Methods of Early Detection and Grading Of Diabetic Peripheral Neuropathy (MEDON)

Study Overview
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Brief Summary
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MEDON aims to examine new methods for early detection and grading of diabetic peripheral neuropathy focusing on both small- and large nerve fibers. Furthermore, MEDON aims to describe differences between people with classic diabetic peripheral neuropathy and those with painful diabetic neuropathy.

Official Title
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Perception Threshold Tracking(PTT): A Novel Method for Early Detection and Grading of Diabetic Peripheral Neuropathy

Conditions
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Neuropathy, Diabetic, Neuropathy, Painful

Intervention / Treatment
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* Diagnostic Test: Perception Threshold Tracking (PTT)
* Diagnostic Test: Axon-flair mediated respons
* Diagnostic Test: Heart rate variability
* Diagnostic Test: Quantitative Sensory Testing (QST)
* Diagnostic Test: Peripheral blood pressure and transcutaneous oxygen tension
* Diagnostic Test: Magnetic Resonance Imaging (MRI)
* Diagnostic Test: Questionnaires
* Diagnostic Test: Corneal Confocal Microscopy /CCM)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women minimum 18 years of age and maximum 75 years of age Signed informed consent form Diagnosed with diabetes type I (for group 1-3) Diagnosed with DPN defined as a threshold above 25-volt biothesiometry or absent feeling on the big toe using 10g-monofilament. (for group 1-2) Answered questionnaire: PainDETECT Nothing abnormal on initial tests (group 4) Accepted initial screening blood samples MRI-compatible participant Exclusion Criteria: 1. Current or previous alcohol- or drug abuse 2. Abnormal screening blood samples 3. Not being able to understand Danish written and/or verbally 4. Not being able to corporate to examination (e.g. not being able to speak, suffering from senile dementia etc.) 5. Previous chemotherapy or intake of experimental medicine 6. Active HSV- or VZV-infection or known HIV 7. Known severe skin disease 8. Known neural damage or disease in the neural system (e.g. MS, Guillain-Barre etc.) 9. Critical limb ischemia defined as in current clinical consensus 10. Allergy or intolerance to histamine or inability to make do without for one day 11. Pregnancy 12. Active cancer-disease

