-UENS questionnaires will be given to screen for polyneuropathy-PN. The patient will also undergo dermal electrochemical conductance-DEC quantification using the Sudoscan® device. | Diagnostic Test: dermal electrochemical conductance (DEC)<br>* The patient will undergo DEC quantification using the Sudoscan® device.(Sudoscan®, Impeto Medical, France)<br>Diagnostic Test: Monofilament testing<br>* Monofilament testing by Semmes-Weinstein 5:07 MFT (10 g),<br>|
| Experimental: control group<br>Patients without glucose alterations (normal glucose tolerance). Intervention(s) to be administered:After verifying the inclusion criteria and receiving written informed consent to participate, during the first visit to the Primary Care centres the medical history of the patient will be obtained and a physical examination will be performed using the Monofilament testing -MFT and the Neuropathy Disability Score-NDS and Utah Early Neuropathy Scale-UENS questionnaires will be given to screen for polyneuropathy-PN. The patient will also undergo dermal electrochemical conductance-DEC quantification using the Sudoscan® device. | Diagnostic Test: dermal electrochemical conductance (DEC)<br>* The patient will undergo DEC quantification using the Sudoscan® device.(Sudoscan®, Impeto Medical, France)<br>Diagnostic Test: Monofilament testing<br>* Monofilament testing by Semmes-Weinstein 5:07 MFT (10 g),<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Presence of diabetic neuropathy diagnosed by EMG | Presence of diabetic neuropathy diagnosed by electromyography | Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neuropathy Disability Score | Presence of diabetic neuropathy diagnosed by Neuropathy Disability Score (NDS). - A NDS score greater than or equal to 6 points will be considered as the presence of diabetic neuropathy. | Day 1 | 
| Utah Early Neuropathy Scale | Presence of diabetic neuropathy diagnosed by Utah Early Neuropathy Scale (UENS). A UENS score greater than or equal to 10 points will be considered as the presence of diabetic neuropathy. | Day 1 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Screening; Sudomotor reflex; DEC; Primary Care