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The Neuroimage Study of the Neuromuscular Disorders.

Sponsor
National Taiwan University Hospital (Other)
Overall Status
Recruiting
CT.gov ID
NCT05048862
Collaborator
(none)
500
Enrollment
1
Location
120
Anticipated Duration (Months)
4.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The neuromuscular disorders could be briefly divided to neuropathy, myopathy, motor neuron disease, and neuromuscular junction disorder. In the past, the evaluation of the neuromuscular disorders depended on several ways (ex. electrodiagnostic studies and biopsy) to evaluate the pathophysiology and the pathological change. However, due to the issue of resolution, few image studies were available to evaluate the structure for clinical practice. With the growing techniques, there are two ways to see the nerve and muscle in vivo, the magnetic resonance imaging (MRI) and the ultrasonography. The availability of the machine, the high cost, inability to change the position for dynamic views of the nerves, and the relative invasion considering the large energy penetrating the patient might limit the clinical use of MRI. The nerve ultrasonography is a safe and easily available technique. The development of high-frequency transducers has led to an improvement in the resolution of ultrasonography and enables the exploration of peripheral nerve and muscle structural changes. In additional to evaluate the morphological changes, ultrasonography has been used extensively for the vessel status assessment through duplex ultrasound. In present study, we will apply variable approaches, including to muscle, nerve, and skin biopsy, electrophysiological study, quantitative sensory testing, autonomic functional tests, pain evoked potentials, MRI, and ultrasonography to integrally investigate the different aspects of neuromuscular disorders. The results of the study will provide integrated insights of (1) the neurophysiology of nerve and vessels and (2) pathogenesis of different neuromuscular disorders.

Condition or Disease Intervention/Treatment Phase
  • Diagnostic Test: Neuromuscular ultrasound
  • Diagnostic Test: Muscle MRI
  • Diagnostic Test: Nerve conduction studies and autonomic function tests
  • Diagnostic Test: Quantitative sensory test
  • Diagnostic Test: Skin biopsy
  • Diagnostic Test: Muscle and nerve biopsy
  • Diagnostic Test: Genomics, transcriptome, and proteomics
  • Diagnostic Test: Laboratory of blood chemical substances, metals and endocrine profiles
  • Diagnostic Test: Contact heat evoked potentials
  • Diagnostic Test: Nerve excitability study
  • Diagnostic Test: Transcranial magnetic stimulation (TMS)
  • Diagnostic Test: fMRI acquisition and image analysis

Detailed Description

This is a prospective observational study which will be performed in both the inpatient and outpatient setting of National Taiwan University Hospital. Patients age at least 20 years, and have been diagnosed as neuromuscular disorders by the neurologist. Patients who are unable to read the questionnaire, fail to accept all the examinations, and refuse to provide inform consent are excluded from this study. The normal group (age at least 20 years) who had no neurological symptoms or signs were also recruited. The neurological examination performed by the board neurologist must be normal in the normal group.

Different interventions were performed periodically to see the serial change. The interval between the interventions is within 1 month and there is no new symptoms or any events.

Study Design

Study Type:
Observational [Patient Registry]
Anticipated Enrollment :
500 participants
Observational Model:
Cohort
Time Perspective:
Prospective
Official Title:
The Neuroimage Study of the Neuromuscular Disorders.
Actual Study Start Date :
Aug 1, 2021
Anticipated Primary Completion Date :
Aug 1, 2031
Anticipated Study Completion Date :
Aug 1, 2031

Arms and Interventions

Arm Intervention/Treatment
Neuromuscular disorder

Patients age at least 20 years, and have been diagnosed as neuromuscular disorders by the neurologist. Patients who are unable to read the questionnaire, fail to accept all the examinations, and refuse to provide inform consent are excluded from this study.

Diagnostic Test: Neuromuscular ultrasound
Ultrasound will be performed with the Affiniti 70 (Philips Medical Instruments, Bothell, WA). all patients following standardized methods of our hospital. All the patient would be checked the skin surface temperature before the ultrasound examination. The image would be exported from the echo machine as DICOM format.
Other Names:
  • Sonography

    • Diagnostic Test: Muscle MRI
    Muscle MRI will be performed on a 3-T MR machine (Trio; Siemens, Erlangen, Germany). Each subject will lie in a supine position comfortably, supplied with ear plugs. A high resolution T1 weighted scan and Short-T1 Inversion Recovery series (STIR) of the four limbs muscle were obtained in axial and coronal plane. MR spectroscopy in interested muscle was also sampled to evaluate the composition of fat, water, lactate, and other studied molecules.

