Periduroscopy: Correlation Between the Outcome of Procedure and Histological-biochemical, Neuroinflammation and Genetic Factors.

A Prospective Study to Analyze, in a Population Undergoing to a Periduroscopy Approach, the Correlation Between Outcome of Procedure and Histological-biochemical Neuroinflammation and Genetic Factors

It is still unknown the pathogenesis of low back pain and a lot of hypothesis were discussed for a long time. Because non-invasive imaging modalities greatly underestimate the prevalence of epidural pathogenesis an endoscopic examination of the epidural space has been advocated as both a diagnostic and therapeutic modality. It seems that immune-inflammatory factors play a more substantial role in pain status. Myeloscopic investigation have shown how morphological pictures of the epidural area in patients with chronic low back pain (CLBP) are much more complex and heterogeneous than what can be identified with traditional investigation suggesting a biochemical involvement. Endoscopy of the epidural space (epiduroscopy) is a minimally invasive technique, used to directly visualize pathological features inside of the lumbar spinal canal to locate tissues responsible of eliciting pain and the presence of any pathological structures within the vertebral channel, such as fibrous adherences, inflammatory processes, severe fibrosis and/or stenoses, in order to realize an effective therapeutic approach in a lot of different CLBP status as those due to spinal stenoses or failed back surgery syndrome. To deepen the molecular causes of interindividual variability of epiduroscopy outcomes in terms of decrease of pain, it is useful to analyze the DNA variants encoding IL6 and IL1 cytokines and to relate them with gene expression levels and with the cytokine dosage. By this technique, it is possible to analyze in the biopsy of the epidural tissue the specific expression of the cytokines: there is already evidence that inflammatory factors may be involved in the genesis of LBP. At this regards, it would be really important to compare systemic cytokine levels before the epiduroscopy with those detected immediately post procedure and after one month, to understand if the cytokines could play a key role and be a biomarker of the epiduroscopy outcome.

Concerning DNA polymorphisms, it has been demonstrated, in many disease-state meta-analyses, that the IL6 variant rs1800795 affect gene transcription and influences the IL-6 levels. Moreover, interleukin 1 (IL-1) is a major factor controlling the inflammatory response. The IL-1 gene family includes the IL-1α, IL-1β and the IL-1 receptor antagonist (IL-1Ra) genes that mediate immune and inflammatory responses. SNPs in IL-1α, IL-1β and IL1Ra modify bone mineral density promoting intervertebral disc disease (IDD). The simultaneous carriage of the IL-1bT3954 and the IL-1Ra A1812 alleles significantly enhances the risk of low back pain (LBP) occurrence, the number of days with pain, and the number of days with limitations in daily activities due to pain.

A recent study suggested that methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and that lower methylation contributes to the risk of developing Rheumatoid Arthritis.

The investigators will try to identify if it there is a correlation with success of the epiduroscopy approach in terms of freedom from pain with genic expression and cytokine dosage.

Finally, the investifators will compare the cytokine gene expression and the DNA methylation status of IL6 promoter in patients with favorable outcome and in no responders, to study the role in gene expression.

This study is addressed to detect if the genetic variability might be used in near future in clinical setting, to predict the success of epiduroscopy.

Study Overview

• Status: Unknown
• Conditions: Chronic Low Back Pain

Detailed Description

It is still unknown the pathogenesis of low back pain and a lot of hypothesis were discussed for a long time. Because non-invasive imaging modalities greatly underestimate the prevalence of epidural pathogenesis an endoscopic examination of the epidural space has been advocated as both a diagnostic and therapeutic modality.

It seems that immune-inflammatory factors play a more substantial role in pain status. Myeloscopic investigation have shown how morphological pictures of the epidural area in patients with chronic low back pain (CLBP) are much more complex and heterogeneous than what can be identified with traditional investigation suggesting a biochemical involvement.

Endoscopy of the epidural space (epiduroscopy) is a minimally invasive technique, which can be used to directly visualize pathological features inside of the lumbar spinal canal to locate tissues responsible of eliciting pain and realize an effective therapeutic approach in a lot of different CLBP status as those due to spinal stenoses or failed back surgery syndrome.

Minimally invasive endoscopic exploration of the lumbar epidural cavity in patients suffering from chronic low back pain has been used to identify the presence of any pathological structures within the vertebral channel, such as fibrous adherences, inflammatory processes, severe fibrosis and/or stenosis. The need to visually inspect the epidural space originally arose as conventional imaging, such as magnetic resonance imaging (MRI), has been shown to be significantly less sensitive in identifying epidural pathology compared with direct visualization. In a cohort of failed back surgery syndrome (FBSS) patients, 80% of those having severe epidural fibrosis diagnosed with epiduroscopy had a normal MRI examination. More, when used to identify the exact spinal level of painful pathology, neither clinical examination nor MRI evaluation strongly correlated with the endoscopy findings.

The combination of a disposable and easily steerable small video-guide, high-resolution optics and specifically designed tools such as mechanical dissectors, electric knife and graspers, makes this technique as a valid option to diagnose and treat epidural pathology in the lumbar region.