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Type 1 diabetes and painful neuropathy<br>No interventions. A series of observationel/expirimental methods for detecting and grading neuropathy will be applied. | Diagnostic Test: Perception Threshold Tracking (PTT)<br>* low-current electrical stimulation of both large- and small nerve fibers.<br>Diagnostic Test: Axon-flair mediated respons<br>* Laser-doppler examination of small blood vessels in the peripheral skin.<br>* Other names: Laser-doppler;Diagnostic Test: Heart rate variability<br>* 4 measurements of heart rate.<br>* Other names: Vagus TM;Diagnostic Test: Quantitative Sensory Testing (QST)<br>* Seven tests measuring 13 parameters including heat- and cold-detection and pain thresholds, mechanical pain treshold, mechanical detection threshold, pressure pain treshold and vibration threshold.<br>* Other names: German Research Network on Neuropathic Pain (DFNS) standard protocol;Diagnostic Test: Peripheral blood pressure and transcutaneous oxygen tension<br>* Ankle/brachial index, toe/brachial index, TcpO2.<br>* Other names: Perimed 6000;Diagnostic Test: Magnetic Resonance Imaging (MRI)<br>* MRI-scans of peripheral nerves and the central nervous system. Blood oxygen level dependent (BOLD) MRI.<br>Diagnostic Test: Questionnaires<br>* Questionnaires for detecting painful neuropathy<br>* Other names: PainDETECT, Douleur Neuropathique 4;Diagnostic Test: Corneal Confocal Microscopy /CCM)<br>* Confocal microscopy of the cornea measuring NBD, NFD, NFL<br>|
| Type 1 diabetes and non-painful neuropathy<br>No interventions. A series of observationel/expirimental methods for detecting and grading neuropathy will be applied. | Diagnostic Test: Perception Threshold Tracking (PTT)<br>* low-current electrical stimulation of both large- and small nerve fibers.<br>Diagnostic Test: Axon-flair mediated respons<br>* Laser-doppler examination of small blood vessels in the peripheral skin.<br>* Other names: Laser-doppler;Diagnostic Test: Heart rate variability<br>* 4 measurements of heart rate.<br>* Other names: Vagus TM;Diagnostic Test: Quantitative Sensory Testing (QST)<br>* Seven tests measuring 13 parameters including heat- and cold-detection and pain thresholds, mechanical pain treshold, mechanical detection threshold, pressure pain treshold and vibration threshold.<br>* Other names: German Research Network on Neuropathic Pain (DFNS) standard protocol;Diagnostic Test: Peripheral blood pressure and transcutaneous oxygen tension<br>* Ankle/brachial index, toe/brachial index, TcpO2.<br>* Other names: Perimed 6000;Diagnostic Test: Magnetic Resonance Imaging (MRI)<br>* MRI-scans of peripheral nerves and the central nervous system. Blood oxygen level dependent (BOLD) MRI.<br>Diagnostic Test: Questionnaires<br>* Questionnaires for detecting painful neuropathy<br>* Other names: PainDETECT, Douleur Neuropathique 4;Diagnostic Test: Corneal Confocal Microscopy /CCM)<br>* Confocal microscopy of the cornea measuring NBD, NFD, NFL<br>|
| Type 1 diabetes and no neuropathy<br>No interventions. A series of observationel/expirimental methods for detecting and grading neuropathy will be applied. | Diagnostic Test: Perception Threshold Tracking (PTT)<br>* low-current electrical stimulation of both large- and small nerve fibers.<br>Diagnostic Test: Axon-flair mediated respons<br>* Laser-doppler examination of small blood vessels in the peripheral skin.<br>* Other names: Laser-doppler;Diagnostic Test: Heart rate variability<br>* 4 measurements of heart rate.<br>* Other names: Vagus TM;Diagnostic Test: Quantitative Sensory Testing (QST)<br>* Seven tests measuring 13 parameters including heat- and cold-detection and pain thresholds, mechanical pain treshold, mechanical detection threshold, pressure pain treshold and vibration threshold.<br>* Other names: German Research Network on Neuropathic Pain (DFNS) standard protocol;Diagnostic Test: Peripheral blood pressure and transcutaneous oxygen tension<br>* Ankle/brachial index, toe/brachial index, TcpO2.<br>* Other names: Perimed 6000;Diagnostic Test: Magnetic Resonance Imaging (MRI)<br>* MRI-scans of peripheral nerves and the central nervous system. Blood oxygen level dependent (BOLD) MRI.<br>Diagnostic Test: Questionnaires<br>* Questionnaires for detecting painful neuropathy<br>* Other names: PainDETECT, Douleur Neuropathique 4;Diagnostic Test: Corneal Confocal Microscopy /CCM)<br>* Confocal microscopy of the cornea measuring NBD, NFD, NFL<br>|
| Matched controls without diabetes<br>No interventions. A series of observationel/expirimental methods for detecting and grading neuropathy will be applied. | Diagnostic Test: Perception Threshold Tracking (PTT)<br>* low-current electrical stimulation of both large- and small nerve fibers.<br>Diagnostic Test: Axon-flair mediated respons<br>* Laser-doppler examination of small blood vessels in the peripheral skin.<br>* Other names: Laser-doppler;Diagnostic Test: Heart rate variability<br>* 4 measurements of heart rate.<br>* Other names: Vagus TM;Diagnostic Test: Quantitative Sensory Testing (QST)<br>* Seven tests measuring 13 parameters including heat- and cold-detection and pain thresholds, mechanical pain treshold, mechanical detection threshold, pressure pain treshold and vibration threshold.<br>* Other names: German Research Network on Neuropathic Pain (DFNS) standard protocol;Diagnostic Test: Peripheral blood pressure and transcutaneous oxygen tension<br>* Ankle/brachial index, toe/brachial index, TcpO2.<br>* Other names: Perimed 6000;Diagnostic Test: Magnetic Resonance Imaging (MRI)<br>* MRI-scans of peripheral nerves and the central nervous system. Blood oxygen level dependent (BOLD) MRI.<br>Diagnostic Test: Questionnaires<br>* Questionnaires for detecting painful neuropathy<br>* Other names: PainDETECT, Douleur Neuropathique 4;Diagnostic Test: Corneal Confocal Microscopy /CCM)<br>* Confocal microscopy of the cornea measuring NBD, NFD, NFL<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diagnostic value of CCM, PTT, AF and MRI | Using Quantitative Sensory Testing (small fibers) and conventional nerve conduction studies (large fibers) as golden standards, we will determine the prognostic value of: Perception Threshold Tracking Corneal Confocal Microscopy Axon-flair mediated response MRI-scans in detecting neuropathy. Sensitivity and specificity will be reported. OBS! Tests will be tested in the initial groups and AFTER a group re-arrangement based on results from QST and NCS. | End of study (when all patients have completed all sessions. Latest 31. december 2021) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Validation of PainDETECT in diabetes | Correlation between PainDETECT and DN4 will be reported. | End of study / end of inclusion (when all patients have completed the screening session. Latest 31. november 2021) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diabetes, neuropathy, early detection, small nerve fibers