    Diagnostic Test: Nerve conduction studies and autonomic function tests
    Nerve conduction study will be performed with a Nicolet Viking IV Electromyographer (Madison, WI) in all patients following standardized methods recommended by the Consensus Development Conference on Standardized Measures in Diabetic Neuropathy. Studied nerves include sural, peroneal, tibial, median and ulnar (motor and sensory) nerves.Autonomic functions will be assessed by the SSR and RRIV with established protocol by using Nicolet Viking IV Electromyographer (Madison, WI).

    Diagnostic Test: Quantitative sensory test
    Quantative sensory test will be performed with a Thermal Sensory Analyzer and Vibratory Sensory Analyzer (Medoc Advanced Medical System, Minneapolis, MN). The procedure is the same as previously described 25. Briefly, the machine delivers to the patient a stimulus of constant intensity which is pre-set by the algorithm. By adjusting the intensity of stimulus (increase or decrease the intensity by a fixed ratio) according to the response of the subject (i.e. whether the subject perceives the stimulus or not), sensory thresholds of the warm, cold and vibratory modalities will be measured.

    Diagnostic Test: Skin biopsy
    A skin specimen of 3 mm in diameter will be taken with a biopsy punch from the lateral side of the distal leg under 2% lidocaine local anaesthesia 26. No suturing is required, and the wounds are covered with a piece of gauze. Wound healing takes 7~10 days, similar to a typical abrasion wound. Informed consent will be obtained from each patient before the skin biopsy. The intraepidermal nerve fiber density and sweat gland nerve innervation will be examined.

    Diagnostic Test: Muscle and nerve biopsy
    Two muscle specimens with 5 x 5 x 5 mm were collected in an open muscle biopsy or needle biopsy at studied muscles under 2% lidocaine local anaesthesia. The wound was about 2-3 cm long, and suture was required. Would healing usually takes 10-14 days. First specimen was undergoing snap freezing fixation in a longitudinal axis perpendicular to the cork with the liquid nitrogen and isopentane. The second specimen was divided into two equiponderous tissues, and one was freezed in liquid nitrogen for DNA and protein analysis. The another one was treated with RNAlater solution in 4°C overnight for RNA analysis. Sural nerve biopsies or superficial peroneal nerve were obtained from a standard site posterior to the lateral malleolus under local anesthesia. The nerves were then fixed in 5% glutaraldehyde in 0.1 M phosphate buffer (PB) at 4 °C overnight. All samples were stored in the -80°C refrigerator for further analysis.

    Diagnostic Test: Genomics, transcriptome, and proteomics
    The DNA, RNA, and protein of the tissues (blood, muscle, nerve and skin) were retrieved and stored in the -80°C refrigerator. The next generation sequencing (whole exon sequencing or whole genome sequencing) and RNA-seq would be performed by NGS & Microarray Core lab in National Taiwan University or another professional team. The protein analysis would be performed by the Proteomics & Protein Function Core Lab in National Taiwan University.

    Diagnostic Test: Laboratory of blood chemical substances, metals and endocrine profiles
    The methods of the measurement will follow the standards set by Department of Laboratory Medicine of National Taiwan University Hospital.

    Diagnostic Test: Contact heat evoked potentials
    A contact heat evoked potential stimulator (Medoc, Ramat Yishai, Israel) will be used for delivering heat stimulation. Stimuli will be delivered repeatedly to the same stimulation site and the inter-stimulus interval will be randomly set to around 18~22 s. CHEP will be recorded using a Nicolet Bravo evoked potential system (Nicolet Biomedical, Madison, WI). The recording electrode was placed at the Cz and P3 of international 10-20 system. The impendence of all recording electrodes was kept below 3 kΩ. The evoked potentials were filtered with a bandpass filter at 0.1~30 Hz. Recording was triggered by the onset of each stimulus, and the sweep time was 1500 ms.

    Diagnostic Test: Nerve excitability study
    Nerve excitability studies will be undertaken on the median, tibial, peroneal and sural nerves as per previously detailed protocols. Skin temperature will be monitored at the site of stimulation and was maintained at >32°C. Stimulation and recording will be controlled by automated computerized system (QTRAC; Institute of Neurology, London, U.K.) and the stimulus current will be administered using an isolated linear bipolar constant-current stimulator (DS5; Digitimer, Welwyn Garden City, U.K.). Responses will be amplified (ICP511 AC amplifier, Grass Technologies, West Warwick, USA) with electronic noise removed (Hum Bug 50/60 Hz Noise Eliminator, Quest Scientific Instruments, North Vancouver, Canada).

