Clinical trial NCT03880500: Spinal Segment MRI Perfusion and Diffusion Response to Spinal Manipulation in Low Back Pain Patients
Official title: MRI-quantified Changes in Perfusion and Diffusion in Spinal Segments After High-Velocity, Low-Amplitude Spinal Manipulation: A Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Pain, Back
Lead sponsor: Balgrist University Hospital
Sponsor class: OTHER
Collaborators: name: Verein Pro Chiropraktik
name: Balgrist Foundation
First posted: 2019-03-19
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 20 Controls, 50 Patients
Primary purpose: TREATMENT

Brief summary: The main objective is to quantify changes in diffusion and perfusion in the intervertebral disc and adjacent spinal muscle tissue of a spinal segment receiving a spinal manipulative or control intervention using diffusion-weighted magnetic resonance Imaging (MRI) (DWI, used for quantifying diffusion) and intravoxel incoherent motion MRI (IVIM, used for quantifying perfusion).

Additional objectives are to test if clinical parameters such as pain and disability, radiological parameters, or pain-related inflammatory parameters in venous blood have predictive value in relation to these perfusion and diffusion effects, and if these effects correlate to clinical outcome.

An additional objective is to test the repeatability of IVIM-MRI in assessing perfusion changes in musculoskeletal tissue, and, as a positive control, assessing diurnal changes in perfusion and diffusion parameters in spinal tissue of healthy controls.

Detailed description: Non-specific low back pain (LBP) is a very common condition in developed countries, with a point prevalence between 15% and 30% and a lifetime prevalence of about 70%. As a non-invasive treatment method, high-velocity, low-amplitude spinal manipulative therapy (SMT) is used in the conservative treatment of non-specific low back pain (LBP). Several studies suggest an association with favourable outcome. However, the overall effect size of clinical improvement following SMT remains modest. Most research on the effectiveness of SMT on back pain is conducted on patients suffering from "non-specific" LBP, the diagnosis of which is usually based upon the criterium that pain is not attributed to a recognizable pathology (e.g., infection, tumor, inflammatory diseases, fractures, disc herniations with nerve compression)8. In most of these studies, it is unclear whether patients' diagnoses were based upon more than history and clinical examination. The investigators argue that in the majority of cases, back pain labelled as non-specific might be more accurately labelled as non-specified and does have an attributable source and cause, whether one is able to recognize it or not. Therefore, if the diagnosis of non-specific LBP comprises heterogenic conditions, it is unlikely that patients will respond to one therapeutic modality equally.

Diffusion-weighted MR-imaging (DWI) is an application of magnetic resonance imaging that allows the measurement of water movement within and between tissues and is increasingly being used to study musculoskeletal physiology. Because DWI is sensitive even to small changes in fluid flow, it is potentially valuable in the study of the influence of therapeutic interventions such as manual therapy, exercise, and physical agents on musculoskeletal tissues. Studies using DWI have suggested that changes in diffusion within lumbar intervertebral discs occur in response to joint mobilization, prone press-ups, spinal traction and spinal manipulative therapy.

Intravoxel incoherent motion (IVIM) is a method proposed in 1988 by Le Bihan et al. which extracts microvascular blood flow information from diffusion-weighted imaging acquired at different b-values. It is used to generate separate images of diffusion and perfusion without requiring the injection of exogenous contrast agents. Originally developed in brain studies, it has been used in recent years to study perfusion in musculoskeletal tissue. There is a paucity of research addressing physiological events following a SMT intervention for patients with low back pain. A deeper understanding of local biomechanical and neurophysiological effects of SMT interventions might help refine its utilization and improve its effectiveness.

The purpose of this study is to quantify changes in diffusion and perfusion parameters within the intervertebral disc and paraspinal muscle tissue of a spinal segment receiving a spinal manipulative or sham intervention and to evaluate whether those changes differ in spinal segments with or without degenerative changes in 50 low-back-pain patients.

Additionally, it is of interest to determine the relationships between baseline parameters and changes in diffusion and perfusion as well as the degree of degenerative changes. Post-intervention changes in segmental spinal muscle perfusion will also be investigated. There will be a clinical follow-up immediately after the second MRI and at 1 week,4 and 12 weeks.

The repeatability and diurnal variation of IVIM imaging in quantifying perfusion in musculoskeletal tissues will be assessed by comparing perfusion parameters of 20 controls who will not receive any intervention. The investigators will perform a diffusion- and perfusion-weighted MRI at the beginning of the visit in the morning, which is repeated after approximately 20 minutes of rest (lying supine). Controls will present for an additional MRI approximately 10 hours later in the evening of the same day.

In participants consenting to venipuncture, approximately 8 ml of venous blood will be withdrawn using serum collection tubes, allowed to clot, and then centrifuged. The resulting serum supernatant is stored in aliquots at Balgrist Campus at -80°C. It will be analysed at the end of data collection for pro- and anti-inflammatory markers (e.g. C-reactive Protein, Interleukin 1-beta, Interleukin 6 and Tumor Necrosis Factor) in order to determine the relationship between inflammatory markers and degenerative changes, pain duration, and pain and disability outcomes.

