Quantitative Imaging of Cervical Spinal Structures in Healthy Participants and Patients with Cervical Degenerative Disc Disease - the DISC Pilot Study -

Cervical degenerative disc disease (CDDD) is the consequence of degeneration of
intervertebral discs and joints and can result in compression of the cervical
nerve root leading to clinical symptoms of radiculopathy, compression of the
spinal cord with symptoms of myelopathy, or a combination of both. The
incidence of CDDD is rising with the aging population, and, consequently, a
significant increase in surgeries for symptomatic CDDD is predicted in the
upcoming years. As such, the decision for- and optimal timing of surgery remain
challenging.

Currently, the decision for surgery in patients with symptomatic CDDD is
related to symptoms, as well as position and size of disc herniation on
conventional Magnetic Resonance Imaging (MRI). However, conventional MRI only
enables qualitative morphological evaluation, leaving space for subjective
individual interpretation. Also, disc herniations on conventional MRI are
frequently found in asymptomatic individuals, while, in symptomatic individuals
type and extent of disc herniation does not correlate to severity of symptoms.
Altogether, the current standard using conventional MRI cannot optimally
predict response to surgery for patients with symptomatic CDDD.

Quantitative imaging is rapidly being recognized as a supplement to
conventional MRI and refers to the direct measurement of physical properties of
tissue. These novel techniques are promising, as they are noninvasive and could
potentially aid in determining objective cut-offs to stage disc herniation.
Diffusion tensor imaging (DTI) is one of the most studied quantitative
techniques and allows for evaluation of microstructural changes. The DTI
fractional anisotropy (FA) metric was demonstrated as valid biomarker for
recovery after surgery in cervical myelopathy as well as surgical selection in
lumbar radiculopathy. Moreover, recent introduction of zoomed-DTI (z-DTI) could
lead to greater imaging accuracy while proven feasible in the cervical spine.

Furthermore, the cervical spinal cord and its nerve roots are highly
vascularized and their perfusion could be compromised by disc-herniation
related compression. Using the endogenous perfusion technique arterial spin
labeling (ASL), as well as contrast-based perfusion techniques such as
susceptibility contrast (DSC) and dynamic contrast enhanced (DCE), degree of
ischemia, hypoxia as well as signal enhancement can be estimated. ASL has been
studied twice for spinal cord perfusion mapping and DSC was demonstrated
feasible in the spine of healthy participants as well as patients with cervical
myelopathy. Additionally, increased signal enhancement was observed for DCE in
degenerative discs of the lumbar spine. To our best knowledge, no studies have
been conducted to assess perfusion of the cervical nerve roots, which are
compromised in cervical radiculopathy due to CDDD.

Besides microstructure and perfusion, viscoelastic properties of cervical
spinal structures may change in relation to disc herniation-related
compression. Therefore, it would be interesting to study mechanical properties
such as stiffness and viscosity, which can be measured with
Tomo-MR-Elastography (TMRE). To our best knowledge, no previous study has
assessed cervical intervertebral discs and spinal structures using TMRE, making
this a promising first study.

Finally, imaging is a relatively time-consuming matter, and including
additional sequences will only increase its lengthiness. Therefore, several
methods are being developed to perform imaging in a more efficient manner. One
novel method is Synthetic MRI (SyMRI). Advantages of SyMRI are a reduced
acquisition time, possibility of performing automatic tissue segmentation and
volume estimation and acquisition of quantitative parameters. SyMRI has been
studied once in the spine, and significant differences in quantitative
intervertebral disc values were found in relation to hydration-status of the
disc.

Since no single measurement has been proven to be the golden standard in
previous studies, it is likely that a combination of measurements is needed for
clinical application. Therefore, the aim of this pilot study is to explore a
multi-parametric quantitative MRI approach including z-DTI, ASL, DSC, DCE,
TMRE, and SyMRI to measure cervical intervertebral discs, the spinal cord and
its nerve roots.

This study will consist of three parts.

Part 1: Feasibility

Primary objective
To evaluate the feasibility and repeatability for the quantitative MRI
sequences (i.e. z-DTI, ASL, DSC, DCE, TMRE, and SyMRI) of cervical spinal
structures (i.e. intervertebral discs, spinal cord, and nerve roots) in healthy
participants and patients with symptomatic CDDD.
Hypothesis:
Quantitative MRI sequences demonstrate repeatability in healthy participants
and patients with symptomatic CDDD.