    Diagnostic Test: Transcranial magnetic stimulation (TMS)
    In simple rTMS protocols, individual stimuli are spaced apart by identical interstimulus intervals (ISI). The stimulation protocol was in accordance with published safety recommendations. The patterned rTMS protocols included (1) Theta burst stimulation, (2) Repetitive paired-pulse TMS. All the above stimulation protocols or paradigms will follow the international guideline of the use of TMS in clinical practice and research (Rossi et al., 2009; Fitzgerald and Daskalakis, 2012; Groppa et al., 2012; Steeves et al., 2012).

    Diagnostic Test: fMRI acquisition and image analysis
    fMRI will be performed on a 3-T MR machine (Trio; Siemens, Erlangen, Germany). Each subject's head will be positioned comfortably inside a receive-only 8-channel birdcage head coil, supplied with ear plugs, heavily padded and secured with a strap across the forehead in order to minimize head motion. All data will be processed using SPM2 (Wellcome Department of Cognitive Neurology, London UK) 36 implemented on MATLAB (Mathworks Inc. Sherborn, MA).
    Normal group

    The normal group (age at least 20 years) who had no neurological symptoms or signs were also recruited. The neurological examination performed by the board neurologist must be normal in the normal group.

    Diagnostic Test: Neuromuscular ultrasound
    Ultrasound will be performed with the Affiniti 70 (Philips Medical Instruments, Bothell, WA). all patients following standardized methods of our hospital. All the patient would be checked the skin surface temperature before the ultrasound examination. The image would be exported from the echo machine as DICOM format.
    Other Names:
  • Sonography

    • Diagnostic Test: Muscle MRI
    Muscle MRI will be performed on a 3-T MR machine (Trio; Siemens, Erlangen, Germany). Each subject will lie in a supine position comfortably, supplied with ear plugs. A high resolution T1 weighted scan and Short-T1 Inversion Recovery series (STIR) of the four limbs muscle were obtained in axial and coronal plane. MR spectroscopy in interested muscle was also sampled to evaluate the composition of fat, water, lactate, and other studied molecules.

    Diagnostic Test: Nerve conduction studies and autonomic function tests
    Nerve conduction study will be performed with a Nicolet Viking IV Electromyographer (Madison, WI) in all patients following standardized methods recommended by the Consensus Development Conference on Standardized Measures in Diabetic Neuropathy. Studied nerves include sural, peroneal, tibial, median and ulnar (motor and sensory) nerves.Autonomic functions will be assessed by the SSR and RRIV with established protocol by using Nicolet Viking IV Electromyographer (Madison, WI).

    Diagnostic Test: Quantitative sensory test
    Quantative sensory test will be performed with a Thermal Sensory Analyzer and Vibratory Sensory Analyzer (Medoc Advanced Medical System, Minneapolis, MN). The procedure is the same as previously described 25. Briefly, the machine delivers to the patient a stimulus of constant intensity which is pre-set by the algorithm. By adjusting the intensity of stimulus (increase or decrease the intensity by a fixed ratio) according to the response of the subject (i.e. whether the subject perceives the stimulus or not), sensory thresholds of the warm, cold and vibratory modalities will be measured.

    Diagnostic Test: Genomics, transcriptome, and proteomics
    The DNA, RNA, and protein of the tissues (blood, muscle, nerve and skin) were retrieved and stored in the -80°C refrigerator. The next generation sequencing (whole exon sequencing or whole genome sequencing) and RNA-seq would be performed by NGS & Microarray Core lab in National Taiwan University or another professional team. The protein analysis would be performed by the Proteomics & Protein Function Core Lab in National Taiwan University.

    Diagnostic Test: Laboratory of blood chemical substances, metals and endocrine profiles
    The methods of the measurement will follow the standards set by Department of Laboratory Medicine of National Taiwan University Hospital.

    Diagnostic Test: Contact heat evoked potentials
    A contact heat evoked potential stimulator (Medoc, Ramat Yishai, Israel) will be used for delivering heat stimulation. Stimuli will be delivered repeatedly to the same stimulation site and the inter-stimulus interval will be randomly set to around 18~22 s. CHEP will be recorded using a Nicolet Bravo evoked potential system (Nicolet Biomedical, Madison, WI). The recording electrode was placed at the Cz and P3 of international 10-20 system. The impendence of all recording electrodes was kept below 3 kΩ. The evoked potentials were filtered with a bandpass filter at 0.1~30 Hz. Recording was triggered by the onset of each stimulus, and the sweep time was 1500 ms.

