Magnetic Resonance Diagnostics of Diabetic Peripheral Neuropathy
Condition: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Polyneuropathy; Hereditary Axonal Neuropathy; Hereditary Demyelinated Neuropathy; Polyneuropathy, Inflammatory Demyelinating, Chronic
MeSH terms: Peripheral Nervous System Diseases; Polyneuropathies; Diabetic Neuropathies; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 1
Study type: Observational

Summary: 
      This project aims to develop high field MR techniques to detect nerve lesions in diabetic
      patients. The MRI findings will be compared to results from conventional evaluations and
      nerve conduction studies to determine the validity as part of a clinical practice.
    

Detailed description: 
      Background

      Diabetes mellitus is a very frequent disorder with an estimated prevalence of 275,000
      patients in Denmark. Diabetic peripheral neuropathy (DPN) is a late complication which often
      remains undiagnosed, but may occur in up to 40% of diabetic patients. Advanced neuropathy may
      induce irreversible damages to the nervous tissue, and to avoid further damages, early
      diagnosis is important followed by optimal treatment of diabetes. DPN is a common
      complication due to long term diabetes in both type 1 and type 2.

      Nerve conduction studies (NCS) is the gold standard method to diagnose DPN. However, the
      technique is time consuming and introduces discomfort to the patient and, furthermore, early
      nerve dysfunction may not be detected by NCS. Magnetic resonance imaging (MRI) (3 Tesla) of
      peripheral nerves is a new technique entitled Magnetic resonance neurography (MRN). In recent
      studies MRN has documented morphological changes in individual nerve fascicles. In
      T2-weighted images hyperintensity is present in proximal parts of nerves from neuropathic
      patients as compared to healthy nerves. This hyperintensity is believed to reflect early and
      more widespread lesions to the nerve fascicles that are not detected by NCS. This is pointing
      towards MRN to become an important tool in the management of patient with peripheral
      neuropathies.

      Recent technical development such as diffusion weighted imaging (DWI) and diffusion tensor
      imaging (DTI) are currently being evaluated for imaging of the peripheral nerve system. DTI
      is expected to provide information about the physiology of the nerves and may reveal vascular
      congestion such as; blockade of axoplasmic flow, leading to abnormal proximal accumulation of
      endoneurial fluid; and distal Wallerian degeneration changes. Fiber tracking used on DTI is
      clinically implemented in some cases of stroke, tumours, neuropathy surgery, and functional
      brain MR imaging. Additionally, fiber tracking has been used on neuropathic patients with
      carpal tunnel syndrome, but has yet to be used in DPN as a measure of physiological function
      of the peripheral nerves.

      Investigator, sponsor and trail setting Patients will be recruited at Department of
      Endocrinology and Internal Medicine from a cohort of more than 1000 well-characterized
      diabetic patients. The main investigator finished his masters as a biomedical engineer at the
      MR Centre at Aarhus University Hospital where he specialized in MR scanning techniques and
      has since been working with research combining diabetes, neuropathy, MR techniques and image
      processing. The studies will be conducted in collaboration between Siemens AG, Copenhagen,
      Department of Endocrinology and Internal Medicine, Department of Neurology, MR Centre at
      Aarhus University Hospital, Department of Endocrinology and Internal Medicine at Odense
      University Hospital and Department of Neuroradiology at Heidelberg University Hospital.

      The main researchers on the project are as follows:

      Main Investigator Michael Vaeggemose, MSc, Biomedical Engineering Department of Neurology,
      Aarhus University Hospital, Denmark

      Supervisor Henning Andersen Professor, MD, PhD, Neurologist Department of Neurology, Aarhus
      University Hospital, Denmark

      Supervisor Niels Ejskjaer Associate Professor, MD, PhD, Endocrinologist Department of
      Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark

      Supervisor Knud Yderstraede Associate Professor, MD, PhD, Endocrinologist Department of
      Endocrinology, Odense University Hospital, Denmark

      Supervisor Steffen Ringgaard Associate Professor, PhD, MR Physicist The MR Centre, Aarhus
      University Hospital, Denmark

      Objective

      This project aims to develop high field MR techniques to detect nerve lesions in diabetic
      patients. The MRI findings will be compared to results from conventional evaluations and
      nerve conduction studies to determine the validity as part of a clinical practice.

      Methods

      Blood sample

      For the diagnosis of diabetes, HbA1c is used. This is the measure of how much glucose binding
      to hemoglobin in the blood. Diabetics have a higher blood sugar levels than healthy, there is
      definitely a threshold for diabetes that are at glucose values exceeding 64mmol/mol (8%).
      HbA1c is determined from a blood sample.