Eligibility criteria: Inclusion criteria:

Patients:

1. Persons over 18 years and under 75 years of age with low back pain of any duration clinically not attributable to "red flags" (infection, trauma, fractures, inflammatory illnesses).
2. Source of LBP clinically at the L4/5 or L5/S1 segment.
3. Duration of LBP is longer than 4 weeks
4. Obtained informed consent.

Controls:

1. Persons over 18 years and under 75 years of age who have not suffered from low back pain in the last year and have never experienced low back pain for longer than 7 consecutive days.
2. Obtained informed consent.

Exclusion criteria:

Subjects are excluded from enrolment if they

1. have undergone prior spinal surgery
2. have undergone facet joint, epidural or periradicular injections in the last 6 months
3. had a spinal manipulative therapy intervention in the past 2 weeks
4. have spinal abnormalities (benign or malignant tumors, congenital abnormalities, isthmic spondylolisthesis)
5. have any contraindication to spinal manipulative interventions or are deemed unable to tolerate SMT to both body sides (e.g. pain attributable to above mentioned red flags, inability to perform side-lying without pain, radiculopathy with motor deficits \<M4-, severe spinal canal stenosis)
6. have any contraindication to MRI (e.g. heart pacemaker, metallic foreign body or claustrophobia)
7. have started a new prescription medication targeting blood circulation within the last 3 months
8. are pregnant or nursing
9. Subjects are excluded from venipuncture if they are known to be HIV-positive or have Hepatitis A, B, or C or have another systemic infection (excludes subjects from venipuncture). No study specific testing for HIV or Hepatitis A, B or C is performed.

Primary outcomes:
measure: Apparent Diffusion Coefficient Change
timeFrame: Measured on day 1 during the study
measure: Capillary Perfusion Change
timeFrame: Measured on day 1 during the study
measure: Diffusion Change
timeFrame: Measured on day 1 during the study
Secondary outcomes:
measure: Change in Apparent Diffusion Coefficient (Control)
timeFrame: Measured approximately 9 hours after the first MRI, during the study
measure: Change in Capillary Perfusion (Control)
timeFrame: Measured approximately 9 hours after the first MRI, during the study
measure: Diffusion change
timeFrame: Measured approximately 9 hours after the first MRI, during the study
Other outcomes:
measure: Pfirrmann-Grade
timeFrame: Measured on day 1, during the study
measure: Weishaupt-Grade
timeFrame: Measured on day 1, during the study
measure: Inflammatory Parameters (interleukins)
timeFrame: Measured on day 1, during the study, and up to 12 months after
measure: Inflammatory Parameters (CRP)
timeFrame: Measured on day 1, during the study
measure: Inflammatory Parameters (TNF-alpha)
timeFrame: Measured on day 1, during the study
measure: Disability Change
timeFrame: Disability change is assessed at 1 week, 1 month and 3 months follow-up
measure: Pain Change: NRS
timeFrame: Pain change is assessed at 1 week, 1 month and 3 months follow-up
measure: Treatment-related adverse events
timeFrame: Treatment-related adverse events are assessed at all time points during the study, starting from the time of inclusion to completion of 3 months follow up
Locations:
city: Zürich
country: Switzerland
facility: University Hospital Balgrist
state: Zurich
Study officials:
affiliation: Balgrist University Hospital
name: Petra Schweinhardt, PhD, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Beattie PF, Butts R, Donley JW, Liuzzo DM. The within-session change in low back pain intensity following spinal manipulative therapy is related to differences in diffusion of water in the intervertebral discs of the upper lumbar spine and L5-S1. J Orthop Sports Phys Ther. 2014 Jan;44(1):19-29. doi: 10.2519/jospt.2014.4967. Epub 2013 Nov 21.
citation: Le Bihan D. What can we see with IVIM MRI? Neuroimage. 2019 Feb 15;187:56-67. doi: 10.1016/j.neuroimage.2017.12.062. Epub 2017 Dec 22.
citation: Nguyen A, Ledoux JB, Omoumi P, Becce F, Forget J, Federau C. Application of intravoxel incoherent motion perfusion imaging to shoulder muscles after a lift-off test of varying duration. NMR Biomed. 2016 Jan;29(1):66-73. doi: 10.1002/nbm.3449.
citation: Wong AY, Parent EC, Dhillon SS, Prasad N, Kawchuk GN. Do participants with low back pain who respond to spinal manipulative therapy differ biomechanically from nonresponders, untreated controls or asymptomatic controls? Spine (Phila Pa 1976). 2015 Sep 1;40(17):1329-37. doi: 10.1097/BRS.0000000000000981.
citation: Klyne DM, Barbe MF, Hodges PW. Systemic inflammatory profiles and their relationships with demographic, behavioural and clinical features in acute low back pain. Brain Behav Immun. 2017 Feb;60:84-92. doi: 10.1016/j.bbi.2016.10.003. Epub 2016 Oct 6.
citation: Chou R, Huffman LH; American Pain Society; American College of Physicians. Nonpharmacologic therapies for acute and chronic low back pain: a review of the evidence for an American Pain Society/American College of Physicians clinical practice guideline. Ann Intern Med. 2007 Oct 2;147(7):492-504. doi: 10.7326/0003-4819-147-7-200710020-00007.