The Neuroimage Study of the Neuromuscular Disorders.

Overview

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.

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.

Interventions

• 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.
• 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 stim
• 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
• 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 belo
• 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.).

Primary outcome measures

• Lean muscle volume and fat fraction in MRI [Time frame: up to 10 years]
• Muscle thickness and echogenecity in ultrasound [Time frame: up to 10 years]

Secondary outcome measures (2)

• Natural History [Time frame: up to 10 years]
• Separate disease functional score [Time frame: up to 10 years]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Observational model

Cohort

Study locations

Taiwan · 1 center

• National Taiwan Univeristy Hospital — Taipei

Publications

• Garg N, Park SB, Vucic S, Yiannikas C, Spies J, Howells J, Huynh W, Matamala JM, Krishnan AV, Pollard JD, Cornblath DR, Reilly MM, Kiernan MC. Differentiating lower motor neuron syndromes. J Neurol Neurosurg Psychiatry. 2017 Jun;88(6):474-483. doi: 10.1136/jnnp-2016-313526. Epub 2016 Dec 21. PMID 28003344
• Pham M, Baumer P, Meinck HM, Schiefer J, Weiler M, Bendszus M, Kele H. Anterior interosseous nerve syndrome: fascicular motor lesions of median nerve trunk. Neurology. 2014 Feb 18;82(7):598-606. doi: 10.1212/WNL.0000000000000128. Epub 2014 Jan 10. PMID 24415574
• Stewart JD. Magnificent MRI and fascinating selective nerve fascicle damage. Neurology. 2014 Feb 18;82(7):554-5. doi: 10.1212/WNL.0000000000000132. Epub 2014 Jan 10. No abstract available. PMID 24415569
• Baumer P, Kele H, Xia A, Weiler M, Schwarz D, Bendszus M, Pham M. Posterior interosseous neuropathy: Supinator syndrome vs fascicular radial neuropathy. Neurology. 2016 Nov 1;87(18):1884-1891. doi: 10.1212/WNL.0000000000003287. Epub 2016 Sep 28. PMID 27683851
• Yoo Y, Kim SJ, Oh J. Postpartum sciatic neuropathy: Segmental fractional anisotropy analysis to disclose neurapraxia. Neurology. 2016 Aug 30;87(9):954-5. doi: 10.1212/WNL.0000000000003051. No abstract available. PMID 27572428
• Diaz-Manera J, Llauger J, Gallardo E, Illa I. Muscle MRI in muscular dystrophies. Acta Myol. 2015 Dec;34(2-3):95-108. PMID 27199536
• Huang YN, Chuang HJ, Hsueh HW, Huang HC, Lee NC, Chao CC, Huang PH, Lee YC, Lin KP, Yang CC, Hsieh ST. A case of GNE myopathy mimicking hereditary motor neuropathy. Eur J Neurol. 2020 Nov;27(11):2389-2391. doi: 10.1111/ene.14489. PMID 32860282
• Buchberger W, Judmaier W, Birbamer G, Lener M, Schmidauer C. Carpal tunnel syndrome: diagnosis with high-resolution sonography. AJR Am J Roentgenol. 1992 Oct;159(4):793-8. doi: 10.2214/ajr.159.4.1529845. PMID 1529845

Identifiers

NCT: NCT05048862 · 201705058RIND

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