      Clinical neurological test

      Diabetics with and without neuropathy, hereditary axonal and demyelinated nerve injury
      patients examined with a clinical neurological test of sensibility, muscle power and
      reflexes. Examination of reflexes in the arms and legs performed with reflex hammer while the
      assessment of muscle strength is performed by trial participants to stretch and bend the arms
      and legs during resistance from the examiner. The subjects' sensibility of the soles is
      tested with a cotton swab and test participant shall so indicate on the touch can be felt.
      Furthermore the trial participants' vibration sensitivity of the soles is tested with a
      tuning fork. There is a possibly that the test of the muscles subsequently lead to slight
      muscle soreness, but otherwise there will be no significant risks, side effects or discomfort
      associated with the clinical neurological testing.

      Neurophysiological studies

      The neurophysiological studies include electroneurography (ENG) and Motor Unit Number
      Estimate (MUNE) and Motor Unit Number Index (MUNIX). The neurophysiological studies performed
      at the Clinical Neurophysiology Department, Aarhus University Hospital using EMG-equipped
      Keypoint (Medtronic, Skovlunde, Denmark).

      Electroneurography (Nerve conduction study)

      Nerve conduction studies are performed with the department's standardized methods and
      include:

        1. Motor nerve conduction study and F-waves with surface electrodes on the ulnar peroneus,
           bilateral and tibial nerve, bilaterally.

        2. Sensory nerve conduction study with surface electrodes of the sural nerve, bilaterally.

      Nerve conduction velocities, amplitudes of the sensory and motor potential, distal motor
      latencies and minimum F-wave latencies are the parameters to be evaluated with nerve
      conduction studies.

      MUNE Multipoint Stimulation & MUNIX

      Motor Unit Number Estimate (MUNE) provides information on the number of functioning motor
      units in the studied muscle. The estimate is based on the ratio of the maximum Compound
      Muscle Action Potential (CMAP) and an average of that muscle on Surface Motor Unit Potentials
      (SMUP). In the current study used Multipoint Stimulation (MPS) for the stimulation of a nerve
      of one lower limb and a nerve in one upper limb per. participant. There is a one supramaximal
      nerve stimulation whereby the maximum CMAP determined with surface electrodes.

      Then the nerve is stimulated, starting from 0 mA and increasing intensity to the first
      all-or-nothing SMUP observed. The intensity varied further until the measured SMUP not show
      variation (alternation.) process is carried out by moving the electrode a few millimetres
      along the nerve. This is done until a representative number SMUP is measured approx. 10 per.
      nerve.

      Motor Unit Number Index (MUNIX) is also a MUNE technique. There will be conducted one
      supramaximal nerve stimulation with surface electrodes to obtain CMAP in the same nerve as
      used above. The next stage is electromyography (EMG) with the inclusion of surface
      interference pattern in voluntary contraction, typically by 10 different contractions between
      10% and 90% of maximal contraction force.

      The neurophysiological studies (ENG, MUNE, MUNIX) takes a total of 2 hours per trial
      participant and performed at the bonded small surface electrodes, respectively in hands or
      feet.

      Muscle potential and nerve potential recorded through these surface electrodes for
      stimulation of the nerve with brief surges through the skin. This feels like a beating or
      pressing in the skin and may be associated with mild discomfort. Otherwise, the studies are
      not associated with any kind of risk or side effects.

      MR Neurography (MRN)

      MRN study will be conducted at Magnetrom Skyra 3 Tesla MR scanner (Siemens AG, Erlangen,
      Germany), which is set up to perform a MRN protocol with the following 5 sequences.

        1. DIXON

        2. Spectral adiabatic inversion recovery (SPAIR)

        3. Short tau inversion recovery (STIR)

        4. T2-weighted turbo spin echo (T2 TSE)

        5. Diffusion weighted imaging (DWI)

      Before the scan test, the subject must complete and comply with the rules of MRI safety. A
      description of the MRI scanning process, alarm ball, and a description of the noises the
      scanner produces is described to the subject. MRI methods for visualization of nerves does
      not use contrast agents, which is advantageous in the study of diabetes patients who may have
      reduced kidney function. The subject is placed supine on a bed with legs towards the scanner.
      To minimize motion artefacts a light fixation of the lower leg with foam pads is used. Around
      the foam pads and lower extremities is a 16-channel Peripheral Angio Array coil (Siemens AG,
      Erlangen, Germany) or multiple 18-channel Body Matrix coils (Siemens AG, Erlangen, Germany)
      located. To avoid hearing damage is a hearing protector placed on the subject's ear. If
      problems occur the test subject can at any time squeeze the alarm ball which is located in
      one hand, with a pressure on it and a direct contact with the investigator will be created
      and the patient can be moved out of the scanner. The scanning process is expected to take 2
      hours with changing cloth, instruction and scanning. MRI scans are not associated with any
      kind of risk or side effects.

