Diabetic Small Fiber Neuropathy: Clinical, Electrophysiological and Neurosonographic Study

Diabetic Neuropathies Clinical Trial

Official title:

Diabetic Small Fiber Neuropathy: Clinical, Electrophysiological and Neurosonographic Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05993871
• Other study ID #: 34059/8/20
• Status: Completed
• Start date: January 1, 2023
• Est. completion date: January 22, 2024

Study information

• Verified date: April 2024
• Source: Tanta University
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 45
• Est. completion date: January 22, 2024
• Est. primary completion date: June 30, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. 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.

2. 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.

3. Age older than 18 years old

Exclusion Criteria:

1. Mental illness that made interviewing ineffective

2. Physical illness leading to language and/or cognitive barrier

3. 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).

4. Atrial Fibrillation

Related Conditions & MeSH terms

• Autonomic Neuropathy
• Diabetic Neuropathies
• Diabetic Peripheral Neuropathy
• Diabetic Polyneuropathy
• Painful Diabetic Neuropathy
• Peripheral Nervous System Diseases
• Polyneuropathies
• Small Fiber Neuropathy

Intervention

Diagnostic Test:
• Clinical Evaluation/Questionnaires
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)
• Nerve Conduction Study
Routine Nerve Conduction Study.
• Small fiber electrodiagnostic tests
R-R interval analysis, Cutaneous Silent Period and Sympathetic Skin Response.
• Nerve Ultrasound
Bilateral vagal, left median, right ulnar, left tibial and right sural nerves ultrasound.
• Skin Biopsy
distal leg 3mm punch skin biopsy

Locations

Country	Name	City	State
Egypt	Ahmed Sami Mahmoud Alkotami	Kafr Ash Shaykh

Sponsors (1)

Lead Sponsor	Collaborator
Tanta University

Country where clinical trial is conducted

Egypt, 

References & Publications (16)

Al Shabasy S, Abbassi M, Finch A, Roudijk B, Baines D, Farid S. The EQ-5D-5L Valuation Study in Egypt. Pharmacoeconomics. 2022 Apr;40(4):433-447. doi: 10.1007/s40273-021-01100-y. Epub 2021 Nov 17. — View Citation

Bekairy AM, Bustami RT, Almotairi M, Jarab A, Katheri AM, Aldebasi TM, Aburuz S. Validity and reliability of the Arabic version of the the EuroQOL (EQ-5D). A study from Saudi Arabia. Int J Health Sci (Qassim). 2018 Mar-Apr;12(2):16-20. — View Citation

Bril V, Perkins BA. Validation of the Toronto Clinical Scoring System for diabetic polyneuropathy. Diabetes Care. 2002 Nov;25(11):2048-52. doi: 10.2337/diacare.25.11.2048. — View Citation

Devigili G, Tugnoli V, Penza P, Camozzi F, Lombardi R, Melli G, Broglio L, Granieri E, Lauria G. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain. 2008 Jul;131(Pt 7):1912-25. doi: 10.1093/brain/awn093. Epub 2008 Jun 4. — View Citation

Ebadi H, Siddiqui H, Ebadi S, Ngo M, Breiner A, Bril V. Peripheral Nerve Ultrasound in Small Fiber Polyneuropathy. Ultrasound Med Biol. 2015 Nov;41(11):2820-6. doi: 10.1016/j.ultrasmedbio.2015.06.011. Epub 2015 Aug 28. — View Citation

Eldokla AM, Mohamed-Hussein AA, Fouad AM, Abdelnaser MG, Ali ST, Makhlouf NA, Sayed IG, Makhlouf HA, Shah J, Aiash H. Prevalence and patterns of symptoms of dysautonomia in patients with long-COVID syndrome: A cross-sectional study. Ann Clin Transl Neurol. 2022 Jun;9(6):778-785. doi: 10.1002/acn3.51557. Epub 2022 Apr 8. — View Citation

Ewing DJ, Martyn CN, Young RJ, Clarke BF. The value of cardiovascular autonomic function tests: 10 years experience in diabetes. Diabetes Care. 1985 Sep-Oct;8(5):491-8. doi: 10.2337/diacare.8.5.491. — View Citation

Lauria G, Hsieh ST, Johansson O, Kennedy WR, Leger JM, Mellgren SI, Nolano M, Merkies IS, Polydefkis M, Smith AG, Sommer C, Valls-Sole J; European Federation of Neurological Societies; Peripheral Nerve Society. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur J Neurol. 2010 Jul;17(7):903-12, e44-9. doi: 10.1111/j.1468-1331.2010.03023.x. — View Citation

Singleton JR, Bixby B, Russell JW, Feldman EL, Peltier A, Goldstein J, Howard J, Smith AG. The Utah Early Neuropathy Scale: a sensitive clinical scale for early sensory predominant neuropathy. J Peripher Nerv Syst. 2008 Sep;13(3):218-27. doi: 10.1111/j.1529-8027.2008.00180.x. — View Citation

Sletten DM, Suarez GA, Low PA, Mandrekar J, Singer W. COMPASS 31: a refined and abbreviated Composite Autonomic Symptom Score. Mayo Clin Proc. 2012 Dec;87(12):1196-201. doi: 10.1016/j.mayocp.2012.10.013. — View Citation

Tankisi H, Pugdahl K, Beniczky S, Andersen H, Fuglsang-Frederiksen A. Evidence-based recommendations for examination and diagnostic strategies of polyneuropathy electrodiagnosis. Clin Neurophysiol Pract. 2019 Nov 18;4:214-222. doi: 10.1016/j.cnp.2019.10.005. eCollection 2019. — View Citation

Tawfik EA, Walker FO, Cartwright MS, El-Hilaly RA. Diagnostic Ultrasound of the Vagus Nerve in Patients with Diabetes. J Neuroimaging. 2017 Nov;27(6):589-593. doi: 10.1111/jon.12452. Epub 2017 May 19. — View Citation

Telleman JA, Herraets IJ, Goedee HS, van Asseldonk JT, Visser LH. Ultrasound scanning in the diagnosis of peripheral neuropathies. Pract Neurol. 2021 Jun;21(3):186-195. doi: 10.1136/practneurol-2020-002645. Epub 2021 Feb 4. — View Citation

Terkawi AS, Abolkhair A, Didier B, Alzhahrani T, Alsohaibani M, Terkawi YS, Almoqbali Y, Tolba YY, Pangililan E, Foula F, Tsang S. Development and validation of Arabic version of the douleur neuropathique 4 questionnaire. Saudi J Anaesth. 2017 May;11(Suppl 1):S31-S39. doi: 10.4103/sja.SJA_97_17. — View Citation

Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, Lauria G, Malik RA, Spallone V, Vinik A, Bernardi L, Valensi P; Toronto Diabetic Neuropathy Expert Group. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010 Oct;33(10):2285-93. doi: 10.2337/dc10-1303. Erratum In: Diabetes Care. 2010 Dec;33(12):2725. — View Citation

Vetrugno R, Liguori R, Cortelli P, Montagna P. Sympathetic skin response: basic mechanisms and clinical applications. Clin Auton Res. 2003 Aug;13(4):256-70. doi: 10.1007/s10286-003-0107-5. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	Diabetic neuropathy severity assessment TCNS	Diabetic neuropathy severity assessment using Toronto clinical neuropathy scale, overall score.	through study completion, an average of 9 months
Secondary	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
Secondary	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.