Definition of Autonomic Nervous System Involvement in Patients With Multiple Sclerosis

Definition of Autonomic Nervous System Involvement in Patients With Relapsing-remitting and Primary Progressive Multiple Sclerosis

The goal of this interventional non-pharmacological study is to evaluate the involvement of the autonomic nervous system in patients with relapsing-remitting and primary progressive multiple sclerosis.

The main questions it aims to answer are:

• Is it possible to define the characteristics of dysautonomia to improve treatment on patients with multiple sclerosis through the management of conditions such as orthostatic hypotension or thermoregulation disorders that inevitably condition the patient's life and the response to rehabilitation ?
• Does the severity of the functional alterations correlate with impairment of small somatic and autonomic cutaneous nerve fibers in patients with multiple sclerosis ?
• How much the involvement of the autonomic nervous system affects the clinical history and progression of the disease ?
• Do different clinical variants of multiple sclerosis manifest with different patterns of involvement of the sensory-autonomic nervous system ?

Participants will be hospitalized in Maugeri Clinical Institute of Telese Terme for a rehabilitation treatment. Patients will perform a sensory and autonomic functional study and a morphological analysis of cutaneous nerves through skin biopsy.

Researchers will compare results between the two groups (relapsing-remitting and primary progressive) and between patients and data from control subjects.

Study Overview

• Status: Recruiting
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Diagnostic test: quantification of sensory and autonomic small nerve fibers by punch skin biopsy; Diagnostic test: Cardiovascular Reflexes testing; Other: Administration of clinical scales evaluating autonomic symptoms, pain small fiber neuropathy symptoms

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Giuseppe Caporaso; Phone Number: +390824909645; Email: giuseppe.caporaso@icsmaugeri.it
• Study Contact Backup: Name: Vincenzo Provitera, MD; Phone Number: +390824909257; Email: vincenzo.provitera@icsmaugeri.it

Study Locations

• Italy
  • Naples, Italy, 80131
    • Recruiting
    • Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples Federico II
    • Contact: Fiore Manganelli, MD; Phone Number: +0817462666; Email: fiore.manganelli@unina.it
    • Contact: Rosa Iodice, MD; Phone Number: +39081746266; Email: rosa.iodice@unina.it
  • Benevento
    • Telese Terme, Benevento, Italy, 82037
      • Recruiting
      • ICS Maugeri - IRCCS of Telese Terme
      • Contact: Vincenzo Provitera, MD; Phone Number: +390824909257; Email: vincenzo.provitera@icsmaugeri.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• diagnosis of relapsing-remitting and primary progressive multiple sclerosis.

Exclusion Criteria:

• other forms of multiple sclerosis,
• known other neurological disorders
• assumption of potentially neurotoxic substances or drugs.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: relapsing-remitting multiple sclerosis; Patients with relapsing-remitting multiple sclerosis will be hospitalized in Maugeri Clinical Institute of Telese Terme for a rehabilitation treatment and will perform a functional and morphological study of sensory and autonomic nervous system, evaluation of peripheral sensory and autonomic nerve fibers performed by skin biopsy.	Diagnostic test: quantification of sensory and autonomic small nerve fibers by punch skin biopsy; We'll perform a punch skin biopsy of 3mm from thigh, leg and fingertip and we'll quantify peripheral sensory and autonomic nerve fibers.; Diagnostic test: Cardiovascular Reflexes testing; Cardiovascular reflex tests including deep breathing, head-up Tilt, standing, isometric exercises, mental arithmetic and Valsalva maneuver.; Other: Administration of clinical scales evaluating autonomic symptoms, pain small fiber neuropathy symptoms; We'll characterize patients' symptoms through the administration of clinical scales such as: COMPASS 31 autonomic symptoms scale; Small Fiber Neuropathy Symptom Inventory Questionnaire (SFN-SIQ), the Pain Detect Questionnaire and the Total neuropathy score
Active Comparator: primary progressive multiple sclerosis; Patients with primary progressive multiple sclerosis will be hospitalized in Maugeri Clinical Institute of Telese Terme for a rehabilitation treatment and will perform a functional and morphological study of sensory and autonomic nervous system, evaluation of peripheral sensory and autonomic nerve fibers performed by skin biopsy.	Diagnostic test: quantification of sensory and autonomic small nerve fibers by punch skin biopsy; We'll perform a punch skin biopsy of 3mm from thigh, leg and fingertip and we'll quantify peripheral sensory and autonomic nerve fibers.; Diagnostic test: Cardiovascular Reflexes testing; Cardiovascular reflex tests including deep breathing, head-up Tilt, standing, isometric exercises, mental arithmetic and Valsalva maneuver.; Other: Administration of clinical scales evaluating autonomic symptoms, pain small fiber neuropathy symptoms; We'll characterize patients' symptoms through the administration of clinical scales such as: COMPASS 31 autonomic symptoms scale; Small Fiber Neuropathy Symptom Inventory Questionnaire (SFN-SIQ), the Pain Detect Questionnaire and the Total neuropathy score