      Quantitative sensory testing

      Quantitative sensory testing (QST) is used to determine vibration threshold via a
      computerized sensory evaluation system (CASE IV WR Medical Electronics, Stillwater, MN, USA).
      This study investigated the trial participants' ability to perceive vibrations caused
      respectively the dominant index finger and the non-dominant foot big toe. In addition,
      temperature variation and pain perception in unity describes the neurological affliction
      stage and scope. The test is evaluated to exceeding patient specific thresholds for normal
      sensitivity or the extent of the patient's reduced or exaggerated sensitivity. The thermal
      test is an electrode applied to the skin. By adjusting the voltage of the electrode modified
      heat of the electrode with a linear increasing or decreasing the development of 40 degrees
      per second. Meanwhile the patient will be asked if he feel a temperature discomfort. QST is
      not associated with side effects, risks or discomfort.

      Isokinetic dynamometry

      The trail subjects' muscular strength is determined by isokinetic dynamometry. The test
      measures the maximum isokinetic strength of the shoulder flexor and extensor muscles of the
      dominant arm and the ankle flexor and extensor muscles in the non-dominant leg. Trials
      participant contract the muscles one at a time during a resistance and the study consists of
      a maximum of eight repetitions. This is done with a Biodex System 3 PRO dynamometer (Biodex
      Medical Systems Inc. NY, USA) and follows a standardized protocol. In very rare cases, muscle
      strain and tendinitis (less than 2 ‰) may occur, further risk, side effects or discomfort is
      not associated with the use of isokinetic dynamometry.

      Statistical considerations

      Comparison between matched groups will be performed using conventional statistic methods
      unpaired t-test or non-parametric tests such as Wilcoxon signed-rank test. In variation
      analyses of several groups ANOVA and ANCOVA will be used. A significant difference of
      p-values below 0.05 has to be determined, to determine the validity of the findings.
      Comparing the conventional methods to the MRI method from the binary outcome of being healthy
      or suffer from DPN, given an estimated sensitivity of 1 and a Specificity of 0.7, makes it
      possible to determine the required sample size. From a McNemar's test with a significant
      level of 5% a power calculation were performed giving a needed sample size of at least 50
      subjects (healthy and diabetic with and without neuropathy). Inclusion of patients with
      axonal and demyelinated nerve lesions, to compare the resemblance of solely axonal and
      demyelinated damage to diabetic peripheral neuropathy, is in its current numbers not based on
      a statistical power calculation.

      Volunteers

      The trail consists of patients with type I and type II diabetes, with and without neuropathy.
      Patients will be recruited at the Department of Endocrinology, Noerrebrogade 44, Aarhus
      University Hospital. Patients with hereditary axonal and demyelinated neuropathy will be
      included at the Department of Neurology, Noerrebrogade 44, Aarhus University Hospital.
      Healthy subjects will be recruited through public media. In the 3 year course of the study it
      is expected to include 90 diabetics with and without neuropathy, 10 patients with hereditary
      axonal neuropathy and 10 patients with demyelinated neuropathy, as well as 35 healthy control
      subjects. This amounts to a total of 145 subjects.

      Side effects, risk and disadvantages

      The clinic neurological examinations test the subjects' reflexes, muscle strength and
      sensibility. The test of muscle strength can cause light muscle aches, but otherwise there
      will be no significant risks, side effects or disadvantages connected to the clinic
      neurological tests.

      Vibration threshold is determined through a computer based sensory evaluation system (CASE
      IV, WE Medical Electronics, Stilwater, MN, USA) and is not connected to significant risks,
      side effects or disadvantages.

      For examination of muscle strength the Biodex System 3 PRO dynamometer (Biodex Medical
      Systems Inc. NY, USA) is used. I very rare cases muscle strain and tendonitis (less than 2 ‰)
      I connection to the examination, otherwise there will be no significant risks, side effects
      or disadvantages connected to tests.

      The neurophysiological examinations (ENG, MUNE, and MUNIX) are performed with surface
      electrodes with short bursts of electrical current through the skin. It feels like a beating
      or pressing under or in the skin and can be connected to discomfort. Besides this the tests
      are not connected to significant risks, side effects or disadvantages.

