Diabetic Small Fiber Neuropathy: Clinical, Electrophysiological and Neurosonographic Study

Study Overview
=================
Brief Summary
-----------------
The aim of work is to study the clinical, electrodiagnostic and neurosonographic characteristics of diabetic patients with small fiber neuropathy in the Egyptian population, and to evaluate both the diagnostic and the prognostic impact of the studied factors on the neuropathy severity and quality of life.

Detailed Description
-----------------
This case-control observational study is aiming to evaluate patients with diabetic small fiber neuropathy in the Egyptian. Diabetic small fiber neuropathy was defined as both of the following: A. Typical clinical symptoms of SFN such as burning or sharp pain in toes and feet, and on clinical examination: loss of small fiber modalities (pinprick and temperature), hyperalgesia, allodynia, and/or autonomic signs. B. Reduced intraepidermal nerve fiber density (IENFD) in distal leg skin punch biopsy. The study includes 3 groups: Group I: Patients with diabetic small fiber neuropathy Group II (Control Group): Patients with diabetic mixed small and large fiber neuropathy Group III (Control Group): Subjects without peripheral neuropathy Clinical evaluation includes: Neuropathic Pain 4 (DN4) questionnaire, 11-point Numeric Pain Scale (NPS), Utah Early Neuropathy Scale (UENS), Toronto Clinical Neuropathy Scale (TCNS), Composite Autonomic Symptom Score (COMPASS-31), an Arabic version, and several anthropometric measures; including: body weight in kilograms, height in centimeters, waist circumference measured in centimeters at the top of the iliac crest, and systolic SBP and diastolic DBP blood pressure measurement in mmHg. Electrodiagnostic evaluation includes: routine nerve conduction study, cutaneous silent period by stimulating left median nerve and right sural nerve and recording from the abductor pollicis brevis and tibialis anterior muscles, respectively, bilateral hand-to hand and foot-to-foot sympathetic skin response, and Ewing battery using R-R interval analysis, in addition to the blood pressure tests. Neurosonographic evaluation includes: bilateral vagal nerve scan at the mid-neck lateral to the thyroid cartilage, left median and right ulnar nerves scan at the mid-forearm, left tibial nerve at the distal ankle 2 to 4 fingerbreadths proximal to the medial malleolus, and right sural nerve 2 to 4 fingerbreadths proximal to the lateral malleolus. Nerves are evaluated for transverse cross-sectional area (CSA). Severity and outcome measures are assessed using: NPS, TCNS, COMPASS-31, and the index score of Euro Quality of Life -5 Dimensions -5 Levels (EuroQOL-5D-5L), the Arabic version.

Official Title
-----------------
Diabetic Small Fiber Neuropathy: Clinical, Electrophysiological and Neurosonographic Study

Conditions
-----------------
Small Fiber Neuropathy, Diabetic Neuropathies, Autonomic Neuropathy, Diabetic Peripheral Neuropathy, Painful Diabetic Neuropathy, Diabetic Polyneuropathy

Intervention / Treatment
-----------------
* Diagnostic Test: Clinical Evaluation/Questionnaires
* Diagnostic Test: Nerve Conduction Study
* Diagnostic Test: Small fiber electrodiagnostic tests
* Diagnostic Test: Nerve Ultrasound
* Diagnostic Test: Skin Biopsy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients diagnosed with diabetes mellitus or impaired glucose intolerance by laboratory investigations including any of the following: HbA1C, fasting blood sugar and 2-hour post prandial blood sugar, and/or antidiabetic medication. Patients presented with small fiber neuropathy (SFN), including all the following: A. Typical clinical symptoms of SFN such as burning or sharp pain in toes and feet, and on clinical examination: loss of small fiber modalities (pinprick and temperature), hyperalgesia, allodynia, and/or autonomic signs. B. Reduced intraepidermal nerve fiber density (IENFD) in distal leg skin punch biopsy. Age older than 18 years old Exclusion Criteria: Mental illness that made interviewing ineffective Physical illness leading to language and/or cognitive barrier Other conditions that could cause neuropathy (e.g., chemotherapy, alcohol intake, established vitamin B12 deficiency, established hereditary neuropathy or first-degree family members, active malignancy, chronic advanced liver or kidney diseases thought to cause neuropathy and history of bariatric surgery). Atrial Fibrillation