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiovascular reflex test	Assessment of Cardiovascular reflex responses to physical challenges.	At the recruitment
Sudomotor function test	Assessment of postganglionic sudomotor function through dynamic sweat test	At the recruitment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantification of peripheral autonomic nerve fibers	Quantification of sweat gland innervation (fiber length /um3) and arrector pili muscle (ff/mm).	At the recruitment
Quantification of peripheral sensory nerve fibers	Quantification of sensory nerve fibers (Intraepidermal nerve fibers (ff/mm)).	At the recruitment

Collaborators and Investigators

• Sponsor: Istituti Clinici Scientifici Maugeri SpA
• Investigators: Principal Investigator: Vincenzo Provitera, MD, ICS MAUGERI - IRCCS TELESE TERME

Publications and helpful links

General Publications

• Brooks BR, Miller RG, Swash M, Munsat TL; World Federation of Neurology Research Group on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000 Dec;1(5):293-9. doi: 10.1080/146608200300079536. No abstract available.
• Mahoney CJ, Ahmed RM, Huynh W, Tu S, Rohrer JD, Bedlack RS, Hardiman O, Kiernan MC. Pathophysiology and Treatment of Non-motor Dysfunction in Amyotrophic Lateral Sclerosis. CNS Drugs. 2021 May;35(5):483-505. doi: 10.1007/s40263-021-00820-1. Epub 2021 May 15.
• Gentile F, Scarlino S, Falzone YM, Lunetta C, Tremolizzo L, Quattrini A, Riva N. The Peripheral Nervous System in Amyotrophic Lateral Sclerosis: Opportunities for Translational Research. Front Neurosci. 2019 Jun 25;13:601. doi: 10.3389/fnins.2019.00601. eCollection 2019.
• Weis J, Katona I, Muller-Newen G, Sommer C, Necula G, Hendrich C, Ludolph AC, Sperfeld AD. Small-fiber neuropathy in patients with ALS. Neurology. 2011 Jun 7;76(23):2024-9. doi: 10.1212/WNL.0b013e31821e553a.
• Truini A, Biasiotta A, Onesti E, Di Stefano G, Ceccanti M, La Cesa S, Pepe A, Giordano C, Cruccu G, Inghilleri M. Small-fibre neuropathy related to bulbar and spinal-onset in patients with ALS. J Neurol. 2015;262(4):1014-8. doi: 10.1007/s00415-015-7672-0. Epub 2015 Feb 17.
• Nolano M, Provitera V, Manganelli F, Iodice R, Caporaso G, Stancanelli A, Marinou K, Lanzillo B, Santoro L, Mora G. Non-motor involvement in amyotrophic lateral sclerosis: new insight from nerve and vessel analysis in skin biopsy. Neuropathol Appl Neurobiol. 2017 Feb;43(2):119-132. doi: 10.1111/nan.12332. Epub 2016 Jul 7.
• deCarvalho M, Gromicho M, Andersen P, Grosskreutz J, Kuzma-Kozakiewicz M, Petri S, Uysal H, Pinto S. Peripheral neuropathy in ALS: phenotype association. J Neurol Neurosurg Psychiatry. 2021 Oct;92(10):1133-1134. doi: 10.1136/jnnp-2020-325164. Epub 2020 Dec 28. No abstract available.
• Chio A, Mora G, Lauria G. Pain in amyotrophic lateral sclerosis. Lancet Neurol. 2017 Feb;16(2):144-157. doi: 10.1016/S1474-4422(16)30358-1. Epub 2016 Dec 8.

Study record dates

Study Major Dates

• Study Start (Actual): March 4, 2021
• Primary Completion (Estimated): November 30, 2026
• Study Completion (Estimated): May 30, 2027

Study Registration Dates

• First Submitted: January 26, 2023
• First Submitted That Met QC Criteria: February 17, 2023
• First Posted (Actual): February 28, 2023

Study Record Updates

• Last Update Posted (Actual): April 17, 2026
• Last Update Submitted That Met QC Criteria: April 14, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: rehabilitation; autonomic nervous system; skin biopsy; sensory nervous system
• Additional Relevant MeSH Terms: Nervous System Diseases; Autoimmune Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Multiple Sclerosis
• Other Study ID Numbers: SBLAB/SM20

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No