      MR scans is not connected to any known risks and the patients ears will be protected with
      soundproofing earplugs or headphones to avoid the discomfort in relation to the high sound
      the scanner makes during the scans. The patients head will be placed outside the scanner,
      with the legs in the scanner, removing the risk of making the patient feel claustrophobic.

      The blood test can be connected to slight discomfort and a small risk of developing
      accumulation of blood and infection at the needle injection site. If any sign of infection
      (rash, heating, tenderness, swelling) the subject must seek the investigator or the emergency
      room. Det combined blood loss in connection to the blood test will not exceed 250ml, which is
      a lot less than a blood donation includes.

      The blood test is analysed and destroyed after. A bio bank will not be established in this
      project.

      Since there's no significant side effects and risks in participating in the project it is
      considered that the project is scientific ethically justifiable.

      Economic conditions

      Expenses in connection to the project are covered by the involved departments. The
      researchers have no economic conflict of interest in the project. Transport expenses in
      connection to oral information and examination is refunded in regard to the guidelines used
      at the departments. In regard to national guidelines the subjects will be paid compensation
      for their partition in the project.

      Publication of results

      The results will be published in a recognized international paper in account to the Vancouver
      regulations regardless of the results are positive, negative or inconclusive.

      Do the subjects wish information about the project results they can inform the investigator
      and he will send the information to the interested subjects.

      National ethical committee review

      The project is reported and approved by the Danish Data Protection Agency, Danish National
      Committee on Health Research Ethics (nr. 1-10-72-85-13) and the department legislations.

      Volunteer recruitment

      Subjects with peripheral nerve disease and non-neuropathic diabetic patients are recruited in
      the clinic at the Department of Neurology and Medical Department of Endocrinology, Aarhus
      University Hospital. Relevant potential subjects will be identified through their planned
      visit to Neurological clinic or Endocrinology clinic. Potential subjects (healthy controls,
      diabetics and patients with peripheral nerve disease) will receive written information about
      the research project with a request to contact the main investigator Michael Vaeggemose per
      letter, e-mail or telephone if they want further information about the research project.
      Healthy control subjects will be recruited by posting information material on public bulletin
      boards and in the local newspaper, indicating the main investigators phone number and e-mail
      address. Potential volunteers who want further information about the project would then
      subsequently receive the written participant information and National Ethics Committees
      information in regard to participating in a health science research project, and call for an
      information interview. The potential subject has the opportunity to bring a companion to the
      information interview and is informed of the right to stop participating in the project is
      he/she chooses to.

      The information interview is conducted by PhD students, MSc biomedical engineer, Michael
      Vaeggemose who with in depth knowledge and close association to the studio has the necessary
      academic qualifications to do so. The conversation held in a conference room in undisturbed
      environment at Aarhus University Hospital, where the potential trial participant has the
      opportunity to bring a companion. Indicated during the interview that there is a request for
      participation in a biomedical research project and given an oral understandable presentation
      of the research project without using technical terms. During the interview, there will be
      enough time for the subject to listen to the oral information and ask questions. The
      conversation adapted beneficiary's individual requirements in terms of experience, maturity,
      age, etc.. The interview will be based on the written participant information and will
      include any foreseeable risks, side effects, complications and inconveniences associated with
      participation in the research project and that there may be unforeseen risks and impacts
      associated with participation in the research project. Furthermore, it is stated that
      information about health conditions, purely private matters and other confidential
      information may be disclosed to and processed by persons responsible for carrying out a
      statutory quality of the study. The subject is informed also about the right to decline
      knowledge of new essential health data in the project.

      After information interview the potential trial participants has at least 1 week to think
      before signing the consent form. The subjects may at any time without consequences withdraw
      from the research project. It is desired to gain access to patient records, as evidenced by
      the written patient information. After the information interview the participant will be
      informed if, during the completion of the study, new data on the risks, complications and
      disadvantages in the trials has changed significantly in regard to the subject's safety. In
      the event that the study show crucial information about the subject's state of health it will
      be disclosed to the individual trial participant, unless they unequivocally expressed that
      this is not desired. The subjects will be informed of the results and of any consequences for
      the individual. There will be, upon completion of the project, a short easy to understand
      report in Danish summarizing the project's main results, as the individual trial participant
      may obtain by contacting the projects main investigator (Michael Vaeggemose). If the research
      project is interrupted the trial participants will be notified of the reason for this.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        In the 3 year course of the study it is expected to include 90 diabetics with and without
        neuropathy, 10 patients with hereditary axonal neuropathy and 10 patients with demyelinated
        neuropathy, as well as 35 healthy control subjects. This amounts to a total of 145
        subjects.
      
Biospecimen description: 
      Blood sample less then 250ml to determine Hba1c (blood glucose level).