To deepen the molecular causes of interindividual variability of epiduroscopy outcomes in terms of decrease of pain, it is useful to analyze the DNA variants encoding IL6 and IL1 cytokines and to relate them with gene expression levels and with the cytokine dosage. By this technique, it is possible to collect a biopsy of the epidural tissue (usually performed during epiduroscopy) analyzing the specific expression of the cytokines: there is already evidence that inflammatory factors may be involved in the genesis of LBP. At this regards, it would be really important to compare systemic cytokine levels before the epiduroscopy with those detected immediately post procedure and after one month, to understand if the cytokines could play a key role and be a biomarker of the epiduroscopy outcome.

Concerning DNA polymorphisms, it has been demonstrated, in many disease-state meta-analyses that the IL6 variant rs1800795 affect IL6 gene transcription and influences the IL-6 levels ensuring the statistical robustness of the associations.

Moreover, interleukin 1 (IL-1) is a major factor controlling the inflammatory response. The IL-1 gene family includes the IL-1α, IL-1β and the IL-1 receptor antagonist (IL-1Ra) genes that mediate immune and inflammatory responses. The IL-1Ra molecule has been shown to be a powerful anti-inflammatory agent inhibiting the activities of IL-1 α and IL-1β. Moreover, SNPs in IL-1α, IL-1β and IL1Ra modify bone mineral density promoting intervertebral disc disease (IDD). Literature data showed that the simultaneous carriage of the IL-1bT3954 and the IL-1Ra A1812 alleles significantly enhances the risk of low back pain (LBP) occurrence, the number of days with pain, and the number of days with limitations in daily activities due to pain.

The investigators will try to identify if it there is a correlation with success of the epiduroscopy approach in terms of freedom from pain with genetic and cytokine expression patterns.

Finally, the investigators will compare the cytokine gene expression and the DNA methylation status of IL6 promoter in patients with favorable outcome and in no responders, to study its role in gene expression. In fact, a recent study suggested for the first time that methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and that lower methylation contributes to the risk of developing Rheumatoid Arthritis.

This study is addressed to detect if the genetic variability might be used in near future in clinical setting, to predict the success of epiduroscopy.

The main aim of this study consists in identifying whether a particular genotype associated with inflammation is able to detect which patients will have a positive epiduroscopy outcome, in terms of decrease of pain.

To achieve it, the investigators will investigate the frequency of some IL1 and IL6 gene polymorphisms: we will analyze and compare IL1β, IL1Ra, IL6 and IFNγ blood cells gene expression (before, immediately post the epiduroscopy and after one month) with that obtained by epiduroscopy biopsy cells.

The investigators will also measure IL1β, IL1Ra, IL6 and IFNγ levels from patient serum before the epiduroscopy, immediately post the procedure and after 1 month.

• Study Type: Observational
• Enrollment (Anticipated): 130

Contacts and Locations

Study Locations

• Italy
  • Parma, Italy, 43100
    • Recruiting
    • University of Parma
    • Contact: Guido Fanelli, Professor; Phone Number: +39 0521 703567; Email: guido.fanelli@unipr.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

We will enroll a well phenotyped cohort of patients with chronic low back pain, sub-grouped into categories: spinal stenosis (congenital or acquired) and failed back surgery syndrome.

Description

Inclusion Criteria:

• Age: 18 - 75 years
• Patients undergone periduroscopy procedure according to good clinical practice.
• Written informed consent signed

Exclusion Criteria:

• Subjects with evidence of clinically unstable disease (without stable treatment that needs continuous pharmacological and drugs dosage changes; physicians requiring further assessments; at instance not-responder hypertension to the pharmacological treatment with pressure values constantly alterated despite the therapy)
• Subjects with a severe psychiatric disorder diagnosed by a psychiatrist and / or neurologist, that are/have been under a pharmacological treatment and under specialist control with particular contraindications to invasive treatments
• Mental impaired patients
• History of spinal fracture
• Spinal tumor or infection of column;
• Visual alterations (glaucoma, diabetic retinopathy)
• Brain vascular disease
• Primary or secondary chronic headache
• For women: positive pregnancy test or pregnancy.
• Coagulopathy (INR>1.5)
• Refusal to participate

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
genetic outcome	the frequency of rs1800795 in the promoter of the IL6 gene	36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
genomic outcome	other known variants related to inflammation in IL1β and IL6 loci	36 months
inflammation outcome	IL-6, IL-1β, IL1Ra and INFγ serum concentration before, immediately post epiduroscopy and after 1 month	36 months
gene expression outcome	IL-6, IL-1β, IL1Ra and INFγ gene expression in blood cells obtained before, immediately post epiduroscopy and after 1 month	36 months
biopsy tissue outcome	IL-6, IL-1β, IL1Ra and INFγ gene expression in biopsy tissue cells	36 months
methylation outcome	the methylation of the promoter of IL6	36 months

Collaborators and Investigators

• Sponsor: University of Parma
• Collaborators: IRCCS Policlinico S. Matteo

Study record dates

Study Major Dates

• Study Start: April 1, 2014
• Primary Completion (Anticipated): April 1, 2017
• Study Completion (Anticipated): April 1, 2017

Study Registration Dates

• First Submitted: February 27, 2014
• First Submitted That Met QC Criteria: February 27, 2014
• First Posted (Estimate): March 3, 2014

Study Record Updates

• Last Update Posted (Estimate): December 31, 2014
• Last Update Submitted That Met QC Criteria: December 30, 2014
• Last Verified: February 1, 2014

More Information

Terms related to this study

• Keywords: low back pain; genetic; inflammation; genomic; periduroscopy
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Back Pain; Low Back Pain
• Other Study ID Numbers: Pain-Omics Periduroscopy