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

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

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

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

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients with diabetic small fiber neuropathy<br>Diabetic Patients presented with pure small fiber neuropathy. | Diagnostic Test: Clinical Evaluation/Questionnaires<br>* Anthropometric measures, somatosensory assessment (NPS, UENS, TCNS), autonomic assessment (COMPASS-31, Ewing battery), and severity and quality of life evaluation (NPS, TCNS, COMPASS-31, and EuroQOL-5D-5L index score)<br>Diagnostic Test: Nerve Conduction Study<br>* Routine Nerve Conduction Study.<br>Diagnostic Test: Small fiber electrodiagnostic tests<br>* R-R interval analysis, Cutaneous Silent Period and Sympathetic Skin Response.<br>Diagnostic Test: Nerve Ultrasound<br>* Bilateral vagal, left median, right ulnar, left tibial and right sural nerves ultrasound.<br>Diagnostic Test: Skin Biopsy<br>* distal leg 3mm punch skin biopsy<br>|
| Patients with diabetic mixed small and large fiber neuropathy<br>Diabetic Patients presented with mixed small and large fiber neuropathy | Diagnostic Test: Clinical Evaluation/Questionnaires<br>* Anthropometric measures, somatosensory assessment (NPS, UENS, TCNS), autonomic assessment (COMPASS-31, Ewing battery), and severity and quality of life evaluation (NPS, TCNS, COMPASS-31, and EuroQOL-5D-5L index score)<br>Diagnostic Test: Nerve Conduction Study<br>* Routine Nerve Conduction Study.<br>Diagnostic Test: Small fiber electrodiagnostic tests<br>* R-R interval analysis, Cutaneous Silent Period and Sympathetic Skin Response.<br>Diagnostic Test: Nerve Ultrasound<br>* Bilateral vagal, left median, right ulnar, left tibial and right sural nerves ultrasound.<br>Diagnostic Test: Skin Biopsy<br>* distal leg 3mm punch skin biopsy<br>|
| Subjects without neuropathy<br>Healthy subjects without any symptoms and/or signs suggesting neuropathy, and within average IENFD on skin biopsy. | Diagnostic Test: Clinical Evaluation/Questionnaires<br>* Anthropometric measures, somatosensory assessment (NPS, UENS, TCNS), autonomic assessment (COMPASS-31, Ewing battery), and severity and quality of life evaluation (NPS, TCNS, COMPASS-31, and EuroQOL-5D-5L index score)<br>Diagnostic Test: Nerve Conduction Study<br>* Routine Nerve Conduction Study.<br>Diagnostic Test: Small fiber electrodiagnostic tests<br>* R-R interval analysis, Cutaneous Silent Period and Sympathetic Skin Response.<br>Diagnostic Test: Nerve Ultrasound<br>* Bilateral vagal, left median, right ulnar, left tibial and right sural nerves ultrasound.<br>Diagnostic Test: Skin Biopsy<br>* distal leg 3mm punch skin biopsy<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Demonstrate the findings of UENS in the studied groups | Demonstrate the findings of Utah early neuropathy scale in the studied groups to screen for neuropathic symptoms, where overall scores of 4 and more are considered positive. | through study completion, an average of 9 months | 
| Demonstrate the findings of TCNS in the studied groups | Demonstrate the findings of Toronto clinical neuropathy scale in the studied groups, to screen for the neuropathic symptoms where overall scores of 6 and more are considered positive. | through study completion, an average of 9 months | 
| Demonstrate the findings of EuroQOL-5D-5L in the studied groups | Demonstrate the findings of Euro quality of life -5 dimensions -5 levels scale in the studied groups, where lesser scores suggest a lower overall quality of life. | through study completion, an average of 9 months | 
| Demonstrate the findings of nerve conduction studies protocol of the performed nerves in the studied groups. | Demonstrate the findings of nerve conduction studies (NCS) to define neuropathy in the studied groups, which include: unilateral sensory studies of sural, superficial peroneal and ulnar nerves, and motor studies of tibial, peroneal, and ulnar motor nerves with ulnar and tibial F wave latencies. Nerves were evaluated according to a recommended protocol for NCS postulated by the American Academy of Neurology in conjunction with the American Association of Electrodiagnostic Medicine and the American Academy of Physical Medicine and Rehabilitation, which include an abnormality of any nerve conduction attribute is in two separate nerves, one of which must be the sural nerve. | through study completion, an average of 9 months | 