Part 2: Correlation to clinical measurements

Primary objective
To determine a correlation of quantitative MRI sequences of cervical spinal
structures to clinical impairment in patients with symptomatic CDDD. Clinical
impairment will be measured with the Neck Disability Index (NDI) for cervical
radiculopathy, modified Japanese Orthopaedic Association Score (mJOA) for
cervical myelopathy, and NDI and mJOA for cervical radiculomyelopathy.
Hypotheses
-In symptomatic CDDD patients with radiculopathy, NDI scores are significantly
correlated to quantitative MRI sequence parameters.
-In symptomatic CDDD patients with myelopathy, mJOA scores are significantly
correlated to quantitative MRI sequence parameters.
-In symptomatic CDDD patients with radiculomyelopathy, NDI and mJOA scores are
significantly correlated to quantitative MRI sequence parameters.

Part 3: 6 months follow-up

Primary objective
To determine a correlation between baseline quantitative MRI sequences of
cervical spinal structures to surgical treatment after 6 months of follow-up in
patients with symptomatic CDDD.
Hypothesis
Being surgically treated after 6 months of follow-up in patients with
symptomatic CDDD is significantly correlated to baseline quantitative MRI
sequences of cervical spinal structures (e.g. patients who were not surgically
treated because of improvement of symptoms also had better baseline
quantitative MRI sequence values of cervical spinal structures).

A prospective pilot study.

All participants will be subjected to several MRI sequences, using a state of
the art 3T Siemens MRI Scanner available in the UMCG. First, all participants
(healthy participants and patients with symptomatic CDDD) undergo baseline
neurologic examination. Additionally, the healthy participants fill out the
following questionnaires: Neck Disability Index (NDI), Visual Analogue Scale
(VAS) for arm and neck pain, modified Japanese Orthopedic Association (mJOA),
Nurick grade, EuroQol 5-Dimension 5-Level (EQ-5D-5L), and Work Ability Single
Item (WAI-SI). Regarding patients with symptomatic CDDD, the abovementioned
questionnaires will be filled out before their visit to the outpatient clinic
as part of clinical routine. The data of these questionnaires will be extracted
from the EPD for this study. If patients did not fill out questionnaires before
their outpatient clinic visit, they will fill out the questionnaires during the
study visit.

Finally, during the same baseline visit, all participants undergo MRI scanning:
localizer & T2-weighted anatomical (conventional MRI), z-DTI, ASL, DSC, DCE,
TMRE, and SyMR. The total scanning time will be approximately 40 minutes. For
assessment of reproducibility, 10 healthy participants and 10 patients will be
scanned 2 times on different days/times. The patients with symptomatic CDDD
will have another study visit after 6 months of follow-up to assess their
treatment status (having had surgery yes/no; in case of yes also the surgery
characteristics), to fill out the abovementioned questionnaires and have an MRI
with additional sequences.

This is a pilot hypothesis-generating study, exploring the feasibility of
quantitative MRI sequences z-DTI, ASL, DSC, DCE, TMRE, and SyMRI and assess a
correlation to clinical impairment and treatment status after 6 months of
follow-up. There is not sufficient data available for a sample size
calculation. Recent TMRE in brain imaging used a cohort of 12-18 subjects,
therefore a pragmatic sample size of 20 healthy volunteers and 20 patients with
symptomatic CDDD is chosen. An interim-analysis will be performed after 10
participants are included for power and sample size calculations. This will be
incorporated in an amendment to inform the METc.

All participants (healthy and patients) will need a conventional MRI scan with
quantitative MRI sequences, which will take approximately 40 minutes. Most MRI
sequences used in this study are non-invasive and do not involve any ionizing
radiation. However, DSC and DCE require administration of a bolus contrast. The
contrast agent that will be used is Dotarem. Without any contra-indications for
an MRI scan or contrast agent, health is not at risk. Scans will be planned
outside of clinical workhours, except for patients with symptomatic CDDD who
did not undergo a conventional MRI before their visit at the outpatient clinic.
Those patients will undergo MRI scanning as part of clinical routine.
Before scanning, all participants undergo neurologic examination. Furthermore,
questionnaires are filled out during the study visits, which will take no
longer than 20 minutes. The patients with symptomatic CDDD already filled out
the same questionnaires before their visit to the outpatient clinic as part of
clinical routine.
There is an overall negligible risk for participants, as based on the Risk
Classification Checklist of the NFU. Therefore, we can conclude that this study
is a low-risk study.