    Diagnostic Test: Nerve excitability study
    Nerve excitability studies will be undertaken on the median, tibial, peroneal and sural nerves as per previously detailed protocols. Skin temperature will be monitored at the site of stimulation and was maintained at >32°C. Stimulation and recording will be controlled by automated computerized system (QTRAC; Institute of Neurology, London, U.K.) and the stimulus current will be administered using an isolated linear bipolar constant-current stimulator (DS5; Digitimer, Welwyn Garden City, U.K.). Responses will be amplified (ICP511 AC amplifier, Grass Technologies, West Warwick, USA) with electronic noise removed (Hum Bug 50/60 Hz Noise Eliminator, Quest Scientific Instruments, North Vancouver, Canada).

    Diagnostic Test: Transcranial magnetic stimulation (TMS)
    In simple rTMS protocols, individual stimuli are spaced apart by identical interstimulus intervals (ISI). The stimulation protocol was in accordance with published safety recommendations. The patterned rTMS protocols included (1) Theta burst stimulation, (2) Repetitive paired-pulse TMS. All the above stimulation protocols or paradigms will follow the international guideline of the use of TMS in clinical practice and research (Rossi et al., 2009; Fitzgerald and Daskalakis, 2012; Groppa et al., 2012; Steeves et al., 2012).

    Diagnostic Test: fMRI acquisition and image analysis
    fMRI will be performed on a 3-T MR machine (Trio; Siemens, Erlangen, Germany). Each subject's head will be positioned comfortably inside a receive-only 8-channel birdcage head coil, supplied with ear plugs, heavily padded and secured with a strap across the forehead in order to minimize head motion. All data will be processed using SPM2 (Wellcome Department of Cognitive Neurology, London UK) 36 implemented on MATLAB (Mathworks Inc. Sherborn, MA).

    Outcome Measures

    Primary Outcome Measures

    1. Lean muscle volume and fat fraction in MRI [up to 10 years]

      Change from Baseline to serial follow-up MRI with the interval of 2 years.

    2. Muscle thickness and echogenecity in ultrasound [up to 10 years]

      Change from Baseline to serial follow-up ultrasound with the interval of 2 years.

    Secondary Outcome Measures

    1. Natural History [up to 10 years]

      To delineate the natural history of different neuromuscular disorders.

    2. Separate disease functional score [up to 10 years]

      Separate disease functional scores were: (1) Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) in ALS. The values are 0-48. A lower score indicates a worse outcome. (2) Neuropathy Impairment Score (NIS) and Nerve Disability Score (NDS) in polyneuropathy. The values are 0-244 in NIS and 0-172 in NDS. A higher score indicates a worse outcome in both scores. (3) Medical Research Council Sum-Score (MRC-SS) in myopathy. The values are 0-60. A lower score indicates a worse outcome. (4) MG Activities of Daily Living (MG-ADL) and the Quantitative Myasthenia Gravis (QMG) Test in myasthenia gravis. The values are 0-24 in MG-ADL and 0-72 in QMG. A higher score indicates a worse outcome in both scores.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    20 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    Inclusion Criteria (Neuromuscular group):

    • been diagnosed as neuromuscular disorders by the neurologist

    • at least 20-year-old

    Inclusion Criteria (Normal group):

    • no past history of neurological disorders.

    • The neurological examination performed by the board neurologist must be normal

    • at least 20-year-old

    Exclusion Criteria (Neuromuscular and normal group):
    • Patients who are unable to read the questionnaire, fail to accept all the examinations, and refuse to provide inform consent

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 National Taiwan Univeristy Hospital Taipei Taiwan 100

    Sponsors and Collaborators

    • National Taiwan University Hospital

    Investigators

    • Principal Investigator: Hsueh-Wen Hsueh, MD, MMS, National Taiwan University Hospital

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    National Taiwan University Hospital
    ClinicalTrials.gov Identifier:
    NCT05048862
    Other Study ID Numbers:
    • 201705058RIND
    First Posted:
    Sep 17, 2021
    Last Update Posted:
    Sep 17, 2021
    Last Verified:
    Jul 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Undecided
    Plan to Share IPD:
    Undecided
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by National Taiwan University Hospital
    neuromuscular disorder
    neuromuscular ultrasonography
    skin biopsy
    muscle biopsy
    nerve biopsy
    magnetic resonance imaging
    electrophysiological study
    Additional relevant MeSH terms:
    Neuromuscular Diseases

    Study Results

    No Results Posted as of Sep 17, 2021