| Demonstrate the findings of cutaneous silent period in the studied groups. | Demonstrate the findings of cutaneous silent period on stimulating left median nerve and recording from the left abductor pollicis brevis muscle, and on stimulating right sural nerve and recording from the tibialis anterior muscle, where abnormal results in encountered when there is delayed onset and/or end latencies, and/or decreased or absent duration. | through study completion, an average of 9 months | 
| Demonstrate the findings of sympathetic skin response in the studied groups. | Demonstrate the findings of sympathetic skin response on hand-to-hand stimulation of both median nerves, and foot-to-foot stimulation of both tibial nerves, where abnormal result is encountered when there is absent response, or delayed onset latency and/or decreased amplitude. | through study completion, an average of 9 months | 
| Demonstrate the findings of Ewing battery in the studied groups. | Demonstrate the findings of Ewing battery in the studied groups, where findings are recorded in all the 5 domains of the battery as normal or borderline or abnormal. Total score ranges from 0-5, and cardiovascular autonomic neuropathy is diagnosed according to the findings o fthe battery, where the findings are classified as follows Normal: If all tests are normal, or one test is borderline. Early: One heart rate test is abnormal or two are borderline. Definite: At least two heart rate tests are abnormal Severe: At least two heart rate tests are abnormal plus either at least one blood pressure test is abnormal or both tests are borderline. Atypical: Any other undefined combination. Further simplified classification is either normal (including normal or early findings) and abnormal (including definite, severe and atypical findings). | through study completion, an average of 9 months | 
| Demonstrate the findings of nerve ultrasound CSA of both vagal nerves. | Demonstrate the findings of nerve ultrasound cross-sectional area of both vagal nerves scanned opposite to the cricoid cartilage in the studied groups. | through study completion, an average of 9 months | 
| Demonstrate the findings of nerve ultrasound CSA of right sural nerve. | Demonstrate the findings of nerve ultrasound cross-sectional area of right sural nerve at the distal calf in the studied groups. | through study completion, an average of 9 months | 
| Demonstrate the findings of nerve ultrasound CSA of left tibial nerve. | Demonstrate the findings of nerve ultrasound cross-sectional area of left tibial nerve at the distal calf in the studied groups. | through study completion, an average of 9 months | 
| Demonstrate the findings of nerve ultrasound CSA of left median nerve. | Demonstrate the findings of nerve ultrasound cross-sectional area of left median nerve at the mid-forearm in the studied groups. | through study completion, an average of 9 months | 
| Demonstrate the findings of nerve ultrasound CSA of right ulnar nerve. | Demonstrate the findings of nerve ultrasound cross-sectional area of right ulnar nerve at the mid-forearm in the studied groups. | through study completion, an average of 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diabetic neuropathy severity assessment using NPS | Diabetic neuropathy severity assessment using 11-item Numeric Pain Scale overall score. | through study completion, an average of 9 months | 
| Diabetic neuropathy severity assessment TCNS | Diabetic neuropathy severity assessment using Toronto clinical neuropathy scale, overall score. | through study completion, an average of 9 months | 
| Diabetic neuropathy severity assessment using COMPASS-31 | Diabetic neuropathy severity assessment using The Composite Autonomic Symptom Score-31, overall score. | through study completion, an average of 9 months | 
| Diabetic neuropathy quality of life evaluation using Euro quality of life -5 dimensions -5 levels scale. | Diabetic neuropathy quality of life evaluation using EuroQOL-5D-5L index value. | through study completion, an average of 9 months. |