State-of-the-art nuclear neuroimaging in failed back surgery syndrome: can we predict the outcome?

Nowadays chronic back pain is a health concern that effects people of all ages
world-wide. It is recognized as one of the main contributors to the number of
disability-adjusted life years (DALYs) globally (1). Most cases of chronic back
pain are caused by failed back surgery syndrome (FBSS) (2). This is a condition
where one or more spinal surgeries fail to relieve lower back pain with or
without pain radiating to the lower limbs. Previous studies report 10-40% of
people who have undergone spinal surgery continue to suffer from their pain
symptoms post-surgery (3). The majority of surgeries were technically carried
out correctly but did not result in improvement of pain symptoms. Studies
investigating the aetiologies of pain persistence provide incongruent reports.
Some studies found that 90-95% of FBSS cases are not caused by surgery, and
that some intrinsic factor must be at play. While other studies have found the
opposite to be true, suggesting 90% of FBSS cases are caused by surgeries. One
of the explanations for this high percentage being misdiagnosis before surgery
(4).

For some patients anatomical abnormalities result in their pain symptoms, but
for others the exact cause is not that clear. For these patients imaging
techniques such as MRI scans are unable to detect any anatomical abnormalities,
which implies functional impairment (5). An example being impairment of the
sympathetic nervous system (SNS), which has been documented in FBSS patients
before (6, 7).

Therapy options after surgery are often aimed at the most probable cause of
pain. Treatment options for FBSS include pharmacological interventions,
physical therapy, exercise, behavioural rehabilitation, neuromodulation and
even re-surgery (8). Remarkably, the chance of clinical improvement is reduced
exponentially with each subsequent surgery (9). In recent years neuromodulation
has been recognized as an effective long-term treatment option for FBSS (8,
10). As a result, neuromodulation treatment has started to become more
customary. (11). Spinal cord stimulation (SCS) being one of the neuromodulation
treatment options. However, SCS treatment is not without its risks and
complications and is thus seen as a last resort treatment option. One of the
most critical risk being infection potentially resulting in meningitis. Other
complications include migraines, reported by 12% of SCS cases, and pain at the
site of implantation, which is reported by 9% of SCS cases (12). Besides these
complications the effectivity of SCS treatment also varies greatly from person
to person, ranging from no pain reduction at all to a reduction of 88% (12,
13). The costs of SCS treatment are not negligible either, the
per-patient-average in the USA is currently $48,357 (14). The investigation of
predictive biomarkers that could foretell the effectiveness of neuromodulation
before treatment could help reduce these unnecessary health and financial
burdens on patients suffering from FBSS.

To date, no studies have been performed on potential imaging biomarkers that
could predict the effectiveness of SCS treatment. However, a recent study has
shed light on imaging biomarkers in a different neuromodulation treatment
option of chronic low back pain. This study investigated patients with low back
pain who received L2-dorsal root ganglion stimulation as treatment. Prior to
the intervention, patients underwent Positron Emission Tomography (PET) imaging
of the brain with the radioactive radiotracer F18-fluorodeoxyglucose (F18-FDG)
to asses cerebral metabolic activity. The study reported increased metabolic
activity in the cerebral areas associated with nociceptive brain matrices (15).
Other studies have also observed metabolic changes in area such as the
thalamus, anterior cingulate cortex and primary and secondary somatic areas.
Changes in these areas could influence cognition, attention, emotions and
perception of pain (16-18). The use of F18-FDG PET-CT scans could further the
understanding of disturbed metabolic glucose activity which could aid in the
search for imaging biomarkers to help predict SCS effectiveness in patients
suffering from chronic back pain.

Therefore, this study aims to map metabolic cerebral activity of patients
suffering from FBSS with F18-FDG PET-CT scans to elucidate biomarkers that
could help predict SCS effectiveness. This study also aims to deepen current
knowledge on dysregulation in the brain of FBSS patients.

Primary Objective: The primary objective of this study is to map cerebral
glucose metabolism of patients diagnosed with FBSS in an effort to elucidate
imaging biomarkers that could predict the effectiveness of SCS treatment.

Secondary Objectives: Secondary objectives of this study are to establish a
better understanding of the pain neuromatrix. Moreover, to better understand
the pathophysiological mechanisms that result in FBSS, by mapping cerebral
glucose metabolism of people who suffer from FBSS and comparing them to an
already existing database of healthy subjects.

The design of this study regards a single-arm prospective observational study.
The intention is to include 20 patients who suffer from FBSS and are scheduled
to receive neuromodulation treatment in the form of SCS. Data collected from
these patients will be compared to available data from healthy individuals.

Patients will be informed about this study and its objectives by a nurse
practitioner/pain physician during regular consultations prior to implantation
of an SCS system. Patients who meet all criteria and are willing to participate
will be informed about this study and will receive a patient information letter
(file E1) after which they will have a reflection period. Patients will have
the possibility to consult an independent physician who is informed about the
protocol but not actively involved in this study. After one to two weeks,
patients will be telephoned to answer remaining questions. If they are willing
to participate, they will sign a written informed consent (file E2).
Thereafter, additional questionnaires which will chart their pain intensity,
pain characteristics, interference of pain with daily life and overall quality
will be provided and filled in prior to PET-CT imaging and the SCS treatment.
The additional questionnaires are provided in file F1.

Patients who are willing to participate in this study will be referred to the
Dutch hospital where PET-CT neuroimaging will take place (Radboudumc,
Department of Nuclear Medicine). The images will be taken by employees of
Radboudumc Nijmegen; Department of Anaesthesiology, Pain and Palliative
Medicine.
Patients will be invited to undergo PET-CT imaging of the brain at least two
weeks prior to receiving SCS implantation surgery. PET-CT imaging of the brain
will not delay the clinical progress of the patient to receive SCS.

The surgical procedure for SCS consists of two phases: a trial phase and an
implant phase, both are performed under sedated analgesia and protocollary
antibiotics. This surgical procedure is safe and has a low rate of
complications (19, 20). SCS is a standard therapy covered by basic health
insurance in the Netherlands. This study is without additional risks.
Therefore, we request a dispensation from the statutory obligation to provide
insurance.

After the SCS system is implanted, the patients will be asked to fill in the
same questionnaires they filled in at baseline. These will be filled in after 1
month, 3 months and 6 months post-implantation. If the SCS system needs to be
removed during this time period (e.g. due to infection), the patient will be
excluded from this study. The duration of the study is six months for each
patient after they have undergone PET-CT neuroimaging.

Patients participating in this study will undergo a F18-FDG PET-CT scan of the
head. The main risk involved with this imaging technique is radiation exposure,
this exposure to radiation adds to the lifetime radiation of participants and
might increase the risk of cancer. To decrease this risk patients will be
exposed to the lowest level of radiation achievable for adequate imaging
results. The radiation dose will be approximately 4 mSv, which is considered to
be minimal to low.

This form of medical imaging is the only way to investigate the study
objectives. Answering these objectives could lead to a better understanding of
FBSS, the pain neuromatrix and predictive biomarkers for SCS outcome. As the
pathophysiology of FBSS is not understood and predictive biomarkers have never
been identified. Failed back surgery syndrome is already a substantial health
concern and the incidence and prevalence is expected to increase as the global
population is aging (1, 22). A recent study has already shed some light on the
neurology of low back pain. This study explored the cerebral glucose metabolism
of patients with discogenic low back pain who received L2 DRG stimulation with
F18-FDG PET-CT scans (15).