My spine is on fire: neuroinflammation in spinal radiculopathy and physiotherapy on it.

Cervical radiculopathy is a specific type of neck pain in which a cervical
nerve root is pinched by intervertebral discus material or osteophytes which
causes inflammation of the nerve. Neuroinflammation can be visualised in vivo
using the [11C]-R-DPA713 tracer combined with a positron emission tomography -
computed tomography (PET-CT) scan. [11C]-R-DPA713 is a second-generation tracer
which binds to the translocator protein (TSPO) which is upregulated in glial
cells within the nervous system during neuroinflammation and is therefore a
marker of neuroinflammation in vivo. In lumbar radiculopathy patients, an
increased tracer uptake within the spinal cord and neuroforamina is found.
Moreover, the tracer uptake was associated with the experienced pain intensity.
Results from preclinical studies show that joint- and neural mobilisation and
therapeutic exercise are able to reduce neuroinflammation in neuropathic pain
models and it is assumed that these findings can be transferred to patients.
There is lack of knowledge if neuroinflammation is also present in patients
with cervical radiculopathy and whether this neuroinflammation (if present) can
be reduced by conservative treatment. Increased knowledge about the
pathophysiological mechanism behind cervical radiculopathy could lead to better
conservative treatment, which is the first and preferred treatment option for
these patients. Conservative treatment targeting at the present
neuroinflammation can contribute to increased recovery. Therefore, in this
study patients with cervical radiculopathy having neuroinflammation will be
randomised into three groups and treated with 1) joint- and neural
mobilisations, 2) therapeutic exercise, or 3) a soft collar. After four weeks
of intervention, potential changes in neuroinflammatio and the correlation with
patient reported outcomes will be assessed. Joint- and neural mobilisation and
therapeutic exercise will be compared to the control intervention: a soft
collar. Six additional cervical radiculopathy patients will be recruited and
will be scanned for neuroinflammation twice with one week between to provide
information regarding test-retest reliability.

The overall aim of this study is to gain insight into the pathophysiological
mechanisms behind cervical radiculopathy and determine if conservative
treatment targets these processes. Different research questions are formulated:
1) Is there any neuroinflammation present in patients with cervical
radiculopathy compared to healthy control measured in vivo using [11C]-R-DPA713
PET imaging?
2) If present, does 4 weeks treatment with a) joint- and neural mobilisations
or b) therapeutic exercise, reduce the present neuroinflammation compared to c)
a soft collar?
3) What is the test-retest reliability of [11C]-R-DPA713 in measuring
[11C]-R-DPA713 binding potential non-displaceable (BPnd) in the neuroforamina
and spinal cord in cervical radiculopathy patients?

The study is a *proof of principle* study with a:
1) Cross-sectional design assessing baseline neuroinflammation between patients
with cervical radiculopathy and healthy control.
2) Randomised controlled design (RCT) with three arms, block randomization with
block sizes of 3, and an 1:1:1 allocation ratio with four weeks treatment
follow up measurement.
3) Test-retest design with one week follow- up.

In the RCT patients will be treated with a) joint- and neural mobilisations, b)
therapeutic exercise, or c) a soft collar (control intervention)

Patients and healthy control will undergo one MRI session of maximum sixty
minutes. Before treatment and after four weeks, for all patients with evident
neuroinflammation and for the healthy controls, a [¹¹C]-R-DPA713 PET-CT scan
will be obtained, which takes maximally 60 minutes. PET-CT scans involve
exposure to a small amount of radiation, as well as venous blood sampling (7 x
5ml) to measure [¹¹C]-R-DPA713 input function. Both visits include examination
of symptomatology. Blood sampling during imaging, MRI and PET-CT are all safe
procedures; standard procedures are followed, which will be performed by
appropriately trained (medical) staff to minimise risks. Maximum total
radiation dose is 4.6 millisievert (mSv) for the cervical radiculopathy
patients, which is of the same order of magnitude as the annual natural
background radiation in the Netherlands for two years. The healthy control will
receive a maximun total radiation dose of 2.3 mSv. This research fits the
radiation-risk 2b conform the NCS-26 (2016) guidelines: 1) new imaging
techniques, 2) provides insight in the pathophysiology of a severe condition.
Before and after four weeks, in total three vacutainer tubes (5ml each) will be
collected for the screening parameters and immune blood markers. The healthy
control will provide two vacutainer tubes (5ml each) during the whole study.
Participation in this study may be of therapeutic benefit to patients since
joint- and neural mobilisations, therapeutic exercise, and a soft collar been
associated with both clinical and functional improvement.
To use BPnd as an outcome measure for the PET signal, a 60 minutes in duration
dynamic scan will be necessary. In part because blood radioactivity can be
calculated and used for the input function.